4 ▼ ULCERATIVE, VESICULAR, AND BULLOUS LESIONS MARTIN S. GREENBERG, DDS ▼ THE PATIENT WITH ACUTE MULTIPLE LESIONS A clinician attempting to diagnose an ulcerative or vesiculobullous disease of the mouth is confronted with the fact that many diseases have a similar clinical appearance. The oral mucosa is thin, causing vesicles and bullae to break rapidly into ulcers, and ulcers are easily traumatized from teeth and food, and they become secondarily infected by the oral flora. These factors may cause lesions that have a characteristic appearance on the skin to have a nonspecific appearance on the oral mucosa. Mucosal disorders may occasionally be correctly diagnosed from a brief history and rapid clinical examination, but this approach is most often insufficient and leads to incorrect diagnosis and improper treatment. The history taking is frequently underemphasized, but, when correctly performed, it gives as much information as does the clinical examination. A detailed history of the present illness is of particular importance when attempting to diagnose oral mucosal lesions. A complete review of systems should be obtained for each patient, including questions regarding the presence of skin, eye, genital, and rectal lesions. Questions should also be included regarding symptoms of diseases associated with oral lesions; that is, each patient should be asked about the presence of symptoms such as joint pains, muscle weakness, dyspnea, diplopia, and chest pains. The clinical examination should include a thorough inspection of the exposed skin surfaces; the diagnosis of oral lesions requires knowledge of basic dermatology because many disorders occurring on the oral mucosa also affect the skin. Dermatologic lesions are classified according to their clinical appearance and include the following basic lesions: Herpesvirus Infections Primary Herpes Simplex Virus Infections Coxsackievirus Infections Varicella-Zoster Virus Infection Erythema Multiforme Contact Allergic Stomatitis Oral Ulcers Secondary to Cancer Chemotherapy Acute Necrotizing Ulcerative Gingivitis ▼ THE PATIENT WITH RECURRING ORAL ULCERS Recurrent Aphthous Stomatitis Behçet’s Syndrome Recurrent Herpes Simplex Virus Infection ▼ THE PATIENT WITH CHRONIC MULTIPLE LESIONS Pemphigus Subepithelial Bullous Dermatoses Herpes Simplex Virus Infection in Immunosuppressed Patients ▼ THE PATIENT WITH SINGLE ULCERS Histoplasmosis Blastomycosis Mucormycosis 1. Macules. Well-circumscribed, flat lesions that are noticeable because of their change from normal skin color. They may be red due to the presence of vascular lesions or inflammation, or pigmented due to the presence of melanin, hemosiderin, and drugs. 50 51 Ulcerative, Vesicular, and Bullous Lesions 2. Papules. Solid lesions raised above the skin surface that are smaller than 1 cm in diameter. Papules may be seen in a wide variety of diseases including erythema multiforme simplex, rubella, lupus erythematosus, and sarcoidosis. 3. Plaques. Solid raised lesions that are over 1 cm in diameter; they are large papules. 4. Nodules. These lesions are present deep in the dermis, and the epidermis can be easily moved over them. 5. Vesicles. Elevated blisters containing clear fluid that are under 1 cm in diameter. 6. Bullae. Elevated blisterlike lesions containing clear fluid that are over 1 cm in diameter. 7. Erosions. Moist red lesions often caused by the rupture of vesicles or bullae as well as trauma. 8. Pustules. Raised lesions containing purulent material. 9. Ulcers. A defect in the epithelium; it is a well-circumscribed depressed lesion over which the epidermal layer has been lost. 10. Purpura. Reddish to purple flat lesions caused by blood from vessels leaking into the subcutaneous tissue. Classified by size as petechiae or ecchymoses, these lesions do not blanch when pressed. 11. Petechiae. Purpuric lesions 1 to 2 mm in diameter. Larger purpuric lesions are called ecchymoses. A detailed history of the present illness is essential in making the diagnosis of oral mucosal disease. Three pieces of information that should be obtained early in the history will help the clinician rapidly categorize a patient’s disease and simplify the diagnosis: length of time the lesions have been present (acute or chronic lesions), past history of similar lesions (primary or recurrent disease), and number of lesions present (single or multiple). In this chapter, the diseases are grouped according to the information just described. This information serves as an excellent starting point for the student who is just learning to diagnose these disorders, as well as the experienced clinician who is aware of the potential diagnostic pitfalls. The first section of this chapter describes acute multiple lesions that tend to occur only once, the second portion of the chapter covers recurring oral mucosal syndromes, and the third portion presents the patient with chronic multiple lesions. The final section describes diseases that present as chronic single lesions. It is hoped that classifying the disorders in this way will help the clinician avoid the common diagnostic problem of confusing viral infections with recurring oral syndromes, such as recurrent aphthous stomatitis, or disorders that present as chronic progressive disease, such as pemphigus and pemphoid. ▼ THE PATIENT WITH ACUTE MULTIPLE LESIONS The major diseases that cause acute multiple oral lesions include viral stomatitis, allergic reactions (particularly erythema multiforme and contact allergic stomatitis), and lesions caused by cancer chemotherapy or blood dyscrasias. Herpesvirus Infections There are 80 known herpesviruses, and eight of them are known to cause infection in humans: herpes simplex virus (HSV) 1 and 2, varicella-zoster virus, Cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6 (HHV6). All herpesviruses contain a deoxyribonucleic acid (DNA) nucleus and can remain latent in host neural cells, thereby evading the host immune response.1 HHV6, a herpesvirus discovered in 1986, has been shown by seroprevalence studies to infect over 80% of the population by adult life. Two variants, HHV6A and HHV6B have been identified. The virus is commonly isolated from saliva and causes roseola infantum (exanthema subitum), a common childhood illness that is characterized by fever and a rash. The virus also is a cause of a mononucleosislike syndrome in older children and adults. In immunocompromised patients, HHV6 can cause interstitial pneumonitis and bone marrow suppression.2 HHV7, which is commonly isolated from saliva, is presently not associated with a specific disease, whereas HHV8 has been closely associated with Kaposi’s sarcoma in human immunodeficiency virus (HIV)–infected patients. There is also evidence linking HHV8 to forms of lymphoma and Castleman’s disease. HSV1, HSV2, and varicella-zoster are viruses that are known to cause oral mucosal disease. Cytomegalovirus is an occasional cause of oral ulceration in immunosuppressed patients, and it is suspected as a cause of salivary gland disease in HIV-infected patients.3 The herpes simplex virus is composed of four layers: an inner core of linear double-stranded DNA, a protein capsid, a tegument, and a lipid envelope containing glycoproteins that is derived from the nuclear membrane of host cells. The two major types, HSV1 and 2, can be distinguished serologically or by restriction endonuclease analysis of the nuclear DNA. Classically, HSV1 causes a majority of cases of oral and pharyngeal infection, meningoencephalitis, and dermatitis above the waist; HSV2 is implicated in most genital infections. Although this distinction applies to a majority of cases, changing sexual habits are making that distinction less important. Both types can cause primary or recurrent infection of either the oral or the genital area, and both may cause recurrent disease at either site.1 Primary infection may also occur concurrently in both oral and genital sites from either HSV1 or HSV2,4 although HSV1 recurs more frequently in the oral region and HSV2 more frequently in the genital region.5,6 Humans are the only natural reservoir of HSV infection, and spread occurs by direct intimate contact with lesions or secretions from an asymptomatic carrier. This latter method of spread of HSV is common; between 2 and 9% of asymptomatic individuals shed HSV in saliva or genital secretions.7–9 Latency, a characteristic of all herpesviruses, occurs when the virus is transported from mucosal or cutaneous nerve endings by neurons to ganglia where the HSV viral genome remains present in a nonreplicating state.10 During the latent phase, herpes DNA is detectable, but viral proteins are not produced.11 Reactivation of the latent virus occurs when HSV switches to a replicative state; this can occur as a result of a 52 Diagnosis and Management of Oral and Salivary Gland Diseases number of factors including peripheral tissue injury from trauma or sunburn, fever, or immunosuppression.12 The concept that HSV is a possible cause of Bell’s palsy was initially suggested in 1972,13 but recent evidence using genetic and molecular techniques has demonstrated that reactivation of HSV is the most common cause of this disorder.14,15 There is evidence linking HSV to carcinogenesis.16 Epidemiologic studies have demonstrated an increased incidence of HSV2 serum antibodies or positive HSV2 cultures in patients with cervical carcinoma. Animal studies on hamster cheek pouches show an enhanced development of invasive squamous cell carcinoma when HSV1 infection is combined with topical snuff.17 Primary Herpes Simplex Virus Infections There are approximately 600,000 new cases of primary HSV infections per year in the United States. Primary HSV infection occurs in patients who do not have immunity resulting from previous contact with the virus. HSV is contracted after intimate contact with an individual who has active HSV primary or recurrent lesions. Primary HSV may also be spread by asymptomatic shedders with HSV present in salivary secretions. The majority of oral HSV infections is caused by HSV1, but primary oral HSV2 infections may also occur chiefly as a result of oral-genital contact.11 Infection of the fingers (herpetic whitlows) of health professionals may occur during treatment of infected patients. Dentists may experience primary lesions of the fingers from contact with lesions of the mouth or saliva of patients who are asymptomatic carriers of HSV, although the incidence of this disorder should be minimal if gloves are worn (Figure 4-1).18 Use of gloves should also prevent the spread of HSV from the fingers of health care workers infected with herpetic whitlows to patients. Primary HSV infection of the newborn was previously believed to be caused by direct contact with vaginal HSV lesions during birth, but it has now been established that a majority of mothers giving birth to children with primary HSV are asymptomatic carriers without lesions.19 These infections of the newborn result in viremia and disseminated infection of the brain, liver, adrenals, and lungs.20 FIGURE 4-1 Primary herpetic whitlow on the finger of a dentist. Newborns of mothers with antibody titers are protected by placentally transferred antibodies during the first 6 months of life. After 6 months of age, the incidence of primary HSV1 infection increases. The incidence of primary HSV1 infection reaches a peak between 2 and 3 years of age. Incidence of primary HSV2 infection does not increase until the age when sexual activity begins. Studies of neutralizing and complement-fixing antibodies to HSV have shown a continual rise in the percentage of patients who have had contact with the virus until 60 years of age, demonstrating that although the primary infection with HSV1 is chiefly a disease of infants and children, new cases continue to appear during adult life. This is consistent with the many reports of adults with primary herpetic gingivostomatitis. The incidence of primary herpes infection has been shown to vary according to socioeconomic group. In lower socioeconomic groups, 70 to 80% of the population have detectable antibodies to HSV by the second decade of life, indicating prior HSV infection, whereas, in a group of middle class individuals, only 20 to 40% of the patients in the same age group have evidence of contact with HSV.21,22 A significant percentage of cases of primary herpes are subclinical, although the apparently low incidence of a history of classic primary herpetic gingivostomatitis is also influenced by the young age of patients who develop the infection, by the improper diagnosis of some cases, and by the cases of primary herpetic pharyngitis that cannot be clinically distinguished from other causes of viral pharyngitis. CLINICAL MANIFESTATIONS OF PRIMARY ORAL HERPES The patient usually presents to the clinician with full-blown oral and systemic disease, but a history of the mode of onset is helpful in differentiating lesions of primary HSV infection from other acute multiple lesions of the oral mucosa. The incubation period is most commonly 5 to 7 days but may range from 2 to 12 days. Patients with primary oral herpes have a history of generalized prodromal symptoms that precede the local lesions by 1 or 2 days. This information is helpful in differentiating this viral infection from allergic stomatitis or erythema multiforme, in which local lesions and systemic symptoms appear together. These generalized symptoms include fever, headache, malaise, nausea, and vomiting. A negative past history of recurrent herpes labialis and a positive history of direct intimate contact with a patient with primary or recurrent herpes are also helpful in making the diagnosis. Approximately 1 or 2 days after the prodromal symptoms occur, small vesicles appear on the oral mucosa; these are thin-walled vesicles surrounded by an inflammatory base (Figure 4-2). The vesicles quickly rupture, leaving shallow round discrete ulcers. The lesions occur on all portions of the mucosa. As the disease progresses, several lesions may coalesce, forming larger irregular lesions. An important diagnostic criterion in this disease is the appearance of generalized acute marginal gingivitis. The entire gingiva is edematous and inflamed (Figures 4-3, A and 53 Ulcerative, Vesicular, and Bullous Lesions FIGURE 4-2 A 12-year-old female with primary herpetic gingivostomatis causing discrete vesicles and ulcers surrounded by inflammation. FIGURE 4-4 Primary herpes infection in a 17-year-old male. Note the unruptured palatal vesicles and intense marginal gingivitis. B, and 4-4). Several small gingival ulcers are often present. Examination of the posterior pharynx reveals inflammation, and the submandibular and cervical lymph nodes are characteristically enlarged and tender. On occasion, primary HSV may cause lesions of the labial and facial skin without intraoral lesions. Primary HSV in otherwise healthy children is a self-limiting disease. The fever ordinarily disappears within 3 or 4 days, and the lesions begin healing in a week to 10 days, although HSV may continue to be present in the saliva for up to a month after the onset of disease. Cytology. For cytology, a fresh vesicle can be opened and a scraping made from the base of the lesion and placed on a microscope slide. The slide may be stained with Giemsa, Wright’s, or Papanicolaou’s stain and searched for multinucleated giant cells (Figure 4-5), syncytium, and ballooning degeneration of the nucleus. Fluorescent staining of cytology smears has been shown to be more sensitive (83%) compared with routine cytology (54%); it is the cytologic test of choice, when available.23 LABORATORY DIAGNOSIS The diagnosis of primary herpetic gingivostomatitis is straightforward when patients present with a typical clinical picture of generalized symptoms followed by an eruption of oral vesicles, round shallow symmetric oral ulcers, and acute marginal gingivitis. Laboratory tests are rarely required in these cases. Other patients, especially adults, may have a less typical clinical picture, making the diagnosis more difficult. This is especially important when distinguishing primary herpes from erythema multiforme since proper therapy differs significantly. The following laboratory tests are helpful in the diagnosis of a primary herpes infection. A HSV Isolation. Isolation and neutralization of a virus in tissue culture is the most positive method of identification and has a specificity and sensitivity of 100%.23 A clinician must remember that isolation of HSV from oral lesions does not necessarily mean that HSV caused the lesions. Patients who have lesions from other causes may also be asymptomatic shedders of HSV. Antibody Titers. Conclusive evidence of a primary HSV infection includes testing for complement-fixing or neutralizing antibody in acute and convalescent sera. However, it is rarely necessary in routine clinical situations and is often not helpful since the results are not available until the infection is gone. In special circumstances, such as immunocompromised B FIGURE 4-3 Acute marginal gingivitis characteristic of primary HSV infection. A, mandibular anterior gingiva; B, vesicles and inflammation around mandibular molars. 54 Diagnosis and Management of Oral and Salivary Gland Diseases Antibiotics are of no help in the treatment of primary herpes infection, and use of corticosteroids is contraindicated. Future therapy may include prevention of the infection with use of a genetically disabled HSV vaccine. Coxsackievirus Infections FIGURE 4-5 Cytology smear stained with Giemsa, demonstrating multinucleated giant cells. patients, an acute serum specimen should be obtained within 3 or 4 days of the onset of symptoms. The absence of detectable antibodies plus the isolation of HSV from lesions is compatible with the presence of a primary HSV infection. Antibody to HSV will begin to appear in a week and reach a peak in 3 weeks. A convalescent serum can confirm the diagnosis of primary HSV infection by demonstrating at least a fourfold rise in anti-HSV antibody. If anti-HSV antibody titers are similar in both the acute and convalescent sera, then the lesions from which HSV was isolated were recurrent lesions. TREATMENT A significant advance in the management of herpes simplex infections was the discovery of acyclovir, which has no effect on normal cells but inhibits DNA replication in HSV-infected cells.24 Acyclovir has been shown to be effective in the treatment of primary oral HSV in children when therapy was started in the first 72 hours. Acyclovir significantly decreased days of fever, pain, lesions, and viral shedding.25 Newer antiherpes drugs are now available, including valacyclovir and famciclovir. The advantage of the newer drugs is increased bioavailability, allowing for effective treatment with fewer doses.26 Milder cases can be managed with supportive care only. The use of antiviral drugs in the management of recurrent disease or in immunocompromised patients is discussed later in this chapter in sections on recurrent and chronic HSV. Routine supportive measures include aspirin or acetaminophen for fever and fluids to maintain proper hydration and electrolyte balance. If the patient has difficulty eating and drinking, a topical anesthetic may be administered prior to meals. Dyclonine hydrochloride 0.5% has been shown to be an excellent topical anesthetic for the oral mucosa. If this medication is not available, a solution of diphenhydramine hydrochloride 5 mg/mL mixed with an equal amount of milk of magnesia also has satisfactory topical anesthetic properties. Infants who are not drinking because of severe oral pain should be referred to a pediatrician for maintenance of proper fluid and electrolyte balance. Coxsackieviruses are ribonucleic acid (RNA) enteroviruses and are named for the town in upper New York State where they were first discovered. Coxsackieviruses have been separated into two groups, A and B. There are 24 known types of coxsackievirus group A and 6 types of coxsackievirus group B. These viruses cause hepatitis, meningitis, myocarditis, pericarditis, and acute respiratory disease. Three clinical types of infection of the oral region that have been described are usually caused by group A coxsackieviruses: herpangina, handfoot-and-mouth disease, and acute lymphonodular pharyngitis. Types of coxsackievirus A have also been described as causing a rare mumpslike form of parotitis. HERPANGINA Coxsackievirus A4 has been shown to cause a majority of cases of herpangina, but types A1 to A10 as well as types A16 to A22 have also been implicated. Because many antigenic strains of coxsackievirus exist, herpangina may be seen more than once in the same patient. Unlike herpes simplex infections, which occur at a constant rate, herpangina frequently occurs in epidemics that have their highest incidence from June to October. The majority of cases affect young children ages 3 through 10, but infection of adolescents and adults is not uncommon. Clinical Manifestations. After a 2- to 10-day incubation period, the infection begins with generalized symptoms of fever, chills, and anorexia. The fever and other symptoms are generally milder than those experienced with primary HSV infection. The patient complains of sore throat, dysphagia, and occasionally sore mouth. Lesions start as punctate macules, which quickly evolve into papules and vesicles involving the posterior pharynx, tonsils, faucial pillars, and soft palate. Lesions are found less frequently on the buccal mucosa, tongue, and hard palate (Figure 4-6). Within 24 to 48 hours, the vesicles rupture, forming small 1 to 2 mm ulcers. The disease is usually mild and heals without treatment in 1 week. Herpangina may be clinically distinguished from primary HSV infection by several criteria: 1. Herpangina occurs in epidemics; HSV infections do not. 2. Herpangina tends to be milder than HSV infection. 3. Lesions of herpangina occur on the pharynx and posterior portions of the oral mucosa, whereas HSV primarily affects the anterior portion of the mouth. 4. Herpangina does not cause a generalized acute gingivitis like that associated with primary HSV infection. 5. Lesions of herpangina tend to be smaller than those of HSV. 55 Ulcerative, Vesicular, and Bullous Lesions patients with this disease than with herpangina, and they should remember to examine the hands and feet for maculopapular and vesicular lesions when patients present with an acute stomatitis and fever. Treatment is supportive. Varicella-Zoster Virus Infection FIGURE 4-6 A cluster of vesicles on the tongue in a patient with herpangina. The patient had lesions of the posterior pharyngeal wall and tonsils, but there was no gingivitis. Coxsackievirus A4 was isolated in tissue culture. Laboratory Studies. A smear taken from the base of a fresh vesicle and stained with Giemsa will not show ballooning degeneration or multinucleated giant cells. This helps to distinguish herpangina from herpes simplex and herpes zoster, which do show these changes. Treatment. Herpangina is a self-limiting disease, and treatment is supportive, including proper hydration and topical anesthesia when eating or swallowing is difficult. Specific antiviral therapy is not available. ACUTE LYMPHONODULAR PHARYNGITIS This is a variant of herpangina caused by coxsackievirus A10. The distribution of the lesions is the same as in herpangina, but yellow-white nodules appear that do not progress to vesicles or ulcers. The disease is self-limiting, and only supportive care is indicated. HAND-FOOT-AND-MOUTH DISEASE Hand-foot-and-mouth disease is caused by infection with coxsackievirus A16 in a majority of cases, although instances have been described in which A5, A7, A9, A10, B2, or B5 or enterovirus 71 has been isolated. The disease is characterized by low-grade fever, oral vesicles and ulcers, and nonpruritic macules, papules, and vesicles, particularly on the extensor surfaces of the hands and feet. The oral lesions are more extensive than are those described for herpangina, and lesions of the hard palate, tongue, and buccal mucosa are common. Severe cases with central nervous system involvement, myocarditis, and pulmonary edema have been reported in epidemics caused by enterovirus 71.27 Adler and colleagues28 studied 20 cases of hand-foot-andmouth disease. The patients ranged in age from 8 months to 33 years, with 75% of cases occurring below 4 years of age. The clinical manifestations lasted 3 to 7 days. The most common complaint of the 20 patients was a sore mouth, and, clinically, all 20 patients had lesions involving the oral mucosa. Because of the frequent oral involvement, dentists are more likely to see Varicella zoster (VZV) is a herpesvirus, and, like other herpesviruses, it causes both primary and recurrent infection and remains latent in neurons present in sensory ganglia.29 VZV is responsible for two major clinical infections of humans: chickenpox (varicella) and shingles (herpes zoster [HZ]). Chickenpox is a generalized primary infection that occurs the first time an individual contacts the virus. This is analogous to the acute herpetic gingivostomatitis of herpes simplex virus. After the primary disease is healed, VZV becomes latent in the dorsal root ganglia of spinal nerves or extramedullary ganglia of cranial nerves. A child without prior contact with VZV can develop chickenpox after contact with an individual with HZ. In 3 to 5 of every 1,000 individuals, VZV becomes reactivated, causing lesions of localized herpes zoster. The incidence of HZ increases with age or immunosuppression.30 Patients who are immunocompromised due to HIV disease, cancer chemotherapy, immunosuppressive drug therapy, or hematologic malignancy have an increased susceptibility to severe and potentially fatal HZ. These HZ infections may be deep-seated and disseminated, causing pneumonia, meningoencephalitis, and hepatitis; however, otherwise normal patients who develop HZ do not have a significant incidence of underlying malignancy. CLINICAL MANIFESTATIONS General Findings. Chickenpox is a childhood disease characterized by mild systemic symptoms and a generalized intensely pruritic eruption of maculopapular lesions that rapidly develop into vesicles on an erythematous base. Oral vesicles that rapidly change to ulcers may be seen, but the oral lesions are not an important symptomatic, diagnostic, or management problem. HZ commonly has a prodromal period of 2 to 4 days, when shooting pain, paresthesia, burning, and tenderness appear along the course of the affected nerve. Unilateral vesicles on an erythematous base then appear in clusters, chiefly along the course of the nerve, giving the characteristic clinical picture of single dermatome involvement. Some lesions spread by viremia occur outside the dermatome. The vesicles turn to scabs in 1 week, and healing takes place in 2 to 3 weeks. The nerves most commonly affected with HZ are C3, T5, L1, L2, and the first division of the trigeminal nerve. When the full clinical picture of HZ is present with pain and unilateral vesicles, the diagnosis is not difficult. Diagnostic problems arise during the prodromal period, when pain is present without lesions. Unnecessary surgery has been performed because of the diagnosis of acute appendicitis, cholecystitis, or dental pulpitis.31 A more difficult diagnostic problem is pain caused by VZ virus without lesions developing along the course of the nerve (zoster sine herpete; zoster sine 56 eruptione). Diagnosis in these cases is based on clinical symptoms and serologic evidence of a rising antibody titer. HZ may also occasionally affect motor nerves. HZ of the sacral region may cause paralysis of the bladder. The extremities and diaphragm have also been paralyzed during episodes of HZ. The most common complication of HZ is postherpetic neuralgia, which is defined as pain remaining for over a month after the mucocutaneous lesions have healed, although some clinicians do not use the term postherpetic neuralgia unless the pain has lasted for at least 3 months after the healing of the lesions. The overall incidence of postherpetic neuralgia is 12 to 14%, but the risk increases significantly after the age of 60 years, most likely due to the decline in cell-mediated immunity.32–34 Immunosuppression does not increase the risk of postherpetic neuralgia.35 Oral Findings. Herpes zoster involves one of the divisions of the trigeminal nerve in 18 to 20% of cases, but the ophthalmic branch is affected several times more frequently than are the second or third divisions. HZ of the first division can lead to blindness secondary to corneal scarring and should be managed by an ophthalmologist. Facial and intraoral lesions are characteristic of HZ involving the second and third divisions of the trigeminal nerve. Each individual oral lesion of HZ resembles lesions seen in herpes simplex infections. The diagnosis is based on a history of pain and the unilateral nature and segmental distribution of the lesions (Figures 4-7 and 4-8). When the clinical appearance is typical and vesicles are present, oral HZ can be distinguished clinically from other acute multiple lesions of the mouth, which are bilateral and are not preceded or accom- FIGURE 4-7 Facial lesions of herpes zoster involving the second division of trigeminal nerve. Diagnosis and Management of Oral and Salivary Gland Diseases FIGURE 4-8 Herpes zoster of the third division of fifth nerve, right side. panied by pain along the course of one trigeminal nerve branch36 (Figure 4-9). HZ has been associated with dental anomalies and severe scarring of the facial skin when trigeminal HZ occurs during tooth formation. Pulpal necrosis and internal root resorption have also been related to HZ.37 In immunocompromised patients, large chronic HZ lesions have been described that have led to necrosis of underlying bone and exfoliation of teeth.38 HZ of the geniculate ganglion, Ramsay Hunt syndrome, is a rare form of the disease characterized by Bell’s palsy, unilateral vesicles of the external ear, and vesicles of the oral mucosa. Because oral lesions occurring without facial lesions are rare, isolated oral HZ can be misdiagnosed, particularly when erythema, edema, and nonspecific ulceration are seen without the presence of intact vesicles. In these cases, a cytology smear or viral culture is often necessary for diagnosis. An incorrect diagnosis can be made when prodromal pain is present prior to the appearance of the characteristic lesions. During this period, endodontic therapy, extractions, or other surgery may be performed unnecessarily. Similar problems occur in zoster sine eruptione. FIGURE 4-9 Unilateral palatal lesions of herpes zoster of the second division of trigeminal nerve. Ulcerative, Vesicular, and Bullous Lesions LABORATORY FINDINGS Cytology is a rapid method of evaluation that can be used in cases in which the diagnosis is uncertain. Fluorescent-antibody stained smears using fluorescein conjugated monoclonal antibodies is more reliable than is routine cytology and is positive in over 80% of cases. The most accurate method of diagnosis is viral isolation in tissue culture, but this test is more expensive and the results take days rather than hours. Demonstration of a rising antibody titer is rarely necessary for diagnosis except in cases of zoster sine eruptione, when it is the only means of confirming suspected cases. TREATMENT Management should be directed toward shortening the course of the disease, preventing postherpetic neuralgia in patients over 50 years of age, and preventing dissemination in immunocompromised patients. Acyclovir or the newer antiherpes drugs valacyclovir or famciclovir accelerate healing and reduce acute pain, but they do not reduce the incidence of postherpetic neuralgia.35 The newer drugs have greater bioavailability and are more effective in the treatment of HZ.39 The use of systemic corticosteroids to prevent postherpetic neuralgia in patients over 50 years of age is controversial; a recent review of the data indicated a reduction of pain and disability during the first 2 weeks but no effect on the incidence or severity of post-herpetic neuralgia.33,34 Some clinicians advocate the use of a combination of intralesional steroids and local anesthetics to decrease healing time and prevent postherpetic neuralgia, but a controlled study of this therapy has not been performed. Effective therapy for postherpetic neuralgia includes application of capsaicin, a substance extracted from hot chili peppers.40 Topical capsaicin is safe but must be used for a prolonged period to be effective and may cause a burning sensation of the skin. When topical capsaicin therapy is ineffective, use of a tricyclic antidepressant or gabapentin is indicated.41 Chemical or surgical neurolysis may be necessary in refractory cases (see Chapter 11, Orofacial Pain). Erythema Multiforme 57 microvasculature of skin and mucosa, or cell-mediated immunity. Kazmierowski and Wuepper studied specimens of lesions less than 24 hours old from 17 patients with EM; 13 of the 17 had deposition of immunoglobulin (Ig) M and complement (C) 3 in the superficial vessels.42 Other health care workers have detected elevated levels of immune complexes and decreased complement in fluid samples taken from vesicles. Although the histopathology is not specific, two major histologic patterns have been described: an epidermal pattern characterized by lichenoid vasculitis and intraepidermal vesicles, and a dermal pattern characterized by lymphocytic vasculitis and subepidermal vesiculation.43 The most common triggers for episodes of EM are herpes simplex virus and drug reactions. The drugs most frequently associated with EM reactions are oxycam nonsteroidal antiinflammatory drugs (NSAIDs); sulfonamides; anticonvulsants such as carbamazepine, phenobarbital, and phenytoin; trimethoprim-sulfonamide combinations, allopurinol, and penicillin.44 A majority of the severe cases of Stevens-Johnson syndrome or TEN are caused by drug reactions. The relationship of HSV to episodes of EM has been known for over 50 years, but improved diagnostic techniques, including polymerase chain reaction (PCR) and in situ hybridization have demonstrated that herpes-associated EM is a common form of the disease, accounting for at least 20 to 40% of the cases of single episodes of EM and approximately 80% of recurrent EM45 (Figures 4-10 and 4-11). Herpes antigens have been demonstrated in the skin and immunocomplexes obtained from patients with EM. Many investigators now believe that the major cause of EM is a cellular immune response to HSV antigens deposited in keratinocytes of the skin and mucosa.46 The tendency to develop mucous membrane lesions during episodes of herpes-associated EM appears to be genetically determined and related to specific human leukocyte antigen (HLA) types.47 Oral mucosal lesions were detected in 8 of 12 children with HSV-associated EM.48 Other triggers for EM include progesterone, Mycoplasma benign and malignant tumors, radiotherapy, Crohn’s disease, sarcoidosis, histoplasmosis, and infectious mononucleosis.49–51 Erythema multiforme (EM) is an acute inflammatory disease of the skin and mucous membranes that causes a variety of skin lesions—hence the name “multiforme.” The oral lesions, typically inflammation accompanied by rapidly rupturing vesicles and bullae, are often an important component of the clinical picture and are occasionally the only component. Erythema multiforme may occur once or recur, and it should be considered in the diagnosis of multiple acute oral ulcers whether or not there is a history of similar lesions. There is also a rare chronic form of EM. EM has several clinical presentations: a milder self-limiting form and severe life-threatening forms that may present as either Stevens-Johnson syndrome or toxic epidermal necrolysis (TEN). ETIOLOGY EM is an immune-mediated disease that may be initiated either by deposition of immune complexes in the superficial FIGURE 4-10 Early vesicular lesions in a patient who develops erythema multiforme after each episode of recurrent herpes labialis. 58 FIGURE 4-11 Target lesion on the arm of the patient with erythema multiforme shown in Figure 4-10. Many cases of EM continue to have no obvious detectable cause after extensive testing for underlying systemic disease and allergy and are labeled idiopathic. CLINICAL MANIFESTATIONS General Findings. EM is seen most frequently in children and young adults and is rare after age 50 years. It has an acute or even an explosive onset; generalized symptoms such as fever and malaise appear in severe cases. A patient may be asymptomatic and in less than 24 hours have extensive lesions of the skin and mucosa. EM simplex is a self-limiting form of the disease and is characterized by macules and papules 0.5 to 2 cm in diameter, appearing in a symmetric distribution. The most common cutaneous areas involved are the hands, feet, and extensor surfaces of the elbows and knees. The face and neck are commonly involved, but only severe cases affect the trunk. Typical skin lesions of EM may be nonspecific macules, papules, and vesicles. More typical skin lesions contain petechiae in the center of the lesion. The pathognomonic lesion is the target or iris lesion, which consists of a central bulla or pale clearing area surrounded by edema and bands of erythema (Figure 4-12). Diagnosis and Management of Oral and Salivary Gland Diseases The more severe vesiculobullous forms of the disease, Stevens-Johnson syndrome and TEN, have a significant mortality rate.52 EM is classified as Stevens-Johnson syndrome when the generalized vesicles and bullae involve the skin, mouth, eyes, and genitals53 (Figure 4-13). The most severe form of the disease is TEN, (tone epidermal neurolysis), which is usually secondary to a drug reaction and results in sloughing of skin and mucosa in large sheets. Morbidity, which occurs in 30 to 40% of patients, results from secondary infection, fluid and electrolyte imbalance, or involvement of the lung, liver, or kidneys.54 Patients with this form of the disease are most successfully managed in burn centers, where necrotic skin is removed under general anesthesia and healing takes place under sheets of porcine xenografts. Oral Findings. Oral lesions commonly appear along with skin lesions in approximately 70% of EM patients55 (Figure 4-14). In some cases, oral lesions are the predominant or single site of disease. When the oral lesions predominate and no target lesions are present on the skin, EM must be differentiated from other causes of acute multiple ulcers, especially primary herpes simplex infection. This distinction is important because corticosteroids may be the treatment of choice in EM, but they are specifically contraindicated in primary herpes simplex infections. When there are no skin lesions and the oral lesions are mild, diagnosis may be difficult and is usually made by exclusion of other diseases. Cytologic smears and virus isolation may be done to eliminate the possibility of primary herpes infection. Biopsy may be performed when acute pemphigus is suspected. The histologic picture of oral EM is not considered specific, but the finding of a perivascular lymphocytic infiltrate and epithelial edema and hyperplasia is considered suggestive of EM. The diagnosis is made on the basis of the total clinical picture, including the rapid onset of lesions. The oral lesions start as bullae on an erythematous base, but intact bullae are rarely seen by the clinician because they break rapidly into irregular ulcers. Viral lesions are small, round, symmetric, and shallow, but EM lesions are larger, irregular, deeper, and often bleed. Lesions may occur anywhere on the oral mucosa with EM, but involvement of the lips is especially prominent, and gingival involvement is rare. This is an important criterion for distinguishing EM from primary herpes simplex infection, in which generalized gingival involvement is characteristic. In full-blown clinical cases, the lips are extensively eroded, and large portions of the oral mucosa are denuded of epithelium. The patient cannot eat or even swallow and drools blood-tinged saliva. Within 2 or 3 days the labial lesions begin to crust. Healing occurs within 2 weeks in a majority of cases, but, in some severe cases, extensive disease may continue for several weeks. TREATMENT FIGURE 4-12 Target lesions in a patient with erythema multiforme. Mild cases of oral EM may be treated with supportive measures only, including topical anesthetic mouthwashes and a soft or liquid diet. Moderate to severe oral EM may be treated with a 59 Ulcerative, Vesicular, and Bullous Lesions FIGURE 4-13 Labial (A), skin (B), and penile (C) lesions in a 17-year-old male with Stevens-Johnson form of erythema multiforme. The lesions began to arise less than 12 hours before the pictures were taken. A B C short course of systemic corticosteroids in patients without significant contraindications to their use. Systemic corticosteroids should only be used by clinicians familiar with the side effects, and, in each case, potential benefits should be carefully weighed FIGURE 4-14 old male. Intraoral lesions of erythema multiforme in an 18-year- against potential risks. Young children treated with systemic steroids for EM appear to have a higher rate of complications than do adults, particularly gastrointestinal bleeding and secondary infections. Adults treated with short-term systemic steroids have a low rate of complications and a shorter course of EM.56 The protein-wasting and adrenal-suppressive effects of systemic steroids are not significant when used short-term, and the clinical course of the disease may be shortened. An initial dose of 30 mg/d to 50 mg/d of prednisone or methylprednisolone for several days, which is then tapered, is helpful in shortening the healing time of EM, particularly when therapy is started early in the course of the disease. It should be noted that the efficacy of this treatment has not been proven by controlled clinical trials and is controversial. Patients with severe cases of recurrent EM have been treated with dapsone, azathioprine, levamisole, or thalidomide. EM triggered by progesterone, also referred to as autoimmune progesterone dermatitis and stomatitis, has been treated successfully with tamoxifen. In resistant cases, oophorectomy has been necessary to cure the disorder.57 Antiherpes drugs such as acyclovir or valacyclovir can be effective in preventing susceptible patients from developing herpes- 60 Diagnosis and Management of Oral and Salivary Gland Diseases associated EM, if the drug is administered at the onset of the recurrent HSV lesion. Prophylactic use of antiherpes drugs is effective in preventing frequent recurrent episodes of HSVassociated EM.56,58 Systemic steroids are recommended for management of Stevens-Johnson syndrome and are considered life saving in severe cases.59,60 Contact Allergic Stomatitis Contact allergy results from a delayed hypersensitivity reaction that occurs when antigens of low molecular weight penetrate the skin or mucosa of susceptible individuals. These antigens combine with epithelial-derived proteins to form haptens that bind to Langerhans’ cells in the epithelium. The Langerhans’ cells migrate to the regional lymph nodes and present the antigen to T lymphocytes, which become sensitized and undergo clonal expansion. After re-exposure to the antigen, sensitized individuals develop an inflammatory reaction confined to the site of contact. Since the reaction resulting from contact allergy appears as nonspecific inflammation, contact dermatitis or stomatitis may be difficult to distinguish from chronic physical irritation. The incidence of contact stomatitis is unknown, but it is believed to be significantly less common than contact dermatitis for the following reasons: Dental materials that have been reported to cause cases of contact allergic stomatitis include mercury in amalgam, gold in crowns, free monomer in acrylic, and nickel in orthodontic wire.62–64 Pyrophosphates and zinc citrate, which are components of tartar control toothpaste, cause superficial peeling of the mucosa in some users, but this reaction is believed to be caused by physical irritation rather than an allergic reaction.65 CLINICAL MANIFESTATIONS Contact stomatitis may result from contact with dental materials, oral hygiene products, or foods. Common causes of contact oral reactions are cinnamon or peppermint, which are frequently used flavoring agents in food, candy, and chewing gum, as well as oral hygiene products such as toothpaste, mouthwash and dental floss61 (Figure 4-15). The clinical signs and symptoms of contact oral allergy are nonspecific and are frequently difficult to distinguish from physical irritation. The reaction occurs only at the site of contact and includes a burning sensation or soreness accompanied by erythema, and occasionally the formation of vesicles and ulcers. Burning sensations without the presence of lesions is not a result of contact allergy, and obtaining allergy tests for patients with burning mouth syndrome with normal-appearing mucosa is not indicated. Lesions that appear lichenoid both clinically and histologically may also be a result of contact allergy when the lichenoid lesion is in direct contact with the potential allergen. These lesions occur most frequently as a result of mercury in amalgam, and appear on the buccal mucosa and lateral border of the tongue in direct contact with the restoration. These lesions disappear when the amalgam is removed. It should be emphasized that there is no evidence that generalized lesions of oral lichen planus not in direct contact with restorations heal when amalgam restorations are removed. Another oral manifestation of contact allergy is plasma cell gingivitis, which is characterized by generalized erythema and edema of the attached gingiva, occasionally accompanied by cheilitis and glossitis66 (Figure 4-16). The histopathology is described as sheets of plasma cells that replace normal connective tissue. Some cases have been related to an allergen present in toothpaste, chewing gum, or candy, whereas other cases remain of unknown etiology even after extensive allergy testing. Plasma cell gingivitis must be distinguished from neoplastic plasma cell diseases such as plasmacytoma or multiple myeloma. FIGURE 4-15 Contact allergy of the labial mucosa, due to peppermint. FIGURE 4-16 Plasma cell gingivitis of unknown etiology. 