1. health and fitness
2. disease

CONTINUING
MEDICAL EDUCATION
Coccidioidomycosis: A review and update
David J. DiCaudo, MD
Scottsdale, Arizona
Coccidioidomycosis occurs in arid and semi-arid regions of the New World from the western United States
to Argentina. Highly endemic areas are present in the southwest United States. Coccidioides species live
in the soil and produce pulmonary infection via airborne arthroconidia. The skin may be involved by
dissemination of the infection, or by reactive eruptions, such as a generalized exanthem or erythema
nodosum. Interstitial granulomatous dermatitis and Sweet’s syndrome have recently been recognized
as additional reactive signs of the infection. Coccidioidomycosis is a ‘‘great imitator’’ with protean
manifestations. Cutaneous findings may be helpful clues in the diagnosis of this increasingly important
disease. ( J Am Acad Dermatol 2006;55:929-42.)
Learning objective: At the conclusion of this learning activity, participants should be familiar with the
pathogenesis, clinical manifestations, risk factors, diagnosis, and treatment of coccidioidomycosis.
C
utaneous findings played an important role
in the first reported case of coccidioidomycosis more than a century ago. In 1892,
Posada1 described an Argentine soldier who had
verrucous facial lesions, which clinically resembled
mycosis fungoides. Distinctive organisms were visualized microscopically in the skin. Although initially
believed to be a protozoan, Coccidiodes immitis was
identified as a fungus in 1900.2 At that time, the
disease was considered to be frequently fatal.3 The
broad clinical spectrum of coccidioidomycosis was
not appreciated until the 1930s, when C immitis
was recognized as the cause of ‘‘valley fever’’ in the
San Joaquin Valley of California.4 This common syndrome was a relatively mild, self-limited respiratory
illness associated with erythema nodosum. Throughout the 20th century, as the desert southwest transformed into a popular destination for tourism and
migration, coccidioidomycosis became an increasingly important and common disease.5 In recent
decades, Coccidioides species have emerged as significant opportunistic pathogens in HIV patients6-15
and in organ transplant recipients16-23 in endemic
areas. In the current era, there is growing concern that certain new biologic therapies may
From the Departments of Dermatology and Pathology, Mayo
Clinic.
Funding sources: None.
Conflict of interest: None identified.
Reprint requests: David J. DiCaudo, MD, Mayo Clinic, 13400 E Shea
Blvd, Scottsdale, AZ 85259. E-mail: [email protected].
0190-9622/$32.00
ª 2006 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2006.04.039
predispose patients to an increased risk of severe
coccidioidomycosis.24,25 The 21st century also brings
the recognition of Coccidioides species as potential
agents of bioterrorism.26,27
COCCIDIOIDES IMMITIS/POSADASII
Coccidioides species are dimorphic fungi with
saprophytic and parasitic phases (Fig 1).28 Humans,
dogs, horses, and other animals may serve as hosts.
The organisms’ life cycle explains several interesting
characteristics of the disease. Coccidioidomycosis is
infectious, but not contagious. Nearly all infections
are acquired from the environment by the inhalation
of airborne arthroconidia from the soil. In laboratory
cultures, the organisms grow as the extremely infectious mycelial form, which may be hazardous to
laboratory workers.
The organisms are considered to be potential
agents of bioterrorism.26,27 Because they are highly
infectious and sporulate easily in culture, Coccidioides species are the only fungi on the Select Agent list
of the Department of Health and Human Services.29
Federal regulations restrict the possession, use, and
transfer of select biological agents. According to a
recent review, however, terrorists would likely
encounter significant difficulties in attempting to
employ the organisms as effective weapons.27
The genus Coccidioides demonstrates genomic
diversity.30,31 DNA polymorphisms distinguish the
California strains of Coccidioides from the nonCalifornia strains.32 A separate species name
(C posadasii) has recently been proposed for the
non-California clade, while the original species
name (C immitis) is reserved for the Californian
clade.33 At the current time, the designation of two
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Fig 1. Life cycle of Coccidioides immitis/posadasii. Filamentous mycelia grow in the soil and
form arthroconidia. After dispersing into the air, arthroconidia may re-implant in the soil or may
be inhaled by a host. If returned to the soil, arthroconidia grow into additional mycelia. If
inhaled by a host, the arthroconidia transform into spherules in the lungs. Spherules produce
and release endospores, which develop into additional spherules within the host tissues. The
organism reverts to the mycelial form if it is grown in culture or if it is returned to the soil (for
example, through a buried animal carcass). (Adapted from the diagram of Dr Hillel Levine in Dr
David A. Stevens’ article28 with the permission of Drs Levine and Stevens.)
