Roadmap To Diagnosis & Treatment Of Extrapulmonary Tb

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Roadmap To Diagnosis & Treatment Of Extrapulmonary Tb

  1. 1. ROADMAP TO DIAGNOSIS & TREATMENT OF EXTRAPULMONARY TB DR. LIZA D. MARIPOSQUE OCTOBER 23, 2008
  2. 2. MOST COMMON EXTRAPULMONARY SITES FOR TB <ul><li>Lymph nodes </li></ul><ul><li>Pleura </li></ul><ul><li>Genitourinary tract </li></ul><ul><li>Bones & joints </li></ul><ul><li>Meninges </li></ul><ul><li>Peritoneum </li></ul><ul><li>pericardium </li></ul>
  3. 3. LYMPADENITIS <ul><li>>40% associated with pulmonary cases. </li></ul><ul><li>Presents as painless swelling of the LN most commonly at posterior cervical & supraclavicular sites. ( scrofula) </li></ul><ul><li>Discrete & nontender LN in early stage but may be inflamed and have a fistulous tract draining caseous material. </li></ul>
  4. 4. <ul><li>Dx: FNAB or Surgical Bx </li></ul><ul><li>50% AFB (+) </li></ul><ul><li>70-80% culture (+) </li></ul><ul><li>Histologic exam shows granulomatous lesions but usually not seen in HIV Pt. </li></ul><ul><li>DDx: neoplastic dses such as lymphomas or metastatic CA ; rarely Kikuchi dse (necrotizing histiocytic lymphadenitis) </li></ul>
  5. 5. PLEURAL TEBERCULOSIS <ul><li>̴20% extrapulmonary TB in the US. </li></ul><ul><li>Common in primary TB & may be due to either contiguous spread of parenchymal inflammation or penetration of the tubercle to the pleural space. </li></ul><ul><li>S/Sx: pleural effusion, fever, pleuritic chest pain & dyspnea; tuberculous empyema is less common </li></ul>
  6. 6. <ul><li>Pleural fluid: straw colored and sometimes hgic, exudative w/ a CHON conc.>50% ( ̴ 4-6g/dl), normal-low glucose conc., pH ̴ 7.3 (<7.2), WBC 500-6000/µL. </li></ul><ul><li>> neutrophils in the early stage & mononuclear cells are the typical findings later. </li></ul><ul><li>AFB smear 10-25% & AFB culture 25-75%. </li></ul><ul><li>Adenosine deaminase (ADA) det.of the pleural fluid is useful screening test. </li></ul>
  7. 7. <ul><li>FNAB- Dx, (+) granuloma </li></ul><ul><li>Culture (+) 80% </li></ul><ul><li>Responds well to chemotherapy & may resolve spontaneously. </li></ul><ul><li>Glucocortecoid? </li></ul>
  8. 8. <ul><li>Tuberculous empyema – less common Cx. </li></ul><ul><li>Usually the result of the rupture of a cavity & spillage of of organism to pleural space. </li></ul><ul><li>CXR – Hydropneumothorax w/ an air fluid level </li></ul><ul><li>Pleural fluid is purulent & thick w/ inc. lymphocytes. </li></ul><ul><li>AFB & Culture (+) </li></ul><ul><li>Rx: surgical drainage, chemotx, decortication </li></ul>
  9. 9. Tuberculosis of the Upper Airways <ul><li>Always a complication of cavitary tuberculosis. </li></ul><ul><li>Involve the larynx, pharyns & epiglottis. </li></ul><ul><li>S/Sx: hoarseness, dysphonia, dysphagia, chronic productive cough. </li></ul><ul><li>Laryngoscopy: (+) ulceration </li></ul><ul><li>AFB sputum (+) </li></ul><ul><li>Biopsy- to R/O laryngeal CA </li></ul>
  10. 10. GENITOURINARY TUBERCULOSIS <ul><li>~ 15% of cases in the US. </li></ul><ul><li>Involved any portion of the GUT and 1/3 have concomitant pulmonary disease. </li></ul><ul><li>S/Sx: inc. urinary freq., dysuria, nocturia, hematuria and flank pain or abdominal pain. </li></ul><ul><li>Pt may be asymptomatic & the dse discovered only after severe destructive lesion of the kidneys dev. </li></ul>
  11. 11. <ul><li>>female, affects fallopian tubes, endometrium – infertility, pelvic pain & menstrual abnormality. </li></ul><ul><li>Dx: Bx & culture </li></ul><ul><li>U/A: 90% abnormal; pyuria & hematuria. </li></ul><ul><li>Culture-negative pyuria in acidic urine raises the suspicion. </li></ul><ul><li>IVP, CT/MRI: deformities, obstruction, calcifications & ureteral strictures. </li></ul><ul><li>Culture of 3 morning urine specimens yields definitive Dx (90%). </li></ul>