1. Saliva quickly dilutes potential antigens and physically washes them away and digests them before they can penetrate the oral mucosa. 2. Since the oral mucosa is more vascular than the skin, potential antigens that do penetrate the mucosa are rapidly removed before an allergic reaction can be established. 3. The oral mucosa has less keratin than does the skin, decreasing the possibility that haptens will be formed. Ulcerative, Vesicular, and Bullous Lesions DIAGNOSIS Contact allergy is most accurately diagnosed by the use of a patch test.67 This test is performed by placing the suspected allergens in small aluminum disks, called Finn chambers, which are taped onto hairless portions of the skin. The disks remain in place for 48 hours. A positive response to a contact allergen is identified by inflammation at the site of the test, which is graded on a scale of 0 to 3. Patch tests should be performed by clinicians trained and experienced in using the test, so the results are interpreted accurately. TREATMENT Management of oral contact allergy depends on the severity of the lesions. In mild cases, removal of the allergen suffices. In more severe symptomatic cases, application of a topical corticosteroid is helpful to speed healing of painful lesions. Oral Ulcers Secondary to Cancer Chemotherapy Chemotherapeutic drugs are frequently used to effect remission of both solid tumors, hematologic malignancies, and bone marrow transplantation. Similar drugs are used for patients with bone marrow transplants. One of the common side effects of the anticancer drugs is multiple oral ulcers. Dentists who practice in hospitals where these drugs are used extensively may see oral ulcers secondary to such drug therapy more frequently than any other lesion described in this chapter.68,69 Anticancer drugs may cause oral ulcers directly or indirectly. Drugs that cause stomatitis indirectly depress the bone marrow and immune response, leading to bacterial, viral, or fungal infections of the oral mucosa. Others, such as methotrexate, cause oral ulcers via direct effect on the replication and growth of oral epithelial cells by interfering with nucleic acid and protein synthesis, leading to thinning and ulceration of the oral mucosa. A recent publication by Sonis describes a new hypothesis that explains the severe stomatitis observed in patients receiving cytotoxic drugs for stem cell transplantation.70 It is noted that an inflammatory reaction precedes ulceration and that anti-inflammatory drugs may be useful in minimizing bone marrow–related ulceration. Details of the diagnosis and management of these lesions are discussed in Chapters 19, Transplantation Medicine, and 16, Hematologic Disease. Acute Necrotizing Ulcerative Gingivitis Acute necrotizing ulcerative gingivitis (ANUG) is an endogenous oral infection that is characterized by necrosis of the gingiva. Occasionally, ulcers of the oral mucosa also occur in patients with hematologic disease or severe nutritional deficiencies (see Chapter 16). ANUG became known notoriously as “trench mouth” during World War I because of its prevalence in the combat trenches, and it was incorrectly considered a highly contagious disease. Since then, studies have shown that the disease is accompanied by an overgrowth of organisms prevalent in nor- 61 mal oral flora and is not transmissible. The organisms most frequently mentioned as working symbiotically to cause the lesions are the fusiform bacillus and spirochetes. Plaque samples taken from ANUG patients demonstrate a constant anaerobic flora of Treponema spp, Selenomonas spp, Fusobacterium spp, and Bacteroides intermedius.71 The tissue destruction is thought to be caused by endotoxins that act either directly on the tissues or indirectly by triggering immunologic and inflammatory reactions. Classic ANUG in patients without an underlying medical disorder is found most often in those between the ages of 16 and 30 years, and it is associated with three major factors: 1. Poor oral hygiene with pre-existing marginal gingivitis or faulty dental restorations 2. Smoking 3. Emotional stress Systemic disorders associated with ANUG are diseases affecting neutrophils (such as leukemia or aplastic anemia), marked malnutrition, and HIV infection. Malnutrition-associated cases are reported from emergent countries where the untreated disease may progress to noma, a large necrotic ulcer extending from the oral mucosa through the facial soft tissues. The prevalence of the disease was reported by Giddon and colleagues,72 who studied the prevalence of ANUG in 12,500 students served by the Harvard University Dental Health Service. About 0.9% of the total sample developed ANUG during the period of study. A 4% prevalence in those students who made use of the dental clinic was observed. Members of the junior class were most often affected. A relation to stress was noted by an increased frequency during examination and vacation periods. Studies of military trainees or college students demonstrated a prevalence of 5 to 7%. There are three forms of periodontal diseases observed in patients with acquired immunodeficiency syndrome (AIDS): linear gingival erythema (LGE), necrotizing ulcerative gingivitis (NUG), and necrotizing ulcerative periodontitis (NUP). LGE is an intense red band involving the marginal gingiva that does not resolve with standard oral hygiene procedures. Some cases are believed to be caused by candidal overgrowth, and these cases resolve with antifungal therapy. NUG and NUP are clinically similar to ANUG; the term “NUG” is used when the disease involves only the gingiva, and “NUP” involves a loss of periodontal attachment.73,74 There is evidence that, in patients with AIDS, the host response in the gingival crevice is altered. Levels of proinflammatory cytokines such as interleukin-1 β are increased in the gingival crevice of patients with human immunodeficiency virus (HIV), which alters the regulation of neutrophils. This alteration in neutrophil function may explain the increase in NUP-related organisms including fusobacteria and Candida, which results in the rapid necrosis of gingival tissues.75 A fulminating form of ulcerative stomatitis related to ANUG is noma (cancrum oris), which predominantly affects children in sub-Saharan Africa. This disease is characterized by 62 Diagnosis and Management of Oral and Salivary Gland Diseases extensive necrosis that begins on the gingiva and then progresses from the mouth through the cheek to the facial skin, causing extensive disfigurement (Figure 4-17). The major risk factors associated with noma include malnutrition, poor oral hygiene, and concomitant infectious diseases such as measles.76 Living in close proximity to livestock is also believed to play a role, and Fusobacterium necrophorum, a pathogen associated with disease in livestock, has been isolated from over 85% of noma lesions.77 The mortality rate without appropriate therapy exceeds 70%. CLINICAL MANIFESTATIONS The onset of acute forms of ANUG is usually sudden, with pain, tenderness, profuse salivation, a peculiar metallic taste, and spontaneous bleeding from the gingival tissues. The patient commonly experiences a loss of the sense of taste and a diminished pleasure from smoking. The teeth are frequently thought to be slightly extruded, sensitive to pressure, or to have a “woody sensation.” At times they are slightly movable. The signs noted most frequently are gingival bleeding and blunting of the interdental papillae (Figure 4-18). The typical lesions of ANUG consist of necrotic punchedout ulcerations, developing most commonly on the interdental papillae and the marginal gingivae. These ulcerations can be observed most easily on the interdental papillae, but ulceration may develop on the cheeks, the lips, and the tongue, where these tissues come in contact with the gingival lesions or following trauma. Ulcerations also may be found on the palate and in the pharyngeal area (Figure 4-19). When the lesions have spread beyond the gingivae, blood dyscrasias and immunodeficiency should be ruled out by ordering appropriate laboratory tests, depending upon associated signs and symptoms. The ulcerative lesions may progress to involve the alveolar process, with sequestration of the teeth and bone. When gingival hemorrhage is a prominent symptom, the teeth may become superficially stained a brown color, and the mouth odor is extremely offensive. The tonsils should always be examined since these organs may be affected. The regional lymph nodes usually are slightly FIGURE 4-17 Cancrum oris or noma. (Courtesy of Dr. Gustavo Berger, Guatemala City, Guatemala). FIGURE 4-18 Extensive necrosis of the interdental papillae, and marginal and attached gingivae caused by acute necrotizing ulcerative gingivitis. enlarged, but occasionally the lymphadenopathy may be marked, particularly in children. The constitutional symptoms in primary ANUG are usually of minor significance when compared with the severity of the oral lesions. Significant temperature elevation is unusual, even in severe cases, and, when it exists, other accompanying or underlying diseases should be ruled out, particularly blood dyscrasias and AIDS. HIV-infected patients with NUG have rapidly progressing necrosis and ulceration first involving the gingiva alone, and then NUP with the periodontal attachment and involved alveolar bone. The ulcerated areas may be localized or generalized and often are very painful. In severe cases, the underlying bone is denuded and may become sequestrated, and the necrosis may spread from the gingiva to other oral tissues. TREATMENT The therapy of ANUG uncomplicated by other oral lesions or systemic disease is local débridement. At the initial visit, the gingivae should be débrided with both irrigation and periodontal curettage. The extent of the débridement depends on the soreness of the gingivae. The clinician should remember that the more quickly the local factors are removed, the faster is the resolution of the lesions. Special care should be taken by the clinician to débride the area just below the marginal gin- FIGURE 4-19 Palatal ulceration in a 21-year-old male with fusospirochetal stomatitis, which began as a necrotizing lesion of a pericoronal flap. 63 Ulcerative, Vesicular, and Bullous Lesions givae. Complete débridement may not be possible on the first visit because of soreness. The patient must return, even though the pain and other symptoms have disappeared, to remove all remaining local factors. Treatment of ANUG is not finished until there has been a complete gingival curettage and root planing, including removal of overhanging margins and other predisposing local factors. After the first visit, careful home care instruction must be given to the patient regarding vigorous rinsing and gentle brushing with a soft brush. Patients should be made aware of the significance of such factors as poor oral hygiene, smoking, and stress. Antibiotics are usually not necessary for routine cases of ANUG confined to the marginal and interdental gingivae. These cases can be successfully treated with local débridement, irrigation, curettage, and home care instruction including hydrogen peroxide (approximately 1.5 to 2% in water) mouth rinses three times a day and chlorhexidine 12% rinses. Antibiotics should be prescribed for patients with extensive gingival involvement, lymphadenopathy, or other systemic signs, and in cases in which mucosa other than the gingivae is involved. Metronidazole and penicillin are the drugs of choice in patients with no history of sensitivity to these drugs. Patients whose lesions have extended from the gingivae to the buccal mucosa, tongue, palate, or pharynx should be placed on antibiotics and should have appropriate studies to rule out blood dyscrasias or AIDS. After the disease is resolved, the patient should return for a complete periodontal evaluation. Periodontal treatment should be instituted as necessary. The patient must be made aware that, unless the local etiologic factors of the disease are removed, ANUG may return or become chronic and lead to periodontal disease. ▼ THE PATIENT WITH RECURRING ORAL ULCERS Recurring oral ulcers are among the most common problems seen by clinicians who manage diseases of the oral mucosa. There are several diseases that should be included in the differential diagnosis of a patient who presents with a history of recurring ulcers of the mouth, including recurrent aphthous stomatitis (RAS), Behçet’s syndrome, recurrent HSV infection, recurrent erythema multiforme, and cyclic neutropenia. Recurrent Aphthous Stomatitis RAS is a disorder characterized by recurring ulcers confined to the oral mucosa in patients with no other signs of disease. Many specialists and investigators in oral medicine no longer consider RAS to be a single disease but, rather, several pathologic states with similar clinical manifestations. Immunologic disorders, hematologic deficiencies, and allergic or psychological abnormalities have all been implicated in cases of RAS. RAS affects approximately 20% of the general population, but when specific ethnic or socioeconomic groups are studied, the incidence ranges from 5 to 50%.78 RAS is classified according to clinical characteristics: minor ulcers, major ulcers (Sutton’s disease, periadenitis mucosa necrotica recurrens), and herpetiform ulcers. Minor ulcers, which comprise over 80% of RAS cases, are less than 1 cm in diameter and heal without scars. Major ulcers, are over 1 cm in diameter and take longer to heal and often scar. Herpetiform ulcers are considered a distinct clinical entity that manifests as recurrent crops of dozens of small ulcers throughout the oral mucosa. ETIOLOGY It was once assumed that RAS was a form of recurrent HSV infection, and there are still clinicians who mistakenly call RAS “herpes.” Many studies done during the past 40 years have confirmed that RAS is not caused by HSV.79,80 This distinction is particularly important at a time when there is specific effective antiviral therapy available for HSV that is useless for RAS. “Herpes” is an anxiety-producing word, suggesting a sexually transmitted disease among many laypersons, and its use should be avoided when it does not apply. There continue to be investigations studying the relationship of RAS to other herpesviruses such as varicella-zoster virus or Cytomegalovirus, but the results of these studies continue to be inconclusive.81,82 The current concept is that RAS is a clinical syndrome with several possible causes. The major factors identified include heredity, hematologic deficiencies, and immunologic abnormalities.83,84 The best documented factor is heredity.85 Miller and colleagues studied 1,303 children from 530 families and demonstrated an increased susceptibility to RAS among children of RAS-positive parents.86 A study by Ship and associates showed that patients with RAS-positive parents had a 90% chance of developing RAS, whereas patients with no RAS-positive parents had a 20% chance of developing the lesions.85 Further evidence for the inherited nature of this disorder results from studies in which genetically specific HLAs have been identified in patients with RAS, particularly in certain ethnic groups.87,88 Hematologic deficiency, particularly of serum iron, folate, or vitamin B12, appears to be an etiologic factor in a subset of patients with RAS.84 The size of the subset is controversial, but most estimates range from 5 to 15%. A study by Rogers and Hutton reported clinical improvement in 75% of patients with RAS when a specific hematologic deficiency was detected and corrected with specific replacement therapy.89 Some cases of nutritional deficiency, such as celiac disease, are reported to be secondary to malabsorption syndrome.90 Most of the research into the etiology of RAS centers on immunologic abnormalities. Early work suggested either an autoimmune disorder or hypersensitivity to oral organisms such as Streptococcus sanguis.91 Investigations using more sophisticated immune assays have not supported the early work and suggest a role of lymphocytotoxicity,92 antibody-dependent cellmediated cytotoxicity, and defects in lymphocyte cell subpopulations.93–95 Burnett and Wray showed that sera and monocytes induced significantly more cytolysis in patients with RAS than in control patients.96 Thomas and colleagues showed that T lymphocytes from patients with RAS had increased cytotoxicity to oral epithelial cells.92 Work by Pedersen and colleagues and other studies demonstrated an alteration in CD4:CD8 lympho- 64 cyte ratio, or a dysfunction of the mucocutaneous cytokine network.97–99 Further work is needed to determine if these are specific or nonspecific responses. Other factors that have been suggested as being etiologic in RAS include trauma, psychological stress, anxiety, and allergy to foods.100 It is well documented that cessation of smoking increases the frequency and severity of RAS.101 In cases of refractory disease, Hay and Reade reported the benefit of an elimination diet in some patients with suspected or proven allergy to foods such as milk, cheese, wheat, and flour.102 A detergent present in toothpaste, sodium lauryl sulfate (SLS), was suspected as an etiologic factor in RAS development,103 but a recent double-blind crossover study showed that use of an SLS-free toothpaste had no significant effect on ulcer development.104 CLINICAL MANIFESTATIONS The first episodes of RAS most frequently begin during the second decade of life and may be precipitated by minor trauma, menstruation, upper respiratory infections, or contact with certain foods. The lesions are confined to the oral mucosa and begin with prodromal burning any time from 2 to 48 hours before an ulcer appears. During this initial period, a localized area of erythema develops. Within hours, a small white papule forms, ulcerates, and gradually enlarges over the next 48 to 72 hours. The individual lesions are round, symmetric, and shallow (similar to viral ulcers), but no tissue tags are present from ruptured vesicles (this helps to distinguish RAS from disease with irregular ulcers such as EM, pemphigus, and pemphigoid). Multiple lesions are often present, but the number, size, and frequency of them vary considerably (Figure 4-20). The buccal and labial mucosae are most commonly involved. Lesions are less common on the heavily keratinized palate or gingiva. In mild RAS, the lesions reach a size of 0.3 to 1.0 cm and begin healing within a week. Healing without scarring is usually complete in 10 to 14 days. Most patients with RAS have between two and six lesions at each episode and experience several episodes a year. The disease is an annoyance for the majority of patients with mild RAS, but Diagnosis and Management of Oral and Salivary Gland Diseases it can be disabling for patients with severe frequent lesions, especially those classified as major aphthous ulcers. Patients with major ulcers develop deep lesions that are larger than 1 cm in diameter and may reach 5 cm (Figure 4-21, A and B). Large portions of the oral mucosa may be covered with large deep ulcers that can become confluent. The lesions are extremely painful and interfere with speech and eating. Many of these patients continually go from one clinician to another, looking for a “cure.” The lesions may last for months and sometimes be misdiagnosed as squamous cell carcinoma, chronic granulomatous disease, or pemphigoid. The lesions heal slowly and leave scars that may result in decreased mobility of the uvula and tongue and destruction of portions of the oral mucosa. The least common variant of RAS is the herpetiform type, which tends to occur in adults. The patient presents with small punctate ulcers scattered over large portions of the oral mucosa. DIAGNOSIS RAS is the most common cause of recurring oral ulcers and is essentially diagnosed by exclusion of other diseases. A detailed history and examination by a knowledgeable clinician should distinguish RAS from primary acute lesions such as viral stomatitis or from chronic multiple lesions such as pemphigoid, as well as from other possible causes of recurring ulcers, such as connective tissue disease, drug reactions, and dermatologic disorders. The history should emphasize symptoms of blood dyscrasias, systemic complaints, and associated skin, eye, genital, or rectal lesions. Laboratory investigation should be used when ulcers worsen or begin past the age of 25 years. Biopsies are only indicated when it is necessary to exclude other diseases, particularly granulomatous diseases such as Crohn’s disease or sarcoidosis. Patients with severe minor aphthae or major aphthous ulcers should have known associated factors investigated, including connective-tissue diseases and abnormal levels of serum iron, folate, vitamin B12, and ferritin (Figure 4-22). Patients with abnormalities in these values should be referred to an internist to rule out malabsorption syndromes and to initiate proper replacement therapy. The clinician may also choose to have food allergy or gluten sensitivity investigated in severe cases resistant to other forms of treatment.102 HIVinfected patients, particularly those with CD4 counts below 100/mm3, may develop major aphthous ulcers (Figure 4-23). TREATMENT FIGURE 4-20 Recurrent aphthous stomatitis of the tongue and floor of the mouth. Medication prescribed should relate to the severity of the disease. In mild cases with two or three small lesions, use of a protective emollient such as Orabase (Bristol-Myers Squibb, Princeton, NJ) or Zilactin (Zila Pharmaceutions, Phoenix, AZ) is all that is necessary. Pain relief of minor lesions can be obtained with use of a topical anesthetic agent or topical diclofenac, an NSAID frequently used topically after eye surgery.105 In more severe cases, the use of a high-potency topical steroid preparation, such as fluocinonide, betamethasone or clobetasol, placed directly on the lesion shortens healing time and reduces the size of the ulcers. The effectiveness of the topical steroid is partially based upon good instruction and 65 Ulcerative, Vesicular, and Bullous Lesions A B FIGURE 4-21 Major aphthous ulcers of the labial mucosa (A) and alveolar mucosa (B). patient compliance regarding proper use. The gel can be carefully applied directly to the lesion after meals and at bedtime two to three times a day, or mixed with an adhesive such as Orabase prior to application. Larger lesions can be treated by placing a gauze sponge containing the topical steroid on the ulcer and leaving it in place for 15 to 30 minutes to allow for longer contact of the medication. Other topical preparations that have been shown to decrease the healing time of RAS lesions include amlexanox paste and topical tetracycline, which can be used either as a mouth rinse or applied on gauze sponges. Intralesional steroids can be used to treat large indolent major RAS lesions. It should be emphasized that no available topical therapy decreases the onset of new lesions. In patients with major aphthae or severe cases of multiple minor aphthae not responsive to topical therapy, use of systemic therapy should be considered. Drugs that have been reported to reduce the number of ulcers in selected cases of major aphthae include colchicine, pentoxifylline, dapsone, short bursts of systemic steroids, and thalidomide.106–108 Each of these drugs has the potential for side effects, and the clinician must weigh the FIGURE 4-22 A 42-year-old woman with a recent increase in severity of recurrent aphthous ulcers. An iron deficiency was detected, and the ulcers resolved when this deficiency was corrected. potential benefits versus the risks. Thalidomide has been shown to reduce both the incidence and severity of major RAS in both HIV-positive and HIV-negative patients, but this drug must be used with extreme caution in women during childbearing years owing to the potential for severe life-threatening and deforming birth defects.109 All clinicians prescribing thalidomide in the United States must be registered in the STEPS (System for Thalidomide Education and Prescribing Safety) program, and patients receiving the drug must be thoroughly counseled regarding effective birth control methods that must be used whenever thalidomide is prescribed. For example, two methods of birth control must be used, and the patient must have a pregnancy test monthly. Other side effects of thalidomide include peripheral neuropathy, gastrointestinal complaints, and drowsiness. Behçet’s Syndrome Behçet’s syndrome, described by the Turkish dermatologist Hulûsi Behçet, was classically described as a triad of symptoms including recurring oral ulcers, recurring genital ulcers, and FIGURE 4-23 Major aphthous ulcer in an HIV-infected patient. 66 eye lesions. The concept of the disease has changed from a triad of signs and symptoms to a multisystem disorder.110 The highest incidence of Behçet’s syndrome has been reported in eastern Asia, where 1 in 10,000 is affected, and the eastern Mediterranean, where it is a leading cause of blindness in young men; however, cases have been reported worldwide, including in North America, where it is estimated that 1 in 500,000 persons is affected. The highest incidence of Behçet’s syndrome is in young adults, but cases of Behçet’s syndrome in children are being reported with increasing frequency.111 ETIOLOGY Behçet’s syndrome is caused by immunocomplexes that lead to vasculitis of small and medium-sized blood vessels and inflammation of epithelium caused by immunocompetent T lymphocytes and plasma cells.112,113 Increased neutrophil activity has also been noted.114 There is a genetic component to the disease, with a strong association with HLA-B51. Studies of the immune abnormalities associated with Behçet’s syndrome have included findings described above for patients with RAS. This has led some investigators to believe that Behçet’s syndrome and RAS are both manifestations of a similar disorder of the immune response. CLINICAL MANIFESTATIONS The most common single site of involvement of Behçet’s syndrome is the oral mucosa. Recurring oral ulcers appear in over 90% of patients; these lesions cannot be distinguished from RAS (Figure 4-24). Some patients experience mild recurring oral lesions; others have the deep large scarring lesions characteristic of major RAS. These lesions may appear anywhere on the oral or pharyngeal mucosa. The genital area is the second most common site of involvement and involves ulcers of the scrotum and penis in males and ulcers of the labia in females. The eye lesions consist of uveitis, retinal infiltrates, edema and vascular occlusion, optic atrophy, conjunctivitis, and keratitis. Generalized involvement occurs in over half of patients with Behçet’s syndrome. Skin lesions are common and usually manifest as large pustular lesions. These lesions may be precipitated by trauma, and it is common for patients with Behçet’s syndrome to have a cutaneous hyper-reactivity to intracuta- Diagnosis and Management of Oral and Salivary Gland Diseases neous injection or a needlestick (pathergy). Positive pathergy is defined as an inflammatory reaction forming within 24 hours of a needle puncture, scratch, or saline injection. Arthritis occurs in greater than 50% of patients and most frequently affects the knees and ankles.115 The affected joint may be red and swollen as in rheumatoid arthritis, but involvement of small joints of the hand does not occur, and permanent disability does not result. In some patients, central nervous system involvement is the most distressing component of the disease. This may include brainstem syndrome, involvement of the cranial nerves, or neurologic degeneration resembling multiple sclerosis that can be visualized by magnetic resonance imaging of the brain. Other reported signs of Behçet’s syndrome include thrombophlebitis, intestinal ulceration, venous thrombosis, and renal and pulmonary disease. Involvement of large vessels is life threatening because of the risk of arterial occlusion or aneurysms. Behçet’s syndrome in children, which most frequently presents between the ages of 9 and 10 years, has similar manifestations as does the adult form of the disease, but oral ulcers are a more common presenting sign in children, and uveitis is less common.116 Oral lesions are the presenting symptom in over 95% of children with Behçet’s syndrome. A variant of Behçet’s syndrome, MAGIC syndrome, has been described. It is characterized by Mouth And Genital ulcers with Inflammed Cartilage.117 DIAGNOSIS Because the signs and symptoms of Behçet’s syndrome overlap with those of several other diseases, particularly the connective-tissue diseases, it has been difficult to develop criteria that meet with universal agreement. Five different sets of diagnostic criteria have been in use during the past 20 years. In 1990, an international study group reviewed data from 914 patients from seven countries.118 A new set of diagnostic criteria was developed that includes recurrent oral ulceration occurring at least three times in one 12-month period plus two of the following four manifestations: 1. Recurrent genital ulceration 2. Eye lesions including uveitis or retinal vasculitis 3. Skin lesions including erythema nodosum, pseudofolliculitis, papulopustular lesions, or acneiform nodules in postadolescent patients not receiving corticosteroids 4. A positive pathergy test TREATMENT FIGURE 4-24 Aphthous-like lesion in a patient with Behçet’s syndrome. The management of Behçet’s syndrome depends on the severity and the sites of involvement. Patients with sight-threatening eye involvement or central nervous system lesions require more aggressive therapy with drugs with a higher potential for serious side effects.119 Azathioprine combined with prednisone has been shown to reduce ocular disease as well as oral and genital involvement.120 Pentoxifylline, which has fewer side effects than do immunosuppressive drugs or systemic steroids, has also been reported to be effective in decreasing disease activity, particularly 67 Ulcerative, Vesicular, and Bullous Lesions eye involvement.121 Cyclosporine or colchicine in combination with corticosteroids has also been shown to be useful in severe disease.122,123 Colchicine124 and thalidomide125 have been shown to be useful in mucocutaneous and gastrointestinal manifestations. Systemic corticosteroids remain a mainstay of treatment and are particularly useful in rapidly controlling the disease until immunosuppressive agents begin to work. Plasmapheresis has also been used successfully in emergencies. Oral mucosal lesions not adequately controlled by systemic therapy may be treated with topical or intralesional steroids in regimens described in the section on RAS. Recurrent Herpes Simplex Virus Infection Recurrent herpes infection of the mouth (recurrent herpes labialis [RHL]; recurrent intraoral herpes simplex infection [RIH]) occurs in patients who have experienced a previous herpes simplex infection and who have serum-antibody protection against another exogenous primary infection. In otherwise healthy individuals, the recurrent infection is confined to a localized portion of the skin or mucous membranes. Recurrent herpes is not a re-infection but a reactivation of virus that remains latent in nerve tissue between episodes in a nonreplicating state.126,127 Herpes simplex has been cultured from the trigeminal ganglion of human cadavers, and recurrent herpes lesions commonly appear after surgery involving the ganglion.128,129 Recurrent herpes may also be activated by trauma to the lips, fever, sunburn, immunosuppression, and menstruation.130 The virus travels down the nerve trunk to infect epithelial cells, spreading from cell to cell to cause a lesion. The published evidence demonstrating that RAS is not caused by herpesvirus induced many to believe that recurrent herpes infection of the oral region occurred only on the lips and not on the oral mucosa; this has been shown to be false. RAS and herpes lesions can both exist intraorally and are two separate and distinct disease processes.131–133 All patients who experience primary herpes infection do not experience recurrent herpes. The number of patients with a history of primary genital infection with HSV1 who subsequently experience recurrent HSV infections is approximately 15%.134 The recurrence rate for oral HSV1 infections is estimated to be between 20 and 40%. Studies have suggested several mechanisms for reactivation of latent HSV, including low serum IgA,135 decreased cellmediated immunity, decreased salivary antiherpes activity,136 and depression of ADCC (antibody-dependent cell-mediated cytotoxicity)137 and interleukin-2 caused by prostaglandin release in the skin. Individuals with T-lymphocyte deficiencies owing to AIDS or transplant or cancer chemotherapy may develop large chronic lesions138 (see “Herpes Simplex Virus Infection in Immunosuppressed Patients,” below) or, rarely, disseminated HSV infection. stress. The lesions are preceded by a prodromal period of tingling or burning. This is accompanied by edema at the site of the lesion, followed by formation of a cluster of small vesicles (Figure 4-25). Each vesicle is 1 to 3 mm in diameter, with the size of the cluster ranging from 1 to 2 cm. Occasionally, the lesions may be several centimeters in diameter, causing discomfort and disfigurement. These larger lesions are more common in immunosuppressed individuals. The frequency of recurrences varies. RIH lesions in otherwise normal patients are similar in appearance to RHL lesions, but the vesicles break rapidly to form ulcers. The lesions are typically a cluster of small vesicles or ulcers, 1 to 2 mm in diameter, clustered on a small portion of the heavily keratinized mucosa of the gingiva, palate, and alveolar ridges, although RIH lesions can occasionally involve other mucosal surfaces139 (Figure 4-26). In contrast, lesions of RAS tend to be larger, to spread over a larger area of mucosa, and to have a predilection for the less heavily keratinized buccal mucosa, labial mucosa, or floor of the mouth.131 DIAGNOSIS If laboratory tests are desired, RIH can be distinguished from RAS by cytology smears taken from the base of a fresh lesion. Smears from herpetic lesions show cells with ballooning degeneration and multinucleated giant cells; those from RAS lesions do not. For more accurate results, cytology smears may also be tested for HSV using fluorescein-labeled HSV antigen. Viral cultures also are used to distinguish herpes simplex from other viral lesions, particularly varicella-zoster infections. TREATMENT Recurrent herpes infections of the lips and mouth are seldom more than a temporary annoyance in otherwise normal individuals and should be treated symptomatically. Patients who experience frequent, large, painful, or disfiguring lesions may request professional consultation. The clinician should first attempt to minimize obvious triggers. Some recurrences can be eliminated by the wearing of sunblock during intense sun exposure. CLINICAL MANIFESTATIONS RHL, the common cold sore or fever blister, may be precipitated by fever, menstruation, ultraviolet light, and perhaps emotional FIGURE 4-25 Crusted lesions of recurrent herpes labialis. 