species is controversial. Some researchers recognize
only a single species, C immitis, and consider the
non-California clade to be a variety (C immitis var
posadasii). The clinical manifestations of coccidioidomycosis are generally similar regardless of geographic location.
IMMUNE RESPONSE
In coccidioidomycosis, cell-mediated immunity
is important in establishing an effective response to
the infection.34-37 The clinical course may be greatly
influenced by whether the immune response is
directed predominantly towards a TH1 pattern or
towards a TH2 pattern.37 Interferon-gamma, a TH1associated cytokine, activates macrophages, which
are subsequently able to inhibit or kill the organisms.
In contrast, TH2-associated cytokines promote the
production of antibodies and down-regulate TH1
functions. The antibodies do not appear to confer
protection against the organisms.
In self-limited infections, patients typically have
strong delayed hypersensitivity responses to coccidioidal antigens and have low antibody titers.
Conversely, patients with disseminated infection
typically manifest weak or absent delayed hypersensitivity responses and have high antibody titers.37-39
An effective cell-mediated response provides resistance to re-infection. Following recovery from selflimited infections, patients typically have lifelong
immunity.40 In addition to the T cellemediated
mechanisms of acquired immunity, natural killer
(NK) cells may play a role in innate resistance to
the organism.37,41 A recent review provides a detailed discussion of innate and adaptive mechanisms
of immunity in coccidioidomycosis.42
EPIDEMIOLOGY
Incidence in endemic areas
An estimated 100,000 cases of coccidioidomycosis
occur annually in the United States.43 The geographic
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Fig 2. Geographic distribution of Coccidioides species. (Adapted from Kirkland et al,45 in the
public domain.)
distribution corresponds to regions with hot, dry
summers, few winter freezes, low annual rainfall, and
alkaline soil.43,44 Highly endemic areas include parts
of Arizona and California (Fig 2).45 Major metropolitan
areas with high incidence rates include Bakersfield,
California; Phoenix, Arizona; and Tucson, Arizona.
Confirmed cases are reportable in some states, including Arizona, California, and New Mexico.
Skin test surveys generally suggest a downward
trend in the incidence of coccidioidomycosis in the
Bakersfield area over the past 60 years.46 This phenomenon is attributed to irrigation and urbanization
of the region. Nevertheless, the same area witnessed
a remarkable resurgence in the number of cases in
the early 1990s. Climatic and demographic factors
may have been responsible.45 Similarly, in Arizona,
the incidence increased by more than 100% between
1990 and 1995,47,48 and by an additional 180%
between 1995 and 2001.49 The incidence in Arizona
has continued to increase, from 43 cases per 100,000
people in 2001 to 63/100,000 in 2004.50
Climatic and environmental factors
Local climatic factors, including precipitation and
temperature, influence the variable yearly incidence
of coccidioidomycosis.44,45,51-53 Seasonal variations
in incidence also occur. In Arizona, the number of
new infections peaks during the winter months.49
In the western United States, epidemics have been
associated with environmental events, such as dust
storms,54 earthquakes,55,56 and droughts.51 An increased risk of infection is seen in persons with
exposure to dust and soil. Outbreaks have occurred with occupational exposure in archeological
workers57-60 and in military personnel.3,61-66 In the
medical community, awareness of coccidioidomycosis is important even in non-endemic areas.
Travelers who are exposed to the organism may
develop symptoms after they return home.67-72
HOST FACTORS
Genetic factors and co-morbid conditions may
influence the host response to coccidioidal infection.
