TUBERCULOSIS
TUBERCULOSIS MICROBIOLOGY Mycobacterium tuberculosis Mycobacterium bovis: rare since pasturization of milk Obligate aerobes, slow growing, tendancy to develop drug resistance High lipid content in walls (mycolic acids) thus AFB (acid fast bacillus) NOT picked up w/ gram stain: pus aspirate w/ -ve gram stain ........... Think TB Person to person spread via air borne droplets from sputum smear +ve Pt Intracellular survival allows it to be dormant for yrs Air exchange is CRUCIAL to preventing spread in the ED Tranmission is rare outdoor b/c of suceptibility to UV light People are non-infectious after 2 weeks of treatment unless cultures stay positiv Four phase of growth: (1) Continous Rapid Growth - extracellular pool in the cavitary form of pulmn TB - oxygen tension is high, replication is fast, and #s are high (2) Extracellular Slow Growth - colony of m/os in caseous material - growth rate in spurts and is relatively slow - extracellular and are particularly sensitive to rifampin (3) Intracellular - inside the macrophage - medium is acid and particularly sensitive to pyrazinamide (4) Dormant, Non-Replicating - areas thruout the host and may not replicate during a course of Rx and therefore remain viable - potential source of relapse when these organisms begin to replicate after the Rx has been stopped - No drugs are bacteriocidal against dormant m/os (must be replicating for drugs to work) EPIDEMIOLOGY 1/3 of world population Mantoux positive Worst infectious disease world wide Very high rates in the Inuit, northern Sask aboriginals, and imigrants (asian, vietnamese, phillipino, mexican Most cases are reactivation and most are pulmonary (characterized by upper lobe disease b/c the m/o is a aerobe :. seeks out the highest O2 env – also renal cortex and bone epiphysis) Bimodal incidence: higher rates in young and old HIV/AIDS: 800X the rates of TB; CD4 cells are very important on CMI for TB Question: NAME 10 RISK FACTORS FOR TB Known TB contact HIV/AIDS Elderly Long term care (nursing homes, prison IVDA Homeless Low income Aboriginals Chronic disease Immunosuppressed Immigrants: Asain, Mexican, Philipino, African Question: NAME 10 RISK FACTORS FOR REACTIVATIO OF TB TB infection within 2 years HIV/AIDS CRF Head and neck cancer IVDA Diabetes Corticosteroid therapy Hematologic or immune diseases CXR shows prior unRx TB Immunosuppressive drugs Low body weith Intestinal bypass or gastrectomy Chronic malabsorption syndrome FOUR STAGES OF PATHOGENESIS STAGE I Alveolar macrophage phagocytosis Bacillus either dies or overcomes the macrophage response STAGE II Bacillus replicates despite the macrophage response (including monocytes) Tubercle develops = primary focus of infection consisting of many bacilli replicating within macrophages The bacillus spreads via lymphatics to blood then to lymphnodes and orgens Spread to the lung predominates in the apices b/c it is an aeorbic organism STAGE III CMI reaction by CD4 T cells limits growth Granulomas develop = destruction of macrophages infected with bacilli Delayed Type Hypersensitivity reaction withCD8 cytotoxic cells leads to destruction and formation of CASEATING NECROTIC GRANULOMAS Bacilli can survive for many years in caseated granlomasw Immunocompetent: primary lesion walled off and disease arrested and the only evidence of the infection is a +ve PPD (Primary TB is stage I-III) Immunocompromised: weak CMI thus caseatious material expands; may be calcified to form a Ghon Complex Primary progressive TB = advancing pneumonia Disseminated TB = lymphohematogenous spread of TB STAGE IV Months to decade later\ Decreased resistance leads to reactivation of dormatnt focus Liquefaction of the tubercle leads to excellent growth medium Reactivation of delayed hypersensitivity reaction leads to tissue destruction, erosion through bornchi thus develops a caseating bronchopneumonia CLINICAL FEATURES Two phases of infection (1) Primary TB - mild flu-like or asymptomatic - infrequently may develop into Miliary TB - disseminated blood infection (2) Secondary TB - usu due to reactivation (rarely due to a second infection) - reactivation common when T cell immunity is impaired - commonly located at lung apex * Lung apex...............Secondary TB * Whole lung.............Miliary TB When to “Think TB” - cough/sputum > 4wks - wt loss - night sweats - unexplained fever > 1wk - antibiotic unresponsive pneumonia - the patient is: aboriginal, foreign born, inner city homeless, elderly, HIV + - do NOT rely on CXR b/c it may be normal History Asymptomatic unless advanced Cytokine effects: anorexia, fatigue, weak, wt loss, fevers, chills, headachee Fevers in afternoon and sweats at night is classsic Chronic cough is the MC pulmonary symptoms Hemopytsis can be absent, mild, or massive Dyspnea and pleuritic chest pain can occur Peds: hilar lymphadenopathy noted on CXR for resp symptoms; may have wheezing, atelectasis, pneumonia, or query foreign body Elderly often only have chronic cough and FTT HIV typically present with extrapulmonary manifestations ASK about risk factors Physical Exam Pneumonia findings D’Espeine’s sign of mediastinal lymphadenopathy Erythema Nodosum Keratoconjunctitive: unilateral eye inflammation General: wasting, fever, pale, thin How common is reactivation? Immunocompetent: 5% per lifetime HIV/AIDS: 10% per year Q: NAME 15 COMPLICATIONS OF TB Pulmonary Pneumothorax: increases with cavitating lesion Pleural effusions Empyema: rare, late in dz, more common with immunosuppressed Superinfection: aspergillus fungal ball superinfection Hemoptyis: mild or massive Endobronchial spread MC complication of cavitary dz Seen as 5-10 mm poorly defined nodules in dependant lung zones which may collasce into parenchymal consolication (galloping consolidation) Airway spread Cavitation drains into broncheal treat where the infection spread throughout the airway Bronchietasis, bronchial stenosis, lobar atelectaisis, tracheal TB, laryngeal TB Extra-Pulmonary (think MSK, GI, GU, Neuro, Renal, ID, Hem) Lymphadenitis Pericarditis Osteomyelitis Septic arthritis Renal TB Scrotal mass, prostatitis, epididymitis, orchitits Endometritis, oopharitis, cervicitis, vaginitis, PID Diseminated (Miliary) TB: multisystem disease Meningitis Brain abscess Spinal abscess Peritonitis GI TB: abdo pain, obstruction, hemorrhage, peritonitis CXR IN THE TB PATIENT General CXR is an important screening tool in the ED as we won’t have definitive tests Classic findings = upper lobe cavitary infiltrates but there are MANY Normal CXR is 99% sensitive (immunocompetent pt) Normal CXR is 85% sensitive in HIV patients Primary TB Pneumonic infiltrate with hilar or mediastinal lymph nodes is very suggestive ( any age); Infiltrates: homgenous, single lobe (may look like regular pneumonia with lymphadenopathy being the only clue of TB) Lymphadenopathy is the main finding in kids; unilateral is most common Massive adenopathy with airway collapse and atelectasis is common in young kids Pleural effusion: moderate to large size Miliar TB: 1-3mm innumerable non-calcified nodules throughout lungs Tuberculomas: well defined nodular lesion of the lung (healed primary TB) Ghon focus: healed primary TB that shows on CXR as calcified scar Ranke complex: Ghon complex associated with calcified hilar lymph nodes Progressive primary TB: extending consolidation with secondary foci often in the upper lobes Post Primary TB Upper lung infiltrate (aerobes) with or without cavitation Fibrosis and cavitation are common Bilateral upper lobe infiltrates is VERY suggestive of TB Fibroproductive lesions: reticular nodular opacification that is seen after the primary infection is taken over by reactive fibrosis Irregular and angular in contour, strands extending toward the hilum, calcification common This pattern is very suggestive of TB Miscellaneous CXR changes over MONTHS can determine active vs inactive TB Cavitating lung lesions should make you think TB U.P.O. Cavitations can heal and leave Bullae HIV: primary TB CXR changes are common but post-primary are not DIAGNOSIS = Mantoux + CXR + Sputum Skin Testing Only tool available for detecting LATENT TB INFECTION Principle: TB infection produces sensitivity to certain antigens (purifiedc protein derivative = PPD) Ttype IV rxn or delayed type hypersensitivity reaction (T cells) means you are infected w/ the bug somewhere (granuloma) PPD will be +ve 3-8 weeks after initial infection How to read: read at 48-72 hrs and measure maximum diameter of palpable induration (NOT erythema) (+) test means that you are infected but does NOT neccessarily mean that you have active disease (+) ve test = 5 mm, 10 mm, 15 mm of induration depending on risks! Special routines required for people getting repeat tests (do test twice) Sputum = Gold Standard for Dx 3 morning specimens are the best samples; observed collection is best Can