68 Diagnosis and Management of Oral and Salivary Gland Diseases ▼ THE PATIENT WITH CHRONIC MULTIPLE LESIONS Patients with chronic multiple lesions are frequently misdiagnosed for weeks to months since their lesions may be confused with recurring oral mucosal disorders. The clinician can avoid misdiagnosis by carefully questioning the patient on the initial visit regarding the natural history of the lesions. In recurring disorders such as severe aphthous stomatitis, the patient may experience continual ulceration of the oral mucosa, but individual lesions heal and new ones form. In the category of disease described in this section, the same lesions are present for weeks to months. The major diseases in this group are pemphigus vulgaris, pemphigus vegetans, bullous pemphigoid, mucous membrane pemphigoid, linear IgA disease, and erosive lichen planus. Herpes simplex infections may cause chronic lesions in patients immunocompromised by cancer chemotherapy, immunosuppressive drugs, or HIV infection. Pemphigus FIGURE 4-26 Typical lesions of recurrent intraoral herpes simplex virus infection in patients with normal immunity are clusters of small vesicles and ulcers on the heavily keratinized oral mucosa. Drugs are available that suppress the formation and shorten the healing time of new recurrent lesions. Acyclovir, the original antiherpes drug, has been shown to be both safe and effective. The newer antiviral drugs such as valacyclovir, a prodrug of acyclovir, and famciclovir, a prodrug of penciclovir, have greater bioavailability than does acyclovir, but they do not eliminate established latent HSV. However, in the mouse model, famciclovir appeared to decrease the rate of HSV latency.140,141 The clinical importance of this finding in human HSV infection is not known. The effectiveness of these antiherpes drugs to prevent recurrences of genital HSV has been studied extensively. Acyclovir 400 mg twice daily, valacyclovir 250 mg twice daily, and famciclovir 250 mg were each highly effective in preventing genital recurrences.142,143 The use of antiherpes nucleoside analogues to prevent and treat RHL in otherwise normal individuals is controversial. Systemic therapy should not be used to treat occasional or trivial RHL in otherwise healthy individuals, but episodic use to prevent lesions in susceptible patients before highrisk activities such as skiing at high altitudes or before undergoing procedures such as dermabrasion or surgery involving the trigeminal nerve is justifiable. Some clinicians advocate the use of suppressive antiherpes therapy for the small percentage of RHL patients who experience frequent deforming episodes of RHL. Acyclovir 400 mg twice daily has been shown to reduce the frequency and severity of RHL in this group of patients.144 Both acyclovir and penciclovir are available in topical formulations, but use of these preparations shortens the healing time of RHL by less than 2 days. Pemphigus is a potentially life-threatening disease that causes blisters and erosions of the skin and mucous membranes. These epithelial lesions are a result of autoantibodies that react with desmosomal glycoproteins that are present on the cell surface of the keratinocyte. The immune reaction against these glycoproteins causes a loss of cell-to-cell adhesion, resulting in the formation of intraepithelial bullae.145,146 There are 0.5 to 3.2 cases reported each year per 100,000 population, with the highest incidence occurring in the fifth and sixth decades of life, although rare cases have been reported in children and the elderly.147 Pemphigus occurs more frequently in the Jewish population, particularly among Ashkenazi Jews, in whom studies have shown a strong association with major histocompatibility complex (MHC) class II alleles HLA-DR4 and DQW3. Familial pemphigus has also been reported. The major variants of pemphigus are pemphigus vulgaris (PV), pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, paraneoplastic pemphigus (PNPP), and drugrelated pemphigus. Pemphigus vegetans is a variant of pemphigus vulgaris, and pemphigus erythematosus is a variant of pemphigus foliaceus. Each form of this disease has antibodies directed against different target cell surface antigens, resulting in a lesion forming in different layer of the epithelium. In pemphigus foliaceus, the blister occurs in the superficial granular cell layer, whereas, in pemphigus vulgaris, the lesion is deeper, just above the basal cell layer. Mucosal involvement is not a feature of the foliaceus and erythematous forms of the disease. PEMPHIGUS VULGARIS PV is the most common form of pemphigus, accounting for over 80% of cases. The underlying mechanism responsible for causing the intraepithelial lesion of PV is the binding of IgG autoantibodies to desmoglein 3, a transmembrane glycoprotein adhesion molecule present on desmosomes. The presence of desmoglein 1 autoantibodies is a characteristic of pemphi- Ulcerative, Vesicular, and Bullous Lesions gus foliaceus, but these antibodies are also detected in patients with long-standing PV. Evidence for the relationship of the IgG autoantibodies to PV lesion formation includes studies demonstrating the formation of blisters on the skin of mice after passive transfer of IgG from patients with PV.148 The mechanism by which antidesmoglein antibodies cause the loss of cell-to-cell adhesion is controversial. Some investigators believe that binding of the PV antibody activates proteases, whereas more recent evidence supports the theory that the PV antibodies directly block the adhesion function of the desmogleins.146,149,150 The separation of cells, called acantholysis, takes place in the lower layers of the stratum spinosum (Figure 4-27). Electron microscopic observations show the earliest epithelial changes as a loss of intercellular cement substance; this is followed by a widening of intercellular spaces, destruction of desmosomes, and finally cellular degeneration. This progressive acantholysis results in the classic suprabasilar bulla, which involves increasingly greater areas of epithelium, resulting in loss of large areas of skin and mucosa. Pemphigus has been reported coexisting with other autoimmune diseases, particularly myasthenia gravis.147 Patients with thymoma also have a higher incidence of pemphigus. Several cases of pemphigus have been reported in patients with multiple autoimmune disorders or those with neoplasms such as lymphoma. Death occurs most frequently in elderly patients and in patients requiring high doses of corticosteroids who develop infections and bacterial septicemia, most notably from Staphylococcus aureus.151,152 Clinical Manifestations. The classical lesion of pemphigus is a thin-walled bulla arising on otherwise normal skin or mucosa. The bulla rapidly breaks but continues to extend peripherally, eventually leaving large areas denuded of skin (Figure 4-28). A characteristic sign of the disease may be obtained by application of pressure to an intact bulla. In patients with PV, the bulla enlarges by extension to an apparently normal surface. Another characteristic sign of the disease is that pressure to an appar- FIGURE 4-27 Histologic picture of pemphigus vulgaris. The bulla is intraepithelial because of acantholysis (×32 original magnification). (Courtesy of Margaret Wood, MD) 69 ently normal area results in the formation of a new lesion. This phenomenon, called the Nikolsky sign, results from the upper layer of the skin pulling away from the basal layer. The Nikolsky sign is most frequently associated with pemphigus but may also occur in epidermolysis bullosa. Some patients with pemphigus develop acute fulminating disease, but, in most cases, the disease develops more slowly, usually taking months to develop to its fullest extent. Oral Manifestations. Eighty to ninety percent of patients with pemphigus vulgaris develop oral lesions sometime during the course of the disease, and, in 60% of cases, the oral lesions are the first sign.153 The oral lesions may begin as the classic bulla on a noninflamed base; more frequently, the clinician sees shallow irregular ulcers because the bullae rapidly break. A thin layer of epithelium peels away in an irregular pattern, leaving a denuded base. The edges of the lesion continue to extend peripherally over a period of weeks until they involve large portions of the oral mucosa. Most commonly the lesions start on the buccal mucosa, often in areas of trauma along the occlusal plane. The palate and gingiva are other common sites of involvement.154 It is common for the oral lesions to be present up to 4 months before the skin lesions appear. If treatment is instituted during this time, the disease is easier to control, and the chance for an early remission of the disorder is enhanced. Frequently, however, the initial diagnosis is missed, and the lesions are misdiagnosed as herpes infection or candidiasis. Zegarelli and Zegarelli studied 26 cases of intraoral PV. The average time from onset of the disease to diagnosis was 6.8 months.155 They also noted that several patients had coexisting candidiasis, which sometimes masked the typical clinical picture of the pemphigus lesions. There is also a subgroup of pemphigus patients whose disease remains confined to the oral mucosa. These patients often have negative results on direct immunofluorescence (DIF). If a proper history is taken, the clinician should be able to distinguish the lesions of pemphigus from those caused by acute viral infections or erythema multiforme because of the acute nature of the latter diseases. It is also important for the clinician to distinguish pemphigus lesions from those in the RAS category. RAS lesions may be severe, but individual lesions heal and recur. In pemphigus, the same lesions continue to extend peripherally over a period of weeks to months. Lesions of pemphigus are not round and symmetric like RAS lesions but are shallow and irregular and often have detached epithelium at the periphery (see Figure 4-27). In early stages of the disease, the sliding away of the oral epithelium resembles skin peeling after a severe sunburn. In some cases, the lesions may start on the gingiva and be called desquamative gingivitis. It should be remembered that desquamative gingivitis is not a diagnosis in itself; these lesions must be biopsied to rule out the possibility of PV as well as bullous pemphigoid, mucous membrane pemphigoid, and erosive lichen planus. Laboratory Tests. PV is diagnosed by biopsy. Biopsies are best done on intact vesicles and bullae less than 24 hours old; however, because these lesions are rare on the oral mucosa, the 70 A Diagnosis and Management of Oral and Salivary Gland Diseases B FIGURE 4-28 A, Shallow irregular erosions on the buccal mucosa and ventral surface of the tongue caused by pemphigus. B, Bullae between the fingers of the same patient. biopsy specimen should be taken from the advancing edge of the lesion, where areas of characteristic suprabasilar acantholysis may be observed by the pathologist. Specimens taken from the center of a denuded area are nonspecific histologically as well as clinically. Sometimes several biopsies are necessary before the correct diagnosis can be made. If the patient shows a positive Nikolsky sign, pressure can be placed on the mucosa to produce a new lesion; biopsy may be done on this fresh lesion. A second biopsy, to be studied by DIF, should be performed whenever pemphigus is included in the differential diagnosis. This study is best performed on a biopsy specimen that is obtained from clinically normal-appearing perilesional mucosa or skin. In this technique for DIF, fluorescein-labeled antihuman immunoglobulins are placed over the patient’s tissue specimen. In cases of PV, the technique will detect antibodies, usually IgG and complement, bound to the surface of the keratinocytes. Indirect immunofluorescent antibody tests have been described that are helpful in distinguishing pemphigus from pemphigoid and other chronic oral lesions and in following the progress of patients treated for pemphigus. In this technique, serum from a patient with bullous disease is placed over a prepared slide of an epidermal structure (usually monkey esophagus). The slide is then overlaid with fluorescein-tagged antihuman gamma globulin. Patients with pemphigus vulgaris have antikeratinocyte antibodies against intercellular substances that show up under a fluorescent microscope. The titer of the antibody has been directly related to the level of clinical disease. An ELISA (enzyme-linked immunosorbent assay) has been developed that can detect desmoglein 1 and 3 in serum samples of patients with PV. These laboratory tests should provide a new tool for the accurate diagnosis of PV and may also prove useful in monitoring the progress of the disease.156,157 Treatment . An important aspect of patient management is early diagnosis, when lower doses of medication can be used for shorter periods of time to control the disease. The mainstay of treatment remains high doses of systemic corticosteroids, usually given in dosages of 1 to 2 mg/kg/d. When steroids must be used for long periods of time, adjuvants such as azathioprine or cyclophosphamide are added to the regimen to reduce the complications of long-term corticosteroid therapy. Prednisone is used initially to bring the disease under control, and, once this is achieved, the dose of prednisone is decreased to the lowest possible maintenance levels. Patients with only oral involvement also may need lower doses of prednisone for shorter periods of time, so the clinician should weigh the potential benefits of adding adjuvant therapy against the risks of additional complications such as blood dyscrasias, hepatitis, and an increased risk of malignancy later in life. There is no one accepted treatment for pemphigus confined to the mouth, but one 5-year follow -up study of the treatment of oral pemphigus showed no additional benefit of adding cyclophosphamide or cyclosporine to prednisone versus prednisone alone, and it showed a higher rate of complications in the group taking the immunosuppressive drug.158 Most studies of pemphigus of the skin show a decreased mortality rate when adjuvant therapy is given along with prednisone.159 One new immunosuppressive drug, mycophenolate, has been effective when managing patients resistant to other adjuvants.160 The need for systemic steroids may be lowered further in cases of oral pemphigus by combining topical with systemic steroid therapy, either by allowing the prednisone tablets to dissolve slowly in the mouth before swallowing or by using potent topical steroid creams. Other therapies that have been reported as beneficial are parenteral gold therapy, dapsone, tetracycline, and plasmapheresis.161 Plasmapheresis is particularly useful in patients refractory to corticosteroids. A therapy described by Rook and colleagues involves administration of 8-methoxypsoralen followed by exposure of peripheral blood to ultraviolet radiation.162 PARANEOPLASTIC PEMPHIGUS PNPP is a severe variant of pemphigus that is associated with an underlying neoplasm—most frequently non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, or thymoma. 71 Ulcerative, Vesicular, and Bullous Lesions Castleman’s disease and Waldenströms macroglobulinemia are also associated with cases of PNPP. Patients with this form of pemphigus develop severe blistering and erosions of the mucous membranes and skin. Treatment of this disease is difficult, and most patients die from the effects of the underlying tumor, respiratory failure due to acantholysis of respiratory epithelium, or the severe lesions that do not respond to the therapy successful in managing other forms of pemphigus.163,164 Histopathology of lesions of PNPP includes inflammation at the dermal-epidermal junction and keratinocyte necrosis in addition to the characteristic acantholysis seen in PV. The results of direct and indirect immunofluorescence also differ from those in PV. DIF shows deposition of IgG and complement along the basement membrane as well as on the keratinocyte surface. Indirect immunofluorescence demonstrates antibodies that not only bind to epithelium but to liver, heart, and bladder tissue as well. PEMPHIGUS VEGETANS Pemphigus vegetans, which accounts for 1 to 2% of pemphigus cases, is a relatively benign variant of pemphigus vulgaris because the patient demonstrates the ability to heal the denuded areas. Two forms of pemphigus vegetans are recognized: the Neumann type and the Hallopeau type. The Neumann type is more common, and the early lesions are similar to those seen in pemphigus vulgaris, with large bullae and denuded areas. These areas attempt healing by developing vegetations of hyperplastic granulation tissue. In the Hallopeau type, which is less aggressive, pustules, not bullae, are the initial lesions. These pustules are followed by verrucous hyperkeratotic vegetations. Biopsy results of the early lesions of pemphigus vegetans show suprabasilar acantholysis.165 In older lesions, hyperkeratosis and pseudoepitheliomatous hyperplasia become prominent. Immunofluorescent study shows changes identical to those seen in PV. FIGURE 4-29 Chronic palatal lesions of pemphigus vegetans. and bullous lichen planus. There is significant overlap among these diseases, and the diagnosis often depends on whether the disease is categorized by clinical manifestations combined with routine histopathology or the newer techniques of molecular biology. Recent research into pathologic mechanisms is defining the specific antigens in the basement membrane complex involved in triggering the autoantibody response. BULLOUS PEMPHIGOID BP, which is the most common of the subepithelial blistering diseases, occurs chiefly in adults over the age of 60 years; it is self-limited and may last from a few months to 5 years. BP may be a cause of death in older debilitated individuals.168 BP has occasionally been reported in conjunction with other diseases, particularly multiple sclerosis and malignancy, or drug therapy, particularly diuretics.169 In pemphigoid, the initial defect is not intraepithelial as in PV, but it is subepithelial in the lamina lucida region of the basement membrane170 (Figure 4-30). There is no acantholysis, but the split in the basement membrane is accompanied by an inflammatory infiltrate that is characteristically rich in eosinophils. Oral Manifestations. Oral lesions are common in both forms of pemphigus vegetans and may be the initial sign of disease.166 Gingival lesions may be lace-like ulcers with a purulent surface on a red base or have a granular or cobblestone appearance (Figure 4-29). Oral lesions that are associated with inflammatory bowel disease and resemble pemphigus vegetans both clinically and histologically are referred to by some authors as pyostomatitis vegetans.167 Treatment. Treatment is the same as that for PV. Subepithelial Bullous Dermatoses Subepithelial bullous dermatoses are a group of mucocutaneous autoimmune blistering diseases that are characterized by a lesion in the basement membrane zone. The diseases in this group include bullous pemphigoid (BP), mucous membrane (cicatricial) pemphigoid (MMP), linear IgA disease (LAD), chronic bullous dermatosis of childhood (CBDC), and erosive FIGURE 4-30 Histologic picture of bullous pemphigoid. The bulla is subepithelial.(Courtesy of Margaret Wood, MD) 72 Direct immunofluorescent study of a biopsy specimen demonstrates deposition of IgG bound to the basement membrane. Indirect immunoflourescent study of serum obtained from patients with BP demonstrates IgG antibodies bound to the epidermal side of salt-split skin onto antigens that have been named BP antigens 1 and 2. This latter test is particularly useful in distinguishing BP from another subepithelial bullous disease, epidermolysis bullosa aquisita, which has IgG antibodies localized to the dermal side of the salt-split skin. Clinical Manifestations. The characteristic skin lesion of BP is a blister on an inflamed base that chiefly involves the scalp, arms, legs, axilla, and groin (Figure 4-31). Pruritic macules and papules may also be a presenting sign. The disease is self-limiting but can last for months to years without therapy. Patients with BP may experience one episode or recurrent bouts of lesions. Unlike pemphigus, BP is rarely life threatening since the bullae do not continue to extend at the periphery to form large denuded areas, although death from sepsis or cardiovascular disease secondary to long-term steroid use has been reported to be high in groups of sick elderly patients.171 Diagnosis and Management of Oral and Salivary Gland Diseases oral lesions of mucous membrane pemphigoid, but early remission of BP is more common. Treatment. Patients with localized lesions of BP may be treated with high-potency topical steroids,168 whereas patients with severe disease require use of systemic corticosteroids alone or combined with immunosuppressive drugs such as azathioprine, cyclophosphamide, or mycophenolate. Patients with moderate levels of disease may avoid use of systemic steroids by use of dapsone or a combination of tetracycline and nicotinamide. MUCOUS MEMBRANE PEMPHIGOID (CICATRICIAL PEMPHIGOID) Oral Manifestations. Oral involvement is common in BP. Lever reported 33 patients with bullous pemphigoid. Oral lesions were present in 11.172 In 3 of the cases, the oral lesions preceded the skin lesions, most frequently on the buccal mucosa. Venning and colleagues reported oral lesions in 50% (18 of 36) of BP patients studied.170 The oral lesions of pemphigoid are smaller, form more slowly, and are less painful than those seen in pemphigus vulgaris, and the extensive labial involvement seen in pemphigus is not present. Desquamative gingivitis has also been reported as a manifestation of BP. The gingival lesions consist of generalized edema, inflammation, and desquamation with localized areas of discrete vesicle formation. The oral lesions are clinically and histologically indistinguishable from MMP is a chronic autoimmune subepithelial disease that primarily affects the mucous membranes of patients over the age of 50 years, resulting in mucosal ulceration and subsequent scarring. The primary lesion of MMP occurs when autoantibodies directed against proteins in the basement membrane zone, acting with complement (C3) and neutrophils, cause a subepithelial split and subsequent vesicle formation (Figure 4-32). The antigens associated with MMP are most frequently present in the lamina lucida portion of the basement membrane, but recent research has demonstrated that the identical antigen is not involved in all cases, and the lamina densa may be the primary site of involvement in some cases. The circulating autoantibodies are not the same in all cases, and subsets of MMP have been identified by the technique of immunofluorescent staining of skin that has been split at the basement membrane zone with the use of sodium chloride.173 The majority of cases of MMP demonstrate IgG directed against antigens on the epidermal side of the salt-split skin, which have been identified as BP 180 (also called type XVII collagen); however, cases of MMP have also been identified where the antigen is present on the dermal side of the split. This latter antigen has been identified as epiligrin (laminin 5), an adhesion molecule that is a component of the anchoring filaments of the basement membrane.174,175 Figure 4-31 Bullous pemphigoid lesion of the scalp. FIGURE 4-32 Histopathology of mucous membrane pemphigoid, demonstrating subepithelial separation at the basement membrane. 73 Ulcerative, Vesicular, and Bullous Lesions Clinical Manifestations. The subepithelial lesions of MMP may involve any mucosal surface, but they most frequently involve the oral mucosa. The conjunctiva is the second most common site of involvement and can lead to scarring and adhesions developing between the bulbar and palpebral conjunctiva called symblepharon (Figure 4-33, A and B). Corneal damage is common, and progressive scarring leads to blindness in close to 15% of patients. Lesions may also affect the genital mucosa, causing pain and sexual dysfunction. Laryngeal involvement causes pain, hoarseness, and difficulty breathing, whereas esophageal involvement may cause dysphagia, which can lead to debilitation and death in severe cases. Skin lesions, usually of the head and neck region, are present in 20 to 30% of patients. Oral Manifestations. Oral lesions occur in over 90% of patients with MMP. Desquamative gingivitis is the most common manifestation and may be the only manifestation of the disease (Figure 4-34). Since these desquamative lesions resemble the lesions of erosive lichen planus and pemphigus, all cases of desquamative gingivitis should be biopsied and studied with both routine histology and direct immunofluorescence to determine the correct diagnosis. Lesions may present as intact vesicles of the gingival or other mucosal surfaces, but more frequently they appear as nonspecific-appearing erosions (Figure 4-35). The erosions typically spread more slowly than pemphigus lesions and are more self-limiting. Diagnosis. Patients with MMP included in the differential diagnosis must have a biopsy done for both routine and direct immunofluorescent study. Routine histopathology shows subbasilar cleavage. Using the direct immunofluorescent technique (see “Laboratory Tests” under “Pemphigus Vulgaris” for description), biopsy specimens taken from MMP patients demonstrate positive fluorescence for immunoglobulin and complement in the basement membrane zone in 50 to 80% of patients. Splitting the biopsy specimen at the basement membrane zone with 1 M NaCl prior to direct immunofluorescence increases the sensitivity of the test. The direct immunofluorescent technique is excellent for distinguishing MMP A from pemphigus, and specimens obtained show immunoglobulin and complement deposition in the intercellular substance of the prickle cell layer of the epithelium. Only 10% of MMP patients demonstrate positive indirect immunofluorescence for circulating antibasement membrane-zone antibodies; however, use of salt-split skin as a substrate increases the sensitivity of this test. Treatment. Management of MMP depends on the severity of symptoms. When the lesions are confined to the oral mucosa, systemic corticosteroids will suppress their formation, but the clinician must weigh the benefits against the hazards from side effects of the drug.176 Unlike pemphigus, MMP is not a fatal disease, and long-term use of steroids for this purpose must be carefully evaluated, particularly because most cases are chronic, most patients are elderly, and treatment is required for a long period of time. Patients with mild oral disease should be treated with topical and intralesional steroids. Desquamative gingivitis can often be managed with topical steroids in a soft dental splint that covers the gingiva, although the clinician using topical steroids over large areas of mucosa must closely monitor the patient for side effects such as candidiasis and effects of systemic absorption. When topical or intralesional therapy is not successful, dapsone therapy may be attempted. Rogers and Mehregan have developed a protocol for use of dapsone in patients with MMP.177 The effectiveness of this protocol for the management of MMP was recently confirmed by Ciarrocca and Greenberg.178 Since dapsone causes hemolysis and methemoglobinemia, glucose-6-phosphate dehydrogenase deficiency must be ruled out, and the patient’s hemoglobin must be closely monitored. Methemoglobinemia can be reduced with the use of cimetidine and vitamin E.151Another rare side effect of dapsone is dapsone hypersensitivity syndrome, an idiosyncratic disorder characterized by fever, lymphadenopathy, skin eruptions, and occasional liver involvement. Patients resistant to dapsone should be treated with a combination of systemic corticosteroids and immunosuppressive drugs,152 particularly when there is risk of blindness from conjunctival involvement, B FIGURE 4-33 Mucous membrane pemphigoid; early (A) and advanced (B) cicatricial pemphigoid of the conjunctiva with symblepharon formation. 74 Diagnosis and Management of Oral and Salivary Gland Diseases The oral lesions of LAD may be managed with the use of topical steroids, but dapsone is effective therapy for more severe cases. Resistant cases may require systemic corticosteroids. CHRONIC BULLOUS DISEASE OF CHILDHOOD FIGURE 4-34 Chronic desquamative gingival lesions of mucous membrane pemphigoid. or significant laryngeal or esophageal damage. Reports suggest that tetracycline and nicotinamide may also be helpful in controlling the lesions of MMP.179,180 LINEAR IGA DISEASE LAD is characterized by the deposition of IgA rather than IgG at the basement membrane zone, and the clinical manifestations may resemble either dermatitis herpetiformis or pemphigoid. The cause of the majority of cases is unknown, but a minority of cases have been drug induced.181 As in MMP, the antigens associated with LAD are heterogeneous and may be found in either the lamina lucida or lamina densa portions of the basement membrane.182,183 The skin lesions of LAD may resemble those observed in patients with dermatitis herpetiformis, which are characterized by pruritic papules and blisters at sites of trauma such as the knees and elbows. Other patients have bullous skin lesions similar to those seen in patients with bullous pemphigoid. Oral lesions are common in LAD and may be seen in up to 70% of patients. These lesions are clinically indistinguishable from the oral lesions of MMP, with blisters and erosions of the mucosa frequently accompanied by desquamative gingivitis. FIGURE 4-35 Mucous membrane pemphigoid causing scarring of the soft palate. CBDC is another blistering disorder, which chiefly affects children below the age of 5 years. It is characterized by the deposition of IgA antibodies in the basement membrane zone,184 which are detected by direct immunofluorescence on the epidermal side of salt-split skin or mucosa. The onset of the disease may be precipitated by an upper respiratory infection or drug therapy.185 The characteristic lesion of CBDC is a cluster of vesicles and bullae on an inflamed base. The genital region is involved; conjunctival, rectal, and oral lesions may also be present. Oral mucosal involvement is present in up to 50% of cases, and the oral lesions are similar to those observed in patients with MMP. Diagnosis is made by biopsy demonstrating a subepithelial lesion on routine histology and by deposition of IgA in the basement membrane zone on direct immunofluorescence. Indirect immunofluorescence demonstrates circulating IgA in 80% of cases.186 This disease is self-limiting, and the lesions characteristically heal within 2 years. As with LAD, the lesions are responsive to sulfapyridine or dapsone therapy. Corticosteroids may be required for severe cases. EROSIVE LICHEN PLANUS The majority of cases of lichen planus present as white lesions (discussed in detail in Chapter 5). An erosive and bullous form of this disease presents as chronic multiple oral mucosal ulcers. Erosive and bullous lesions of lichen planus occur in the severe form of the disease when extensive degeneration of the basal layer of epithelium causes a separation of the epithelium from the underlying connective tissue.187,188 In some cases, the lesions start as vesicles or bullae—this has been classified as “bullous lichen planus”; in a majority of cases, the disease is characterized by ulcers and is called “erosive lichen planus.” Both of these disorders are variations of the same process and should be considered together. The erosive form of lichen planus has been associated with drug therapy, underlying medical disorders, and reactions to dental restorations.189 The drugs most commonly associated with severe lichenoid reactions include NSAIDs, hydrochlorothiazide, penicillamine, and angiotensin-converting enzyme inhibitors. The most frequently reported underlying disease associated with oral lichenoid reactions is chronic hepatitis caused by hepatitis C, particularly in Japan and the Mediterranean region.190,191 Contact allergic reactions to flavoring agents such as cinnamon and peppermint and to dental materials such as mercury in amalgam may also result in lichenoid reactions of the oral mucosa.192,193 Lichen planus lesions suspected of being caused by contact allergy should be in direct contact with the suspected allergen. Graft-versus-host disease due to bone marrow transplantation also causes oral lichenoid lesions.194 The association between erosive lichen planus and squamous cell carcinoma remains controversial. There have been 75 Ulcerative, Vesicular, and Bullous Lesions many case reports of carcinoma developing in areas of lichen planus.195–198 A case by Massa and colleagues shows histologic progression from lichen planus, lichen planus with epithelial atypia, and frank squamous cell carcinoma.199 Reviews of large numbers of patients with lichen planus by Silverman and colleagues and Murti and associates show an association between the two diseases of between 0.4 and 1.2%.200,201 Affected patients were frequently tobacco users; this leads to speculation that lichen planus is a cofactor in malignant transformation. Clinical Manifestations. Erosive lichen planus is characterized by the presence of vesicles, bullae, or irregular shallow ulcers of the oral mucosa187 (Figures 4-36 and 4-37). The lesions are usually present for weeks to months and thus can be distinguished from those of aphthous stomatitis, which form and heal in a period of 10 days to 2 weeks. A significant number of cases of erosive lichen planus present with a picture of desquamative gingivitis202 (Figure 4-38). It is important to remember that desquamative gingivitis is not a disease entity but a sign of disease that can be caused by erosive lichen planus, pemphigus vulgaris, or cicatricial pemphigoid. Desquamative gingivitis caused by lichen planus may be accompanied by characteristic Wickham’s striae, simplifying the diagnosis, or they may be present without other lesions. Diagnosis. A diagnosis of erosive lichen planus should be suspected when erosive or bullous lesions are accompanied by typical lichenoid white lesions. Biopsy is necessary for definitive diagnosis. Biopsy of the erosive lesions shows hydropic degeneration of the basal layer of epithelium. This can help to distinguish it from mucous membrane pemphigoid, which is also a subepithelial lesion but which shows an intact basal layer, or from pemphigus vulgaris, in which acantholysis is demonstrated. Direct immunofluorescence should be performed on biopsy specimens when pemphigus, pemphigoid, or discoid lupus erythematosus is included in the differential diagnosis. FIGURE 4-37 Palatal lesions of erosive lichen planus. distressingly painful. The treatment of choice is topical corticosteroids (Figure 4-39). Intralesional steroids can be used for indolent lesions, and, in cases of severe exacerbation, systemic steroids may be considered for short periods of time. Cyclosporine rinses may be effective for patients with severe erosions resistant to topical steroids, although the expense may be a limiting factor.203,204 Tacrolimus, another immunosuppressive drug, has recently been marketed in a topical form and has been reported useful in the management of oral erosive lichen planus. Systemic etretinate, dapsone, or photochemotherapy have also been reported to be effective in severe resistant cases.205–207 Because patients with oral lichen planus appear to be in a higher risk group for development of squamous cell carcinoma, it is prudent to periodically evaluate all patients with erosive and bullous forms of lichen planus for the presence of suspicious lesions requiring biopsy (Figure 4-40). Herpes Simplex Virus Infection in Immunosuppressed Patients Management. Patients with severe lichen planus should have drug therapy and underlying disease ruled out as possible causes. The bullous and erosive forms of lichen planus can be Immunosuppressed patients may develop an aggressive or chronic form of herpes infection; therefore, herpes simplex infection should be included in the differential diagnosis when immunosuppressed patients develop chronic oral FIGURE 4-36 Erosive lichen planus of the labial mucosa. FIGURE 4-38 Desquamative gingival lesions in a patient with erosive lichen planus. 76 FIGURE 4-39 Soft medication splint used to treat desquamative gingivitis secondary to erosive lichen planus. Diagnosis and Management of Oral and Salivary Gland Diseases hematologic malignancies. Fourteen of the 18 patients had oral or perioral lesions. Greenberg and colleagues studied 98 immunosuppressed patients: 68 renal transplant patients and 30 acute leukemic patients receiving chemotherapy.209 Fifty percent of the leukemic patients and 15% of the transplant patients developed aggressive or chronic recurrent HSV. HSV was the most common cause of oral lesions in both groups, producing lesions that were previously thought to be due to the toxic effects of chemotherapy or bacterial infection. The oral lesions may be small, round, symmetric, and associated with recurrent herpes infection, or they may be large and deep and often confused with lesions of other diseases (see Figure 4-41, A and B) The lesions last from weeks to months and may reach several centimeters in diameter. The larger lesions often have raised white borders composed of small vesicles (Figure 4-42). DIAGNOSIS ulcers. The chronic form of herpes is a variation of recurrent herpes simplex infection rather than a primary infection.208,209 AIDS patients, transplant patients taking immunosuppressed drug therapy, patients on high doses of corticosteroids, and patients with leukemia, lymphoma, or other disorders that alter the T-lymphocyte response are those most susceptible to aggressive HSV lesions. Lesions appear on the skin or the mucosa of the mouth, rectal, or genital area. They begin as an ordinary recurrent herpes infection but remain for weeks to months and develop into large ulcers up to several centimeters in diameter (Figure 4-42). Chronic herpes simplex infection has been reported with both type 1 and type 2 herpesviruses. This disease causes significant local morbidity and occasional dissemination. ORAL MANIFESTATIONS Lesions of chronic or aggressive recurrent HSV may occur on the lips or intraoral mucosa. Schneidman and colleagues210 reviewed 18 cases of chronic herpes infection; 7 cases occurred in renal transplant patients, and 8 occurred in patients with FIGURE 4-40 Squamous cell carcinoma forming on the buccal mucosa of a patient with erosive lichen planus. HSV must be ruled out whenever oral mucosal vesicles or ulcers occur in immunosuppressed or myelosuppressed patients. Both a cytology for staining with fluorescent HSV antibody and a viral culture should be obtained. If these lesions occur in a patient without an obvious known cause, they should be thoroughly evaluated for an immunologic deficiency disease. TREATMENT Immunosuppressed patients with HSV infection respond well to acyclovir administered orally or intravenously. 21 Occasional cases of acyclovir-resistant HSV have been reported in AIDS patients. Foscarnet has been effective therapy for these patients.211 ▼ THE PATIENT WITH SINGLE ULCERS The most common cause of single ulcers on the oral mucosa is trauma. Trauma may be caused by teeth, food, dental appliances, dental treatment, heat, chemicals, or electricity (Figure 4–43). The diagnosis is usually not complicated and is based on the history and physical findings. The most important differentiation is to distinguish trauma from squamous cell carcinoma. The dentist must examine all single ulcers for significant healing in 1 week; if healing is not evident in this time, a biopsy should be done to rule out cancer. (Cancer of the mouth is discussed in detail in Chapter 8.) Infections that may cause a chronic oral ulcer include the deep mycoses histoplasmosis, blastomycosis, mucormycosis, aspergillosis, cryptococcosis, and coccidioidomycosis as well as a chronic herpes simplex infection. Syphilis, another infection that may cause a single oral ulcer in the primary and tertiary stages, is described in Chapter 20. The deep mycoses were rare causes of oral lesions prior to HIV infection and immunosuppressive drug therapy. The dentist must consider this group of diseases in the differential diagnosis whenever isolated ulcerative lesions develop in known or suspected immunosuppressed patients. Biopsy of 77 Ulcerative, Vesicular, and Bullous Lesions A B FIGURE 4-41 A, This large ulcer of the buccal mucosa was caused by a chronic herpes simplex infection in a kidney transplant patient receiving immunosuppressive drug therapy. B, A herpetic ulcer near the eye of the same patient. suspected tissue, accompanied by a request for appropriate stains, is necessary for early diagnosis (Figure 4-44). Deep mycoses in immunosuppressed patients are discussed in greater detail in Chapters 16 and 18. Histoplasmosis Histoplasmosis is caused by the fungus Histoplasma capsulatum, a dimorphic fungus that grows in the yeast form in infected tissue. Infection results from inhaling dust contaminated with droppings, particularly from infected birds or bats. An African form of this infection is caused by a larger yeast, which is considered a variant of H. capsulatum and is called H. duboisii. Histoplasmosis is the most common systemic fungal infection in the United States; in endemic areas such as the Mississippi and Ohio River valleys, serologic evidence of previous infection may be found in 75 to 80% of the population. In most cases, particularly in otherwise normal children, primary infection is mild, manifesting as a self-limiting pulmonary disease that heals to leave fibrosis and calcification similar to tuberculosis. In a small percentage of cases, progressive disease FIGURE 4-42 Chronic herpes simplex infection of the palate in a patient taking chemotherapy for acute leukemia. results in cavitation of the lung and dissemination of the organism to the liver, spleen, adrenal glands, and meninges. Patients with the disseminated form of the disease may develop anemia and leukopenia secondary to bone marrow involvement. Immunosuppressed or myelosuppressed patients are more likely to develop the severe disseminated form of the disease. During the past decade, most reported cases of oral lesions of histoplasmosis have been reported in HIV-infected individuals who live in or have visited endemic areas. ORAL MANIFESTATIONS Oral involvement is usually secondary to pulmonary involvement and occurs in a significant percentage of patients with disseminated histoplasmosis. Oral mucosal lesions may appear as a papule, a nodule, an ulcer, or a vegetation. If a single lesion is left untreated, it progresses from a firm papule to a nodule, which ulcerates and slowly enlarges. The cervical lymph nodes are enlarged and firm. The clinical appearance of the lesions, as well as the accompanying lymphadenopathy, often resembles that of squamous cell carcinoma, other chronic fungal infections, or even Hodgkin’s disease. FIGURE 4-43 Traumatic ulcer of the buccal mucosa secondary to cheek biting. 