The incidence of primary pulmonary coccidioidomycosis appears to be similar among different ethnic
groups. However, specific groups, such as Filipinos
and African Americans, have a markedly increased
risk of severe disease and dissemination.73,74
HIV-infected persons,6-15,75-82 organ transplant recipients,16,17,19-22,83-85 other immunocompromised patients,23,86-92 and pregnant women82,93-97 also have
an increased risk of severe disease and dissemination.
Coccidioidomycosis is an AIDS-defining illness.
Patients with CD4 counts less than 0.250 3 109/L have
an increased risk of active coccidioidomycosis.8,10
In endemic areas, antiretroviral therapy appears to
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have decreased the incidence of coccidioidomycosis
in the HIV-infected population.9,13
By impairing cell-mediated immunity, immunosuppressive medications, such as prednisone and
cyclosporine, may predispose to severe primary
infection or may permit re-activation of the latent
infection. Similar concerns may apply to tumor
necrosis factor (TNF)ealpha antagonists, which are
approved for the treatment of rheumatoid arthritis,
ankylosing spondylitis, Crohn’s disease, and psoriasis. In a retrospective case series, coccidioidomycosis
was documented in 13 patients receiving TNF-alpha
antagonists (infliximab or etanercept) for inflammatory arthritis. Two of the patients, who were receiving both infliximab and methotrexate, died
of disseminated coccidioidomycosis.25 In endemic
areas, Crum et al24 recommend chest radiographs
and serologies at baseline and every 3 to 4 months
during treatment with TNF-alpha antagonists. Similar
testing is recommended for patients who have previously resided in an endemic area.24 Further studies
are needed to define the risk of severe coccidioidomycosis in patients receiving biologic therapies.
CLINICAL FEATURES
Approximately 60% of individuals with primary
coccidioidomycosis are asymptomatic.3 Most of
the remaining 40% experience mild to moderate
influenza-like symptoms, including cough, fever,
arthralgias, myalgias, and fatigue. In most patients,
symptoms resolve or significantly improve within
2 to 3 weeks. Protective immunity follows recovery
from the infection.40,98 Coccidioidomycosis occasionally produces prolonged morbidity or death. In
a recent series of 223 patients, 2 died of respiratory
failure. An additional 8 suffered chronic morbidity
from disseminated involvement of the bones or
meninges.74
The lungs are nearly always the primary focus
of infection. Pulmonary manifestations may include
pneumonia, pleural effusion, hilar lymphadenopathy, and lung nodules.43 Severe pulmonary involvement may occur, especially in immunocompromised
patients. Rarely, a chronic progressive pneumonia
may continue for years and produce pulmonary
cavities and fibrosis.
Disseminated infection occurs in approximately
1% of patients.3 Almost all patients with disseminated
infection experience systemic symptoms, such as
fever, cough, and night sweats.74 In rare cases of
disseminated infection, there may be no clinical or
radiographic evidence of a preceding respiratory
illness.28 Dissemination may occur acutely with the
primary pulmonary infection, or may be chronic
and relapsing. Like Mycobacterium tuberculosis,
C immitis/posadasii may be contained, rather than
destroyed, by the immune response.99 In some
cases, viable organisms may persist indefinitely
within the tissues. If the host subsequently becomes
immunocompromised, the quiescent infection may
reactivate and disseminate.
Common sites of disseminated coccidioidomycosis include the skin, meninges, bones, and joints.
Coccidioidal meningitis is potentially lethal.100 Early
manifestations of meningitis include headache,
nausea, vomiting, and altered mental status. Nuchal
rigidity and cranial neuropathies may occur.
Dissemination to the bones and joints produces
osteomyelitis and synovitis.101,102 Like tuberculosis
and syphilis, coccidioidomycosis is a ‘‘great imitator’’
with protean manifestations.103,104
CUTANEOUS MANIFESTATIONS
Cutaneous manifestations may be categorized as
organism-specific or reactive.105 Organism-specific
lesions contain the organisms, which may be identified in skin biopsy specimens by histopathologic
examination or by culture. Organism-specific lesions
result from hematogenous dissemination to the skin
or, much more rarely, from a primary cutaneous
infection. Reactive eruptions, which contain no
viable organisms, include erythema nodosum, an
acute generalized exanthem, erythema multiforme,
Sweet’s syndrome, and reactive interstitial granulomatous dermatitis.