be induced with nebs or gastric washings (children) Fiberoptics with BAL or biopsy may be needed if sputum can’t be done or suspicion remains despite -ve sputum Testing of Sputum Direct microscopy = Acid Fast Bacillus Stain: most rapid, relatively insensitive unless TB is active; does not r/o TB; three morning sputum samples helps increase yeild Culture: MORE sensitive than AFB staining Other Testing PCR is being developed Mycobacterium TB direct test, Tuberculosteric acid test, detection of adenosine deaminase activity and serologic testing are all being developed Midstream urine for GU TB Blood cultures also important (esp. w/ HIV) Lymph nodes sent to micro for culture and pathology for cytology DIFFERENTIAL DIAGNOSIS AND COMPLICATIONS Pulmonary TB Bacterial pneumonia: more systemic effects, shorter duration, less lymphadenopathy, wbc count changes, responds to abx Fungal infections: histo, coccidio, blastomyocsis, other mycobacterium HIV patient with pneumonia: PCP, fungi, etc, differential is extensive, needs bronchoscopy for dx Q: name causes of cavitary lung lesions TB Staph pyogenes Klebsiella pneumonia Bronchogenic carcinoma Pulmonary infarction Wegener’s granulomatosis Upper lobe bullous emphysema Upper lobe neurofibromas Differential of predominantly upper lobe infiltrates TB (calcification suggests TB) Atypical myocobacteria Ankylosing spondylitis Silicosis Collagen vasc dz Lymphomas Actinomyces Extrinsic alveolitis Aspergillosis Sarcoidosis Lymphadenitis TB lymphadenitis = scrofula MC form of extrapulmonary TB (EPTB) Enlarged painless, red, firm mass in region of lymph nodes Cervical chains or supraclavicular fossa are most common Skin inflammation in later stages, may have fistula or sinus tract Ddx: lymphoma, cancer, fungus, cat scratch, sarcoid, reactive, bacterial, etc Lymph node biopsy is or FNA is diagnostic THINK OF with persistent lymph nodes that don’t resolve w/ abx course Pleural Effusion Thought to represent hypersensitivity rxn to TB Ags in pleural space Skin test initially -ve Usu straw colored effusion, unilateral and Parenchymal abnormalities in 50% Culture +ve in minority Pleural Bx for culture and histology establishes the Dx Rx = TB Rx Bone and Joint infections Spinal TB = Pott’s disease is the most common (60%) Has been described in almost any joint Majority have prior hx of TB or concurent pulmonary TB CXR may be normal in up to ½ lesion: paraspinal abscess skips vertebral bodies Renal dz Parenchymal tuberculomas, granulomas Scarring and obstruction anywhere along urinary tract CRF, stones, pyelo, HTN Sterile pyuria is Classic Genital Male: TB is on ddx of orchitis, prostatitis, epididymitis Female: TB is on ddx of vaginitis, cerviticitis, endometritis, oophoritis Multisystem dz Miliar tb = massive dissemination of TB that leads to systemic illness More common in immunocompromised with recent or remote infection Most common in elderly and immunusuppressed with AIDS etc Fever, anorexia, weight loss Multiple presentations Miliary TB pattern on CXR only in 50% Definitive dx: liver bx, BM bx, lymph node bx, pulmonary bx TB meningitis Occurs from rupture of a tubercle into the subarachnoid space (not blood spread) Insidious onset w/ progressive headache, fever, lethargy, mild neck stiffness No response to conventional treatment Seizure, focal neurological findings, and papilledema common Strokes common bc/ of associated vasculitis: aneuryms, thrombosis, hemorrhage TB accumulates at base of brain :. cranial nerve palsies common Hyponatremia from SIADH common CT may show tuberculomas Elderly, homeless, immunosuppressed, poor living conditions ------- Think TB Sensitivity of AFB culture on one LP is 35%; increases to 90% with repeat LP Other CNS effects Spinal meningitis Incracranial abscess GI Pain Obstruction Bleeding Peritonitis: spread from a lymph node to the peritoneum; paracentesis AFB staining and culture only positive in 30%; biopsy may be required for dx TREATMENT ED Management Most important is to consider dx and isolate appropriately Most emergent is massive hemoptysis: intubate, bronchoscopy/angiography/surgery to stop hemorrhage Severely ill: treat on spec if you have reason to suspect TB as it will not preclude diagnosis Ideal environment for treatment: at home antibiotics with household member receiving prophylaxis The best way to administer drugs is Directly Observed Therapy (DOT) Two weeks of treatment with make the patient “non-infectious” TB requires long periods of treatment (6-9 months) Extrapulmonary TB usually requires even long treatment (>12 months) ID and public health should be involved with treatment decisions Surgery: localized disease that is multi-drug resistant should be REMOVED Drugs: ID and pulmonary will decide treatment; we need to know that multiple drugs are indicated, for long periods of time, and their complications Corticosteroids are used for TB pericarditis Pregnancy is not a contraindictation to treatment: INH, rifampin, ethambutol + supplemental pyridoxime Prophylaxis is used in some HIV +ve patients (INH alone) Multi drug resistant TB is VERY serious and all efforts to prevent spread should be made as treatment is very difficult TB drugs P Pyrazinamide I Isoniazid R Rifampin E Ethambutol S Streptomycin Side effects Summary PYR - hepatitis, inc uric acid, arthralgia (serum sickness) INH - hepatitis, paresthesia RIF - hepatitis, flu like illness, birth ctrl ETH - retrobulbar neuritis – check eyes STREPT - vertigo, tinitis and ototoxicity, renal failure * all can give rash, fever, N + V * hepatitis most important, stop if symptomatic (RUQ pain) Pyrazinamide Hepatitis and hepatoxicity is the main problem; Increased uric acid Serum sickness, arthralgias can occur Isoniazid Hepatitis: 2%, increases with age Polyneuropathy: increases with higher doses, decreased if pyridoxime used Net effect of INH = prevents the activation of pyridoxime (vit B6) to its active form thus decreased GABA synthesis Seizures occur because of lack of GABA (main inhibitory neurotransmitter) Mortality may be 20% after acute large ingestion Main problem is severe, prolonged, refractory seizures Lactic acidosis and AGMA also occurs Prolonged coma also occurs PYRIDOXIME IS THE ANTIDOTE OF CHOICE (B6); Mainstay of treatment as it attempts overcome pyridoxime inhibition by INH Rapidly terminates seizures, corrects acidosis, and improves LOC Dose of pyridoxime = dose of INH ingested (GRAM FOR GRAM) Empiric dosing = 5 gm in adults, 70 mg/kg in peds BCG vaccine Bacille Calmette Guerin Immunoprophylaxis live attenuated M. bovis strain stimulates an immune response which should cross react with Mycobacterium tuberculosis Liver vaccine thus CONTRAINDICATED in AIDS Efficacy is largely debatable Europe used BCG vaccination for workers Precludes the use of serial skin testing for surveillance Indication: skin test -ve infants and kids who cannot take INH and have ongoing exposure to untreated or inadequately treated active TB patient doesn’t work very well Isolation and Prevention of spread Patient who you consider the dx should be in a negative pressure room Surgical masks should be placed on the patient Surgical masks are not adequate for health care workers N-95 masks are convenient but not 100% protective Respiratorys are the best and are indicated during intubation, bronchoscopy or sputum induction ED managament after Inadevertent Exposure of staff EXAM QUESTION!!!!!!!!!!!! See Box 129-8 TB testing program Skin testing surveillance is mandatory in high risk env of ED Treat if you turn positive! TB in the HIV +ve PATIENT the major opportunist w/ HIV (PCP not transmissable, MAC not curable) HIV is the major factor affecting reactivation of previous TB exposure - 10% per year reactivation - 10% per lifetime reactivation in general population occurs early in the disease (CD4 <200-500) HIV immunosuppression may prevent immune response thus a -ve mantoux signs and symptoms are nonspecific (wt loss, cough) +ve sputum - could be typical (Mycobacterium tuberculosis) or atypical (MAC = Mycobacterium intracellurae) - atypical is non-infectious but difficult to treat - approach = assume typical and change when cultures come back compare EARLY IN DISEASE - mantoux +ve 50-80% - good response to Rx - cavitation more frequent - CXR typical - 90% pulmonary LATE IN DISEASE - mantoux +ve <40% - good response to Rx - CXR less typical - increased extrapulmonary involvement >1 infection is very common therefore send culture for everything (TB,PCP, MAC) treatment - same except more problems w/ s/es b/c of polypharmacy surveillence - screen all HIV +ve Pts for TB; ask about previous contacts; test sputum prevention - mantoux >5mm + NO s/s ........................................ Prophylaxis with 2 drugs DOT for 6mnths (if actual disease is ruled out) - do not give BCG
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