78 Diagnosis and Management of Oral and Salivary Gland Diseases infection commonly follows a chronic course beginning with mild symptoms such as malaise, low-grade fever, and mild cough. If the infection goes untreated, the symptoms worsen to include shortness of breath, weight loss, and production of blood-tinged sputum. Infection of the skin, mucosa, and bone may also occur, resulting from metastatic spread of organisms from the pulmonary lesions through the lymphatic system. The skin and mucosal lesions start as subcutaneous nodules and progress to well-circumscribed indurated ulcers. ORAL MANIFESTATIONS FIGURE 4-44 Palatal ulcer can be the initial sign of Cryptococcus in an AIDS patient. Cases of oral histoplasmosis have been reported as the initial sign of HIV infection. The most common oral lesion of histoplasmosis in patients with HIV is an ulcer with an indurated border, which is most commonly seen on the gingiva, palate, or tongue.212 These oral histoplasmosis lesions in patients with HIV may occur alone or as part of a disseminated infection.213,214 DIAGNOSIS Definitive diagnosis of histoplasmosis is made by a culture of infected tissues or exudates on Sabouraud’s dextrose agar or other appropriate media. Biopsy of infected tissue shows small oval yeasts within macrophages and reticuloendothelial cells as well as chronic granulomas, epithelioid cells, giant cells, and occasionally caseation necrosis. Skin tests and serology are not definitive because of significant numbers of false-negative and false-positive reactions. TREATMENT Mild to moderate cases of histoplasmosis can be treated with ketoconazole or itraconazole for 6 to 12 months. Immunosuppressed patients or patients with severe disease require intravenous amphotericin B for up to 10 weeks. Blastomycosis Blastomycosis is a fungal infection caused by Blastomyces dermatitidis. This dimorphic organism can grow in either a yeast or as a mycelial form. The organism is found as a normal inhabitant of soil; therefore, the highest incidence of this infection is found in agricultural workers, particularly in the middle Atlantic and southeastern portions of the United States. This geographic distribution of the infection has led to the designation by some as “North American blastomycosis.” Infection by the same organism, however, has also been found in Mexico and Central and South Americas. Infection with Blastomyces begins in a vast majority of cases by inhalation; this causes a primary pulmonary infection. Although an acute self-limiting form of the disease exists, the Oral lesions are rarely the primary site of infection. When oral lesions have been reported as a first sign of blastomycosis, they have occurred in patients with mild pulmonary symptoms that have been overlooked by the patient or physician. Most cases of oral involvement demonstrate concomitant pulmonary lesions on chest radiographs. The most common appearance of the oral lesions of blastomycosis is a nonspecific painless verrucous ulcer with indurated borders, often mistaken for squamous cell carcinoma. Occasionally, this mistake is perpetuated by an inexperienced histopathologist who confuses the characteristic pseudoepitheliomatous hyperplasia with malignant changes. Other oral lesions that have been reported include hard nodules and radiolucent jaw lesions. Page and colleagues reported two cases of painless oral mucosal ulcers as the first sign of blastomycosis; in both cases, a careful history taking revealed mild respiratory symptoms.215 Bell and colleagues reported 7 cases of oral lesions occurring in patients with blastomycosis; 4 presented as chronic oral ulcers and 3 as radiolucent bone lesions.216 Chest radiographs showed concomitant pulmonary involvement in all cases. Dentists should include the diagnosis of blastomycosis in the differential diagnosis of a chronic oral ulcer. The diagnosis cannot be made on clinical grounds alone. The index of suspicion should increase when a chronic painless oral ulcer appears in an agricultural worker or when the review of systems reveals pulmonary symptoms. Diagnosis is made on the basis of biopsy and on culturing the organism from tissue.217 The histologic appearance shows pseudoepitheliomatous hyperplasia with a heavy infiltrate of chronic inflammatory cells and microabscesses. TREATMENT Treatment for blastomycosis is similar to that described for histoplasmosis. Mucormycosis Mucormycosis (phycomycosis) is caused by an infection with a saprophytic fungus that normally occurs in soil or as a mold on decaying food. The fungus is nonpathogenic for healthy individuals and can be cultured regularly from the human nose, throat, and oral cavity. (The organism represents an opportunistic rather than a true pathogen.) Infection occurs in individuals with decreased host resistance, such as those with poorly controlled diabetes or hematologic malignancies, 79 Ulcerative, Vesicular, and Bullous Lesions or those undergoing cancer chemotherapy or immunosuppressive drug therapy.218,219 In the debilitated patient, mucormycosis may appear as a pulmonary, gastrointestinal, disseminated, or rhinocerebral infection. The rhinomaxillary form of the disease, a subdivision of the rhinocerebral form, begins with the inhalation of the fungus by a susceptible individual. The fungus invades arteries and causes damage secondary to thrombosis and ischemia. The fungus may spread from the oral and nasal region to the brain, causing death in a high percentage of cases. Symptoms include nasal discharge caused by necrosis of the nasal turbinates, ptosis, proptosis secondary to invasion of the orbit, fever, swelling of the cheek, and paresthesia of the face. ORAL MANIFESTATIONS The most common oral sign of mucormycosis is ulceration of the palate, which results from necrosis due to invasion of a palatal vessel.218,220 The lesion is characteristically large and deep, causing denudation of underlying bone (Figure 4-45). Ulcers from mucormycosis have also been reported on the gingiva, lip, and alveolar ridge. The initial manifestation of the disease may be confused with dental pain or bacterial maxillary sinusitis caused by invasion of the maxillary sinus. The clinician must include mucormycosis in the differential diagnosis of large oral ulcers occurring in patients debilitated from diabetes, chemotherapy, or immunosuppressive drug therapy. Early diagnosis is essential if the patient is to be cured of this infection. Negative cultures do not rule out mucormycosis because the fungus is frequently difficult to culture from infected tissue; instead, a biopsy must be performed when mucormycosis is suspected. The histopathologic specimen shows necrosis and nonseptate hyphae, which are best demonstrated by a periodic acid–Schiff stain. TREATMENT When diagnosed early, mucormycosis may be cured by a combination of surgical débridement of the infected area and sys- FIGURE 4-45 Mucormycosis of the palate in a kidney transplant patient taking immunosuppressive drugs (azathioprine and prednisone). temic administration of amphotericin B for up to 3 months. Proper management of the underlying disorder is an important aspect affecting the final outcome of treatment. All patients given amphotericin B must be closely observed for renal toxicity by repeated measurements of the blood urea nitrogen and creatinine. ▼ REFERENCES 1. Scully C. Orofacial herpes simplex virus infections. Current concepts in the epidemiology, pathogenesis and treatment. Oral Surg 1989;68:701–10. 2. Levy JA. Three new human herpesviruses (HHV-6, 7 and 8). Lancet 1997;349:558–62. 3. Greenberg MS, Glick M, Nghiem L, et al. Relationship of cytomegalovirus to salivary gland dysfunction in HIV-infected patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:334–9. 4. Embil JA, Manuel R, McFarlane S. Concurrent oral and genital infection with an identical strain of herpes simplex type I. Sex Transm Dis 1981;8:70–2. 5. Fife KH, Schmidt O, Remington M, Corely L. Primary and recurrent concomitant genital infection with herpes simplex virus types 1 and 2. J Infect Dis 1983;147:163. 6. Christenson B, Bottinger M, Svenson A, Jeansson S. A 15 year surveillance study of antibodies to herpes simplex types 1 and 2 in a cohort of young girls. J Infect 1992;25:147. 7. Scott DA, Coulter WA, Lamey PJ. Oral shedding of herpes simplex virus type 1: a review. J Oral Pathol Med 1997;26:441–7. 8. Wheeler CE. The herpes simplex problem. J Am Acad Dermatol 1988;18:163–8. 9. Wald A. Herpes. Transmission and viral shedding. Dermatol Clin 1998;16:795–7. 10. Roizman B, Sears AE. An inquiry into the mechanisms of herpes simplex virus latency. Ann Rev Microbiol 1987;41:543–57. 11. Riley LE. Herpes simplex virus. Semin Perinatol 1998;22:284–92. 12. Miller CS, Danaher RJ, Jacob RJ. Molecular aspects of herpes simplex virus I latency, reactivation, and recurrence. Crit Rev Oral Biol Med 1998;9:541–62. 13. McCormick DD. Herpes simplex virus as cause of Bell’s palsy. Lancet 1972;1:937–9. 14. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bell’s palsy and herpes simplex virus. Ann Intern Med 1996;124:27–30. 15. Rodriguez AS, Martin Oterino JA, Ruiz VA. Arch Intern Med 1998;158:1577–78. 16. Rapp F, Duff R. Transformation of hamster embryo fibroblasts by herpes simplex viruses type 1 and type 2. Cancer Res 1973;33:1527. 17. Scully C. Herpes simplex virus (HSV). In: Millard HD, Mason DK, editor. 1988 World Workshop on Oral Medicine. Yearbook Medical Publishers, 1988. Ann Arbor, MI. p. 160. 18. Brightman VJ, Guggenheimer JG. Herpetic paronychia—primary herpes simplex infection of the finger. J Am Dent Assoc 1970;80:112. 19. Stone KM, Brooks CA, Guinan ME, Alexander ER. National surveillance for neonatal herpes simplex infections. Sex Transm Dis 1989;16:152–6. 20. Nahmias AJ. Disseminated herpes simplex virus infections. N Engl J Med 1970;282:684. 21. Whitley RJ, Kimberlin DW, Roizman B. Herpes simplex viruses. Clin Infect Dis 1998;26:541–53. 80 22. Greenberg MS, Brightman VJ, Ship II. Clinical and laboratory differentiation of recurrent intraoral herpes simplex infections following fever. J Dent Res 1969;48:435. 23. Bagg J, Mannings A, Munso J, Walker DM. Rapid diagnosis of oral herpes simplex or zoster virus infections by immunofluorescence: comparison with Tzanck cell preparations and viral culture. Br Dent J 1989;167:235. 24. Penna JJ, Eskinazi DP. Treatment of oro-facial herpes simplex infections with acyclovir: a review. Oral Surg 1988;65:689. 25. Amir J, Harel L, Smetana Z, Varsano I. Treatment of herpes simplex gingivostomatitis with acyclovir in children: a randomized double blind placebo controlled study. J Pediatr 1998;132:185. 26. Balfour HH. Antiviral drugs. N Engl J Med 1999;340:1255–68. 27. Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. N Engl J Med 1999;341:929. 28. Adler L, Epidemiologic investigation of hand-foot-and-mouth disease. Am J Dis Child 1970;120:309. 29. Dueland AN. Latency and reactivation of varicella zoster virus infections. Scand J Infect Dis 1996;100:46–50. 30. Morgan R, King D. Shingles: a review of diagnosis and management. Hosp Med 1998;59:770–6. 31. Lopes MA, de Souza Filho FJ, Jorge J Jr, de Almeida OP. Herpes zoster infection as a differential diagnosis of acute pulpitis. J Endod 1998;24:143–4. 32. Petursson G, Helgason S, Gudmundsson S, Sigurdsson JA. Herpes zoster in children and adolescents. Pediatr Infect Dis J 1998;17:905–8. 33. MacFarlane LL, Simmons MM, Hunter MH. The use of corticosteroids in the management of herpes zoster. J Am Board Fam Pract 1998;11:224–8. 34. Kost RG, Straus SE. Postherpetic neuralgia—pathogenesis, treatment, and prevention. N Engl J Med 1996;335:32–42. 35. Kost RG, Straus SE. Postherpetic neuralgia: predicting and preventing risk. Arch Intern Med 1997;157:1166–7. 36. McKenzie CD, Gobetti JP. Diagnosis and treatment of orofacial herpes zoster: report of cases. J Am Dent Assoc 1990;120:679. 37. Solomon CS, Coffiner MO, Chalfin HE. Herpes zoster revisited: implicated in root resorption. J Endod 1986;12:210. 38. Schwartz O, Kvorning SA. Tooth exfoliation, osteonecrosis of the jaw and neuralgia following herpes zoster of the trigeminal nerve. Int J Oral Surg 1982;11:364. 39. Wood MJ, Shukla S, Fiddian PA, Crooks RJ. Treatment of acute herpes zoster: effect of early (< 48 h) versus late (48–72 h) therapy with acyclovir and valacyclovir on prolonged pain. J Infect Dis 1998;178 Suppl 1:S81–4. 40. Menke JJ, Heins JR. Treatment of postherpetic neuralgia. J Am Pharm Assoc 1999;39:217–21. 41. Robotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. J Am Med Assoc 1998;280:1837–42. 42. Kazmierowski JA, Wuepper KD. Erythema multiforme: immune complex vasculitis of the superficial cutaneous microvasculature. J Invest Dermatol 1978;71:366. 43. Reed RJ. Erythema multiforme: a clinical syndrome and a histologic complex. Am J Dermatopathol 1985;7:143. 44. Roujeau J-C, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333:1600–7. 45. Huff JC. Erythema multiforme and latent herpes simplex infection. Semin Dermatol 1992;11:207–10. Diagnosis and Management of Oral and Salivary Gland Diseases 46. Aurelian L, Kokuba H, Burnett JW. Understanding the pathogenesis of HSV-associated erythema multiforme. Dermatology 1998;197:219–22. 47. Malo A, Kampgen E, Wank R. Recurrent herpes simplex virus induced erythema multiforme: different HLA-DQB1 alleles associate with severe mucous membrane versus skin attacks. Scand J Immunol 1998;47:408–11. 48. Weston WL, Morelli JG. Herpes simplex virus–associated erythema multiforme in prepubertal children. Arch Pediatr Adolesc Med 1997;151:1014–6. 49. Wojnarowska F Progesterone induced erythema multiforme. J R Soc Med 1985;78:407. 50. Kroonen LM. Erythema multiforme: case report and discussion. J Am Board Fam Pract 1998;11:63–5. 51. Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. A population based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 1990;126:43. 52. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia. Am J Dis Child 1922;24:526. 53. Lever WF. My concept of erythema multiforme. Am J Dermatolpathol 1985;7:141. 54. Patterson R, Dykewicz MS, Gonzales A, et al. Erythema multiforme and Stevens-Johnson syndrome. Descriptive and therapeutic controversy. Chest 1990;98:331. 55. Pisanty S, Tzukert A, Sheskin J. Erythema multiforme: a clinical study on ninety patients. Ann Dent 1986;45:23. 56. Fine JD. Drug therapy: management of acquired bullous skin diseases. N Engl J Med 1995;333:1475–84. 57. Rodenas JM, Herranz MT, Tercedor J. Autoimmune progesterone dermatitis: treatment with oophorectomy. Br J Dermatol 1998;139:508–11. 58. Tatnall FM, Schofield JK, Leight IM. A double-blind, placebocontrolled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol 1995;132:267–70. 59. Patterson R, Miller M, Kaplan M, et al. Effectiveness of early therapy with corticosteroids in Stevens-Johnson syndrome: experience with 41 cases and a hypothesis regarding pathogenesis. Ann Allergy 1994;73:27–34. 60. Cheriyan S, Patterson R, Greenberger PA, et al. The outcome of Stevens-Johnson syndrome treated with corticosteroids. Allergy Proc 1995;16:151–5. 61. DeRossi SS, Greenberg MS. Intraoral contact allergy: a literature review and case reports. J Am Dent Assoc 1998;129:1435. 62. Pang BK, Freeman S. Oral lichenoid lesions caused by allergy to mercury in amalgam fillings. Contact Dermatitis 1995;33:423–7. 63. Marcusson JA. Contact allergies to nickel sulfate, gold sodium thiosulfate and palladium chloride in patients claiming sideeffects from dental alloy components. Contact Dermatitis 1996;34;320–3. 64. Rasanen L, Laimo K, Laine J, et al. Contact allergy to gold in dental patients. Br J Dermatol 1996;134:673–7. 65. Kowitz G, Jacobson J, Meng Z, Lucatorto F. The effects of tartar-control toothpaste on the oral soft tissue. Oral Surg Oral Med Oral Pathol 1990;70:529–36. 66. Sollecito TP, Greenberg MS. Plasma cell gingivitis: a report of two cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1992;73:690. 67. Alanko K, Kanerva L, Jolanki R, et al. Oral mucosal diseases investigated by patch testing with a dental screening series. Contact Dermatitis 1996;34:263–7. Ulcerative, Vesicular, and Bullous Lesions 68. Dreizen S, Bodey GP, Rodriquez V. Oral complications of cancer chemotherapy. Postgrad Med 1975;58:75. 69. Dreizen S, McCredie KB, Keating MJ. Chemotherapy induced oral mucositis in adult leukemia. Postgrad Med 1981;69:103. 70. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapy induced stomatotoxicity. Oral Oncol 1998;34:39. 71. Loesche WJ, Syed SA, Laughon BE, Stoll J. The bacteriology of acute necrotizing ulcerative gingivitis. J Periodontol 1982;53:223. 72. Giddon DB, Zackin SJ, Goldhaber P. Acute necrotizing ulcerative gingivitis in college students. J Am Dent Assoc 1964;68:381. 73. Winkler JR, Grassi M, Murray PA. Clinical description and etiology of HIV-associated periodontal diseases. In: Robertson PB, Greenspan JS, editors. Perspectives on oral manifestations of AIDS. Proceedings of First International Symposium on Oral Manifestations of AIDS. Littleton (MA): PSG Publishing Company; 1988. p. 49. 74. Holmstrup P, Westergaard J. HIV infection and periodontal disease. Periodontol 2000 1998;18:37. 75. Lamster IB, Grbic JT, Mitchell-Lewis DA, et al. New concepts regarding the pathogenesis of periodontal disease in HIV infection. Ann Periodontol 1998;3:62. 76. Enwonwu CO, Falker WA, Idigbe EO, Savage KO. Noma (cancrum oris) questions and answers. Oral Dis 1999;5:144. 77. Falker WA, Enwonwa CO, Idigbe EO. Microbiological understandings and mysteries of noma. Oral Dis 1999;5:150. 78. Roger RS. Recurrent aphthous stomatitis: clinical characteristics and associated systemic disorders. Semin Cutan Med Surg 1997;16:278–83. 79. Ship II, Ashe WK, Scherp HW. Recurrent “fever blister” and “canker sore” tests for herpes simplex and other viruses with mammalian cell cultures. Arch Oral Biol 1961;3:117. 80. Lennette EH, Magoffin RL. Virologic and immunologic aspects of major oral ulcerations. J Am Dent Assoc 1973;87:1055. 81. Peterson A, Hornsieth A. Recurrent aphthous ulceration: possible clinical manifestations of varicella zoster in cytomegalovirus infection. J Oral Pathol Med 1993;22:64–8. 82. Ghodratnama F, Riggio MP, Wray D. Search for human herpesvirus 6, human cytomegalovirus and varicella zoster virus DNA in current aphthous stomatitis tissue. J Oral Pathol Med 1997;26:192–7. 83. Scully C, Porter S. Recurrent aphthous stomatitis current concepts of etiology, pathogenesis and management. J Oral Pathol Med 1989;18:21. 84. Challacombe SJ, Barkhan P, Lehner T. Hematologic features and differentiation of recurrent oral ulcerations. Br J Oral Surg 1977;15:37. 85. Ship JJ. Epidemiologic aspects of recurrent aphthous ulcerations. Oral Surg 1972;33:400. 86. Miller MF, Garfunkel AA, Ram CA, Ship II. The inheritance of recurrent aphthous stomatitis observations on susceptibility. Oral Surg 1980;49:409. 87. Savage NW, Seymour AJ, Kruger BJ. Expression of class I and class II major histocompatibility complex antigens on epithelial cells in recurrent aphthous stomatitis. J Oral Pathol 1986;15:191. 88. Eversole LR. Immunopathogenesis of oral lichen planus and recurrent aphthous stomatitis. Semin Cutan Med Surg 1997;16:284–94. 81 89. Rogers RS, Hutton KP. Screening for haematinic deficiencies in patients with recurrent aphthous stomatitis. Aust J Dermatol 1986;27:98. 90. Ferguson MM, Wray D, Carmichael HA, et al. Coeliac disease associated with recurrent aphthae. Gut 1980;21:223. 91. Donatsky O, Bendixen G. In vitro demonstration of cellular hypersensitivity to Strep 2A in recurrent aphthous stomatitis by means of the leukocyte migration test. Acta Allergol 1972;27:137. 92. Thomas DW, Bagg J, Walker DM. Characterization of the effector cells responsible for the in vitro cytotoxicity of blood leucocytes from aphthous ulcer patients for oral epithelial cells. Gut 1990;31:294. 93. Hoover CI, Olson JA, Greenspan JA. Humoral responses and cross-reactivity to viridians streptococci in recurrent aphthous ulceration. J Dent Res 1986;65:1101. 94. Savage NW, Seymour GJ, Kruger BJ. T-lymphocyte subset changes in recurrent aphthous stomatitis. Oral Surg 1985;60:175. 95. Greenspan JL, Gadol N, Olson JA, et al. Lymphocyte function in recurrent aphthous ulceration. J Oral Pathol 1985;14:592. 96. Burnett PR, Wray D. Tyler effects of serum and mononuclear leukocytes on oral epithelial cells in recurrent aphthous stomatitis. Clin Immunol Immunopathol 1985;34:197. 97. Pedersen A, Klausen B, Hougen HP, Stenvang JP. T-lymphocyte subsets in recurrent aphthous ulceration. J Oral Pathol Med 1989;18:59. 98. Galliani EA, Infantolino D, Tarantello M, et al. Recurrent aphthous stomatitis: which role for viruses, food and dental materials? Ann Ital Med Int 1998;13:152–6. 99. Buno IJ, Huff JC, Weston WL, et al. Elevated levels of interferon gamma, tumor necrosis factor alpha, interleukins 2, 4, 5, but not interleukin 10, are present in recurrent aphthous stomatitis. Arch Dermatol 1998;134:827–31. 100. Rennu JS, Reade PC, Hay KD, Scully C. Recurrent aphthous stomatitis. Br Dent J 1985;159:361. 101. Axell T, Henricsson V. Association between recurrent aphthous ulcers and tobacco habits. Scand J Dent Res 1985;93:239. 102. Hay KD, Reade PC. The use of elimination diet in the treatment of recurrent aphthous ulceration in the oral cavity. Oral Surg 1984;57:504. 103. Chahine L, Sempson N, Wagoner C. The effect of sodium lauryl sulfate on recurrent aphthous ulcers: a clinical study. Comp Continu Educ Dent 1997;18:1238–40. 104. Healy CM, Paterson M, Joyston-Bechal S, et al. The effect of sodium lauryl sulfate-free dentifrice on patients with recurrent oral ulceration. Oral Dis 1999;5:39–43. 105. Saxen MA, Ambrosius WT, Rehemtula al-KF, Eckert GJ. Sustained relief of oral aphthous ulcer pain from topical diclofenac in hyaluronan: a randomized, double-blind clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:356–61. 106. Wahba-Yahav AV. Pentoxifylline in intractable recurrent aphthous stomatitis: an open trial. J AM Acad Dermatol 1995;33:680. 107. Katz J, Langeritz P, Shemer J. Prevention of RAS with colchicines: an open trial. J Am Acad Dermatol 1994;31:459–61. 108. Tananis R, DeRossi S, Sollecito TP, Greenberg MS. Management of recurrent aphthous stomatitis with colchicine and pentoxifylline. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:449. 82 109. Jacobson JM, Greenspan J, Spritzler N, et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 1997;336:1487–93. 110. O’Duffy JD. Behçet’s syndrome. N Engl J Med 1990;322:326. 111. Kone-Paut I, Yurdakul S, Bahabri SA, et al. Clinical features of Behçet’s disease in children: an international collaborative study of 86 cases. J Pediatr 1998;132:721–5. 112. Matsumoto T, Vekusa T, Fukuda Y. Vasculo-Behçet’s disease; a pathologic study of eight cases. Hum Pathol 1991;22:45. 113. O’Duffy JD. Vasculitis in Behçet’s disease. Rheum Dis Clin North Am 1990;16:423. 114. Yasui K, Ohta K, Kobayashi M, et al. Successful treatment of Behçet disease with pentoxifylline. Ann Intern Med 1996; 124:891–3. 115. Benamour S, Zeroual B, Alaoui FZ. Joint manifestation in Behçet’s disease: a review of 340 cases. Rev Rhum 1998; 65:299-307. 116. Krause I, Uziel Y, Guedj D, et al. Mode of presentation and multisystem involvement in Behçet’s disease: the influence of sex and age of disease onset. J Rheumatol 1998;25:1566–9. 117. Imai H, Motegi M, Mizuki N, et al. Mouth and genital ulcers with inflamed cartilage (MAGIC syndrome): a case report and literature review. Am J Med Sci 1997;314:330–2. 118. International Study Group. Criteria for diagnosis of Behçet’s disease. Lancet 1990;335:1078. 119. Bang D. Treatment of Behçet’s disease. Yonsei Med J 1997; 38:401–10. 120. Yazici H, Yurdakul S, Hamuryudan V. Behçet’s syndrome. Curr Opin Rhematol 1999;1:53–7. 121. Arici, M, Kiraz S, Ertenli I. Treatment of Behçet disease with pentoxifylline. Ann Intern Med 1997;126:493–4. 122. Masuda K, Nakajima A, Urayama A. Double-masked trial of cyclosporine versus colchicine and long term open study of cyclosporine in Behçet’s disease. Lancet 1989;1:1093. 123. O’Duffy JD, Robertson DM, Goldstein NP. Chlorambucil in the treatment of uveitis and meningoencephalitis of Behçet’s disease. Am J Med 1984;76:75. 124. Muzulu SI, Walton S, Keczkes K. Colchicine therapy in Behçet’s syndrome. A report of five cases. Clin Exp Dermatol 1989;14:298. 125. Eisenbud L, Horowitz I, Kay B. Recurrent aphthous stomatitis of the Behçet’s type: successful treatment with thalidomide. Oral Surg 1987;64:289. 126. Blyth WA, Hill TJ. Establishment, maintenance and control of herpes simplex virus (HSV-1) latency. In: Rouse BT, Lopez C, editors. Immunobiology of herpes simplex virus infection. Boca Raton: CRC Press; 1984. p. 9. 127. Roizman B, Sears AE. An inquiry into the mechanism of herpes simplex virus latency. Ann Rev Microbiol 1987;41:543. 128. Croen KD, Ostrove JM, Dragovic MD, et al. Latent herpes simplex virus in human trigeminal ganglia: detection of an immediate early gene “antisense” transcript by in situ hybridization. N Engl J Med 1987;317:1427. 129. Carton CA, Kilbourne ED. Activation of latent herpes simplex by trigeminal sensory-root section. N Engl J Med 1952;246:172. 130. Halford WP, Gebhardt BM, Carr DJ. Mechanisms of herpes simplex virus type 1 reactivation. J Virol 1996;70:5051–60. 131. Greenberg MS, Brightman VJ, Ship II. Clinical and laboratory differentiation of recurrent intra-oral herpes simplex virus infections following fever. J Dent Res 1969;48:435. Diagnosis and Management of Oral and Salivary Gland Diseases 132. Griffin JW. Recurrent intraoral herpes simplex virus infection. Oral Surg 1965;19:209. 133. Weathers DR, Griffin JW. Intraoral ulcerations of recurrent herpes simplex and recurrent aphthae—two distinct clinical entities. J Am Dent Assoc 1970;81:81. 134. Reeves WC, Corey L, Adams HG. Risk of recurrence after first episodes of genital herpes: relation of HSV type and antibody response. N Engl J Med 1981;305:315. 135. Greenberg MS, Brightman VJ. Serum immunoglobulins in patients with recurrent intraoral herpes simplex infections. J Dent Res 1971;50:781. 136. Heineman HS, Greenberg MS. Cell protective effect of human saliva specific for herpes simplex virus. Arch Oral Biol 1980; 25:257–61. 137. Greenberg MS, Friedman H, Cohen SG, et al. A comparative study of herpes simplex infections in renal transplant and leukemic patients. J Infect Dis 1987;156:280. 138. Greenberg MS, Cohen SG, Boosz B, Friedman H. Oral herpes simplex infections in patients with leukemia. J Am Dent Assoc 1987;114:483. 139. Eisen D. The clinical characteristics of intraoral herpes simplex virus infection in 52 immunocompetent patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:432-7. 140. Thackray AM, Field HJ. Famciclovir and valacyclovir differ in the prevention of herpes simplex virus type 1 latency in mice: a quantitative study. Antimicrob Agents Chemother 1998;42:1555–62. 141. Thackray AM, Field HJ. Differential effects of famciclovir and valacyclovir on the pathogenesis of herpes simplex virus in a murine infection model including reactivation from latency. J Infect Dis 1996;173:291–9. 142. Reitano M, Tyring S, Lang W, et al. Valacyclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dosage range-finding study. International Valacyclovir HSV Study Group. J Infect Dis 1998;178:603–10. 143. Diaz-Mitoma E, Sibbald RG, Shafran SD, et al. Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. Collaborative Famciclovir Genital Herpes Research Group. JAMA 1998;280:887–92. 144. Rooney JF, Straus SE, Mannix ML, et al. Oral acyclovir to suppress frequently recurrent herpes labialis: a double-blind, placebo-controlled trial. Ann Intern Med 1993;118:268–72. 145. Amagai M, Koch PJ, Nishikawa T, Stanley JR. Pemphigus vulgaris antigen (desmoglein 3) is localized in the lower epidermis, the site of blister formation in patients. J Invest Dermatol 1996;106:351–5. 146. Mahoney MG, Wang Z, Rothenberger K, et al. Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest 1999;103:461–8. 147. Williams DM. Vesiculobullous mucocutaneous disease: pemphigus vulgaris. J Oral Pathol Med 1989;18:544. 148. Anhalt GJ, Labib RS, Voorhees JJ, et al. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med 1982;506:1189–96. 149. Jensen PJ, Baird J, Morioka S, et al. Epidermal plasminogen activation is abnormal in cutaneous lesions. J Invest Dermatol 1988;90:777. 150. Stanley JR. Cell adhesion molecules as targets of autoantibodies in pemphigus and pemphigoid, bullous diseases due to defective epidermal cell adhesion. Adv Immunol 1993; 53:291–325. Ulcerative, Vesicular, and Bullous Lesions 151. Coleman MD. Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance. Br J Dermatol 1993;129:507–13. 152. Anhalt GJ. Pemphigoid: bullous and cicatricial. Dermatol Clin 1990;8:701. 153. Gilmore HK. Early detection of pemphigus vulgaris. Oral Surg 1978;46:641. 154. Lamey PJ, Rees TD, Binnie WH, et al. Oral presentation of pemphigus vulgaris and its response to systemic steroid therapy. Oral Surg 1992;74:54. 155. Zegarelli DJ, Zegarelli EV. Intraoral pemphigus vulgaris. Oral Surg 1977;44:384. 156. Lenz P, Amagai M, Volc-Platzer B, et al. Desmoglein 3-ELISA: a pemphigus vulgaris–specific diagnostic tool. Arch Dermatol 1999;135:143–148. 157. Nishikawa T. Desmoglein ELISAs: a novel diagnostic test for pemphigus. Arch Dermatol 1999;135:195–6. 158. Chrysommlis F, Ioannides D, Teknetzis A, et al. Treatment of oral pemphigus vulgaris. Int J Dermatol 1994;33:803–7. 159. Stanley JR. Therapy of pemphigus vulgaris. Arch Dermatol 1999;135:76–7. 160. Enk AH. Mycophenolate is effective in the treatment pemphigus vulgaris. Arch Dermatol 1999;135:54–6. 161. Calebotta A, Saenz AM, Gonzalez F, et al. Pemphigus vulgaris: benefits of tetracycline as adjuvant therapy in a series of thirteen patients. Int J Dermatol 1999;38:217–21. 162. Rook AH, Jegasothy BV, Heald P, et al. Extracorporeal photochemotherapy for drug-resistant pemphigus vulgaris. Ann Intern Med 1990;112:303. 163. Nousari HC, Deterding R, Wojtczak KH, et al. The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med 1999;340:1406–10. 164. Anhalt GJ. Paraneoplastic pemphigus. Adv Dermatol 1997;12:77–96. 165. Virgils A, Trombelli L, Calura G. Sudden vegetation of the mouth. Pemphigus vegetans of the mouth (Hallopeau type). Arch Dermatol 1992;128:398. 166. Iwata M, Watanabe S, Tamaki K. Pemphigus vegetans presenting as scrotal tongue. J Dermatol 1989;16:159. 167. Thornhill MH, Zakrzewska JM, Gilkes JJ. Pyostomatitis vegetans. Report of three cases and review of the literature. J Oral Pathol Med 1992;21:128. 168. Korman NJ. Bullous pemphigoid: the latest in diagnosis, prognosis and therapy. Arch Dermatol 1998;134:1137–41. 169. Bastuji-Garin S, Joly P, Picard-Dahan C, et al. Drugs associated with bullous pemphigoid: a case-control study. Arch Dermatol 1996;132:272–6. 170. Venning VA, Frith PA, Bron AJ, et al. Mucosal involvement in bullous and cicatricial pemphigoid. A clinical and immunopathological study. Br J Dermatol 1988;118:7. 171. Roujeau JC, Lok C, Bastuji-Garin S, et al. High risk of death in elderly patients with extensive bullous pemphigoid. Arch Dermatol 1998;134:465. 172. Lever WF. Pemphigus and pemphigoid. J Am Acad Dermatol 1979;1:2. 173. Chan LS, Hammerberg C, Cooper KD. Cicatricial pemphigoid. Identification of two distinct sets of epidermal antigens by IgA and IgG class circulating autoantibodies. Arch Dermatol 1990;126:1466. 174. Albritton JI, Nousari HC, Anhalt GJ. Antiepiligrin (laminin-5) cicatricial pemphigoid. Br J Dermatol 1997;137:992–6. 83 175. Nousari HC, Rencic A, Hsu R, et al. Anti-epiligrin cicatricial pemphigoid with antibodies against the gamma2 subunit of laminin 5. Arch Dermatol 1999;135:173–6. 176. Lamey PJ, Rees TD, Binnie WH, Rankin KV. Mucous membrane pemphigoid. Treatment experience at two institutions. Oral Surg 1992;74:50. 177. Rogers RS, Mehregan DA. Dapsone therapy of cicatricial pemphigoid. Semin Dermatol 1988;7:201. 178. Ciarrocca KN, Greenberg MS. A retrospective study of the management of oral mucous membrane pemphigoid with dapsone. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:159–63. 179. Berk MA, Lorincz AL. The treatment of bullous pemphigoid with tetracycline and nicotinamide. Arch Dermatol 1986;122:670. 180. Korman NJ, Eyra RW, Zone J, Stanley JR. Drug-induced pemphigus. J Invest Dermatol 1991;96:273. 181. Wakelin SH, Allen J, Zhou S, Wojnarowska F. Drug-induced linear IgA disease with antibodies to collagen vii. Br J Dermatol 1998;138:310. 182. Zhou S, Ferguson DJ, Allen J, Wojnarowska F. The localization of target antigens and autoantibodies is variable. Br J Dermatol 1998;139:591. 183. Dabelsteen E. Molecular biological aspects of acquired bullous diseases. Crit Rev Oral Biol Med 1998;9:162. 184. Marsden RA. Linear IgA disease of childhood. In: Wojnarowska F, Briggaman RA, editors. Management of blistering diseases. New York: Chapman & Hall; 1990. p. 119–26. 185. Lear JT, Smith AG. Multiple blisters in a young boy. Arch Dermatol 1998;134:625. 186. Marsden RA, Mckee PH, Bhogal B, et al. A study of chronic bullous disease of childhood and comparison with dermatitis herpetiformis and bullous pemphigoid occurring in childhood. Clin Exp Dermatol 1980;5:159. 187. Greenspan JS, Yeoman CM, Harding SM. Oral lichen planus. Br Dent J 1978;144:83. 188. Walsh LJ, Savage NW, Ishii T, Seymour GJ. Immunopathogenesis of oral lichen planus. J Oral Pathol Med 1990;19:389. 189. Bolewska J, Hansen HJ, Holmstrup P, et al. Oral mucosal lesions related to silver amalgam restorations. Oral Surg 1990;70:55. 190. Carrozzo M, Gandolpho S, Carbone M, et al. Hepatitis C virus infection in Italian patients with oral lichen planus: a prospective case controlled study. J Oral Pathol Med 1997:26:36. 191. Bagan JV, Ramon C, Gonzalez L, et al. Preliminary investigation of the association of oral lichen planus and hepatitis C. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:532. 192. DeRossi S, Greenberg MS. Intraoral contact allergy: a literature review and case reports. J Am Dent Assoc 1998;129:1435. 193. Yiannias JA, el Azhary RA, Hand JH, et al. Relevant contact sensitivities in patients with the diagnosis of oral lichen planus. J Am Acad of Dermatol 2000;42:177. 194. Schubert MM, Sullivan KM. Recognition, incidence and management of oral graft-versus-host disease. N C I Monogr 1990;9:135. 195. Fowler CB, Rees TD, Smith BR. Squamous cell carcinoma on the dorsum of the tongue arising in a longstanding lesion of erosive lichen planus. J Am Dent Assoc 1987;15:707. 196. Katz RW, Brahim JS, Travis WD. Oral squamous cell carcinoma arising in a patient with longstanding lichen planus: a case report. Oral Surg 1990;70:282. 84 197. Lind PO, Koppang HS, Eigil AAS. Malignant transformation in oral lichen planus. Int J Oral Surg 1985;14:509. 198. Kaplan B, Barnes L. Oral lichen planus and squamous carcinoma: case report and update of the literature. Arch Otolaryngol 1985;111:543. 199. Massa MC, Greancy V, Kron T, Armin A. Malignant transformation of oral lichen planus: case report and review of the literature. Cutis 1990;45:45. 200. Silverman S, Gorsky M, Lozada-Nur F. A prospective followup study of 570 patients with oral lichen planus: persistence, remission and malignant association. Oral Surg 1985;60:30. 201. Murti PR, Daftary DK, Bhonsle RR, et al. Malignant potential of oral lichen planus: observations in 722 patients from India. J Oral Pathol 1986;15:71. 202. Jungell P. Oral lichen planus. A review. Int J Oral Maxillofac Surg 1991;20:129. 203. Eisen D, Ellis CN, Duell EA, et al. Effect of topical cyclosporine rinse on oral lichen planus. A double blind analysis. N Engl J Med 1990;323:290. 204. Jungell P, Malmstrom M. Cyclosporin A mouthwash in the treatment of oral lichen planus. Int J Oral Maxillofac Surg 1996;25:60. 205. Gorsky M, Raviv M. Efficacy of etretinate (Tigason) in symptomatic oral lichen planus. Oral Surg 1992;73:52. 206. Lundquist G, Forsgren H, Gajecki M, et al. Photochemotherapy of oral lichen planus. A controlled study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:554 207. McCreary CE, McCartan BE. Clinical management of oral lichen planus. Br J Oral Maxillofac Surg 1999;37:338. 208. Greenberg MS, Cohen SG, Boosz B, Friedman H. Oral herpes simplex infections in patients with leukemia. J Am Dent Assoc 1987;114:483. Diagnosis and Management of Oral and Salivary Gland Diseases 209. Greenberg MS, Friedman H, Cohen SG, et al. A comparative study of herpes simplex infections in renal transplant and leukemic patients. J Infect Dis 1987;156:280. 210. Schneidman DW, Barr RJ, Graham JH. Chronic cutaneous herpes simplex. JAMA 1979;241:542. 211. MacPhail LA, Greenspan D, Schiodt M, et al. Acyclovir-resistant Foscarnet-sensitive oral herpes simplex type 2 lesion in a patient with AIDS. Oral Surg 1989;67:427. 212. Economopoulou P, Laskaris G, Kittas C. Oral histoplasmosis as an indicator of HIV infection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:203. 213. Warnakulasuriya KAAS, Harrison JD, Johnson NW, et al. Localized oral histoplasmosis associated with HIV infection. J Oral Pathol Med 1997;26:294. 214. Chinn H, Chernoff DN, Migliorati CA, et al. Oral histoplasmosis in HIV infected patients: a report of two cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:710. 215. Page LR, Drummond JF, Daniels HT, et al. Blastomycosis with oral lesions. Oral Surg 1979;47:157. 216. Bell WA, Gamble GE, Garrington GE. North American blastomycosis with oral lesions. Oral Surg 1969;28:914. 217. Rose HD, Gingrass DJ. Localized oral blastomycosis mimicking actinomycosis. Oral Surg 1982;54:12. 218. Cohen SG, Greenberg MS. Rhinomaxillary mucormycosis in a kidney transplant patient. Oral Surg 1980;50:33. 219. Salisbury PL, Caloss R, Cruz JM, et al. Mucormycosis of the mandible after dental extractions in a patient with acute myelogenous leukemia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:340. 220. Jones AC, Bentsen TY, Freedman PD. Mucormycosis of the oral cavity. Oral Surg 1993;75:455. 20 ▼ INFECTIOUS DISEASES JOHN A. MOLINARI, PHD MICHAEL GLICK, DMD ▼ BACTERIAL INFECTIONS In the early 1960s, Sir MacFarlane Burnet proclaimed, “One can think of the middle of the twentieth century as the end of one of the most important social revolutions in history, the virtual elimination of the infectious disease as a significant factor in social life.”1 This was not an uncommon sentiment among the medical community and resulted in a decrease in awareness, research, and funding to combat emerging, re-emerging, and drug-resistant infections. Consequently, the medical community was ill prepared when diseases thought to be conquered, and new diseases, started to emerge in the 1980s and 1990s. In a recent report from the Institute of Medicine, six major factors were identified as contributors to the emergence and re-emergence of infectious disease, as follows:2 Tuberculosis Legionella ▼ PROTOZOAL INFECTION: CRYPTOSPORIDIUM Microbial Characteristics Epidemiology and Transmission Clinical Syndrome Treatment and Control ▼ VIRAL INFECTIONS Hepatitis C Virus HIV Infection 1. Changes in human demographics and behavior 2. Advances in technology and changes in industry practices 3. Economic development and changes in land use patterns 4. Dramatic increases in volume and speed of international travel and commerce 5. Microbial adaptation and change 6. Breakdown of public health capacity required to handle infectious diseases Although the number of deaths from infectious diseases has decreased dramatically in the United States during the twentieth century, there was a temporary increase between 1980 and 1995, mainly due to human immunodeficiency virus (HIV) disease.3 HIV and other emerging and re-emerging infectious diseases are recognized as significant health hazards and have become the focus of many federal and academic health initiatives. Efforts in controling infectious diseases have addressed sanitation and hygiene, vaccination, the use of 525 526 antibiotics and other antimicrobial medications, and improved technology in detection and monitoring. Oral health care providers are not excluded from these efforts, as many of these endeavors impact directly on dental care. This chapter highlights a few infectious diseases that are of importance to dentistry. Some of these diseases are well established, whereas others are emerging and may become important sources of both contamination and transmission in dental settings. Oral health care providers need to be able to assess and evaluate patients who are carriers of infectious diseases with the purpose of providing appropriate and safe dental care. Principles of Medicine TABLE 20-1 Summary of Reported Cases of Tuberculosis in the United States by Year Year Total Number of Cases 1954 79,775 1967 45,647 1970 37,137 1975 33,989 1980 27,749 1985 22,201 1986 22,768 ▼ BACTERIAL INFECTIONS 1990 25,701 1992 26,673 Tuberculosis 1993 25,313 1994 24,361 1995 22,860 1996 21,337 1997 19,851 1998 18,361 1999 16,607 2000 12,942 There is a well-known phrase that states, “The more things change, the more they stay the same.” This expression continues to apply to tuberculosis (TB), a widespread infectious disease scourge traced back to the earliest of centuries. As a result of a resurgence of TB cases in the United States during the 1980s, attention refocused on the factors associated with the observed reversal of a previous declining disease trend; transmission modes of Mycobacterium tuberculosis, occupational infection risks associated with health care, and airborne-hazard infection control precautions.4–8 Despite dramatic improvements in public health measures associated with M. tuberculosis infection and disease, such as living conditions, nutrition, and antimicrobial chemotherapy, that resulted in an observed dramatic decline in the incidence of TB in the United States and certain other countries during the past century, TB remains a major public health concern for much of the world’s population.9,10 Evidence supporting this statement includes the following: 1. TB is the most common cause of death from a single microbial agent. 2. TB is responsible for almost 1 in 4 preventable deaths in the world. 3. The World Health Organization estimates that worldwide there are approximately 20 million active TB cases. 