Erythema nodosum
Erythema nodosum (EN) is generally considered
to be the most characteristic reactive cutaneous
manifestation of coccidioidomycosis.106 One to three
weeks after the onset of the illness,107 patients
develop painful subcutaneous red nodules, typically
on the lower extremities. The diagnosis of EN is
frequently based upon the clinical features. If an
excisional biopsy is performed, the characteristic
histopathologic pattern is a septal granulomatous
panniculitis. Other well-recognized causes of EN
include sarcoidosis, streptococcal infection, other
infections, inflammatory bowel disease, pregnancy,
and oral contraceptives.108,109
Both ethnicity and gender appear to influence
the incidence of EN in coccidioidomycosis.64,107 In
a large study of military personnel from the early
1940s, EN developed in 50% of white women and
in 18% of white men with the diagnosis of coccidioidomycosis.3 EN appears to be rare in African
American men with the infection.3,64,107
EN may reflect the presence of a vigorous cellmediated immune response, which may confer a
protective advantage against the organism.95 In
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Fig 3. Acute exanthem of coccidioidomycosis. A generalized morbilliform eruption.
patients with EN, the onset of the eruption tends to
coincide with the acquisition of delayed hypersensitivity, as determined by coccidioidal skin testing.107
In a report of 61 pregnant women with coccidioidomycosis, EN was associated with a favorable
outcome.93 Of the 30 pregnant women with EN,
none developed disseminated disease, and only one
experienced chronic infection. Of the 31 pregnant
women without EN, 11 developed disseminated disease, 11 experienced chronic infection, and one died.
Acute exanthem
An acute generalized exanthem or ‘‘toxic erythema’’ (Fig 3) frequently begins early in the course
of coccidioidomycosis, typically within 48 hours of
the patient’s first symptoms.110 In some cases, the
cutaneous eruption may be the chief complaint111,112
and may precede the development of detectable
antibodies in the serum.111 The cutaneous lesions
have been clinically described as macular, papular,
urticarial, morbilliform, or target-like.63,111,113 The
clinical appearance may be mistaken for severe,
generalized allergic contact dermatitis112 or erythema multiforme (EM).111 Pruritus is severe in
some cases.64,111,113 An oral enanthem may be associated.110,114 The exanthem may persist up to several
weeks, and occasionally is followed by desquamation of the palms.111
Skin biopsies demonstrate a non-specific pattern
of spongiotic dermatitis and/or interface dermatitis
with a mild perivascular inflammatory infiltrate including lymphocytes, neutrophils, eosinophils, and
karyorrhectic debris.111 In contrast to EM, necrotic
keratinocytes are rare.
Erythema multiforme
For more than six decades, EM has been reported to be associated with coccidioidomycosis.63,107,110,113 The clinical spectrum of EM appears
to overlap with those of the acute exanthem and
Fig 4. Sweet’s syndrome in a patient with pulmonary
coccidioidomycosis. A, Annular vesiculated plaques clinically mimicking erythema multiforme. B, Skin biopsy
consistent with Sweet’s syndrome. Dense dermal infiltrate
including neutrophils, macrophages, and karyorrhectic
debris (Hematoxylin-eosin stain; original magnification:
3600).
Sweet’s syndrome. Like the acute exanthem, EM is
reported to occur early in the course of the coccidioidomycosis,113 often within 48 hours of the first
symptoms.110 Target-like lesions, oral involvement,110 pruritus,111,113 and palmar desquamation111
have been reported to occur in both conditions.
Thus, the acute exanthem may clinically mimic EM,
although the two entities differ histopathologically.
Similarly, Sweet’s syndrome (see below) may have
annular or target-like features which clinically resemble EM, although the histopathologic findings
are extremely different (Fig 4, A and B).
In a comprehensive review of EM, Huff et al115 did
not consider coccidioidomycosis to be among the
well-documented causes. While EM-like eruptions
are described in numerous different infectious diseases, the association is well documented only in
recurrent herpes simplex infection and in very few
other specific infections. In published cases of coccidioidomycosis, the diagnosis of EM has almost
always been based solely upon the clinical features.