4. Approximately 3 million people die each year from TB, with 80% of this total occurring in developing countries. In short, many problems associated with tuberculosis as a significant world health problem 100 years ago remain as this debilitating illness continues to be an even greater infectious disease concern at the end of the twentieth century. The United States witnessed a dramatically different pattern of TB incidence from much of the rest of the world, documenting a three-decade decline through to 1984 (Table 20-1). Based on that rate of decline, the Centers for Disease Control and Prevention (CDC) projected that TB would be eliminated within the United States by the year 2010. These optimistic predictions were quietened in 1985, when the number of reported cases showed a smaller decrease compared to the previous 2 years. In 1986, the number of reported cases actually exceeded CDC. Reported tuberculosis in the United States, 2000. Surveillance Reports; 2001. the 1985 figure. This trend continued until the peak year of 1992 (26,673 cases). With the development and institution of appropriate infection control policies and procedures aimed at minimizing airborne spread of M. tuberculosis, continued decrease in new TB cases has been noted in each subsequent year.11,12 ETIOLOGY AND PATHOGENESIS The genus Mycobacterium contains a variety of species, ranging from human pathogens to relatively harmless organisms. As the major cause of TB, a chronic communicable disease, M. tuberculosis is by far the most historically prominent member of this group of bacteria. In addition to their very slow growth on special enriched media, these aerobic slender rods are characterized by their acid-fast staining feature. The unusually high lipid content of the cell wall confers the organisms with an ability to strongly retain a red dye (carbolfuchsin) after treatment with an acid-alcohol solution. This unique structure also allows the bacteria to survive outside a host’s body, suspended in airborne microdroplet nuclei for extended periods of time. Contrary to a perception believed through the ages, M. tuberculosis is not a highly contagious bacterium. It does not synthesize potent exotoxins or extracellular enzymes, and it is not surrounded by an antiphagocytic capsule. Onset of infection appears to be related to the ability of tubercle bacilli to multiply within host cells and tissues while at the same time resisting host defenses. Infection with M. tuberculosis typically requires prolonged close contact of a susceptible host with an infectious source. The closeness of the contact with aerosolized bacilli and the degree of infectivity of the Infectious Diseases mycobacterial source are the most important considerations for infection. The overwhelming majority of primary human infections involve inhalation of mycobacteria-laden respiratory microdroplets.13,14 The diameter of these aerosolized droplets ranges from 1 to 5 microns. Dispersal of M. tuberculosis occurs via these droplets as a result of coughing, sneezing, or even speaking. Microdroplet nuclei are small enough to bypass protective host bronchial mucocilliary defenses, leading to mycobacteria subsequently replicating in both free alveolar spaces and within phagocytic cells (Figure 20-1). Repeated prolonged exposure to air that has been contaminated by droplets from a person with TB predisposes others to infection. This rationale is illustrated by the fact that people who live in the same home with an infected individual, or close friends or co-workers who routinely breathe the same mycobacteria-contaminated air from an undiagnosed or untreated person with pulmonary TB, have a high risk of acquiring infection. The organisms’ oxygen requirement predisposes the lungs as primary infection sites, with the potential for subsequent dissemination to other tissues. Cross-infection or spread of tubercle bacilli does not result from casual or sporadic exposure. Onset of clinical disease is characterized by gradual infiltration of neutrophils, macrophages, and T lymphocytes. Distinctive granulomatous TB lesions called tubercles may appear anywhere in the lung parenchyma; however, they are most evident in the periphery (Figure 20-2). Because TB is the prototype microbial infection for inducing protective cellular immunity, the immunocompetence of the affected host plays a significant role in controlling the extent and severity of resultant disease.15,16 It is important to remember that most people infected with M. tuberculosis develop a positive type IV hypersensitive skin test reaction when challenged (Figure 203) but do not progress to clinical disease. For those infected individuals who develop clinical symptoms, fatigue, malaise, weight loss, night sweats, and fever are most commonly noted FIGURE 20-1 Sequence of infection from a Mycobaterium tuberculosis–laden microdroplet in a susceptible person. 527 FIGURE 20-2 Chest radiograph of lungs in a patient with primary symptomatic tuberculosis. Multiple areas of disease are visible, with radiographic evidence of chronic granulomatous tubercles. in addition to positive chest radiograph manifestations. Pulmonary manifestations most frequently are chest pain, bloody sputum, and the presence of a prolonged productive cough of greater than 3 weeks’ duration. Initial mycobacterial infection may progress to several different states depending on the extent of M. tuberculosis exposure and resistance of the patient. These include (1) asymptomatic primary tuberculosis, (2) symptomatic primary tuberculosis, (3) progressive primary tuberculosis, and (4) reactivation tuberculosis. A major risk factor for progression of initial infection with tubercle bacilli to more severe disease stages is the absence of an adequate host acquired cellular immune response to mycobacterial antigens. The ability of an infected individual to develop dual cellular and humoral immune responses against M. tuberculosis antigens thus greatly influences disease onset and progression. FIGURE 20-3 Positive 48-hour skin test following purified protein derivative intradermal challenge of a person with primary asymptomatic tuberculosis. No evidence of clinical disease was present, and the patient remained asymptomatic following a prolonged course of isoniazid chemotherapy. 528 Principles of Medicine Asymptomatic Primary Tuberculosis. Individuals may be infected with M. tuberculosis without apparent clinical manifestations. When skin tested, individuals with asymptomatic primary tuberculosis display a positive tuberculin reaction indicating that they have been infected and have developed cell-mediated immunity against the bacteria. This protective immune response prevents the continued multiplication and dissemination of the bacteria, but it does not destroy all of the bacteria present. The remaining bacteria are sequestered within tubercles in the affected tissues and may be the source of bacteria that initiate reactivation tuberculosis. Symptomatic Primary Tuberculosis. In symptomatic primary tuberculosis, M. tuberculosis is spread via the lymphatics to cause granulomatous inflammation in both the lung periphery and hilar nodes, and it is accompanied by respiratory symptoms. The usual result is one of healing and development of cell-mediated immunity. The Ghon complex, a remnant of this infection, most often occurs in infants and children and is comprised of small calcified lung nodules and lymphadenopathy of the hilar lymph nodes. Progressive Primary Tuberculosis. A much more serious disease may develop in those individuals who are less resistant to tubercle bacilli. In these patients, microorganisms may spread throughout the body either (1) by means of the blood, resulting in miliary tuberculosis; (2) via the respiratory tissues, inducing a bronchopneumonia; or (3) through the gastrointestinal tract as a result of the organisms being coughed up. In miliary tuberculosis, foci of infection occur in distant organs and tissues but most frequently develop in the meninges, lungs, liver, and renal cortex. Although cell-mediated immunity may develop in some patients, others may not react (anergy) when skin tested with tuberculin protein preparations. Anergic patients have a poor prognosis for recovery and often die without rapid treatment. Reactivation Tuberculosis. Reactivation tuberculosis occurs in individuals who have developed primary tuberculosis and who are asymptomatic, but who still carry the bacteria within tubercles. These patients exhibit positive tuberculin skin tests and thus demonstrate cellular immunity. Reactivation of disease is thought to be due to the activation of persistent bacteria in the tubercles of a previous infection, which become activated by some alteration in host resistance. Infection is characterized by tubercle formation, caseation, fibrosis, and further extension of the lesion. Progression may advance into a bronchus, leading to cavitation of the lung and secretion of an infectious sputum. ORAL MANIFESTATIONS Oral manifestations of tuberculosis occur in approximately 3% of cases involving long-standing pulmonary and/or systemic infection.17,18 The bacteria can infect oral tissues and lymph nodes (scrofula) (Figure 20-4). Within the oral cavity, lesions can occur in the soft tissues and supporting bone FIGURE 20-4 Cervical tuberculosis lymphadenitis (scrofula) secondary to pulmonary tuberculosis in a 16-year-old male. (Figure 20-5) and in tooth extraction sites, and may even affect the tongue and floor of the mouth (Figure 20-6). When reviewing this information, it becomes apparent that progression of infection with tubercle bacilli to more severe disseminated stages occurs in the absence of adequate cellular immunity to infection. Thus, the ability of an infected individual to develop a dual immune response against M. tuberculosis antigens greatly influences disease onset and progression. These crucial protective responses are (1) acquired immunity to infection and (2) development of tuberculin hypersensitivity. DIAGNOSIS A diagnosis of infection with M. tuberculosis relies on (1) development of a positive delayed hypersensitivity (tuberculin) skin reaction to purified protein derivative (PPD), a mycobacterial antigen isolated from bacterial cultures, and (2) demonstration of acid-fast mycobacteria in clinical specimens. Information obtained while collecting a patient’s medical history can provide evidence for suspicion of TB (Table 20-2). RISK FACTORS The re-emergence of M. tuberculosis infection as a significant US public health problem appears to be the result of a combination of changing host susceptibility factors and declining societal conditions for particular population groups. Among TABLE 20-2 Patient History Prompting Suspicion of Active Tuberculosis 1. Productive cough (> 3 wk)— pulmonary tuberculosis 2. Other symptoms (eg, fever, chills, night sweats, fatigue) 3. Extrapulmonary tuberculosis (occurs in 15% of cases) 4. Patients with tuberculosis and HIV infection—40–75% have extrapulmonary tuberculosis and pulmonary tuberculosis 5. History of tuberculosis exposure and/or previous tuberculosis infection (active disease) 529 Infectious Diseases FIGURE 20-5 Partially calcified oral tuberculosis localized in the soft tissue at the angle of the mandible. FIGURE 20-6 Oral tuberculosis in the soft tissue of mandible. the most frequently noted risk factors is infection with HIV.19–23 The suppressive effect of HIV infection on cellmediated immunity increases host susceptibility to a variety of microbial pathogens that are normally controlled by these defense mechanisms. It should be noted, however, that current information does not suggest HIV-infected persons are more susceptible to M. tuberculosis infection, but they can present with earlier clinical manifestations of the disease. Increased immigration of people to the United States from countries with high TB prevalence rates adds to the reservoir for mycobacterial transmission.24 Unfortunately, funding for TB research, screening programs, and epidemiologic tracking lagged in the 1980s as attention focused on other infectious diseases, such as those caused by herpesviruses, hepatitis B, and HIV/acquired immunodeficiency syndrome (AIDS). These factors, together with documented societal tragedies such as increased parenteral drug abuse, homelessness, malnutrition, and crowding, especially in larger US cities, have exacerbated the potential for the spread of TB (Table 20-3).13 onset of symptoms.24 Regimens of multiple antibiotics are currently used to treat patients with active TB to ensure tissue penetration and minimize emergence of resistant organisms. General guidelines for appropriate TB chemotherapy include necessity for long-term treatment interval (up to 2 years), initiation of treatment if sputum smear is positive for acid-fast bacilli, and patient compliance (a major factor in determining chemotherapy success). Isoniazid (INH) is the antimycobacterial therapy cornerstone and is included in all routine drug regimens. People who develop a positive tuberculin skin reaction but do not have active disease, as well as close contacts of patients who develop TB, are placed on INH for 6 months to 1 year. For treatment of patients with active TB, combinations of three or more drugs are chosen based on the nature and site of disease (Table 20-4). In addition to INH, rifampin, pyrazinamide, and ethambutol are the most frequently applied drug combinations unless a specific instance of mycobacterial resistance is noted.25,26 Hepatotoxicity is a frequent adverse effect noted with prolonged administration of antimycobacterial chemotherapy. Unfortunately, a major complication preventing successful elimination of acid-fast organisms in TB patients is noncompliance to the prolonged drug regimens. Patients often notice a substantial decline in symptoms within a few weeks of therapy and prematurely discontinue their medications. Consequently, bacterial strains causing multidrug-resistant tuberculosis (MDR-TB) have emerged and spread throughout the world.27–30 TREATMENT Prior to the advent of antimicrobial chemotherapy, approximately 50% of persons with active TB died within 2 years after TABLE 20-3 Persons at High Risk for Contracting Tuberculosis 1. Persons with HIV infection 2. Persons with close contacts with infectious patients 3. Persons with medical conditions that increase risk of contracting TB 4. Persons from countries with high rates of TB 5. Persons in low-income populations 6. Alcoholics 7. Intravenous drug abusers 8. Prisoners 9. Nursing home residents 10. Health care workers in certain work settings (local risk) TB = tuberculosis TABLE 20-4 Chemotherapy for Tuberculosis Combination therapy: usually 3–4 drugs to prevent resistance, chosen from the following: isoniazid, rifampin, ethambutol, rifabutin, streptomycin, pyrazinamide Prolonged therapy—6 mo minimum— indicated for slow growth rate of bacteria, increasing incidence of Mycobacterium tuberculosis drug resistance 530 TUBERCULOSIS VACCINES Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, has been used for more than 80 years to protect humans against TB. The original mycobacterial isolates were responsible for causing TB in cattle. Calmette and Guerin attenuated these bacteria by culturing, passaging, and maintaining them in specialized growth media for more than 10 years. Humans began receiving the BCG preparations in 1921, with resultant protection observed in vaccinated children. Most countries currently vaccinate children against TB, and this preventive approach has been shown to result in a 60 to 80% reduction in disease in treated individuals. 31 Unfortunately, the vaccine is much less effective in adults, for reasons that are still unexplained. With adults comprising the major sources of infection, the expected worldwide success of the BCG vaccine has not been accomplished. The successful sequencing of the complete M. tuberculosis genome has provided new opportunities for vaccine development. Ongoing efforts are being directed at using combinations of established approaches to vaccine composition, with newer deoxyribonucleic acid (DNA) technologies that look at the roles of host and mycobacterial genetic factors, to better ascertain the development of protective immune responses.32 ORAL HEALTH CONSIDERATIONS The risk of TB transmission from patients to dental care providers is considered to be minimal.33 Responding to reports and confirmation of M. tuberculosis transmission in institutional settings occurring the 1980s, the CDC developed a series of guidelines for prevention of the spread of TB in health care environments. Special emphasis within the document was directed at the heightened TB risks for those persons living with HIV infection or AIDS as a result of virus-induced suppression of cellular immune defenses. As more clinical data and scientific input were obtained from health care and public sources, the CDC incorporated that information in updated draft recommendations. The finalized document released in 1994 provided the following: 1. Guidance for assessing potential TB risks in a variety of health care facilities 2. Detailed description of administrative procedures, infection control practices, engineering controls, and respiratory personal equipment appropriate for minimizing airborne microbial transmission 3. Suggestions for ongoing health care worker (HCW) training and education.34 Specific considerations for dentistry were delineated within this document and provided well–thought out administrative and infection control practice for the range of possible dental exposure categories. The efforts of the CDC have been very effective, yet they represent only one component of the governmental response to the public health threat posed by mycobacterial infection and TB. The Labor Coalition to fight TB in the Workplace submitted a request to Occupational Safety and Health Principles of Medicine Administration (OSHA) in December 1992 to issue national enforcement guidelines to protect workers against M. tuberculosis exposure. This was followed by the coalition of labor unions petitioning OSHA in 1993 to develop a permanent set of rules to protect workers (mostly in patient care facilities) from occupational TB transmission. Serious concern was expressed by these groups about the emergence of cases of MDR-TB, along with the contention that nonmandatory recommendations and guidelines would not be fully implemented or enforced appropriately in many workplaces. The final OSHA-proposed rule incorporated many of the components of the 1994 CDC guidelines but also added a number of mandatory regulations that have stirred considerable controversy within the CDC, among numerous hospital-based infection-control professionals, and infection-control groups. A few of the areas of contention include (1) overstatement of the current TB risk to HCWs in lieu of the effectiveness of the 1994 CDC TB control guidelines; (2) elimination of the CDC-recommended facility TB risk assessment protocol; (3) additional respirator fit-testing requirements; (4) more frequent skintesting requirements for employees, including TB skin testing within 30 days of job termination; and (5) increased facility costs to implement new regulations. OSHA’s rationale for mandatory TB controls stemmed from the assessment that TB is still endemic in certain population groups, and HCWs and other employees who come into contact with persons manifesting active TB may have significantly increased infection risks above that of the general population. The agency also made a preliminary determination that the portions of the standard directing engineering, work practice, and administrative controls, respiratory protection, training, and medical surveillance are technologically and economically feasible for affected workplaces. Few OSHA proposals for worker protection in any American workplace have sparked as much debate and resistance as the proposed rules regarding tuberculosis. The issue may have been resolved in favor of continuing the successful adherence to the 1994 CDC guidelines in early 2001, but the Institute of Medicine then published a report that critically reviewed the proposed standard and found numerous problems with some of mandatory aspects of the legislation.35 Legionella Scientists, clinicians, and the public officially became acquainted with Legionella pneumophila as a result of the outbreak of “legionnaires’ disease” in a Philadelphia hotel housing the 1976 American Legion convention. As a result of the first reports of sudden severe pneumonia among conventioneers, multiple epidemiologic groups were rapidly mobilized in an effort to determine both the cause(s) and contributory factors responsible for the 221 total cases and 34 illness-associated deaths.36 MICROBIAL CHARACTERISTICS When the elusive etiologic bacterium was eventually isolated in 1977, using lung tissue from patients in the 531 Infectious Diseases TABLE 20-5 Bacteriologic Characteristics of Legionella pneumophila Family: Legionellaceae Morphology: gram-negative non-spore-forming motile unencapsulated bacilli Physiology: aerobic and nutritionally fastidious; does not grow on standard bacteriologic media; requires charcoal yeast extract at pH 6.9; L-cysteine is essential nutrient Ecology: natural habitat: rivers, lakes, streams, thermally polluted waters; can survive water treatment processes; chlorine tolerant; proliferates in man-made water habitats (cooling towers, water distribution systems) Philadelphia epidemic, it became apparent that the aerobic gram-negative bacillus represented a previously unrecognized species. Table 20-5 summarizes representative bacteriologic features of this organism.37–39 One of the early surprises stemming from these studies was that L. pneumophila had actually first been isolated from the blood of a patient with respiratory illness in 1947.40 Improved more-sensitive research technologies provided better cultural and serologic methodologies for isolation and characterization. As a result, scientists began to appreciate (1) the ubiquity of L. pneumophila and related species in manmade waterborne environments, (2) the role of this bacterial species as one of the three most common microbial etiologies of community-acquired pneumonia, and (3) the multiple forms of disease that can develop in immunocompetent and immunocompromised individuals. L. pneumophila serogroup 1 is still the most clinically important pathogenic species, causing the overwhelming majority of illnesses after exposure to contaminated water. MAJOR HABITATS Legionella species are found extensively in natural bodies of water. Most samples from colonized rivers, lakes, and other sources typically contain only low concentrations of L. pneumophila. However, the species is remarkably chlorine tolerant. This feature appears to allow for microbial survival during treatment procedures, leading to subsequent entrance and proliferation in water distribution systems. Multiple studies have shown that the presence of amebae and other waterborne microbes offers L. pneumophila a unique opportunity for initial parasitism, leading to ultimate survival and proliferation. Amebae appear to serve as primary natural hosts for the bacteria in man-made water environments such as water distribution systems.41–43 This intracellular parasitic characteristic allows the legionellae to thrive and replicate, protected from adverse external surroundings. When the infected amebae die and lyse, both the water source and other susceptible single-cell organisms are then exposed to a much higher concentration of Legionella. CLINICAL SYNDROME Clinical conditions caused by L. pneumophila and other Legionella species are grouped under the term “legionellosis.” With regard to virulence factors, neither exotoxins nor destructive enzymes have been associated with the pneumonia caused by L. pneumophila. The acute inflammatory infiltration and febrile nature of clinical illness appear to be consistent with the biologic manifestations of released endotoxin in tissues. MODES OF TRANSMISSION Legionella infections differ from other kinds of pneumoniainducing conditions in that the bacteria are not transmitted from person to person but from contaminated environmental reservoirs. Evidence accumulated from outbreaks of the disease and experimental investigations suggests that Legionella species may be passed to susceptible hosts via multiple routes: aspiration, aerosolization, and instillation into the lungs. Aspiration of contaminated water appears to be the major means of human infection.44 In one study, passage of microorganisms via this mechanism appeared to be exceptionally serious in patients after surgery for head and neck cancer because of the patients’ frequency of aspiration of fluids.45 Aerosolization of contaminated water occurs from such sources as humidifiers, nebulizers, and cooling tower air conditioners. Because the organisms are resistant to destruction in moist environments, it is believed that exposure to legionellae is common. Reports in the literature in recent years have implicated potable water harboring L. pneumophila as an important source of community-acquired pneumonia. As a result, investigation of legionellosis cases now includes examination of water supplies in patients’ rooms, homes, and workplaces.46–48 CLINICAL FEATURES Two disparate forms of clinical disease can develop after Legionella infection. The most common manifestation, known as Pontiac fever, presents as an acute influenza-like illness without any evidence of pneumonia. There is a 24- to 48-hour incubation period, and many patients experience fever, chills, malaise, and headaches. Patients typically recover from this self-limiting illness within 7 to 10 days.49 Although the attack rate for Pontiac fever among exposed persons is high (Tables 20-6 and 20-7), many cases of legionellosis are never diagnosed because symptoms are either absent or mild. Published reports suggest that dental professionals may have a significant occupational exposure to Legionella from aerosolization of contaminated dental-unit water, resulting in the formation of anti-Legionella antibodies.50,51 Individuals similarly exposed in a variety of environments may have subsequently developed Pontiac fever and not been aware of it. The second, more publicized, type of legionellosis is a potentially life-threatening illness termed “legionnaires’ disease.” The incubation period (2 to 10 days) is longer than that for Pontiac fever. An individual may abruptly exhibit fever, chills, headache, and other nonspecific signs of acute infection. Subsequently, multisystem involvement becomes evident with pneumonia as the pathognomonic feature.52 If untreated, this form of severe pneumonia can result in a 15% 532 Principles of Medicine TABLE 20-6 Clinical Conditions Caused by Legionella Conditions Characteristic Legionnaires’ Disease Pontiac Fever Epidemiology Attack rate < 5% > 90% Person-to-person spread Clinical manifestations Incubation period No No 2–10 d 1–2 d Clinical features Pneumonia is dominant feature; spectrum from mild cough to stupor with multisystem failure; cough initially mild; only slightly productive Acute self-limiting influenza-like illness; no pneumonia; fever, malaise, myalgia, chills, and headache are predominant symptoms Course Requires antibiotic therapy (eg, erythromycin) Self-limiting Mortality 15–20%; higher if diagnosis is delayed < 1% or higher patient mortality rate (see Tables 20-6 and 20-8). Legionnaires’ disease in healthy immunocompetent persons appears infrequently because of efficient innate and specific host defenses. Most patients diagnosed with legionnaires’ disease present with previous immunosuppressive disorders. Investigation of nosocomially acquired legionnaires’ disease suggests that patients recovering from surgery may be at greatest risk of contraction.53–55 Other conditions identified as legionellosis risk factors include advanced age, cigarette smoking, chronic obstructive pulmonary disease, neoplasia, and immunosuppressive therapy. TREATMENT Erythromycin was the historic antibiotic of choice for treatment of legionnaires’ disease. Timely appropriate chemotherapy can dramatically reduce the mortality rate of legionnaires’ disease, with many patients showing signs of recovery within 3 to 5 days. With the advent of later-generation macrolides, azithromycin has replaced erythromycin because of azithromycin’s lower toxicity potential in a range of infected patients.52 Quinolones also have been shown to be effective antimicrobial agents in studies of patients with communityacquired pneumonia who are suspected of having L. pneumophila legionnaires’ disease.56,57 Antibiotic therapy is not indicated for patients diagnosed with Pontiac fever because of the self-limiting nature of the infection. ▼ PROTOZOAL INFECTION: CRYPTOSPORIDIUM Although first isolated and identified in 1907,58 the protozoan genus Cryptosporidium was not associated with human disease until 1976.59 Only a few cases of cryptosporidiosis were reported over the next few years, with those occurring in persons having severely compromised immune defenses. Since the early 1980s, however, Cryptosporidium parvum has emerged as a major etiology of persistent diarrhea in people of developing countries, of severe life-threatening diarrhea in persons with AIDS and other immunosuppressive conditions, and in previously healthy individuals, as well as an increasingly serious threat to the safety of the US water supply. Microbial Characteristics Among the most common of human pathogens, the diversity of members within the protozoa has required their classification to be accomplished via disparate criteria, including phylogeny, epidemiology, and clinical manifestations. Protozoa such as Plasmodium, Entamoeba, and Trypanosoma have long been recognized as leading causes of human disease and mortality in many parts of the world. The dramatic increase in numbers of individuals with less-than-adequate immune defenses throughout the world, in part related to HIV infection with subsequent progression to AIDS, has also been related to significant increases in other protozoan infections, such as those caused by Cryptosporidium species.60–65 TABLE 20-7 Characteristics of Pontiac Fever Acute self-limiting influenza-like illness TABLE 20-8 Characteristics of Legionnaires’ Disease 24- to 48-hour incubation period Early influenza-like symptoms—initial cough Malaise, myalgia, fever, chills, headache 2- to 10-day incubation period > 90% of those exposed develop symptoms Chest pain may be prominent Only symptomatic treatment necessary Pneumonia is dominant finding Complete recovery within 1 wk Spectrum from mild cough to stupor with multisystem failure Most cases undiagnosed Treatment: erythromycin and other macrolides 533 Infectious Diseases The type-species of this genus is C. parvum, which measures approximately 2.5 µm in diameter, about the same size and shape as yeast cells. It is capable of infecting and causing disease in both humans and mammals. The infectious form of C. parvum is a thick-walled oocyst that is excreted in feces from infected hosts. Oocysts are resistant to standard municipal chlorination procedures, and this feature is important in distinguishing cryptosporidia from many other unicellular waterborne organisms. Because the oocysts can be found in numerous natural water sources, they can readily cause large cryptosporidiosis outbreaks when water treatment is less than optimal and community supplies become contaminated. Cryptosporidia are also unlike many other single-celled waterborne organisms in that they are highly resistant to the chlorine treatments used in municipal water facilities. In addition, they are difficult to filter out because of their small size, and thus they can escape the standard water treatment processes. Epidemiology and Transmission As awareness of the potential threat of cryptosporidiosis has increased, so have efforts to investigate water sources for evidence of contamination. Unfortunately, accumulated data suggest that Cryptosporidium is found in numerous municipal water supplies, public pools, nursing homes, and hospitals. It is also highly infectious, with an inoculum of 30 to 100 oocysts capable of initiating infection.66,67 Numerous outbreaks have been demonstrated over the past 20 years. With the development of better detection techniques, some important epidemiologic features have become apparent (Table 209). Most cases in the United States have occurred as a result of environmental water contamination related to treatment facility failures.68–71 As reports of the wide distribution of this pathogen accumulate, so have the number of cryptosporidiosis cases with life-threatening acute diarrhea, mostly seen in immunocompromised persons but also in previously healthy individuals. A dramatic rise in the number of large outbreaks and individual cases has been noted since 1982, corresponding to the early days of the AIDS epidemic. Multiple reports have shown persons with AIDS to be among the most susceptible immunocompromised groups.63–65 The largest documented outbreak occurred in 1993, involving the entire city of Milwaukee, in which over 400,000 people became ill after drinking parasite-contaminated water. Defective filtration of the city’s water supply was determined to be the prime factor responsible for the epidemic, which resulted in the death of a number of severely immunocompromised patients. 68 Other instances of waterborne TABLE 20-9 Epidemiology of Cryptosporidium Infection C. parvum is a highly infectious enteric pathogen. The protozoa are ubiquitous in many mammals. Infections can occur worldwide. It is the leading cause of persistent diarrhea in developing countries. C. parvum infection have been traced back to ingestion of water from oocyst-contaminated swimming pools and amusement park wave pools.70 A second mode of parasite infection is person-to-person spread. Fecal-oral transmission of oocysts within day care centers, hospitals, and households is probably much more common than accumulated statistics suggest.72–74 The route of microbial passage can place child care workers, children in day care facilities, and other health care providers, who come into direct contact with feces while attending to cryptosporidiosis patients, at increased risk for acquiring the infection. The ability of C. parvum to infect and colonize a variety of mammals has also led to investigation of suggested animal-toperson cryptosporidiosis. Multiple investigations have shown protozoal transmission from calves to humans, and these have triggered intense study of potential risks for those persons who have constant close contact on dairy farms.75 The least proven risk factor for cryptosporidiosis involves food. Although the CDC confirmed an outbreak in children in 1994 traced to fresh-pressed apple cider unknowingly contaminated with animal feces, contaminated hands were also thought to have substantially contributed to oocyst cross-infection.76 Clinical Syndrome The complex C. parvum life cycle occurs within a single host.77 Symptoms of cryptosporidiosis may develop within 2 to 10 days after a person has swallowed environmentally contaminated water. The most common manifestations of C. parvum infection are a profuse watery diarrhea, accompanied by fever, severe abdominal cramping, and pain. Rapid dehydration of patients is a major concern for physicians, as onset of diarrhea can be quite sudden and can last for over 2 weeks. Gastrointestinal symptoms abate in many patients with healthy immune systems in about 2 weeks, although some may suffer a relapse of the syndrome.78 The infection is typically more protracted and severe in immunocompromised hosts, however, as extensive dehydration and weight loss may occur over a prolonged period of longer than 2 weeks. In some cases, multiple intravenous infusions of fluids are required to replace body fluids lost owing to diarrhea. Even after symptoms of cryptosporidiosis diminish or disappear, the patient can still transmit infectious parasites to others for months via contaminated stools (fecal-oral transmission). Infected individuals with debilitated immune systems can remain infectious much longer. Treatment and Control Currently, there is no generally accepted antimicrobial agent available to treat cryptosporidiosis, and thus, supportive care of patients remains the treatment of choice.77 As expected, this problem is a major area of research, with certain experimental antibiotic regimens showing some promise. Because the thick-walled oocyst portion of the C. parvum life cycle is so resistant to chlorine, new approaches to control the spread of these infectious particles are also being pursued. Reverse osmosis, better filtration techniques, and other efficient procedures are under investigation. 534 ▼ VIRAL INFECTIONS Hepatitis C Virus Traditional health care concerns about viral hepatitis focused primarily on hepatitis B virus (HBV) from the late 1940s to the early 1980s. Yet, despite accumulated evidence for the documented occupational risks for HBV over a three-decade period, significant voids from other potentially serious hepatitis challenges continue to require definition. Although the routine application of specific serologic tests was valuable in screening and diagnosing infections caused by hepatitis A virus (HAV) and HBV, a number of reports, written beginning in 1975, described a form of bloodborne post-transfusion hepatitis that could not be attributed to any known microorganism.79,80 Since diagnosis of this type of hepatitis was based on abnormal liver function in the absence of positive blood markers for HAV, HBV, and other viruses known to cause hepatitis, the term “non-A, non-B hepatitis” (NANBH) was introduced. Most of the risk factors associated with NANBH transmission were identified prior to recognition and characterization of its viral etiology. These included blood transfusion, parenteral drug use, health care worker exposure in clinical settings, sexual transmission from a person with a history of hepatitis, and low socioeconomic status. Significant advances in recombinant DNA technology were instrumental in the later isolation and cloning of the responsible microorganism in 1989—the hepatitis C virus (HCV).81 A initial diagnostic serologic assay was also developed for detection of antibodies to HCV (antiHCV) produced by infected persons against a recombinant viral antigen c100-3.82 Later generations of more sensitive immunoassays have been implemented since 1990. Currently, at least six viral agents appear to account for the majority of viral hepatitis cases (Table 20-10), with new information emerging to expand this list. VIROLOGY HCV is a single-stranded positive-sense ribonucleic acid (RNA) virus whose structure appears closely related to the genera Flavivirus and Pestivirus. Because of the similarities to these viral types, HCV is currently classified as a separate genus in the family Flaviviridae. Detailed molecular biologic studies have shown that different HCV strains can have substantial differences in genome sequencing. These are due to the ability of the virus to mutate and modify surface components during replication within an infected host. As a result, several genotypes, or quasi-species, have been described that can exhibit significant differences throughout the RNA genome83–85 and contribute to the observed alarming high rate of chronic infection. EPIDEMIOLOGY AND TRANSMISSION HCV has a primary bloodborne mode of transmission and is a dominant cause of chronic liver disease throughout the world. Data using anti-HCV as a marker have been used to approximate both worldwide infection prevalence and HCV incidence Principles of Medicine in various geographic areas, in an attempt to better define infection and disease patterns.86 Infection with HCV is also the most common chronic bloodborne infection in the United States. Current estimates range from 2.7 (1.3%) to 3.9 (1.8%) million HCV-infected persons in the United States (Table 20-11).87,88 Approximately 2.7 million people are thought to have persistent chronic hepatitis C infection, and thus are classified as potentially infectious viral carriers. Mortality in the United States from all forms of hepatitis C infection is believed to occur in 8,000 to 10,000 people each year. With the advent of widespread use of anti-HCV assays and increased awareness of documented risks and changing viral transmission patterns, the incidence of new cases of acute hepatitis C has declined by greater than 80% since 1989. Statistics acquired during the 1970s and 1980s indicated that parenteral NANBH was responsible for nearly 90% of the reported US transfusion-associated hepatitis cases. Accumulated data suggested that approximately 150,000 persons (5 to 10%) of 3,000,000 who received transfusions developed acute NANBH.89,90 With the advent of routine testing using sensitive anti-HCV tests, however, the current risk for acquiring transfusion-associated hepatitis C is 1/100,000 per unit transfused.91 According to CDC national surveillance data, parenteral drug use was the most common risk factor reported by patients with NANBH between 1990 and 1992. Injection-drug use remains the primary risk factor for new cases of HCV infection. In addition, persons with hemophilia who routinely received factor VIII or IX before 1987 and chronic hemodialysis patients have also been considered at risk. Occasionally, health care workers who have frequent contact with blood and personal contact with others who may be infected have been documented to have an increased incidence for hepatitis C compared with that of the general population.91,92 A summary of these and other epidemiologic estimates is presented in Table 20-12. In recent years, other serologic surveys have revealed a large previously undetected group of persons at risk for HCV: military veterans, especially Vietnam-era veterans. Testing at multiple Veterans Administration (VA) hospitals found an 8 to 10% HCV prevalence rate, which is over four times that of the general population. Other reports indicate that more than half of the patients receiving liver transplants in VA medical centers were diagnosed with HCV infections.93–95 Unfortunately, even with improved epidemiologic tracking, published studies continue to report that greater than 40% of the hepatitis C patients do not have any identifiable risk factors.91 Evidence of sexual transmission and of perinatal passage from HCV-infected mothers to their offspring suggest possible, but not efficient, modes of viral exposure. In summary, transmission data still strongly implicate parenteral exposure as the primary mechanism for HCV transmission. SEROLOGY In May 1990, the US Food and Drug Administration (FDA) licensed two anti-HCV screening tests.96 Almost immediately, blood donation centers began testing for HCV infection Picornaviridae; non-enveloped single-stranded RNA 15–40 d Usually acute Not present Fecal-oral; poor sanitation No None reported 0.1–0.2 Anti-HAV Family characteristics Incubation period Onset Prodome: arthritis/rash Transmission Carrier state Possible manifestations Mortality rate (%) Homologous immunity Anti-HBsAg 1–2; higher in adults > 40 yr Hepatocellular carcinoma; cirrhosis Yes (5–10%) Parenteral; sexual contact; perinatal; other secretions (eg, saliva) Sometimes Usually insidious 50–180 d Hepadnaviridae; doublestranded DNA Hepatitis B Virus (HBV) Not defined 1–2 Hepatocellulalr carcinoma; cirrhosis Yes (> 85%) Usually parenteral; sexual contact less common; perinatal Sometimes Usually insidious 1–5 mo Flaviviridae; enveloped single-stranded RNA Hepatitis C Virus (HCV) Anti-HBsAg 2–20 Hepatocellular carcinoma; cirrhosis Yes Usually parenteral; sexual contact less common Unknown Usually acute 21–90 d Satellite; non-enveloped single-stranded RNA Hepatitis D Virus (HDV) Anti-HEV 1–2 in gen population; 20 in pregnant women None reported No Fecal-oral; waterborne (common in developing countries) Not present Usually acute 2–9 wk Caliciviridae; RNA Hepatitis E Virus (HEV) Adapted from Krugman S. Viral hepatitis: A, B, C, D, and E—infection. Pediatr Rev 1992;13:203; Molinari JA. Hepatitis C virus infection. Hepatitis C virus infection. Dent Clin North Am 1996;40:309–25. DNA = deoxyribonucleic acid; HBsAg = hepatitis B surface antigen; NA = not applicable; RNA = ribonucleic acid. Hepatitis A Virus (HAV) Feature TABLE 20-10 Comparison of Major Microbiologic and Clinical Features of Hepatitis Viruses Anti-HGV NA None reported Yes Parenteral; perinatal frequent co-infection with HCV NA Acute disease spectrum unknown NA Flaviviridae; RNA Hepatitis G Virus (HGV) Infectious Diseases 535 536 TABLE 20-11 Hepatitis C Incidence in the United States Approximately 3.9 million HCV-infected persons (1.8% of population) 4 times HIV infection incidence 2.7 million chronic potentially infectious carriers 10,000 HCV-related deaths/yr 80% decline in new cases since 1989 > 50% new cases related to IV-drug users Incidence of transfusion cases is declining rapidly. Principles of Medicine administered to patients. In addition, false-positive test results are possible for those donors with certain immunopathologic conditions, such as hypergammaglobulinemia, liver disease, or autoimmune connective-tissue disorders.98 More recently, blood tests have used other recombinant HCV synthetic peptide antigens, and these assays have increased sensitivity and specificity (Table 20-13).91 As a result, the incidence of transfusion-associated hepatitis C has become increasingly uncommon. Most cases are mild to asymptomatic. PATHOGENESIS Many cases still have no risk factors. Presentation of viral hepatitis in patients ranges from asymptomatic illness to a fulminant chronic form in which severe sequelae and high mortality rates are seen. Many chronic hepatitis carriers are also at increased risk for hepatocellular carcinoma. For those individuals who develop icteric manifestations of acute viral hepatitis, symptomatologies may vary in intensity; yet they can be strikingly similar in their spectrum, regardless of the etiology. Disease presentations may include jaundice, malaise, fever, anorexia, nausea, abdominal pain, dark (“stormy,”“foamy”) urine, chalky gray stools, rash, and arthritis. The clinical features of HCV infection can be variable, in patterns reminiscent of those observed for other hepatitis viruses. Less than one-third of HCV-infected individuals HCV = hepatitis C virus; HIV = human immunodeficiency virus; IV = intravenous. as a component of their routine donor screening. In a noteworthy positive outcome, the use of this radioimmunoassay was found to yield positive anti-HCV results in 80 to 90% of specimens from potential donors thought to be infectious for HCV.97 Unfortunately, false-negative results are possible at early stages of HCV infection since development of detectable antibody could be delayed for months post viral infection. This prolonged delay in seroconversion suggests that some potentially infectious donors could pass undetected through screening, and their blood subsequently TABLE 20-12 Estimated Average Prevalence of Hepatitis C Virus Infection in the United States* Infection Prevalence of Persons with Prevalence Characteristic Persons with hemophilia treated with products made before 1987 % Range % Characteristic (%) 87 74–90 < 0.01 79 72–86 0.5 Injection-drug users Current No data — Persons with abnormal alanine aminotransferase levels History of prior use 15 10–18 5 Chronic hemodialysis patients 10 0–64 ≥ 50 9 6–16 4 10–49 3 3–4 22 2–9 2 1–2 52 6 1–10 17 5 0.1 Persons with multiple sex partners (lifetime) Persons reporting a history of sexually transmitted diseases Persons receiving blood transfusions before 1990 6 5–9 6 Infants born to infected mothers 5 0–25 0.1 Men who have sex with men 4 General population 1.8 2–18 5 1.5–2.3 NA Health care workers 1 1–2 9 Pregnant women 1 — 1.5 Military personnel 0.3 0.2–0.4 0.5 Volunteer blood donors 0.16 — NA = not applicable. *By various characteristics and estimated prevalence of persons with these characteristics in the population. 5 537 Infectious Diseases TABLE 20-13 Tests for Hepatitis C Virus Infection Test/Type Applications Comments Hepatitis C virus antibody (anti-HCV) EIA (enzyme immunoassay); supplemental assay (ie, recombinant immunoblot assay [RIBA]) Indicates past or present infection but does not differentiate between acute, chronic, or resolved infection All positive EIA results should be verified with supplemental assay Sensitivity ≥ 97% EIA alone has low positive-predictive value in lowprevalence populations HCV RNA (hepatitis C virus ribonucleic acid) Qualitative tests *†: reverse transcriptase polymerase chain reaction (RT-PCR) amplification of HCV RNA by in-house or commercial assays (eg, Amplicor HCV) Detect presence of circulating HCV RNA Monitor patients on antiviral therapy Detect virus as early as 1–2 wk after exposure Detection of HCV RNA during course of infection might be intermittent; single negative RT-PCR is not conclusive False-positive and false-negative results might occur Quantitative tests *†: RT-PCR amplification of HCV RNA by in-house or commercial assays (eg, Amplicor HCV Monitor) Branched-chain DNA (bDNA) assays (eg, Quantiplex HCV RNA Assay) Determine concentration of HCV RNA Might be useful for assessing the likelihood of response to antiviral therapy Less sensitive than qualitative RT-PCR Should not be used to exclude the diagnosis of HCV infection or to determine treatment end point Genotype *†: several methodologies available (eg, hybridization, sequencing) Group isolates of HCV on the basis ofgenetic differences into 6 genotypes and > 90 subtypes With new therapies, length of treatment might vary based on genotype Genotype 1 (subtypes 1a and 1b) most common in United States and associated with lower response to antiviral therapy No clinical utility Cannot distinguish between subtypes Dual infections often observed Serotype*: EIA based on immunoreactivity to synthetic peptides (eg, Murex HCV Serotyping 1–6 Assay) DNA = deoxyribonucleic acid; HCV = hepatitis C virus. *Currently not approved by US Food and Drug Administration; lack standardization. †Samples require special handling (eg, serum must be separated within 2–4 h of collection and stored frozen [-20˚C or -70˚C]; frozen samples should be shipped on dry ice). manifest jaundice after receiving contaminated units of blood. 99,100 They may appear healthy with normal liver function and no pathologic sequelae, or develop acute and/or chronic disease manifestations. Although acute hepatitis C can resemble hepatitis A and hepatitis B clinically, HCV infection often induces less hepatic inflammatory reactions and thus usually manifests milder symptoms. Serologic demonstration of anti-HCV often does not occur for weeks to months after viral infection, thereby providing a prolonged undetected period during which the patient continues to be infectious. As occurs with HBV infection, pathologic sequelae can occur in persons who have chronic HCV infection, often with life-threatening ramifications. Unfortunately, as many as 50% of long-term chronic hepatitis C cases may progress to chronic hepatitis C liver disease. This develops far more often than the 5 to 10% carrier rate observed with HBV infection. Persons with chronic hepatitis C can present with few initial clinical manifestations of liver disease and remain so as inactive viral carriers, or persistent viral infection can predispose a person later to increased risk for hepatic failure and hepatocellular carcinoma. 101 Patients with pre-existent immunosuppressive conditions, such as those with HIV infection and others undergoing kidney or liver transplantation, also have been found to have higher hepatitis C morbidity. Transmission here is most probably due to the patients’ potential to expe- rience frequent parenteral exposure to HCV via blood transfusion or intravenous drug use. High-risk sexual activity may also be a factor. At the present time, the demonstration and characterization of a protective host immune response against HCV have not been accomplished. Presence of anti-HCV in a person’s blood does not distinguish between cases of acute or chronic hepatitis C, nor can a positive test for this immunoglobulin discriminate between a person who has recovered from infection with natural active immunity from one who has developed chronic hepatitis C. OCCUPATIONAL RISKS TO HEALTH CARE PROFESSIONALS Health care workers are at risk for exposure to patient blood and possible subsequent infection from bloodborne diseases, such as those caused by members of the hepatitis virus group. Early observation that a form of NANBH has a bloodborne etiology spurred intense occupational-risk investigations by clinical scientists. Accidental injuries from contaminated sharps have been associated with resulting onset of both hepatitis B and hepatitis C. Information describing occupational HCV transmission in hospital settings was investigated and published even before cloning of the virus was accomplished. Multiple investigations documented HCV transmission to health care workers and to other patients following percutaneous accidents involving blood (Table 20-14).102–106 538 Principles of Medicine TABLE 20-14 Modes of Transmission of Hepatitis C Virus in Health Care Settings Accidental needlesticks Blood splashes into eyes Blood transfusion (incidence declining rapidly) Association with contaminated immune globin Organ/tissue transplantation Infected cardiac surgeon to patients Infected patient to anesthesia assistant to other patients Patient to patient via colonoscope Relatively few studies have looked at HCV transmission in dental treatment facilities. Initial reports showed oral surgeons had a significantly higher incidence of positive anti-HCV results than did general dentists and the general population, owing to greater potential exposures to blood.107 These and other data have been summarized by Cleveland and colleagues.108 When taken together, accumulated findings suggest that although hepatitis C remains a bloodborne infection of occupational concern, the long-term application of universal infection-control precautions targeting HBV as the most infectious bloodborne pathogen has significantly lowered the dental provider’s risks for contracting HCV infection. The most hazardous type of exposure that can increase the possibility of HCV acquisition is an on-the-job needlestick injury. A second primary characteristic of HCV risks to health care workers is related to the virus life cycle and the titers of infectious particles in blood. HCV is present in concentrations ranging from only a few virions to 100,000 or more particles per milliliter of a patient’s blood. Although this reinforces HCV’s position as being a greater occupational infectious risk than HIV, the concentrations fall far below those routinely seen in HBV-infected persons. Thus, the substantially lower HCV titer in blood offers less opportunity for occupational transmission per exposure incident. Table 20-15 puts this into perspective by summarizing potential transmission risks to health care workers for HBV, HIV, and HCV, by comparing viral concentrations found in blood and calculated infection rates following needlestick accidents.109 TABLE 20-15 Risks of Transmission to Health Care Workers Concentration/mL Pathogen HBV of Serum/Plasma 1,000,000–100,000,000 Transmission Rate (%)* 6.0–30.0 HCV 10–1,000,000 2.7–6.0 HIV 10–1,000 0.30 Adapted from Lanphear BP.109 HBV = hepatitis B virus, HCV=hepatitis C virus; HIV = human immunodeficiency virus. *As a result of a needlestick accident. Infection control precautions against bloodborne disease have correctly focused on prevention of hepatitis B transmission in health care facilities, in large part because of the high HBV concentrations that can be reached in the blood of infected patients and the high potential of infection after exposure to certain contaminated body fluids. With regard to hepatitis C, sizable volumes of HCV-contaminated blood, such as those used for blood transfusion, can readily cause infection. Despite apparent lower risks from sharps, however, HCV infection carries with it the increased possibility of chronic liver disease. The progression from persistent viral infection to either hepatic cirrhosis in about one-quarter of infected persons or to hepatocellular carcinoma in others presents real challenges to infection control for care providers. HCV THERAPY AND PREVENTIVE APPROACHES Preliminary studies began appearing in the literature in the mid1980s that suggested that a prolonged course of therapy with interferon-α could have beneficial effects for persons with chronic hepatitis C.110,111 These beneficial effects occurred rapidly during therapy, with alanine aminotransferase (ALT) levels eventually falling to within the normal range. Follow-up testing after completion of the regimen unfortunately found the ALT decline to be transient in most of the patients. Later investigations involving larger numbers of HCV-infected persons led to FDA approval of a recombinant form of this antiviral agent for treatment of chronic hepatitis C in 1991.112 Additional studies have attempted to further refine therapeutic dosages and drug regimen intervals.113 Combination of chemotherapeutic agents has shown promising results in recent years. Currently, a daily regimen of interferon α-2b plus ribavirin for 6 to 12 months has demonstrated a significant improvement in patient biochemical and virologic responses when compared with interferon monotherapy. Approximately 50% of treated patients have a sustained beneficial response, compared with response rates of 15 to 25% using interferon alone.114 Future therapies will probably include additional multidrug approaches, such as other forms of interferon and specific HCV enzyme inhibitors.115 An effective vaccine for hepatitis C is not yet commercially available. Multiple factors have hindered research efforts directed at prophylactic strategies. Two principal factors are the failure to define a protective host immune response against HCV infection, and the antigenic heterogeneity described for different viral strains. Until scientists ascertain how host resistance develops during recovery from hepatitis C, and against what antigen(s) the immunity is directed, vaccine studies will continue to be limited. At present, routine use of universal precautions during patient care and anti-HCV screening of potential blood donors appears to be successful in reducing health care provider, patient, and public exposures. HIV Infection Since the early 1980s, HIV has been recognized as one of the most devastating infectious diseases of the twentieth century. By the end of the century, almost 60 million people Infectious Diseases worldwide had been infected with the virus, and the rate of infection continued unabated. 116 The vast majority of exposed and at-risk individuals had no access to effective medications to combat the virus or its associated opportunistic infections. Even in the early stage of the twenty-first century, there are few indications that there soon will be any effective and affordable vaccines or anti-HIV medications available for most people afflicted by this disease. This chapter explores many different aspects of HIV disease and emphasizes oral health considerations, which impact on the overall health of HIV-infected individuals. EPIDEMIOLOGY In June and July of 1981, the Centers for Disease Control published two reports on several clusters of young homosexual men who developed opportunistic infections that were chiefly detected in severely immunodeficient individuals.117,118 It was not clear what caused this apparent immunodeficiency, and the disease was initially referred to as “gay-related immune deficiency,” or “GRID.” Several theories focusing on the lifestyle of homosexual and bisexual men were put forth to explain the cause of this illness. However, soon after, it became clear that there were other groups in society who also developed this rapidly evolving disease and that the cause was most probably an infectious pathogen and not sexual preference.119–125 It became evident that finding a causative agent, developing an accurate test to detect this pathogen, and elucidating the modes of transmission were imperative to slow down the quickly expanding epidemic. The etiologic agent of this disease, now termed “human immunodeficiency virus,” was recognized within 2 years of the first reported cases.126,127 Due to the severe immunosuppression observed in affected individuals, this disease was eventually given the name “acquired immunodeficiency syndrome.” The CDC quickly put a surveillance system in place. This surveillance system was based on standard case definitions. Due to the changing nature of this disease, the original case definition from 1985 was expanded in 1987 and again in 1993 to better incorporate specific illnesses in different populations as well as reflect changes in infected individuals’ immune status128 (Table 20-16). AIDS, the stage of HIV disease when individuals start to develop opportunistic infections or have severe immunosuppression, is a reportable condition in all 50 states, the District of Columbia, and the US territories. At the time of this writing, HIV infection is not a reportable condition in all states. The number of total accumulated cases of AIDS and the rate of AIDS in the United States are reported by the CDC on a biannual basis129 (Table 20-17). Although the number of total accumulated cases of AIDS changes over time, the ranking of states and metropolitan areas remains fairly stable. More important than the actual number of cases and rates is the trend of change. The directions of these trends reflect the course of the HIV epidemic. Between June 1999 and June 2000, there were an additional 42,563 persons who developed AIDS in the United States. However, this represented a decrease of 7.6% of new cases from 1998 to 1999. Also, the rate of AIDS per 100,000 population decreased by 8.2%. A decrease of 8.6% in new cases 539 among males and a decrease of 3.4% in new cases among females were noted for the same period. Thus, even though new cases were reported, there was a marked decrease in the rate of new AIDS cases. Taking into consideration that there are between 40,000 to 50,000 new HIV infections annually in the United States, the decreasing number of AIDS cases suggests that infected individuals are remaining healthier and that the disease is progressing more slowly over time. Since the introduction of more potent anti-HIV medications in the middle 1990s, an initial dramatic decrease in the rate of death of persons with AIDS has been observed (Table 20-18).129 However, this trend has tapered off due to factors such as increased resistance to medications and patients reaching the limits of extending survival with these medications. By the end of the 1990s, it was estimated that there were 650,000 to 900,000 HIV-infected persons in the United States; approximately 500,000 of these persons were aware of their HIV infection, and an estimated 335,000 of these received medical care.130 There are two different types of HIV: HIV-1 and HIV-2. Both viruses cause immune deterioration and AIDS, but HIV-2 has been associated with a more indolent course and a less efficient transmission. The median time from infection to AIDS has been reported to be approximately 10 years for those infected with HIV-1 but almost 20 years for those with HIV-2. The vast majority of HIV infections are caused by HIV-1, except in particular geographic areas, such as the western parts of Africa. Unless specified, “HIV” in this chapter refers to HIV-1. Mainly through phylogenic analyses, it has been possible to extrapolate that HIV-1, HIV-2, and the simian immunodeficiency virus (SIV) may have originated from the same source in Africa and started to separate into different viruses in the beginning of 1900s. It is not clear when HIV was introduced into the human host, but it likely happened in the 1920s or 1930s, with a more rapid sustained spread around the mid1940s. The prevailing theory suggests that the human variant of this immunodeficiency virus originated from different types of primates. It is assumed that SIV from chimpanzees (SIVCPZ) is the source of HIV-1, whereas HIV-2 originated from monkeys, predominantly sooty mangabeys (SIVSM).131,132 The earliest reported cases of AIDS in Europe were observed in the 1950s; approximately 10 years later, AIDS was reported in the United States. HIV is transmitted sexually through contaminated blood and products, and vertically from mother to child. It is important to realize that since the recognition of HIV disease, the modes of transmission have not changed and are not likely to change in the future. Although extraordinary cases of HIV transmission by other means have been reported, they are extremely rare or are based on faulty documentation. There has never been any documented case of occupational transmission of HIV from patients to dental health care workers. In one celebrated case from 1990, an HIV-infected dentist was implicated in transmitting the virus to several of his patients. Although this case was thoroughly investigated by CDC and other agencies, how the transmission occurred was never fully elucidated.133 540 Principles of Medicine TABLE 20-16 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS among Adolescents and Adults CD4+ T-Lymphocyte Categories The lowest accurate CD4+ T-lymphocyte count should be used for classification purposes, even though more recent and possibly different counts may be available. Clinical Categories Clinical category A Conditions: Asymptomatic human immunodeficiency virus (HIV) infection Persistent generalized lymphadenopathy (PGL) Acute HIV infection with accompanying illness or history of acute HIV infection Conditions listed in category B and category C must not have occurred. Clinical category B Symptomatic conditions in HIV-infected adolescents or adults that are not included in clinical category C and meet at least one of the following criteria: (a) the conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; (b) the conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection. Examples of, but not limited to, the following conditions: Bacillary angiomatosis Candidiasis, oropharyngeal (thrush) Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy Cervical dysplasia (moderate or severe)/cervical carcinoma in situ Constitutional symptoms, such as fever (38.5˚C) or diarrhea lasting > 1 mo Herpes zoster (shingles) involving at least two distinct episodes or more than one dermatome Idiopathic thrombocytopenia purpura Listeriosis Oral hairy leukoplakia Pelvic inflammatory disease, particular if complicated by tubo-ovarian abscess Peripheral neuropathy Clinical category C Conditions: Candidiasis of bronchi, trachea, or lung Candidiasis, esophageal Cervical cancer, invasive Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (> 1 mo duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) Encephalopathy, HIV related Herpes simplex: chronic ulcer(s) (> 1 mo duration); or bronchitis, pneumonitis, or esophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal ( > 1 mo duration) Kaposi’s sarcoma Lymphoma, Burkitt’s (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium-intracellulare complex or Mycobacterium kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary) Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis carinii pneumonia Pneumonia, recurrent Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis Wasting syndrome due to HIV infection Clinical Categories CD4+ T Cells/mm3 or CD4+ Percentage A: Asymptomatic Acute HIV or PGL B: Symptomatic, no A or C Conditions C: AIDS-Indicator Conditions ≥ 500 or ≥ 29% 200–499 or 14–28% < 200 or < 14% A1 A2 A3* B1 B2 B3* C1* C2* C3* Adapted from Centers for Disease Control and Prevention.128 * Expanded acquired immunodeficiency syndrome (AIDS) surveillance case definition. 541 Infectious Diseases TABLE 20-17 Ranking of AIDS Cases and Rates per 100,000 Population* Area of Residence New York California Florida Texas New Jersey Illinois Puerto Rico Pennsylvania Georgia Maryland Total Cases 139,248 117,521 78,043 52,667 41,245 24,425 24,061 23,678 22,197 20,833 Area of Residence Rates District of Columbia New York Virgin Islands, US Florida Maryland Puerto Rico Delaware Massachusetts New Jersey South Carolina 189.4 39.4 37.6 33.4 27.2 26.4 26.3 24.4 23.6 20.9 Metropolitan Area of Residence New York, NY Los Angeles, CA San Francisco, CA Miami, FL Washington, DC Chicago, IL Houston, TX Philadelphia, PA Newark, NJ Atlanta, GA Metropolitan Area of Residence New York, NY Miami, FL Fort Lauderdale, FL San Francisco, CA West Palm Beach, FL Jersey City, NJ Newark, NJ Columbia, SC Baltimore, MD Washington, DC Total Cases 117,792 42,394 27,567 23,521 22,321 21,173 18,735 18,348 16,739 15,524 Rates 68.1 58.3 56.9 52.6 50.5 43.2 40.3 39.7 35.9 35.8 Adapted from Centers for Disease Control and Prevention.129 *In the United States reported through June 2000. PATHOGENESIS Early in the HIV epidemic, it was recognized that this disease was caused by a virus that gradually destroyed a host’s immune defenses, making virtually all infected individuals susceptible to opportunistic infections. The particular immunodeficiency in HIV disease was attributed to CD4+ lymphocyte depletion, enabling the development of specific opportunistic infections that were associated with a high degree of morbidity and mor- tality. More than 20 years after the recognition of this disease and its causative agents, it has been possible, with the help of improved and new molecular biologic tools and methods, to explain in more detail the pathogenesis of HIV disease. HIV is a retrovirus harboring its genetic information in two copies of a single-stranded RNA. The viral genome is contained within a protein core, which also contains the enzyme reverse transcriptase. Surrounding the core particle is a lipid membrane. Embedded within this membrane are two envelope glycoproteins, gp 41 and gp 120, both essential for the recognition and binding of target cells. These two glycoproteins are subunits generated by the cleavage of the gp 160 precursor. HIV targets cells expressing CD4 molecules, particularly CD4+ T lymphocytes, monocytes, and macrophages, taking advantage of the affinity between the viral gp 120 and the cellular CD4 receptor. The binding of gp 120 to CD4 receptors causes a conformational change in gp 120, which exposes and stabilizes a cellular chemokine receptor called CCR5. These interactions activate gp 41, resulting in fusion of the viral membrane with the cellular membrane, which allows the viral RNA and reverse transcriptase to enter into the target cell. The reverse transcriptase transcribes the viral RNA into DNA, which integrates into the target cell’s genome. With the successful integration of viral DNA into the cellular genetic material, an infection has occurred. HIV gains entry into the body directly through the blood or at mucosal surfaces. The virus establishes itself within lymphoid tissues, where it replicates, makes itself available to the cells of the immune system (such as T lymphocytes, monocytes, and macrophages), and slowly brings about destruction of the lymphoid tissue. Mucosal surfaces have an abundance of dendritic cells, such as Langerhans’ cells, that trap the virus and enable the uptake of the virus into lymphoid aggregates below the surface. Contact between mucosal surfaces and HIV can result in infection of Langerhans’ cells after only a couple of hours. Within a few days, the virus can be detected in regional lymph nodes. The rapid replication of HIV results in an initial viremia causing seeding of the virus to lymphoid tissue throughout the body. It is estimated that more than 10 billion virions, with a half-life of approximately 1.6 days, are produced daily in infected individuals.134,135 This continuous turnover of viruses results in one-half of the circulating viruses being replaced with newly formed virions every day. Furthermore, almost 2 billion CD4+ lymphocytes are destroyed and replaced every day. Activated CD4+ lymphocytes express high levels of chemokine receptors and are primary targets of HIV. However, although these activated cells usually die within a few days, a latent reservoir of HIV is established among CD4+ cells. An extremely high viral titer can be detected in the blood during the primary stage of HIV infection, but, over time, infectious virions became undetectable in the plasma. The initial control of viral replication is associated with antibody-dependent cellular cytotoxicity activity and HIV-specific cytotoxic T lymphocytes. However, neutralizing antibodies also develop. 542 Principles of Medicine TABLE 20-18 Estimated Deaths and Rate of Change of Death of Persons with AIDS, in the United States Measure 1993 1994 1995 1996 1997 1998 1999 Estimated number of deaths 45,381 49,869 50,610 37,787 21,923 17,930 16,273 +9.9 +1.5 –25.3 –42.0 –18.2 –9.2 Change (%) — Unfortunately, HIV replication is associated with a very high mutation rate, resulting in a great genetic diversity of HIV quasispecies in individual patients.136 This heterogeneity increases over time. Consequently, it is important to initiate viral suppression as early as possible after infection. This will accomplish a decrease in viral diversity, resulting in more effective immune control and less drug resistance. Even a single nucleotide change in the HIV-1 transcriptase gene is enough to confer high levels of drug resistance to particular anti-HIV medications.137 The hallmark of HIV disease is the progressive loss of CD4+ lymphocytes. Without intervention, an average of 60 to 80 cells/mm3 are lost every year; this loss is highly variable and occurs in periods of more stability and rapid decline.138 An estimation of the plasma level of these cells (a CD4 cell count) indicates an individual’s immune status. Normal CD4 cell counts are usually above 500 to 600 cells/mm3, whereas levels below 200 cells/mm3 are considered to indicate severe immune suppression. The lower the CD4 cell count, the more susceptible is a patient to develop opportunistic infections. As part of the latest AIDS definition, a patient has an AIDS diagnosis when the CD4 cell count drops below 200 cells/mm3 (see Table 20-16). At this level the patient is at very high risk of developing specific major opportunistic infections, such as Pneumocystis carinii pneumonia (PCP), and prophylactic medications are administered to ward off these infections. Although the CD4 cell count was used for many years as a marker for HIV disease progression, other biologic indicators, such as the level of plasma viral RNA, or viral load, have since proven to be more reliable and accurate.139 Today, CD4 cell counts are mainly used to assess a patient’s immune status, to determine when to institute antiretroviral medications, to determine when to institute prophylaxis against opportunistic infections, and as an indicator for AIDS. Recent advances in molecular biology have enabled detection of HIV RNA in plasma and within different tissues.140 The most common method used for clinical HIV care is reverse transcription coupled to the polymerase chain reaction (RT-PCR). This method uses a PCR-based assay to assess the presence, as well as measure the quantity, of HIV RNA. Numerous retrospective studies have determined the progression of HIV disease, as well as the prognosis, based on the quantity of plasma HIV-1 RNA139 (Table 20-19). Many of these studies show surprising consistency.141–144 According to these studies, the risk for disease progression and death is reduced by 30% when the viral load is halved, by 55% with a four-fold reduction in viral load, and by 65% with a 10-fold reduction in viral load. As viral load significantly corresponds with changes in disease progression, this measure has also been used to assess efficacy of antiretroviral medications.145 Effective drug therapy is reflected in reduced viral loads; no or little viral load change suggests less effective therapy. This association has created new standards of care for patients with HIV. Acute HIV infection occurs 2 to 6 weeks after exposure. During the acute stage of the disease, affected individuals develop high plasma levels of the virus. An antibody response can only be detected approximately 2 to 3 months after exposure. Twenty to 90% of exposed individuals develop a self-limited nonspecific illness characterized by fever, lymphadenopathy, myalgia, arthralgia, sore throat, and occasional rashes and oral ulcerations. This illness has sometimes been described as a “mononucleosis-like” syndrome and is referred to as the acute seroconversion syndrome or acute retroviral syndrome. Identification of individuals at this stage of the disease is important for several reasons. Of primary importance is the potential for further transmission. As affected individuals have very high viral loads, they are highly infectious and can unwittingly transmit the virus to unsuspected partners.146 There is epidemiologic evidence that suggests that recently infected individuals are responsible for a high percentage of transmissions.147 Evaluation of individuals during the acute retroviral syndrome needs to include both a virologic test and an antibody test. A positive HIV RNA test, together with a negative HIV-antibody test, is diagnostic for primary HIV infection. Due to the possible false-positive result from an HIV RNA PCR-based assay, a true positive result is considered when the viral load is above 100,000 copies/mL. Results below 5,000 copies/mL are more likely to be false-positive than true positive.148 Another benefit of early recognition of HIV infection is the potential to achieve viral suppression during this stage of the disease. This may facilitate a more effective immune response and diminish viral diversity. Institution of antiretroviral therapy during this stage of the disease has been shown to enhance the immune system’s ability to destroy infected cells and to diminish CD4 cell depletion.149–151 After the acute retroviral syndrome, most individuals remain asymptomatic for many years. However, the deteriorating immune system eventually gives way, and opportunistic infections develop. Without treatment, the median time from primary infection to AIDS is approximately 10 years.152 In most industrialized countries, individuals with HIV have access to antiretroviral therapy. Consequently, the epidemiology of HIV disease has changed dramatically since the mid-1990s. At that point, new and more potent antitretroviral medications were introduced that decreased the incidence of opportunistic infections and death rate153 (see Tables 2018 and 20-20). Unfortunately, the rate of decline in the inci- 543 Infectious Diseases TABLE 20-19 Prediction of Immune Deterioration, HIV Disease Progression, and AIDS by HIV-1 RNA HIV-1 RNA Copies/mL < 500 501–3,000 3,001–10,000 10,001–30,000 > 30,000 Decrease in Yearly Individuals Developing AIDS Individuals Dying CD4+ Cell Count/mm3 Within 6 Years (%) Within 6 Years (%) 5.4 16.6 31.7 55.2 80.0 0.9 6.3 18.1 34.9 69.5 36.3 44.8 55.2 64.8 76.5 Adapted from Coffin JM.136 AIDS = acquired immunodeficiency syndrome; HIV-1 = human immunodeficiency virus type 1; RNA = ribonucleic acid. dence of opportunistic infections, AIDS incidence, and AIDSrelated deaths has slowed down. These latest trends are most probably related to the development of resistance to antiretroviral drugs, transmission of HIV-resistant strains, and the inability to maintain complete viral suppression for extended periods of time in all individuals. Furthermore, several new opportunistic syndromes have been described in patients given antiretroviral medications.154 It is possible that this phenomenon, termed “reversal syndromes,” is due to a rebounding immune system that initially does not have the same antigenic divergence as developing naïve CD4+ lymphocytes. This immune dysfunction may facilitate the development of latent opportunistic infections or unmask an undiagnosed opportunistic infection. Apparently, not all individuals exposed to HIV become infected. Furthermore, the rate of HIV disease progression in individuals is highly variable. Some infected persons may progress from infection to AIDS within months, whereas others have no signs of opportunistic infections or immune suppression even after 15 to 20 years. Approximately 10% of HIVinfected persons progress to AIDS within the 2 to 3 years after infection, whereas 10 to 17% of infected individuals may not develop AIDS even 20 years after infection.155 Obviously, these subgroups of infected persons are of great interest, as they may provide invaluable information regarding the variables associated with infection, progression, and even immunity to HIV, and subsequent treatment. Numerous studies have focused on the ability and inability of HIV to enter into target cells, and the capability of the immune system to rid the body of the virus. During the earliest stages of HIV infection, the virus particularly seeks out and TABLE 20-20 Decrease in Rate of Opportunistic Infections in HIV-Positive Individuals Rate of Decrease Disease Pneumocystis carinii pneumonia Mycobacterium avium-intracellulare complex Esophageal candidiasis Adapted from Kaplan JE et al.153 1992–1995 –3.4 –4.7 –0.2 1996–1998 –21.5 –39.9 –16.7 infects macrophages and memory T lymphocytes, using, in addition to these cells’ CD4 receptors, the cells’ chemokine receptors. The chemokine receptor used in these cells as a coreceptor for HIV is CCR5. At this stage of the disease it is common that the virus is referred to as “macrophage-tropic,” or “Mtropic.” M-tropic viruses do not have the ability to form syncytia in vitro; they are therefore also referred to as “non–syncytia-inducing isolates.” In addition, due to the virus’s predilection for cells expressing CCR5, the virus is referred to as an “R5 isolate.” Investigations of chemokine receptors have indicated that individuals with a homozygous mutation of CCR5 may be almost completely resistant to HIV. This specific mutation has been referred to as “CCR5 δ 32,” indicating a characteristic 32 base-pair deletion in the gene encoding CCR5. Individuals with a heterozygous mutation of CCR5 δ 32, one normal and one altered allele, tend to progress more slowly to AIDS and live longer than individuals without this mutation.156,157 Furthermore, a promoter mutation in CCR5 has also been associated with a slower progression to AIDS.158 Interestingly, persons harboring these chemokine receptor changes do not exhibit any pathologic effects due to these polymorphisms. Unfortunately, very few individuals, approximately 1% of Caucasians, exhibit homozygous deletion of the 32 base pair; 10% are heterozygotes. CCR5 δ 32 is rare among Africans, Native Americans, and East Asians. All chemokine receptors have natural ligands, cytokines that bind to the receptor. Three main cytokines have been identified that bind to and block the CCR5 receptor: MIP-1α, MIP-1- β and RANTES. Interestingly, these cytokines are generated by CD8+ T lymphocytes, which are cells that have been implicated in releasing factors suppressing HIV infection.159 Selective blockage of CCR5 with these cytokines has been shown to occur. During the later stages of HIV disease, the virus predominantly infects T lymphocytes expressing CD4 receptors and a chemokine co-receptor designated CXCR4. These T-tropic viruses can cause multinucleated syncytia formation in vitro and are therefore referred to as “syncytia-inducing isolates” and “X4 isolates.” The use of the CXCR4 receptor by HIV is associated with a more rapid depletion of CD4+ T lymphocytes and disease progression.160 Chemokines SDF-1-α and SDF-1-β have been identified as ligands to CXCR4 and can selectively inhibit T-tropic HIV-1 strains. 