To the best of this author’s knowledge, the only
published histologic description116 would not fulfill
currently accepted criteria for EM.117,118 Necrotic
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Fig 5. Reactive interstitial granulomatous dermatitis associated with pulmonary coccidioidomycosis. Firm coalescent papules and plaques on the knee.
Fig 6. Disseminated coccidioidomycosis. Ulcerated frambesiform papules.
keratinocytes, which are the most characteristic histologic feature, were lacking in the description.
It is unclear whether true EM occurs in coccidioidomycosis, or whether the EM-like eruptions actually
represent the acute exanthem or Sweet’s syndrome.
Regardless of whether or not the eruptions are truly
EM, EM-like eruptions are important clues to the
diagnosis of coccidioidomycosis.
in 2004, I have encountered 5 additional similar
patients. Skin lesions resolve as the patient recovers
from the underlying pulmonary infection. In most
clinical situations, systemic corticosteroids are the
mainstay of therapy for Sweet’s syndrome. In cases
associated with coccidioidomycosis, however, recognition of the pulmonary infection is important so that
treatment with systemic corticosteroids is avoided.127
Sweet’s syndrome
Sweet’s syndrome (acute febrile neutrophilic dermatosis) is a distinctive, reactive, immunologicallyinduced eruption, which may be associated with a
variety of underlying systemic diseases. Well-demarcated, boggy, tender red papules and plaques
develop abruptly in association with fever and
peripheral blood leukocytosis.119,120 The lesions
may sometimes have vesicular or pustular features.
Skin biopsies reveal a diffuse, dense dermal inflammatory infiltrate with numerous neutrophils and
leukocytoclastic debris, but no microorganisms are
detected in the skin. Common associations include
nonspecific upper respiratory infections, hematologic
malignancies, inflammatory bowel diseases, and connective tissue diseases.121-125
Only three patients have been reported with
Sweet’s syndrome associated with acute pulmonary
coccidioidomycosis.126,127 Yet, the association is
likely more common than has been recognized.
Since the publication of 2 cases with my coworkers
Interstitial granulomatous dermatitis
Granulomatous dermatitis may be seen not only
in a variety of cutaneous infections, but also in
immunologically-induced eruptions. Granulomatous tissue reactions, which resemble granuloma
annulare or necrobiosis lipoidica, may occur as a
reactive manifestation of diverse systemic diseases,
such as connective tissue diseases, systemic vasculitis, lymphoma, infectious diseases, and inflammatory
bowel disease.128
A single case series described 5 patients who
presented with interstitial granulomatous dermatitis
in association with acute pulmonary coccidioidomycosis. Edematous or indurated cutaneous papules,
nodules, and plaques develop abruptly at the onset
of the illness (Fig 5).105 Skin biopsies reveal interstitial dermal inflammation with macrophages, often
accompanied by eosinophils, neutrophils, and leukocytoclastic debris. Fungal stains and cultures reveal no organisms within the skin biopsy specimens.
In the published series, cutaneous lesions resolved
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Fig 7. Chronic disseminated coccidioidomycosis resembling lupus vulgaris. Despite previous systemic antifungal
therapy, the plaque on the cheek has persisted for 10
years.
over 1 week to 2 months, as the patients recovered
from their respiratory symptoms.
Since publication of the 5 cases with my coworker
in 2001, I have encountered similar biopsy findings
in 3 additional patients with serologically confirmed
coccidioidomycosis. Further observation has revealed that the neutrophilic component of the infiltrate may vary greatly. Neutrophil-rich cases may lie
on a continuum with Sweet’s syndrome. In other
cases, the dermis may contain only a sparse collection of interstitial macrophages with rare neutrophils. Nevertheless, the histopathologic pattern is
often distinctive and may raise suspicion for coccidioidomycosis, even in the absence of clinical history.
Interstitial granulomatous dermatitis and Sweet’s
syndrome may clinically and histopathologically
resemble a disseminated infection. Skin biopsy specimens should be evaluated by culture and by histopathologic examination, in order to distinguish these
two reactive eruptions from a disseminated infection.