544 Use of these chemokine receptors is not exclusive, and about 40% of HIV-positive individuals use CXCR4 instead of, and sometimes in addition to, CCR5.161 These viral isolates are referred to as “R5X4.” Unfortunately, several other chemokine receptors are involved in HIV’s selection of target cells, increasing the complexity of all HIV–target cell interactions (Table 20-21).161–163 MEDICAL TREATMENT A better understanding of the pathogenesis of HIV disease has, in recent years, changed many of the treatment paradigms for infected individuals during the course of their illness. The recognition that there exist different individual responses to HIV infection, and even resistance, has provided clues to intervention strategies based on more accurate predictions of disease progression. Furthermore, better knowledge of the mechanisms for viral entry into target cells, integration, transcription, and subsequent viral replication has enabled a more varied and focused treatment strategy. Although the mainstay of HIV therapy is based on trying to slow down viral replication with antiretroviral medications, an important part of treatment for patients with HIV disease is also the prevention and treatment of opportunistic infections. HIV-infected individuals therefore take many different medications, some which impact on oral health and provision of dental care (Table 20-22). The first antiretroviral drug was introduced in 1997. This medication, AZT or zidovudine (ZDV), belongs to a group of medications called nucleoside reverse transcriptase inhibitors (NRTIs). These medications competitively inhibit the reverse transcriptase from converting the viral RNA into viral DNA. Other nucleoside analogues are abacavir (ABC), didanosine (ddI), lamivudine (3TC), stavudine (d4T), and zalcitabine (ddC). A similar group of medications that also inhibits reverse transcriptase is the non-nucleoside reverse transcriptase inhibitors (NNRTIs). NNRTIs include efavirenz (EFV), delaviridine (DLV), and nevirapine (NVP). In the mid-1990s, a new class of antiretroviral medications was introduced— protease inhibitors. These powerful medications prevent the breakdown of viral proteins into appropriate building blocks TABLE 20-21 Characteristics of Individuals with Slow Disease Progression Attenuated virus Reduced replication kinetics Low viral load Effective cellular immune response Strong HIV-1–specific cytotoxic T lymphocytes Effective antibody-dependent cellular cytotoxicity Increased levels of CD8+ T lymphocytes Increased divergence of the CD4+ T-lymphocyte repertoire, possibly due to exposure to greater viral diversity Polymorphisms and inhibition/blockage of chemokine receptors Homozygote CCR5-δ 32 genotype Heterozygote CCR5-δ 32 genotype Inhibition/blockage by MIP-1-α, MIP-1-β, RANTES generated by CD8+ T cells Data from Berger EA et al;161 Learmont J et al;162 Klein MR et al.163 Principles of Medicine for viral replication. Included in these medications are amprenavir (APV), indinavir (IDV), nelfinavir (NFV), ritonavir (RTV), and saquinavir (SQV). Due to the high level of toxicity and the rapid development of drug resistance, antiretroviral medications are given as double or triple therapy. This combination therapy is referred to as highly active antiretroviral therapy, or HAART. Antiretroviral therapy is usually instituted when a patient’s CD4 cell count drops below a critical value and/or when a patient’s viral load exceeds a critical level. These predetermined values vary as better scientific information regarding the pathogenesis of HIV disease is elucidated and depending on how patients react and respond to new and better combinations of medications. Prophylaxis against opportunistic infections is instituted according to a patient’s immune status. Usually patients with CD4 cell counts below 200 cells/mm3 are considered for prophylaxis to prevent Pneumocystis carinii pneumonia, and, at even lower levels, prophylaxis is instituted against various fungal and mycobacterial infections. Knowledge about the type of medications used to treat and prevent opportunistic infections helps the dental provider to attain additional insight into a patient’s health status. ORAL HEALTH CONSIDERATIONS Oral health considerations for persons infected with HIV focus on provision of dental care and oral conditions associated with their underlying disease.164–166 An appropriate work-up for an HIV-infected patient needs to ascertain a patient’s overall health, immune status, prognosis, presence and history of opportunistic infections, risk for developing more severe opportunistic infections and oral lesions, current medications, and chance for long-term survival (Figure 20-7). The patient may be able to provide all necessary information, but it is appropriate to have the patient sign a consent form that enables the provider to obtain more medical information from the patient’s primary care physician (Figure 20-8). As a general rule, no dental modifications are required for patients based on their HIV status. Most individuals presenting for outpatient dental care are sufficiently healthy to tolerate all types of dental procedures, ranging from scaling to implants.167 Also, numerous studies have indicated that patients with HIV disease are not more susceptible to complications after dental care, regardless of CD4 cell count.168,169 As with other medically complex patients, the major concerns are impaired hemostasis, susceptibility to dentally induced infections, drug actions and interactions, and the patient’s ability to withstand the stress and trauma of dental procedures. Few patients present with increased bleeding tendencies, unless they have concomitant liver disease or idiopathic thrombocytopenic purpura.170 Even when patients’ CD4 cell counts are very low, they are not more susceptible to dentally induced bacteremia. Thus, there are no indications for routine use of antibiotic prophylaxis based on patients’ HIV status. However, patients with neutrophil counts below 500 to 750 cells/mm3 require antibiotic prophylaxis. Furthermore, some patients may be at an increased risk for developing sub- 545 Infectious Diseases TABLE 20-22 Impact of Treatments for HIV Infection Drug Name* Type of Drug Adverse Effects of Significance for Dentists Co.† 12 (+)-calanolide A* NNRTI Dysgeusia 3TC or lamivudine, Epivir; also in Combivir and Trizivir NRTI Peripheral neuropathy 9 Abacavir (ABC), Ziagen; also in Trizivir NRTI Associated with liver damage 9 IBT Not known 2 Aldesleukin or interleukin-2 (IL-2), Proleukin IBT Not known 6 Amprenavir (APV), Agenerase PI Associated with hyperglycemia, dygeusia, and paraoral tingling sensations Do not use with the following medications: midazolam, triazolam, ergotamine, tricyclic antidepressants, vitamin E Avoid use with the following medications: erythromycin, benzodiazepine, or itraconazole 9 AZT or zidovudine, Retrovir; also in Combivir and Trizivir NRTI Associated with seizures, rapid, uncontrollable eye movements, decreased coordination, liver damage, and peripheral neuropathy 9 BCH-10652* or dOTC* NRTI None 3 ABC, see abacavir AG1661* or HIV-1 Immunogen* or Salk vaccine*, Remune* Agenerase, see amprenavir APV, see amprenavir Bis(POC) PMPA*, see tenofovir disoproxil fumarate* BMS-232632* PI Not known 5 Capravirine* (CPV) Coactinon*, see emivirine* NNRTI Dysgeusia 2 Combivir combination of zidovudine + lamivudine NRTI Associated with liver damage and peripheral neuropathy 9 Coviracil*, see emtricitabine* and FTC* CPV*, see capravirine* Crixivan, see indinavir d4T or stavudine, Zerit NRTI Peripheral neuropathy DAPD* NRTI Not known 13 5 ddC or zalcitabine, Hivid NRTI Associated with oral ulcerations, liver damage, and peripheral neuropathy 11 ddI or didanosine, Videx or Videx EC (delayed-release capsules) NRTI Associated with xerostomia, liver damage, and peripheral neuropathy Do not take the following medications within 2 hours of ddI: tetracycline, doxycycline, minocycline, and ciprofloxacin Take the following medications at least 2 hours before ddI: ketoconazole and itraconazole 5 Delaviridine (DLV), Drescriptor NNRTI Do not use with orange and cranberry juice Do not use with the following medications: clarithromycin, dapsone, ergotamine, alprazolam, midazolam, triazolam, carbamazepine, phenobarbital, and cimetidine 2 DMP-450* PI Not known 13 DOTC* or BCH-10652* NRTI Not known 3 NNRTI Associated with confusion, abnormal behavior, or hallucinations Do not use together with the following medications: midazolam and triazolam 7 Didanosine, see ddI DLV, see delaviridine Drescriptor, see delavirdine Droxia, see hydroxyurea Efavirenz (EFV), Sustiva Continued 546 Principles of Medicine TABLE 20-22 Impact of Treatments for HIV Infection (Continued) Type of Drug Adverse Effects of Significance for Dentists Co.† Emivirine* (EMV), Coactinon* NNRTI Not known 13 Emtricitabine* or FTC*, Coviracil* NNRTI Not known 13 PI 11 Drug Name* EFV, see efavirenz EMV*, see emivirine* Epivir, see lamivudine or 3TC Fortovase, see saquinavir (soft gel cap) FTC*, see emtricitabine* GW-420867X* NNRTI Not known 9 GW-433908* or VX-175* PI Associated with hyperglycemia, dysgeusia, and paraoral tingling sensations Do not use with the following medications: midazolam, triazolam, ergotamine, tricyclic antidepressants, or vitamin E Avoid use together with the following medications: erythromycin, benzodiazepine, or itraconazole 9 HIV-1 Immunogen* or Salk vaccine* or AG1661*Remune* IBT Not known 2 CI Oral ulcerations; associated with bleeding and bruising 5 Indinavir (IDV), Crixivan PI Do not use with the following medications: midazolam, triazolam, or ergotamine Avoid use with the following medications: ketoconazole and dexamethasone Interleukin-2 (IL-2), or aldesleukin, Proleukin IBT Not known 6 Lamivudine or 3TC, Epivir; also in Combivir and Trizivir NRTI Peripheral neuropathy 9 Lopinavir + ritonavir, Kaletra PI Associated with hyperglycemia Do not use with the following medications: midazolam or triazolam Avoid use with metronidazole 1 Nelfinavir (NFV), Viracept PI Do not use with the following medications: midazolam, triazolam, or ergotamine 2 Nevirapine (NVP), Viramune NNRTI Associated with liver damage 4 PI Not known 4 PI Do not use with the following medications: ergotamine, diazepam, midazolam, triazolam, meperidine, piroxicam, or propoxyphene Avoid use with the following medications: phenobarbital, dexamethasone, or metronidazole 1 Salk vaccine* or HIV-1 Immunogen* or AG1661*, Remune* IBT Not known 2 Saquinavir (SQV) (HGC) (hard gel cap), Invirase PI Associated with liver damage, peripheral neuropathy, and oral ulcerations Do not use with the following medications: midazolam, triazolam, or ergotamine Avoid use with the following medications: clarithromycin, phenobarbital, carbamazepine, dexamethasone, ketoconazole, itraconazole, or clindamycin Hivid, see zalcitabine or ddC HU, see hydroxyurea Hydroxyurea (HU), Droxia IDV, see indinavir 10 Invirase, see saquinavir (hard gel cap) Kaletra, see lopinavir + ritonavir NFV, see nelfinavir Norvir, see ritonavir NVP, see nevirapine PNU-140690* or tipranavir* Proleukin, see aldesleukin or interleukin-2 Remune,* see HIV-1 Immunogen* or Salk vaccine* or AG1661* Retrovir, see zidovudine Ritonavir (RTV), Norvir; also in Kaletra RTV, see ritonavir 11 Continued 547 Infectious Diseases TABLE 20-22 Impact of Treatments for HIV Infection (Continued) Drug Name* Type of Drug Adverse Effects of Significance for Dentists Co.† Saquinavir (SQV) (SGC) (soft gel cap), Fortovase PI Associated with liver damage, peripheral neuropathy, and oral ulcerations Do not use with the following medications: midazolam, triazolam, or ergotamine Avoid use with the following medications: clarithromycin, phenobarbital, carbamazepine dexamethasone, ketoconazole, itraconazole, or clindamycin 11 NRTI Peripheral neuropathy EI Not known 14 Tenofovir disoproxil fumarate* (TDF) NtRTI Not known 8 Tipranavir* or PNU-140690* PI Not known 4 SVX-175* or GW-433908* PI Associated with hyperglycemia, dygeusia, and paraoral tingling sensations Do not use with the following medications: midazolam, triazolam, ergotamine, tricyclic antidepressants, or vitamin E Avoid use with the following medications: erythromycin, benzodiazepine, or itraconazole 9 Zalcitabine or ddC, Hivid NRTI Associated with oral ulcerations, liver damage, and peripheral neuropathy 11 NRTI Associated with seizures, rapid uncontrollable eye movements, decreased coordination, liver damage, and peripheral neuropathy 9 SQV, see saquinavir Stavudine or d4T, Zerit 5 Sustiva, see efavirenz T-20* TDF*, see tenofovir disoproxil fumarate* Trizivir, see abacavir + zidovudine +lamivudine Videx, see didanosine or ddI Videx EC, see didanosine or ddI Viracept, see nelfinavir Viramune, see nevirapine ZDV, see zidovudine Zerit, see stavudine or d4T Ziagen, see abacavir Zidovudine (ZDV) or AZT, Retrovir; also in Combivir and Trizivir CI = cellular inhibitor; EI = entry inhibitor (also fusion inhibitor); IBT = immune-based therapy; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NtRTI = nucleotide reverse transcriptase inhibitor; PI = protease inhibitor. *Drug not approved by US Food and Drug Administration. †Pharmaceutical companies: 1-Abbott Laboratories; 2-Agouron Pharmaceuticals; 3-BioChem Pharma; 4-Boehringer Ingelheim ; 5-Bristol-Myers Squibb; 6-Chiron Corporation; 7-DuPont Pharmaceuticals; 8-Gilead Sciences; 9-Glaxo Wellcome; 10-Merck & Co.; 11-Roche Laboratories; 12-Sarawak Medichem; 13-Triangle Pharmaceuticals; 14- Trimeris. acute bacterial endocarditis if they are former intravenous drug users.171 Most side effects from medications used to treat HIV disease are associated with xerostomia. Drug interactions with medications commonly used in a dental setting also exist (see Table 20-22). Patients with HIV disease have been shown to survive longer and are therefore more susceptible to develop complications, particularly from drug side effects. A trend suggesting increased frequency of cardiovascular disease has been noticed and should be considered in patients who have taken protease inhibitors for long periods of time. Treatment planning for HIV-positive patients needs to address numerous considerations. The vast majority of patients have some degree of xerostomia, ranging from very mild to severe. Thus, when performing simple restorative pro- cedures or fabricating fixed or removable prosthodontics, the type of restorative material, long-term use, and maintenance of a restoration need to be taken into consideration. ORAL LESIONS There are no oral lesions that are unique to HIV-infected individuals. All lesions found among HIV-positive patients also occur with other diseases associated with immune suppression. It is therefore not surprising to find a clear correlation between the appearance of oral lesions and a decreased immune system. Several lesions such as oral candidiasis, oral hairy leukoplakia, necrotizing ulcerative periodontal disease, and Kaposi’s sarcoma are strongly suggestive of impaired immune response with CD4 cell counts below 200 cells/mm3.172–174 Using oral lesions for markers of immune 548 Principles of Medicine Date: Name and address of person permitted to disclose information: Personal and demographic data (including other care providers): ............................................................................................................................... Chief complaint: ............................................................................................................................... History of chief complaint: Name and address of individual or organization to which the disclosure is to be made: Past medical history (including last visit to primary care provider): ............................................................................................................................... HIV test with dates: ............................................................................................................................... First HIV test— Last negative HIV test— First positive HIV test— Name and address of patient: ............................................................................................................................... Reason for HIV test: ............................................................................................................................... Risk factor(s) for HIV: Purpose of disclosure: History of HIV disease (illnesses, signs and symptoms): CD4 cell count with dates: Initial count— Lowest count— Latest count— ............................................................................................................................... ............................................................................................................................... Information to be disclosed: ............................................................................................................................... ............................................................................................................................... Viral load and dates: Highest rate— Lowest rate— Latest rate— Complete blood cell count with a differential: I, ........................................................, hereby give my permission for the above mentioned individual and/or organization/hospital/clinic/laboratory to disclose pertinent medical records to the individual/organization listed above. I further understand that I may revoke this consent at anytime. Unless revoked earlier by me, this consent expires ......................................................................... Medications with dosage and schedules: Antiretrovirals— Anti-infectives— Patient signature: ..................................................... Date................................... Other— Witness signature: ................................................... Date................................... Allergies and drug sensitivity: Hepatitis (type and status): FIGURE 20-8 Consent for transmittal of HIV-related information. Sexually transmitted diseases (type and status): Tuberculosis (date of test[s] and present status): Tobacco use (history and present status): Alcohol use (history and present status): Recreational drug use (history and present status): FIGURE 20-7 HIV-relevant history questionnaire. suppression and HIV disease progression is important and can impact on medical intervention and treatment strategies. T-lymphocyte depletion renders affected individuals more susceptible to fungal infections, viral infections, and neoplastic growth. Some immune surveillance is also diminished, enabling bacterial infections to flourish. Thus, it is not surprising to find oral infections of these types in patients with HIV disease. Fungal Infections. Candidiasis. Intraoral candidiasis,175,176 which is mainly caused by Candida albicans, is the most common oral manifestation in patients with HIV disease. Although it is not in itself pathognomonic for HIV disease, oral candidiasis may be an indication of immune dete- Infectious Diseases 549 rioration.177 A tentative diagnosis of oral candidiasis is usually based on clinical appearance but should be confirmed by laboratory tests. These tests include cytologic smears with potassium hydroxide, biopsy for periodic acid–Schiff and Gram staining for tissue infiltration by spores and hyphae, or culture.178 In general, oral candidiasis has four different clinical presentations, as follows: 1. Pseudomembranous candidiasis, or thrush. This condition is a common type of oral candidiasis. It manifests as white or yellowish single or confluent plaques that can easily be rubbed off from the oral mucosa (Figure 20-9). It is found on all oral surfaces and may leave an erythematous or even bleeding underlying mucosa. Most patients are not aware of the presence of this form of candidiasis as pseudomembranous candidiasis is predominantly asymptomatic. The condition is noticed most commonly when CD4 cells counts drop below 400 cells/mm3. 2. Erythematous or atrophic candidiasis. This condition appears on any mucosal surface as a reddish macular lesion, atrophic patches, or depapillation on the dorsum of tongue (Figure 20-10). Erythematous candidiasis may be present alone or in combination with the pseudomembranous type. Patients may complain of an occasional burning sensation in the mouth. Long-standing lesions may even present as mucosal ulcerations. 3. Hyperplastic or chronic candidiasis. This form of candidiasis is relatively uncommon and is found mainly in persons who are severely immunocompromised. Hyperplastic candidiasis, manifesting as white or discolored plaques that may be solitary or confluent and cannot be wiped off the mucosa, may be confused with oral hairy leukoplakia when located on the tongue only (Figure 20-11). Complaints of a burning sensation, dysphagia, and a feeling of having a large piece of cotton in the mouth are not unusual. This type of oral candidiasis is often present with esophageal candidiasis. FIGURE 20-9 Pseudomembranous candidiasis (thrush) on the hard and soft palate in a patient with HIV disease. These white plaques can be wiped off, leaving an erythematous mucosa. FIGURE 20-10 Erythematous or atrophic candidiasis on the hard palate. These erythematous lesions are usually asymptomatic. 4. Angular cheilitis. This condition, which is predominantly a mixed infection involving C. albicans and Staphyloccocus aureus, manifests itself as red fissures originating from the labial commissures of the mouth (Figure 20-12). Angular cheilitis may be present with intraoral candidiasis. Concurrent oral dryness also is not uncommon. Angular cheilitis has been associated with vitamin B deficiency and decreased vertical dimension of occlusion from either periodontal disease or ill-fitting dentures. Therefore, it is important to address concurrent conditions as antifungal treatment is instituted. FIGURE 20-11 Hyperplastic or chronic candidiasis on the soft and hard palate of a severely debilitated HIV-infected patient. These lesions cannot be wiped off and do not respond well to topical antifungal medications. This type of candidiasis is almost exclusively seen in patients with extremely low CD4 cell counts and diminished salivary flow. 550 A Principles of Medicine B FIGURE 20-12 A, Angular cheilitis is commonly caused by Candida albicans. This lesion usually manifests with an ulcer at the corner of the mouth, with erythematous fissures radiating from the ulcer. A pseudomembrane sometimes covers the ulcers. B, Treatment with topical antifungal medications and antibiotics, for bacterial superinfections, is usually efficacious. Treatment of oral candidiasis includes topical and systemic antifungal medications. Appropriate treatment should be instituted to reduce symptoms ranging from localized discomfort to significant dysphagia. Topical therapies include mouth rinses, troches, ointments, and creams. These formulations should be used concurrently with systemic agents to resolve the infection when there is a risk of esophageal candidiasis. Since there is a high sucrose content in these preparations, which predisposes patients to develop dental caries, a strict oral hygiene program and daily flouride treatment should be instituted while the patient is taking topical antifungal medications. Topical antifungal therapies are most efficacious in patients with CD4 counts above 150 to 200 cells/mm3. In patients with atrophic candidiasis, troches should be used with care since they may aggravate existing ulcerations through mechanical abrasion against the lesions.179 Common topical treatments include nystatin oral suspension (100,000 units/mL; 10 mL swished and swallowed four to five times per day) and nystatin troche (dissolved in the mouth four to five times per day). Ointments and creams such as 1% clotrimazole ointment, 2% ketoconazole cream, or nystatin cream are efficacious in treating angular cheilitis. The efficacy of systemic antifungal medications may be significantly reduced by impaired gastric acid secretion and by drug interactions with medications such as rifampin. Furthermore, there exists a potential for liver toxicity that needs to be addressed. Common systemic antifungals include ketoconazole (200 mg tablets; one tablet twice a day with food), fluconazole (100 mg tablets; 200 mg on day 1, followed by 100 mg daily for 14 days),4 and itraconazole (100 mg tablets; 200 mg daily with food). Resistance to fluconazole has been reported to occur in patients with severe immune deficiency. Treatment of patients who are resistant to fluconazole with a combination of fluconazole and terbinafine has been successful.180 It is also possible to increase the fluconazole dosage to 600 to 700 mg/d in order to improve efficacy. Another approach to treat fluconazole-resistant fungal infections is to add a topical medication such as clotrimazole troches. This is successful if the resistance is owing to the emergence of Candida krusei, a species resistant to fluconazole but susceptible to clotrimazole. Protease inhibitor therapy has been associated with a decreased incidence of oral candidiasis.177,181 This is owing mainly to improved immune status but may also be a direct result of the protease inhibitors. Deep-Seated Infections. Intraoral manifestations of deepseated fungal infections, caused by Cryptococcus neoformans, Histoplasma capsulatum, Geotrichum candidum, and Aspergillus spp, are uncommon and are usually an indication of a disseminated disease.182,183 Intraoral lesions associated with cryptococcosis, histoplasmosis, and aspergillosis have been reported as being ulcerative, nodular, or necrotic in nature, whereas geotrichosis lesions are described as being pseudomembranous. Since oral lesions of this category are nonspecific, definitive diagnosis requires histologic verification. Treatment of these lesions is usually reserved for intravenous amphotericin B. Viral Infections. Although there are no specific oral lesions caused by HIV infection, a patient can display oral manifestations as an early sign of HIV infection. Such oral symptoms may include nonspecific oral ulcerations, sore throat, exudative pharyngitis, and oral candidiasis during the initial acute infection state.179 These nonspecific manifestations disappear after the acute phase. Herpesvirus. Oral herpes simplex virus (HSV) presents both as a local and a disseminated infection. The presence of intraoral HSV-associated lesions is usually the result of recurrent infections caused by reactivation of latent viruses. This lesion is not specifically related to HIV; it is also a fairly common occurrence among non-HIV infected individuals. However, Infectious Diseases HSV infections among immunocompromised individuals may be more severe and manifest differently than what is noticed in immunocompetent patients. Although ulcerations caused by HSV-1 and HSV-2 are clinically indistinguishable, HSV-1 is more frequently associated with oral lesions. However, oral lesions caused by HSV-2 appear to have a higher recurrence rate and are associated with a higher incidence of resistance to acyclovir.164 HSV in the oral cavity manifests as single or coalescent crops of vesicles with subsequent ulceration and healing. The ulcers are small, shallow, and round to elliptical. In general, recurrent HSV infections occur primarily on more keratinized epithelium such as the gingiva. However, there are numerous reports of oral ulcerations caused by HSV infections on nonkeratinized epithelium in HIV-infected patients. HSVassociated ulcerations are usually accompanied by increased pain during the acute stage, which can affect an individual’s nutritional intake. These ulcerations tend to heal in 7 to 10 days, although this may be extended in immunocompromised patients. In this particular patient population, lesions tend to be larger and occur with increased frequency. Furthermore, in these patients, recurrent HSV may exhibit clinical signs and symptoms that are similar to those of primary HSV infection, such as malaise, cervical lymphadenopathy, and intensely painful linear gingival erythema.164 Oral manifestations of HSV can be mistaken for other viral infections such as Cytomegalovirus and varicella-zoster virus, infection or for aphthous ulcers, and a definitive diagnosis should be made based on the clinical history and laboratory tests, such as cytologic staining for Tzanck cells, viral culture from the ulcer, biopsy, or HSV-1 detection via monoclonal-antibody testing. Treatment for HSV-1 infections usually consists of acyclovir (200 mg orally five times daily). Although famciclovir can also be used, valacyclovir is a poor alternative because it may cause severe side effects in immunocompromised patients. Foscarnet may be used for resistant infections.184 Cytomegalovirus. Oral manifestation of Cytomegalovirus (CMV) infection is only observed in patients with CD4 counts below 100 cells/mm3. Lesions associated with CMV are nonspecific ulcerations that usually appear as a single ulcer, without preceding vesicles, on any oral mucosal tissue. These ulcers are painful and tend to heal poorly. Differential diagnosis should include recurrent aphthous ulcers and HSV-associated lesions. A definitive diagnosis must include a biopsy specimen that shows basophilic intranuclear inclusions of CMV, or CMV identification via monoclonal-antibody assay or in situ hybridization.185 A recommended regimen for intraoral lesions is high-dose acyclovir therapy (800 mg orally five times a day) for a minimum of 2 weeks. Oral manifestations of CMV may be associated with disseminated disease, and the patient needs to be evaluated for ophthamologic and other CMVassociated diseases once an oral diagnosis is confirmed.186 Epstein-Barr Virus. Epstein-Barr virus (EBV) infections have been associated with numerous manifestations, including 551 infectious mononucleosis, Burkitt’s lymphoma, nasopharyngeal carcinoma, and oral hairy leukoplakia. Oral hairy leukoplakia was initially described in individuals with HIV disease, but it has since been found in many other patient populations. This lesion may be present in all phases of HIV disease, but it is most commonly found in individuals with CD4 cell counts below 200 cells/mm3. It manifests as an asymptomatic white lesion, most frequently with vertical hyperkeratotic striae that are usually seen on the lateral borders of the tongue187 (Figure 20-13). The lesion may vary from linear striae to white patches that cannot be wiped off, and they often have white hyperkeratotic hairlike projections. Because of its clinical characteristics, differential diagnosis should include hyperplastic candidiasis. Although it is not thought that Candida albicans contributes to the clinical appearance of oral hairy leukoplakia, C. albicans may be present in more than 50% of oral hairy leukoplakia lesions. When definitive diagnosis of oral hairy leukoplakia needs to be established, it is necessary to verify the presence of EBV in the superficial layers of the involved epithelium. Owing to the significant association between this lesion and HIV, a biopsy is necessary to rule out oral hairy leukoplakia in patients yet to be tested for HIV. In HIV-positive individuals, an empiric diagnosis can be inferred when a clinical lesion resembling oral hairy leukoplakia does not respond to antifungal medications. It is important to assure the patient that the presence of oral hairy leukoplakia has not been associated with person-toperson transmission of EBV. Treatment of this lesion usually is not indicated unless the patient complains of esthetic disfiguration or masticatory functional impairment. Antiviral therapy (acyclovir 800 mg orally five times a day) is effective to achieve resolution of the FIGURE 20-13 Oral hairy leukoplakia is an asymtomatic white lesion, caused by Epstein-Barr virus, that is usually found on the tongue. It is rare to find this lesion on other sites in the oral cavity. The lateral borders of the tongue are most commonly affected. 552 lesion within 2 weeks. Prophylactic therapy with 800 mg acyclovir per day may be necessary to prevent recurrence. Varicella-Zoster Virus. There have been reports of increased incidence of human varicella-zoster virus (HZV) infections among HIV-infected persons, relative to increased age and degree of immunosuppression. Complications associated with HZV in immunocompromised patients are common and can be severe, especially for those individuals with CD4 counts fewer than 200 cells/mm3.188 Clinically, oral HZV infection presents as vesicles that quickly rupture, resulting in ulcerations. The ulcers are multiple, shallow, and small, with an erythematous base, and are characteristically distributed unilaterally along a division of the fifth cranial nerve. Patients frequently complain of pain, neuropraxia, and tenderness. Although clinical presentation is distinct for HZV infection, a definitive diagnosis should be confirmed by laboratory tests such as histologic staining for multinucleated giant cells with intranuclear inclusions, direct immunofluorescence, and cytology smears taken from the lesion. Treatment usually is focused on supportive care and is centered on the prevention of postherpetic neuralgia and dissemination. High doses of oral acyclovir (800 mg orally five times a day), famciclovir (500 mg orally three times a day), or valacyclovir (500 mg orally three times a day) have been efficacious in treating HZV infection. Caution is needed when using valacyclovir in severely immunosuppressed patients as this medication has been associated with hemolysis in this particular patient population. For greatly immunosuppressed patients, intravenous acyclovir therapy may be more appropriate. Foscarnet also may be useful for acyclovir-resistant herpes zoster.189 It has been reported that there are high incidences of herpes zoster in patients shortly after they start treatment with protease inhibitors, which might suggest a need for prophylaxis for those at increased risk for developing herpes zoster infection.190 A Principles of Medicine Human Herpesvirus 8. Recently, human herpesvirus 8 (HHV8) has been linked to the etiology of Kaposi’s sarcoma (KS).191 Most intraoral KS lesions are found on the hard and soft palates, manifesting as red-blue or purple-blue macules or nodules (Figure 20-14). The lesions are initially asymptomatic, but due to trauma and secondary ulcerations, they can become symptomatic as they get larger in size. Large lesions may interfere with the individual’s ability to speak, swallow, and masticate. Lesions on the gingiva and tongue are also common; however, extrapalatal lesions are associated with a more rapid progression of KS, as well as HIV disease. Oral KS is usually seen in patients with CD4 counts below 200 cells/mm3 but can be seen in all stages of HIV disease. The macular lesions can be confused with physiologic pigmentation; a differential diagnosis should also include bacillary (epithelioid) angiomatosis, lymphoma, and trauma.192 As KS is an AIDS-defining lesion, a definitive diagnosis requires a biopsy. Treatment for KS includes radiation (800 to 2,000 rad), surgical excision, and intralesional injections with chemotherapeutic agents such as vinblastine sulfate (0.1 mg/mm2 ) or sodium tetradecyl sulfate (0.1 mg/mm2 ). Intralesional injections are most effective for small nodular lesions and as an adjuvant to radiation. It is important to realize that most of these treatments do not result in a cure but are used to reduce the size and number of lesions.193 Recent studies show some efficacy with antiangiogenesis agents, such as thalidomide, and oral 9-cis retinoic acid.194 No antiherpetic medications have shown any benefit as prophylaxis or treatment for KS. Human Papillomavirus. Oral manifestations with papillomaviruses are similar to human papillomavirus (HPV) infections at other sites. Infections with HPV may cause different distinct appearances, including oral squamous cell papilloma, verruca vulgaris, focal epithelial hyperplasia, and condyloma acuminatum (Figure 20-15). Each lesion has a specific expression of an identified HPV genotype. Oral B FIGURE 20-14 A, Initial lesions of Kaposi’s sarcoma are usually found on the hard and soft palates. These lesions are commonly bluish-red macules. B, Long-standing palatal lesions may become nodular and even ulcerative. 553 Infectious Diseases A B FIGURE 20-15 Human papillomavirus has become more common in individuals whose immune system is undergoing changes, such as reconstitution after severe CD4 cell depletion. Florid lesions may affect the lips (A) and intraoral mucosa (B). squamous cell papillomas may present as exophytic pedunculated papules with a cauliflower-like appearance. Verruca vulgaris (the common wart) is a firm, sessile, exophytic, and whitish lesion. This form of HPV presentation also has a hyperkeratinized superficial epithelium with a slight invagination of the center of the lesion. Focal epithelial hyperplasia (Heck’s disease) may present as a single or multiple, smooth or pebble-like, hyperplastic leukoplakic lesion. Focal epithelial hyperplasia is commonly found on keratinized tissues such as the alveolar mucosa and the lips. Condyloma acuminatum presents as small white-to-pink nodules with a pebbled surface and is most commonly found on the soft and hard palates and the tongue.195 The presence of HPVassociated lesions is not pathognomonic for HIV infection or progression. However, an increase in the prevalence of oral HPV infections among HIV-infected persons has been reported since the introduction of protease inhibitors. Although most of oral HPV manifestations are asymptomatic, unless lesions are induced by trauma, they can interfere with mastication and may raise cosmetic concerns. Treatments for HPV include surgical removal, laser ablation, cryotherapy, and topical application of keratinolytic agents. For smaller lesions, topical application of 25% podophyllum resin may be used to reduce the size. A more novel approach has been the use of intralesional injection of antiviral agents. Interferon-α in intralesional injections (1,000,000 IU/cm2 once weekly) and subcutaneous injections (3,000,000 IU/cm2 twice weekly) have been shown to be effective in long-term resolution of lesions.196 Bacterial Infection. Periodontal Disease. The most common oral manifestations of bacterial origin are associated with periodontal conditions. These conditions are usually categorized by their clinical appearance and include linear gingival erythema (LGE), necrotizing ulcerative gingivitis (NUG), and necrotizing ulcerative periodontitis (NUP). It has also been noted that HIV-seropositive patients with previous periodontal disease may show faster rates of conventional periodontal deterioration as compared with those of HIV-seronegative persons. Lamster and colleagues have suggested that the progression of periodontal disease in HIVinfected persons is dependent on the immunologic competency of the host and local host response to typical and atypical microorganisms related to periodontal disease.197 Thus, the level of immune suppression, as demonstrated by decreasing number of T-cell lymphocytes, in combination with the degree of plaque accumulation, may explain these conditions in HIV-infected patients.173 Linear gingival erythema is an atypical gingivitis that is depicted as a 2 to 3 mm distinct band of fiery redness at the marginal gingiva around the teeth (Figure 20-16). Such erythema is not proportional to the plaque accumulation and seems to only affect the soft tissue, without any ulcerations, increased pocket depths, or any attachment loss. Patients with this condition are usually asymptomatic. The true prevalence of LGE is difficult to determine due to variable diagnostic criteria that have been put forth. Differential diagnosis should include a localized erythema due to dry mucosa associated with mouth breathing, lichen planus, mucous membrane pemphigoid, or an allergic reaction. The most recent theory regarding the pathogenesis of this lesion implicates subgingival candida infection as a possible cause.197 FIGURE 20-16 Linear gingival erythema of the gingival margin. 