Disseminated infection
The skin is the most common site of disseminated coccidioidomycosis.43,129 When dissemination
occurs, it usually begins within several weeks or
months after the primary infection,3 but occasionally
it may be the initial manifestation.130 Almost all
disseminated cases arise from a primary pulmonary
infection, which spreads hematogenously to the skin.
A variety of cutaneous lesions may occur, including papules, nodules, verrucous plaques, abscesses,
pustules, and sinus tracts.129,131 Skin lesions may be
solitary or multiple and may ulcerate (Fig 6). Even
after resolution of other symptoms, disseminated
skin lesions may rarely become chronic (Figs 7 and
8). The diverse presentations include unusual cases
that clinically resemble tumor-stage mycosis fungoides1,74 or lepromatous leprosy.132
Fig 8. Chronic disseminated coccidioidomycosis of 5
years’ duration. Tumid, indurated plaques on the cheeks,
nose, and upper lip.
In disseminated coccidioidomycosis, skin biopsies reveal granulomatous and/or suppurative inflammation in the dermis or subcutaneous adipose
tissue. The inflammatory infiltrate often includes
numerous eosinophils.131 The overlying epidermis
may show pseudocarcinomatous hyperplasia with
or without ulceration. Organisms are identified by
histopathologic examination and by cultures of
skin biopsy specimens, although either method
may sometimes yield falsely negative results.131 If
the organism is identified in the skin, other possible
sites of dissemination should be investigated.43,130,133
Primary cutaneous infection
Only approximately 20 cases of primary cutaneous coccidioidomycosis have been reported in the
literature.134-142 A comprehensive review of the
subject has recently been published.141 Traumatic
inoculation of the organism results from direct contact with a source in the environment or in the
laboratory. Primary cutaneous infections have been
reported in agricultural workers,136 laboratory
workers,137,139,142 an embalmer,140 and in persons
suffering splinter injuries or lacerations.134,135,138
Primary cutaneous coccidioidomycosis typically
manifests as an ulcerated nodule on an extremity,
although other sites may also be affected (Fig 9).
In a pattern resembling sporotrichosis, secondary
nodules sometimes arise in a linear distribution
along the lymphatic pathways of an extremity.135
Fever and regional lymphadenopathy may be associated, and the affected lymph nodes may ulcerate.
Though primary cutaneous infections sometimes
resolve spontaneously, at least one patient experienced a severe clinical course with meningeal dissemination.135
In some cases, a primary pulmonary infection may
disseminate to a single focus in the skin and may
mimic a primary cutaneous infection. If the patient’s
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Fig 9. Primary cutaneous coccidioidomycosis resulting
from a cactus spine injury on the abdomen. After initial
treatment with excision and systemic antifungal therapy,
the infection recurred within the surgical scar.
pulmonary symptoms are minimal or absent, it may
be difficult to distinguish a disseminated infection
from a primary cutaneous infection. The histopathologic features in the skin are similar in both
instances. Organisms may be detected by histopathology or by culture in both situations. Even a
history of localized trauma to the affected area
does not completely rule out the possibility of a
disseminated infection. In some cases, disseminated
organisms in the bloodstream may specifically localize to the site of an injury (blunt trauma, laceration,
or surgical wound). This phenomenon, termed locus
minoris resistentiae, is well documented in disseminated coccidioidomycosis.143
Several clues may support the possibility of a
primary cutaneous infection. Regional lymphadenopathy, a relatively low complement fixation titer,
and a history of a trauma-induced break in the skin
are all typical of primary cutaneous infection.143
Nevertheless, these findings are not entirely specific.
In some cases of isolated cutaneous coccidioidomycosis, it may not be possible to distinguish primary
cutaneous infection from a disseminated infection.
DIAGNOSIS
Serology
Both qualitative and quantitative serologic tests
are useful in the diagnosis of coccidioidomycosis.
Enzyme immunoassay, latex particle agglutination,
and immunodiffusion may be used as qualitative
techniques, which yield positive results early in the
course of the infection. Enzyme immunoassay provides rapid qualitative assessment of both IgM and
IgG coccidioidal antibodies.144 While this test is
highly sensitive, false positive reactions do sometimes occur.98,145 Positive reactions may require
confirmation by another more specific technique.
IgM antibodies occur mostly during early primary
Fig 10. Coccidioidal spherule within a giant cell in the
papillary dermis (Hematoxylin-eosin stain; original magnification: 3600).
infection, although occasionally they may persist in
chronic infections.98,145
IgG complement-fixing antibodies may appear
within 2 to 3 weeks of the onset of symptoms, and
are assessed quantitatively in the serum and other
body fluids by quantitative immunodiffusion or
complement fixation techniques.98 These techniques
yield highly specific results.145 Even low titers of
complement-fixing antibodies (1:2) are likely to signify a true infection. Complement-fixing antibodies
usually disappear as the infection resolves but may
persist in chronic infections. The titer generally correlates with the severity of the disease. Patients with
disseminated infections typically have high titers
(1:16, 1:32, or 1:64, depending upon the individual
laboratory).98 However, some patients with limited
dissemination to the skin may have lower titers, such
as 1:4 or 1:8.98 Quantitative serologies are also useful
in monitoring response to therapy.
False negative serologic results do sometimes
occur, particularly early in the course of infection.
Some cutaneous manifestations, such as the acute
exanthem, occur within the first 48 hours of the
illness, and may precede the development of detectable antibodies. If clinically indicated, serologic
testing may be repeated once or twice over the
following 2 months, in order to document seroconversion.146 Persistently false negative serologies may
occur in a small percentage of HIV-infected patients,
other immunosuppressed patients, and even occasionally in immunocompetent individuals.98
Culture and microscopy
The organism may be detected by culture of tissue
specimens on most mycologic or bacteriologic media.146 Growth is rapid, occurring in as early as 2 days
to more than 5 days.43 The colonies are typically
white and cottony, but the morphology and color
are variable.146 The microscopic appearance also
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is nonspecific in cultured specimens. Arthroconidia
are typically barrel-shaped. The cultured organism is
specifically identified by DNA probes or by detection
of specific coccidioidal exoantigens.147-149 When
specimens are submitted for culture, the laboratory
should be appropriately notified because of the
potential danger to laboratory workers.
Direct microscopic visualization provides another
means of identification. In tissue specimens and in
cytologic smears, the spherules may be visualized
with fungal stains or with a routine hematoxylin-eosin
stain (Fig 10). The thick-walled spherules are usually
distinguishable from other parasitic fungi by their
relatively large size (10 to 80 microns). Characteristic
endospores are frequently seen within the spherules.
Molecular techniques
Molecular techniques, such as in situ hybridization (ISH) and polymerase chain reaction (PCR), may
assist in the identification of C immitis/posadasii in
paraffin-embedded tissue. ISH is less sensitive but
more specific than standard histochemical stains,
such as methenamine silver stain.150 In cases where
the visualized organisms are not morphologically
distinctive, ISH may provide specific confirmation
in histologic sections. This technique may be particularly useful in distinguishing small, immature
spherules of C immitis/posadasii from Blastomyces
dermatitidis and Cryptococcus neoformans.150 It
should be noted that the spherules generally must
be visible with standard histochemical stains, in
order for ISH to be helpful. In addition to ISH
techniques, PCR assays have recently been described
for identification of C posadasii DNA in paraffinembedded specimens.151
Skin testing
Delayed hypersensitivity skin tests for coccidioidal antigens are useful in population studies, which
evaluate overall trends in the incidence of coccidioidomycosis. However, skin testing is of limited
usefulness in the diagnosis of an acute infection.
A positive skin test does not distinguish current infection from prior infection. In addition, anergy
may develop during active infection in some cases.
Individuals with reactive skin tests often show waning in reactivity after approximately 12 to 15 years.46
Currently, the delayed hypersensitivity skin tests for
coccidioidal antigens are not generally available for
clinical use in the United States.