554 Treatments include improved oral home care and conventional dental scaling and root planing, along with the use of chlorhexidine gluconate (0.12%) mouth rinses (15 mL swished and expectorated twice a day) for up to 3 months. Additionally, concomitant use of topical antifungal medications may be beneficial. Manifestations of NUG and NUP are triggered by changes in the immune status, most probably aggravated by intraoral bacteria. The two entities may present as a continuum of the same disease but also may appear as separate entities. NUG is limited to the gingiva (Figure 20-17), whereas NUP is characterized by localized to generalized aggressive alveolar bone and attachment destruction (Figure 20-18). Occurrence of NUG has been associated with stress, anxiety, malnutrition, and smoking. Patients with NUG complain of spontaneous gingival bleeding and mild to moderate gingival pain. NUP is associated with complaints of deep-seated bone pain, spontaneous gingival bleeding, halitosis, and tooth mobility. Clinically, these conditions are presented with initial lesions of limited craterlike necrosis of gingival papillae. When untreated, NUP may progress at a rate of 1 to 2 mm of soft- and hard-tissue destruction per week. NUP is mostly seen with severe immune suppression, with CD4 counts below 100 cells/mm3.173 A definitive diagnosis is based on clinical evaluation and radiologic evaluation with panoramic radiographs or specific periapical dental radiographs. Specific laboratory tests may be needed to rule out conditions and lesions such as bullous lesions of benign mucous membrane pemphigoid, erythema multiforme, acute forms of leukemia, and major aphthous ulceration. Treatment for both NUG and NUP consists of débridement of necrotic soft and hard tissue, antibiotic therapy with metronidazole or tetracycline (500 mg four times a day) for a week, and a follow-up with scaling and débridement.173 Due to the high risk for fungal infections in these patients, an antifungal regimen may be prescribed together with the antibiotics. Chlorohexidine gluconate (0.12%) mouth rinses are recommended as maintenance therapy. Metronidazole should be used with caution in patients who are taking lopinavir and retonavir. FIGURE 20-17 Necrotizing ulcerative gingivitis localized to the lower first and second molars. Principles of Medicine Tuberculosis. Intraoral lesions associated with TB may present as single nonhealing caseating granulomatous ulcerations that are accompanied by deep-seated pain. The lesions have been noted on the tongue, the palate, the buccal mucosa, and the angles of the mouth.198 Diagnosis by clinical presentation alone is difficult and needs to be complemented with demonstration of acid-fast TB bacilli within the lesion.199 Treatment is locally palliative as an adjunct to systemic TB therapy. Syphilis. Clinical presentation of syphilis includes chancres, snail-track ulcers, and gumma formation.200 Chancres are mostly asymptomatic indurated ulcers with a brown crusted appearance that are usually seen on the lips, oral mucosa, tongue, palate, and posterior pharyngeal wall. Secondary syphilis is characterized by highly infectious mucosal ulcers with an appearance of white lesions surrounded by an erythematous base. Frank ulceration is most common in tertiary syphilis as a result of gummatous destruction. It is usually seen on the palate and tongue. Differential diagnosis should include herpetic cold sores, deep-seated fungal infections, mycobacteria-associated ulcer, malignant ulcers, and trauma. A definitive diagnosis is made by dark-field microscopy that demonstrates the etiologic agent, Treponema pallidum. Treatment is based on appropriate systemic antibiotic therapy. Nonspecific Ulcerations. Necrotizing Stomatitis. Necrotizing stomatitis is a localized acute painful ulcerative lesion on mucosal surfaces overlying bone (Figure 20-19). This condition eventually leads to necrosis of tissue and subsequent bone exposure. No specific microbial agent or mechanism has been linked to its etiology. This condition is seen in patients with CD4 cells fewer than 100 cells/mm3.168 Differential diagnosis includes aphthous ulcer and NUP. Treatment consists of careful débridement, local or systemic steroid therapy, antibiotics, and institution of a soft-tissue stent to protect the affected area from further trauma and for delivery of topical medications.201 Aphthous Ulcers. Recurrent aphthous ulcerations (RAUs) are idiopathic oral ulcerations. There are three disease entities of RAUs: minor, major, and herpetiform. Diagnosis of RAUs is a diagnosis of exclusion; the clinical impression should be confirmed with histologic examination and by response to treatment.179 Minor (recurrent) aphthous ulcerations are smaller than 10 mm in diameter, well-circumscribed, round, sometimes covered by a yellow-gray pseudomembrane, and surrounded by an erythematous halo. The erythematous halo may be absent in severely immunocompromised patients due to their lack of an intact inflammatory response. Minor aphthous ulcerations are usually confined to the nonkeratinized oral mucosa and tend to recur, often at the same site. Their duration is about 1 to 2 weeks, and healing occurs without scarring. Minor aphthous ulcerations are prevalent in both non–HIVinfected populations and HIV-infected populations. 555 Infectious Diseases FIGURE 20-18 Necrotizing ulcerative periodontitis of the lower anterior region. A, Both gingival and alveolar bone are affected. B, Submandibular lymphadenopathy can also be present. A Differential diagnosis includes recurrent HSV infection. Treatment is focused to provide symptomatic relief. An analgesic mouth rinse, such as 2 to 4% viscous lidocaine solution (10 mL swished and expectorated), is most commonly instituted for relief. Major (recurrent) aphthous ulcerations are larger than 10 mm in diameter, well-circumscribed, round, and shallow or deep with indurated margins (Figure 20-20). A gray pseudomembrane covering the lesion may sometimes be present. Major aphthous ulcerations can occur on any area of the oral mucosa. They are usually single ulcerations, but in immunosuppressed individuals, groups of up to 10 lesions have been observed. These ulcers tend to persist for more than 3 weeks and to heal with a scar formation. In patients with FIGURE 20-19 Necrotizing stomatitis on the palatal area of the upper first and second molars. B HIV, major aphthous ulcers have been associated with severe immune suppression, with CD4 counts below 100 cells/mm3, and are markers for HIV disease progression.202 Treatment for major aphthous ulcerations includes administration of systemic corticosteroids. Topical formulations of clobetasol or fluocinonide gel applied directly to the lesion, dexamethasone elixir mouth rinses (0.5 mg/5 mL), and systemic administration of 60 to 80 mg of prednisone per day for 10 days have been used successfully. For steroid-resistant patients, alternative therapy of 100 to 200 mg thalidomide may be used. Thalidomide needs to be used with caution because of its severe adverse side effects. However, despite its severe side effects, thalidomide has been used with some success to treat both oral and esophageal ulcerations. Refractory cases may be treated with other agents including colchicine or levamisole.203 Antibiotics and antifungal agents may be used concurrently when appropriate to prevent bacterial or fungal superinfections. Herpetiform ulcers are the least common type of aphthous ulcers. These ulcers are pinpoint (smaller than 1 mm in diameter) and round, with perilesional erythema. They are usually found in batches of up to 100, appearing on nonkeratinized mucosa such as the ventral surface of the tongue and soft palate. Healing occurs without scarring. Treatments are similar to those for minor aphthous ulcers and include symptomatic relief, suppression of the local pathologic immune reaction, and treatment of any concomitant superinfection. Drug-Induced Ulcerations. Several medications that are frequently used for HIV-infected patients have been associated with the development of oral ulcerations.204–206 These medications include zidovudine, zalcitabine, foscarnet, interferon, and ganciclovir.207 Drug-induced ulcerations are mainly seen on nonkeratinized mucosa, but they tend to affect keratinized mucosa in more severely immunocompromised patients. 556 Principles of Medicine A FIGURE 20-20 B A, Major aphthous ulcer in the retromolar region in an HIV-infected patient. B, The same major aphthous ulcer, after treatment. Certain antiretroviral therapies induce neutropenia and are thereby linked to the occurrence of oral ulcerations. Administration of a growth factor such as granulocytemacrophage colony-stimulating factor has shown to be successful in resolving ulcerations associated with neutropenia.208 Xerostomia. Xerostomia, or dry mouth, is a subjective symptomatic complaint that is frequently noted by HIV-infected patients. It has been reported that reduced salivary flow occurs in 2 to 10% of HIV-infected individuals.207 However, the true prevalence is 80 to 90% of all patients taking HAART. The effect of oral dryness on quality of life is profound, and many patients with severe xerostomia sometimes opt to change or stop their antiretroviral medications in order to regain better salivary functions. The most common cause of decreased salivary flow in HIVinfected patients is side effects of pharmocotherapeutic agents. Many medications, such as antiretroviral medications (including nucleoside transcriptase inhibitors, protease inhibitors) as well as antihistamines, anticholinergics, antihypertensives, decongestants, narcotic analgesics, and tricyclic antidepressants, have been associated with xerostomia. In addition, xerostomia may be a result of HIV-associated salivary gland disease in this population. The parotid glands are most frequently affected; however, minor salivary glands can also be affected by viral infection such as with CMV.209 Another cause of reduced salivary flow is radiation therapy to the head and neck area, causing functional impairment of salivary glands in the radiated area. Treatment for xerostomia focuses on symptomatic relief by encouraging patients to hydrate themselves frequently and to minimize the intake of caffeine and alcohol, which act as diuretics. Patients are also recommended to use commercially available artificial saliva substitutes (Xero-lube, Sali-synt, Moistir, Orex) to achieve relief. The use of pilocarpine and bethanechol to stimulate salivary flow can also be useful. Ultimately, discontinuation or substitution of xerostomiainducing drugs may be necessary. Oral Lesions in the Pediatric Population. HIV-infected children may also develop a spectrum of oral lesions. These lesions can affect children more severely than adults and can be a significant source of pain with subsequent limitation of oral intake of nutrition and medications. The most common oral manifestation in immunocompromised children is candidiasis.210 The presence of oral candidiasis in HIV-infected infants, as well as other clinical symptoms, is used as a clinical marker for disease progression in a prognosis-based clinical staging system. Clinical presentation of oral candidiasis in the pediatric population is similar to that of the adult population. Some reports suggest that erythematous candidiasis is more common than the pseudomembranous type in HIV-infected children.211 A definitive diagnosis should be accompanied by laboratory tests, as described previously. Both topical and systemic treatment with antifungal medications can be used to treat oral candidiasis. Several reports have shown that there are subtypes of Candida that are isolated in candidal lesions.211,212 Therefore, it is not unreasonable to determine a specific subtype of Candida and to select a specific antifungal agent directed toward the subtype. A report has shown that fluconazole suspension (6 mg/kg loading dose followed by 3 mg/kg/d) has been highly effective and is superior to routine nystatin rinses.213 In children who are fed by bottle, it is possible to place the antifungal medication inside the nipple, as well as to cover the nipple with a thin layer of topical medication. Several of the medications used by children are made to taste better by the addition of sugar formulations, which also make them syrupy and sticky. It is advisable to have children rinse their mouths with water after administration of these medications in order to reduce the incidence of tooth decay. Infectious Diseases ▼ REFERENCES 1. Burnet M. Natural history of infectious disease. Cambridge: Cambridge University Press; 1962. 2. Institute of Medicine. Emerging infections: microbial threats to health in the United States. Washington: National Academy Press; 1992. 3. Centers for Disease Control and Prevention. Achievements in public health, 1990–1999: control of infectious diseases. MMWR Morb Mortal Wkly Rep 1999;48:621–9. 4. Centers for Disease Control and Prevention. Tuberculosis and acquired immunodeficiency syndrome—Florida. MMWR Morb Mortal Wkly Rep 1986; 35:587. 5. Centers for Disease Control and Prevention. Tuberculosis morbidity in the United States: final data, 1990. MMWR Morb Mortal Wkly Rep 1991;40(SS-3):23. 6. Bernardo J. Tuberculosis: a disease of the 1990’s. Hosp Pract 1991;26:195. 7. Centers for Disease Control and Prevention. Tuberculosis morbidity—United States, 1997. MMWR Morb Mortal Wkly Rep 1998;47:253. 8. American Thoracic Society. Control of tuberculosis in the United States. Am Rev Respir Dis 1992;146:1623. 9. Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis incidence and mortality during 1990–2000. Bull World Health Org 1994;72:213. 10. World Health Organization. Report on the tuberculosis epidemic. Geneva, Switzerland: WHO; 1997. 11. Centers for Disease Control and Prevention. Summary of notifiable diseases—1998. MMWR Morb Mortal Wkly Rep 1999;47:70. 12. Centers for Disease Control and Prevention. World TB day— March 24, 2001. MMWR Morb Mortal Wkly Rep 2001;50:201. 13. Centers for Disease Control and Prevention. Core curriculum on tuberculosis. 3rd ed. Atlanta: US Department of Health and Human Services; 1994. 14. Bates JH, Stead WW. The history of tuberculosis as a global epidemic. Med Clin North Am 1993;77:1205. 15. Orme IM, Anderson P, Boom WH. T cell response to Mycobacterium tuberculosis. J Infect Dis 1993;167:1481. 16. Ellner JJ. The immune response in human tuberculosis: implications for tuberculosis control. J Infect Dis 1997;176:1351. 17. Mani NJ. Tuberculosis initially diagnosed by asymptomatic oral lesions. J Oral Med 1985;40:39. 18. Molinari JA, Chandrasekar PH. Mycobacteria. In: Willett NP, White RR, Rosen S, editors. Essential dental microbiology. Norwalk: Appleton and Lange; 1991. p. 181. 19. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989;320:545. 20. Reider HL, Jereb JA, Frieden TR, et al. Epidemiology of tuberculosis in the United States. Epidemiol Rev 1989;11:79. 21. Theuer CP, Hopewell PC, Elias D, et al. Human immunodeficiency virus infection in tuberculosis patients. J Infect Dis 1990;162:8. 22. Small PM, Schecter GF, Goodman PC, et al. Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 1991;324:289. 23. Barnes PF, Bloch AB, Davidson PT, et al. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991;324:1644–50. 557 24. Styblo K. Recent advances in epidemiological research in tuberculosis. Adv Tuberc Res 1980;20:1. 25. Van Scoy RE, Wilkowske CJ. Antituberculous agents. Mayo Clin Proc 1992;67:179. 26. Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance: recommendations of the Advisory Council for the Elimination of Tuberculosis. J Am Med Assoc 1993;270:696. 27. Cohen ML. Epidemiology of drug resistance: implications for a post-antimicrobial era. Science 1992;257:1050. 28. Frieden TR, Sterling T, Pablos-Mendez A, et al. The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 1993;328:521. 29. Shearer BG. MDR-TB: another challenge from the microbial world. J Am Dent Assoc 1994;125:43. 30. Raviglione MC, Dye C, Schmidt S, et al. Assessment of worldwide tuberculosis control. WHO global surveillance and monitoring project. Lancet 1997;350:624. 31. Luelmo F. BCG vaccination. Am Rev Respir Dis 1982;125:70. 32. Jacobs JR Jr. Advances in mycobacterial genetics: new promises for old diseases. Immunobiol 1992;184:147. 33. Cleveland JL, Gooch DF, Bolyard EA, et al. TB infection control recommendations from the CDC, 1994: considerations for dentistry. J Am Dent Assoc 1995;126:593. 34. US Department of Health and Human Services, Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare facilities. MMWR Morb Mortal Wkly Rep 1994;43(RR-13):1. 35. Field MJ, editor. Tuberculosis in the workplace. Washington (DC): National Academy Press; 2001. 36. Fraser DW, Tsai TR, Orenstein W, et al. Legionnaires’ disease: description of an epidemic of pneumonia. N Engl J Med 1977;297:1189. 37. Centers for Disease Control and Prevention. Follow-up on respiratory illness—Philadelphia. MMWR Morb Mortal Wkly Rep 1977; 26:9. 38. McDade JE, Shepard CC, Fraser DW, et al. Legionnaires’ disease: isolation of a bacterium and demonstration of its role in other respiratory disease. N Engl J Med 1977;297:1197. 39. Brenner DJ, Steigerwalt AG, McDade JE. Classification of the legionnaires’ disease bacterium: Legionella pneumophila, genus novum, species nova, of the family Legionellaceae, family nova. Ann Intern Med 1978;90:656. 40. McDade JE, Brenner DJ, Bozeman FM. Legionnaires’ disease bacterium isolated in 1947. Ann Intern Med 1979;90:659. 41. Rowbotham TJ. Current views on the relationship between amoebae, legionellae, and man. Isr J Med Sci 1986;22:1218. 42. Rowbotham TJ. Isolation of Legionella pneumophila from clinical specimens via amoebae, and the interaction of those and other isolates with amoebae. J Clin Pathol 1983;36:978. 43. Stout JE, Yu VL, Best M. Ecology of Legionella pneumophila within water distribution systems. Appl Environ Microbiol 1985;49:221. 44. Muder R, Yu VL, Woo A. Mode of transmission of Legionella pneumophila: a critical review. Arch Intern Med 1986;146:1607. 45. Johnson JT, Yu VL, Best M, et al. Nosocomial legionellosis uncovered in surgical patients with head and neck cancer: implications for epidemiologic reservoir and mode of transmission. Lancet 1985;2:298. 46. Stout JE, Yu VL, Muraca ME, et al. Potable water as a cause of sporadic cases of community-acquired pneumonia. N Engl J Med 1992;326:151. 558 47. Shands K, Ho J, Meyer R, et al. Potable water as a source of legionnaires’ disease. J Am Med Assoc 1985;253:1412. 48. Stout JE, Yu VL, Muraca P. Legionnaires’ disease acquired within the homes of two patients: link to the home water supply. J Am Med Assoc 1987;257:1215. 49. Kaufman AF, McDade J, Patton C, et al. Pontiac fever: isolation of the etiologic agent (Legionella pneumophila) and demonstration of its mode of transmission. Am J Epidemiol 1981;114:337. 50. Fotos PG, Westfall HN, Snyder IS, et al. Prevalence of Legionella–specific IgG and IgM antibody in a dental clinic population. J Dent Res 1985;64:1382. 51. Reinthaler FF, Mascher F, Stunzer D. Serological examinations for antibodies against Legionella species in dental personnel. J Dent Res 1988;67:942. 52. Yu VL. Legionella pneumophila (legionnaires’ disease). In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 5th ed. Churchill Livingstone; 2000. p. 2424. 53. Centers for Disease Control and Prevention. Sustained transmission of nosocomial legionnaires’disease—Arizona and Ohio. MMWR Morb Mortal Wkly Rep 1997;46:416. 54. Lowry PW, Tompkins LS. Nosocomial legionnellosis: a review of pulmonary and extrapulmonary syndromes. Am J Infect Control 1993;21:21. 55. Kirby BD, Snyder KM, Meyer RD, et al. Legionnaires’ disease: report of sixty-five nosocomially-acquired cases and review of the literature. Medicine 1980;59:188. 56. Seu P, Winston DJ, Olthoft KM, et al. Legionnaires’ disease in liver transplant recipients. Infect Dis Clin Pract 1993;2:109. 57. Singh N, Muder RR, Yu VL, et al. Legionella infection in liver transplant recipients: implications for management. Transplantation 1993;56:1549. 58. Tyzzer EE. A sporozoan found in the peptic glands of the common mouse. Proc Soc Exp Biol Med 1907;5:12. 59. Nime FA, Burek JD, Page DL, et al. Acute gastroenterocolitis in a human being infected with the protozoan Cryptosporidium. Gastroenterol 1976;70:592. 60. Current WL. Human cryptosporidiosis. N Engl J Med 1983;309:1325. 61. Peterson C. Cryptosporidiosis in patients infected with the human immunodeficiency virus. Clin Infect Dis 1992;15:903. 62. Laughon BE, Druckman DA, Vernon A, et al. Prevalence of enteric pathogens in homosexual men with and without acquired immunodeficiency syndrome. Gastroenterol 1988;94:984. 63. Smith PD, Lane HC, Gill VJ, et al. Intestinal infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1988;108:328. 64. Pederson C, Danner S, Lazzarin A, et al. Epidemiology of cryptosporidiosis among European AIDS patients. Genitourin Med 1996;72:128. 65. Vakil NB, Schwartz SM, Buggy BP, et al. Biliary cryptosporidiosis in HIV-infected people after the waterborne outbreak of cryptosporidiosis in Milwaukee. N Engl J Med 1996;334:19. 66. Haas CN, Rose JB. Reconciliation of microbial risk models and outbreak epidemiology: the case of the Milwaukee outbreak. Proc Am Water Works Assoc 1994;517. 67. Fricker C, Crabb J. Waterborne cryptosporidiosis: detection methods and treatment options. Adv Parasitol 1998;40:242. Principles of Medicine 68. MacKenzie WR, Hoxie NJ, Proctor ME, et al. A massive outbreak in Milwaukee of Cryptosporidium infection transmitted through the public water supply. N Engl J Med 1994;331:161. 69. Hayes EB, Matte TD, O’Brien TR, et al. Large community outbreak of cryptosporidiosis due to contamination of a filter public water supply. N Engl J Med 1989;320:1372. 70. McAnulty JM, Fleming DW, Gonzalez AH. A community-wide outbreak of cryptosporidiosis associated with swimming at a wave pool. J Am Med Assoc 1994;272:1597. 71. Goldstein ST, Juranek DD, Ravenholt O, et al. Cryptosporidiosis: an outbreak associated with drinking water despite state-of-theart water treatment. Ann Intern Med 1996;124:459. 72. Newman RD, Zu S-X, Wuhib T, et al. Household epidemiology of Cryptosporidium parvum infection. Ann Intern Med 1994;120:500. 73. Cordell RL, Addiss DG. Cryptosporidiosis in child care settings: a review of the literature and recommendations for prevention and control. Pediatr Infect Dis 1994;13:311. 74. Koch RL, Phillips DJ, Aber RC, et al. Cryptosporidiosis in hospital personnel. Ann Intern Med 1985;102:593. 75. Miron D, Kenes J, Dagan R. Calves as a source of an outbreak of cryptosporidiosis among young children in an agricultural closed community. Pediatr Infect Dis 1991;10:438. 76. Millard PS, Gensheimer KF, Addiss DG, et al. An outbreak of cryptosporidiosis from fresh-pressed apple cider. J Am Med Assoc 1994;272:1592. 77. Ungar BLP. Cryptosporidium. In: Mandell GL, Bennett JE, Dolan R, editors. Principles and practice of infectious diseases. 5th ed. New York: Churchill Livingstone; 2000. p. 2903. 78. Dupont H, Chappell C, Sterling C, et al. The infectivity of Cryptosporidium parvum in healthy volunteers. N Engl J Med 1995;332:885. 79. Alter HJ, Holland PV, Purcell RH. The emerging pattern of post-transfusion hepatitis. Am J Med Sci 1975;270:329. 80. Alter HJ, Purcell RH, Holland PV, et al. Clinical and serological analysis of transfusion-associated hepatitis. Lancet 1975;2:838. 81. Choo Q-L, Kuo G, Weiner, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244:359. 82. Kuo G, Choo Q-L, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989;244:362. 83. Bukh J, Miller RH, Purcell RH. Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Semin Liver Dis 1995;15:41. 84. Cha T-A, Beall E, Irvine B, et al. At least five related, but distinct, hepatitis C viral genotypes exist. Proc Natl Acad Sci U S A 1992;89:7144. 85. Chan S-W, McOmish F, Holmes EC, et al. Analysis of a new hepatitis C virus type and its phylogenetic relationship to existing variants. J Gen Virol 1992;73:1131. 86. Rall CJN, Dienstag JL. Epidemiology of hepatitis C virus infection. Semin Gastrointest Dis 1995;6:3. 87. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556. 88. Seeff LB. Natural history of viral hepatitis, type C. Semin Gastrointest Dis 1995;6:20. 89. Dienstag JL. Non-A, non-B hepatitis. I. Recognition, epidemiology, and clinical features. Gastroenterology 1983;85:439. 559 Infectious Diseases 90. Koretz RL, Abbey H, Coleman E, et al. Non-A, non-B posttransfusion hepatitis: looking back on the second decade. Ann Intern Med 1993;119:110. 91. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic diseases. MMWR Morb Mortal Wkly Rep 1998;47(RR-19):1. 92. Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C virus from mothers to infants. N Engl J Med 1994;330:744. 93. Liang JT, Rhermann J, Seeff LB, et al. NIH conference: pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med 2000;132:296. 94. Armstrong GL, Alter MJ, McQuillan GM, et al. The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States. Hepatology 2000;31:777. 95. American Health Consultants. Fasten your seat belts: hospitals face a bumpy ride as hepatitis C cases peak. Hosp Infect Cont 2000;27:129. 96. Food and Drug Administration. New blood screening tests for hepatitis C. FDA Drug Bull 1990; October: 9. 97. Roth WK, Lee JH, Ruster B, et al. Comparison of two quantitative hepatitis C virus reverse transcriptase PCR assays. J Clin Microbiol 1996;34:261. 98. Alter MJ, Hadler SC, Judson FN, et al. The natural history of community-acquired hepatitis C in the United States. N Engl J Med 1992;327:1899. 99. Aach RD, Stevens CE, Hollinger FB, et al. Hepatitis C infection in post-transfusion hepatitis: an analysis with first- and second-generation assays. N Engl J Med 1991;325:1325. 100. Tremolada F, Casarin C, Alberti A, et al. Long-term follow-up of non-A, non-B (type C) post-transfusion hepatitis. J Hematol 1992;16:273. 101. Alter HJ, Seeff LB: Recovery, persistence and sequelae in hepatitis C infection: a perspective on long-term outcome. Semin Liver Dis 2000;20:17. 102. Kiyosawa K, Sodeyama T, Tanaka E, et al. Hepatitis C in hospital employees with needlestick injuries. Ann Intern Med 1991;115:367. 103. Lanphear BP, Linneman CC Jr, Cannon CG, et al. Hepatitis C virus infection in healthcare workers: risk of exposure and infection. Infect Control Hosp Epidemiol 1994;15:745. 104. Schlipkoter U, Roggendorf M, Cholmakow K, et al. Transmission of hepatitis C (HCV) from a hemodialysis patient to medical staff member. Scand J Infect Dis 1990;22:757. 105. Vaglia A, Nicolin R, Puro V, et al. Needlestick hepatitis C seroconversion in a surgeon. Lancet 1990;336:1315. 106. Ippolito G, Puro V, Petrosillo N, et al. Simultaneous infection with HIV and hepatitis C virus following occupational conjunctival blood exposure. J Am Med Assoc 1998;280:28. 107. Klein RS, Freeman K, Taylor PE, et al. Occupational risk for hepatitis C infection among New York City dentists. Lancet 1991;338:1539. 108. Cleveland JL, Gooch BF, Shearer BG, et al. Risk and prevention of hepatitis C infection: implications for dentistry. J Am Dent Assoc 1999;130:641. 109. Lanphear BP. Trends and patterns in the transmission of bloodborne pathogens to health care workers. Epidemiol Rev 1994;16:437. 110. Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. alpha interferon: a preliminary report. N Engl J Med 1986;315:1575. Thomson BJ, Doran M, Lever AML, et al. Alpha-interferon therapy for non-A, non-B hepatitis transmitted by gammaglobulin replacement therapy. Lancet 1987;1:539. Food and Drug Administration. Interferon alfa-2b approved for hepatitis C. FDA Med Bull 1991;21(2):5. National Institute of Health Consensus Development Conference Panel Statement. Management of hepatitis C. Hepatology 1997;26 Suppl 1:28. Alter MJ, Mast EE, Moyer LA. Hepatitis C. Infect Dis Clin North Am 1998;12:13. Keeffe E. Hepatitis C: current and future treatment. Infect Med 2000;17:603. AIDS epidemic update: December 2000. UNAIDS/WHO; 2000. Centers for Disease Control and Prevention. Pneumocystis pneumonia—Los Angeles. MMWR Morb Mortal Wkly Rep 1981;30:250. Centers for Disease Control and Prevention. Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men—New York City and California. MMWR Morb Mortal Wkly Rep 1981;30:305. Centers for Disease Control and Prevention. A cluster of Kaposi’s sarcoma and Pneumocystis carinii pneumonia among homosexual male residents of Los Angeles and Orange counties, California. MMWR Morb Mortal Wkly Rep 1982;31:305. Jaffe HW, Choi K, Thomas PA, et al. National case-control study of Kaposi’s sarcoma and Pneumocystis carinii pneumonia in homosexual men: part 1, epidemiologic results. Ann Intern Med 1983;99:145. Centers for Disease Control and Prevention. Immunodeficiency among female sexual partners of males with acquired immune deficiency syndrome (AIDS)—New York. MMWR Morb Mortal Wkly Rep 1983;31:697. Harris C, Small CB, Klein RS, et al. Immunodeficiency in female sexual partners of men with the acquired immunodeficiency syndrome. N Engl J Med 1983;308:1181. Centers for Disease Control and Prevention. Pneumocystis carinii pneumonia among persons with hemophilia A. MMWR Morb Mortal Wkly Rep 1982;31:365. Centers for Disease Control and Prevention. Possible transfusion-associated acquired immune deficiency syndrome (AIDS)— California. MMWR Morb Mortal Wkly Rep 1982;31:652. Centers for Disease Control and Prevention. Unexplained immunodeficiency and opportunistic infections in infants— New York, New Jersey, and California. MMWR Morb Mortal Wkly Rep 1982;31:665. Barre-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a Tlymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983;220:868. Gallo RC, Salahuddin SZ, Popovic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 1984;224:500. Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep 1992;41:1. Centers for Disease Control and Prevention. HIV/AIDS surveillance report. 2000;12:1. 560 130. Bozzette S, Berry SH, Duan N, et al. The care of HIV-infected adults in the United States. N Engl J Med 1998;339:1897. 131. Gao F, Bailes E, Robertson DL, et al. Origin of HIV-1 in the chimpanzee Pan troglodytes. Nature 1999;396:437. 132. Hahn BH, Shaw GM, De Cook KM, et al. AIDS as a zoonosis; scientific and public health implications. Science 2000;287:6076. 133. Ciesielski CA, Marianos DW, Schochetman G, et al. The 1990 Florida dental investigation. The press and the science. Ann Intern Med 1994;121:886. 134. Piatak M, Saag MS, Lang LC, et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 1993;259:1749. 135. Perelson AS, Neumann AU, Markowitz M, et al. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996;271:1582. 136. Coffin JM. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 1995;267:483. 137. Schuurman R, Nijhuis M, van Leeuwen R, et al. Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine (3TC). J Infect Dis 1995;171:1411. 138. Stein DS, Korvick JA, Vermund SH. CD4+ lymphocyte cell enumeration for prediction of clinical course of human immunodeficiency virus disease: a review. J Infect Dis 1992;165:352. 139. Mellors JW, Munoz A, Giorgi J, et al. Plasma load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997;126:946. 140. Mulder J, McKinney N, Christopherson C, et al. A rapid and simple PCR assay for quantification of HIV-1 RNA in plasma: application to acute retroviral infection. J Clin Microbiol 1994;32:292. 141. Welles SL, Jackson JB, Yen-Lieberman B, et al. Prognostic value of plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in patients with advanced HIV-1 disease and with little or no prior zidovudine therapy. J Infect Dis 1996;174:696. 142. Coombs RW, Welles SL, Hooper C, et al. Association of plasma human immunodeficiency virus type 1 RNA level with risk of clinical progression in patients with advanced HIV infection. J Infect Dis 1996;174:704. 143. O’Brien WA, Hartigan PM, Martin D, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. N Engl J Med 1996;334:425. 144. Katzenstein DA, Hammer SM, Hughes MD, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. N Engl J Med 1996;335:1091. 145. Marschner IC, Collier AC, Coombs RW, et al. Use of changes in plasma levels of human immunodeficiency virus type-1 RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis 1998;177:40. 146. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med 2000;342:921. 147. Jacquez J, Koopman J, Simon C, et al. Role of the primary infection in epidemics of HIV infection in gay cohorts. J Acquir Immune Defic Syndr 1994;7:1169. 148. Rich JD, Merriman NA, Mylonakis E, et al. Misdiagnosis of HIV infection by HIV-1 plasma viral load testing: a case series. Ann Intern Med 1999;130:37. Principles of Medicine 149. Musey L, Hughes J, Schacker T, et al. Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. N Engl J Med 1997;337:1267. 150. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1-specific CD4+ T-cell responses associated with control of viremia. Science 1997;278:1447. 151. Daar ES, Little SJ, Pitt JA, et al. Protease inhibitor (PI)- and non-PI-containing antiretroviral therapy (ART) compared to no treatment in primary HIV infection (PHI) [abstract402]. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; 2001 Feb 4–8; Chicago, Illinois. 152. Lifson AR, Rutherford TW, Jaffe HW. The natural history of human immunodeficiency virus infection. J Infect Dis 1988;158:1360. 153. Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 2000;30:S5. 154. Michelet C, Arvieux C, François C, et al. Opportunistic infections occurring during highly active antiretroviral treatment. AIDS 1998;12:1815. 155. Haynes BF, Pantaleo G, Fauci AS. Toward an understanding of the correlates of protective immunity to HIV infection. Science 1996;271:324. 156. Dean M, Carrington M, Winkler C, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 1996;273:1856. 157. Horuk R. Chemokine receptors and HIV-1: the fusion of two major research fields. Immunol Today 1999;20:89. 158. McDermott DH, Zimmerman PA, Guignard F, et al. CCR5 promoter polymorphism and HIV-1 disease progression. Lancet 1998;352:866. 159. Levy JA, Mackewicz CE, Barker E. Controlling HIV pathogenesis: the role of the noncytotoxic anti-HIV response of CD8(+) T cells. Immunol Today 1996;17:217. 160. Richman DD, Bozzette SA. The impact of the syncytiuminducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis 1994;169:968. 161. Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Ann Rev Immunol 1999;17:657. 162. Learmont J, Geczy A, Raynes-Greenow C, et al. The Sydney Blood Bank Cohort infected with attenuated quasispecies of HIV-1: long-term nonprogression [abstract 13350]. XII World AIDS Conference; 1998 June 28–July 3;Geneva, Switzerland. 163. Klein MR, VanBaalen CA, Holwerden AM, et al. Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med 1995;181:1365. 164. Glick M. Dental management of patients with HIV. Carol Stream (IL): Quintessence Publishing Co, Inc.; 1994. 165. Abel SN, Croser D, Fischman SL, et al. Dental Alliance for AIDS/HIV Care (DAAC): principles of dental management for the HIV-infected patient. Dental Alliance for AIDS/HIV Care; 1999. 166. Patton LL, Glick M. Clinician’s guide to treatment of HIVinfected patients. 3rd ed. American Academy of Oral Medicine; 2001. Infectious Diseases 167. Glick M, Abel S. Dental implants and HIV disease. Implant Dent 1993;2:149. 168. Dodson TB, Perrott DH, Gongloff RK, et al. Human immunodeficiency virus serostatus and the risk of postextraction complications. Int J Maxillofac Surg 1994;2:100. 169. Glick M, Abel S, Muzyka B, et al. Dental complications after treating patients with AIDS. J Am Dent Assoc 1994;125:296. 170. Patton LL, Shugars DC. Immunologic and viral markers of HIV-1 disease progression: implications for dentistry. J Am Dent Assoc 1999;130:1313. 171. Glick M. Intravenous drug users: a consideration for infective endocarditis in dentistry? [editorial] Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;80:125. 172. Glick M, Muzyka BC, Lurie D, et al. Oral manifestations associated with HIV disease as markers for immune suppression and AIDS. Oral Surg Oral Med Oral Pathol 1994;77:344. 173. Glick M, Muzyka BC, Salkin LM, et al. Necrotizing ulcerative periodontitis: a marker for immune deterioration and a predictor for the diagnosis of AIDS. J Periodontol 1994;65:393. 174. Patton LL. Sensitivity, specificity, and positive predictive value of oral opportunistic infections in adults with HIV/AIDS as markers of immune suppression and viral burden. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:182. 175. Glick M, Berthold P. Oral manifestations and conditions found in individuals with HIV infection. In: Buckley RM, editor. HIV infection in primary care. Philadelphia (PA): W. B. Saunders; [In press] 176. Muzyka BC, Glick M. A review of oral fungal infections and appropriate therapy. J Am Dent Assoc 1995;126:63. 177. Patton LL, McKaig R, Strauss R, et al. Changing prevalence of oral manifestations of human immunodeficiency virus in the era of protease inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:299. 178. Barr CE, Glick M. Diagnosis and management of oral and cutaneous lesions in HIV-1 disease. Oral Maxillofac Surg Clin North Am 1998;1:25. 179. Kademani D, Glick M. Oral ulcerations in individuals infected with human immunodeficiency virus: clinical presentations, diagnosis, management, and relevance to disease progression. Quintessence Int 1998;29:523. 180. Ghannoum MA, Elewski B. Successful treatment of fluconazole resistant oropharyngeal candidiasis by a combination of fluconazole and terbinafine. Clin Diagn Lab Immunol 1999;6:921. 181. Diz Dios P, Ocampo A, Miralles C, et al. Frequency of oropharyngeal candidiasis in HIV-infected patients on protease inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999:87;437. 182. Glick M, Cohen SG, Cheney RT, et al. Oral manifestations of disseminated Cryptococcus in a patient with acquired immunodeficiency syndrome. Oral Surg Oral Med Oral Pathol 1987;64:454. 183. Heinic GS, Greenspan D, MacPhail LA, et al. Oral Geotrichum candidum infection associated with HIV infection. A case report. Oral Surg Oral Med Oral Pathol 1992;73:726–8. 184. MacPhail LA, Greenspan D, Shiodt M, et al. Acyclovir-resistant, foscarnet-sensitive oral herpes simplex type 2 lesion in a patient with AIDS. Oral Surg Oral Med Oral Pathol 1989;67:427. 185. Heinic GS, Northfelt DW, Greenspan JS, et al. Concurrent oral CMV and HSV infection in association with HIV infection: a case report. Oral Surg Oral Med Oral Pathol 1993;75:488. 561 186. Glick M, Cleveland DB, Salkin LM, et al. Intraoral Cytomegalovirus lesion and HIV-associated periodontitis in a patient with acquired immunodeficiency syndrome. Oral Surg Oral Med Oral Pathol 1991;72:716. 187. Kabani S, Greenspan D, deSouze Y, et al. Oral hairy leukoplakia with extensive oral mucosal involvement. Oral Surg Oral Med Oral Pathol 1989;67:411. 188. Glesby MJ, Moore RD, Chaisson RE. Clinical spectrum of herpes zoster in adults infected with human immunodeficiency virus. Clin Infect Dis 1995;21:370. 189. Breton G, Fillet AM, Katlama C, et al. Acyclovir-resistant herpes zoster in human immunodeficiency virus–infected patients: results of foscarnet study. Clin Infect Dis 1998;27:1525. 190. Martinez E, Gatell J, MoranY, et al. High incidence of herpes zoster in patients with AIDS soon after protease inhibitor therapy. Clin Infect Dis 1998;27:1510. 191. Ensoli B, Sgadari C, Barillari G, et al. Biology of Kaposi’s sarcoma. Eur J Cancer 2001;1251. 192. Glick M, Cleveland DB. Oral mucosal bacillary (epithelioid) angiomatosis in a patient with AIDS-associated with rapid alveolar bone loss: a case report. J Oral Pathol Med 1993; 22:235. 193. Muzyka BC, Glick M. Sclerotherapy for the treatment of nodular intraoral Kaposi’s sarcoma in patients with AIDS [correspondence]. N Engl J Med 1993;328:210. 194. Yarchoan R. Therapy for Kaposi’s sarcoma: recent advances and experimental approaches. J AIDS 1999;21:S66. 195. Itin PH, Latenschlager S. Viral lesions of the mouth in HIVinfected patients. Dermotology 1997;194:1. 196. Lozada-Nur F, Glick M, Shubert M, et al. Use of intralesional interferon-alpha for the treatment of recalcitrant oral warts in patients with AIDS: report of 4 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. [In press] 197. Lamster IB, Grbic JT, Mitchell-Lewis D, et al. New concepts regarding the pathogenesis of periodontal disease in HIV infection. Ann Periodontol 1998;3:62. 198. Dimitrakopolous I, Zouloumis L, Lazaridis N, et al. Primary tuberculosis of the oral cavity. Oral Surg Oral Med Oral Pathol 1991;72:712. 199. Eng HL, Lu SY, Yang CH, et al. Oral tuberculosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:415. 200. Ficarra G, Zaragoza AM, Stendardi L, et al. Early oral presentation of lues maligna in a patient with HIV infection. Oral Surg Oral Med Oral Pathol 1993;75:728. 201. Muzyka BC, Glick M. Necrotizing stomatitis and AIDS. Gen Dent 1994;42:66. 202. Muzyka BC, Glick M. Major aphthous ulceration in patients with HIV disease. Oral Surg Oral Med Oral Pathol 1994;77:116. 203. Glick M, Muzyka BC. Alternative therapies for major aphthous ulcers in AIDS patients. J Am Dent Assoc 1992;123:61. 204. Gilquin J, Weiss L, Kazatchkine MD. Genital and oral erosions induced by foscarnet. Lancet 1990;335:287. 205. McLeod GX, Hammer SM. Zidovudine: five years later. Ann Intern Med 1992;117:487. 206. McNeely MC, Yarchoan R, Broder S, et al. Dermatologic complications associated with administration of 2’3’-dideoxycytidine in patients with human immunodeficiency virus. J Am Acad Dermatol 1989;21:1213. 207. Shiodt M. Less common oral lesions associated with HIV infection: prevalence and classification. Oral Dis 1997;3:S208. 562 208. Luzzi GA, Jones BJ. Treatment of neutropenic oral ulceration in human immunodeficiency virus infection with G-CSF. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:53. 209. Greenberg MS, Glick M, Nghiem L, et al. Relationship of Cytomegalovirus to salivary gland dysfunction in HIV-infected patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:334. 210. Flaitz CM, Hicks MJ. Oral candidiasis in children with immune suppression: clinical appearance and therapeutic considerations. ASDC J Dent Child 1999;66:161. Principles of Medicine 211. Nicolatou O, Theodoridou M, Mostrou G, et al. Oral lesions in children with perinatally acquired human immunodeficiency virus infection. J Oral Pathol Med 1999;28:49. 212. Velegraki A, Nicolatou O, Theodoridou M, et al. Paediatric AIDS-related linear gingival erythema: a form of erythematous candidiasis? J Oral Pathol Med 1999;28:178. 213. Flynn PM, Cunningham CK, Kerkering T, et al. Oropharyngeal candidiasis in immunocompromised children: a randomized, multicenter study of orally administered fluconazole suspension versus nystatin. J Pediatr 1995;127;322.
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