Imaging studies
In acute symptomatic pulmonary coccidioidomycosis, chest radiographs demonstrate parenchymal
abnormalities in almost 75% of cases.152 Segmental
pneumonia is the most common pattern. Other
common findings include single or multiple pulmonary nodules, hilar or mediastinal lymphadenopathy, and pleural effusions. The findings are not
specific and may mimic bacterial pneumonia, tuberculosis, or a malignancy.153 Approximately 5% of
patients will develop chronic abnormalities, such
as pulmonary cavities or persistent nodules.153 In
disseminated infections, chest radiographs may reveal a reticulonodular or diffuse military pattern.
In complicated or disseminated infections, other
imaging modalities may be indicated in addition to
standard chest radiographs.153,154 Computed tomography of the lungs and central nervous system may
be helpful in individual cases.154-157 Scintigraphy
provides a useful screening tool when disseminated
skeletal involvement is suspected.158 With plain
radiographs, skeletal lesions usually have a lytic,
‘‘punched out’’ appearance. Nearly any bone can be
affected, but the axial skeleton is most frequently
involved.159 Computed tomography and magnetic
resonance imaging may be useful in evaluating
involvement of the soft tissues and spine.159
TREATMENT
The therapeutic approach to coccidioidomycosis
is based predominantly upon three factors: (1) the
severity of the pulmonary infection, (2) the presence
or absence of dissemination, and (3) the individual
patient’s risk factors.160,161 Treatment guidelines
have recently been published160,162 and are also
currently available online at the Infectious Diseases
Society of America Web site (http://www.IDSociety.
org) under the heading of Practice Guidelines.
In immunocompetent patients with primary uncomplicated pulmonary infection, antifungal therapy
is controversial. Prospective controlled trials have
not been performed. There is no evidence that
treatment of the primary infection mitigates the
severity of the illness or prevents complications.43
For most patients with a mild respiratory illness,
many authorities believe that antifungal therapy is
not necessary.43 Patients should be periodically
evaluated clinically and radiographically for one to
two years, in order to document resolution of the
infection. On the other hand, some experts advocate
systemic antifungal therapy for all symptomatic
patients. Either itraconazole 200 mg twice daily or
fluconazole 400 mg/d may be given by mouth for
approximately 3 to 6 months.
If risk factors for dissemination are present,
antifungal therapy should be given.160,162,163 HIV
patients, allograft recipients, and other immunosuppressed patients may be treated with systemic antifungal agents. Specific ethnic backgrounds, such as
938 DiCaudo
J AM ACAD DERMATOL
DECEMBER 2006
Filipino or African American ancestry, may also be
considered a risk factor for dissemination. Regardless
of the patient’s ethnicity, antifungal therapy may be
strongly considered for symptomatic pregnant patients (particularly during the third trimester) and in
the post-partum period. During pregnancy, amphotericin B is the treatment of choice. In pregnant
women, the azoles are contraindicated because of
the risk of teratogenicity.
Prophylactic therapy may have a role in the care
of some immunosuppressed patients, who have a
high risk of developing coccidioidomycosis. Targeted azole chemoprophylaxis may be considered
for specific groups of organ transplant recipients and
HIV patients.9,21,164
Antifungal therapy is indicated in patients with
disseminated infection or severe pulmonary infection. Treatment recommendations for severe infections are included in the recently published
comprehensive guidelines160,162 and are beyond
the scope of this review. After initial treatment of
disseminated infection, lifelong therapy with azoles
may be required in some cases. Azoles are fungistatic, rather than fungicidal. Recurrences are common after discontinuing therapy. In the future, a
variety of new antifungal medications may prove
to be useful in the treatment of coccidioidomycosis.43,165-173 Efforts to develop a vaccine are in
progress.42,174-180
CONCLUSION
Coccidioidomycosis is a ‘‘great imitator’’ with
protean clinical manifestations. Knowledge of the
diverse cutaneous clues can be helpful in the diagnosis of this increasingly important disease.
The author is grateful for the assistance of Ms Aimee
Volner in the Section of Illustration & Design at Mayo
Clinic in Rochester, Minnesota. Ms Volner designed the
adaptions of the diagrams in Figs 1 and 2. The author’s
colleague Dr Joseph P. Fiore is thanked for contributing
the cases shown in Figs 7 and 8.
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