  12. 12. <ul><li>Male: >epididymis – tender </li></ul><ul><li>orchitis, prostatitis, UTI </li></ul><ul><li>Responds well to chemo. </li></ul>
  13. 13. SKELETAL TUBERCULOSIS <ul><li>~10% of the cases involves bones & joints in the US. </li></ul><ul><li>Pathogenesis: reactivation of hematogenous foci or to spread from adjacent paravertebral LN. </li></ul>
  14. 14. Weight-bearing joints are most commonly affected. <ul><li>Spine (Pott’s dse) = 40% </li></ul><ul><li>Hips = 30% </li></ul><ul><li>Knees = 10% </li></ul><ul><li>Involves 2 or more adjacent vertebral bodies. </li></ul><ul><li>Upper thoracic spine is the most common site in children. </li></ul><ul><li>Lower thoracic & lumbar vertebra are common in adults. </li></ul>
  15. 15. <ul><li>Dx: CT/MRI; Aspiration of abscess & bone Bx confirms </li></ul><ul><li>synovial fluid – culture (+); thick in appearance w/ high protein content & variable cell ct. </li></ul><ul><li>Respond well to chemo but in severe cases may require surgery. </li></ul>
  16. 16. TUBERCULOUS MENINGITIS & TUBERCULOMA <ul><li>~5% CNS TB in the US. </li></ul><ul><li>Most often seen in adults, esp. HIV infected. </li></ul><ul><li>Pathogenesis: hematogenous spread of primary or postprimary pulmonary dse or from the rupture of a subependymal tubercle into the subarachnoid space. </li></ul><ul><li>CXR: (+) old pulmonary lesion or miliary pattern </li></ul>
  17. 17. <ul><li>S/Sx: often presents subtly as HA, slight mental changes after a prodrome of wks of low-grade fever, malaise, anorexia & irritability severe HA, confusion, lethargy, altered sensorium & neck rigidity. </li></ul><ul><li>Typically, the disease evolves over 1-2 wks, a course longer than that of bacterial meningitis. </li></ul><ul><li>Paresis of CN (ocular) is a frequent findings. </li></ul>
  18. 18. <ul><li>Cerebral art. Focal ischimia coma </li></ul><ul><li>Dx: Lumbar puncture </li></ul><ul><li>- CSF – high leukocyte ct. (up to 1000/ µL) but sometimes with increase neutrophils in the early stage. </li></ul><ul><li>- CHON 1-8g/L (100-800mg/dl) </li></ul><ul><li>- low glucose conc. </li></ul><ul><li>AFB OF CSF – (+) 1/3 of cases. </li></ul><ul><li>Culture of CSF – gold standard, 80% </li></ul><ul><li>PCR – 80% sensitive, 10% false (+) </li></ul>
  19. 20. GASTROINTESTINAL TB <ul><li>Uncommon, 3.5% in the US </li></ul><ul><li>MOT: swallowing of sputum w/ direct seeding, hematogenous spread, ingestion of infected milk. </li></ul><ul><li>Most commonly affected are terminal ileum & the cecum. </li></ul><ul><li>Mimic appendicitis. </li></ul><ul><li>Surgery is required in most cases. </li></ul><ul><li>Dx: histopath & culture of specimes obtained intraoperatively. </li></ul>
  20. 21. Tuberculous peritonitis <ul><li>Ff either the direct spread of tubercle bacilli fr ruptured LN & intraabdominal organs or hematogenous seeding. </li></ul><ul><li>S/Sx: nonspecific abdominal pain, fever & ascites </li></ul><ul><li>Paracentesis: exudative fluid w/ a high CHON content & leukocytosis, sometimes occ. Neutrophils predominate </li></ul><ul><li>Gram stain & culture. </li></ul>
  21. 22. PERICARDIAL TB (TUBERCULOUS PERICARDITIS) <ul><li>Pathogenesis: </li></ul><ul><li>1.Direct progression of a primary focus w/n the pericardium. </li></ul><ul><li>2. Reactivation of the latent focus. </li></ul><ul><li>3. Rupture of an adjacent subcarinal LN </li></ul><ul><li>Case-fatality rate of 40%. </li></ul>
  22. 23. <ul><li>S/Sx: dysnea, fever, dull retrosternal pain, pericardial friction rub, pericardial effusion, cardiac tamponade. </li></ul><ul><li>Dx: pericardiocentesis under echocardiographic guidance – definitive. </li></ul><ul><li>Pericardial fluid for biochemical, cytologic, microbiologic study. </li></ul><ul><li>Exudative, leukocytosis, frequently hgic. </li></ul><ul><li>Smear rarely (+) & culture 2/3 </li></ul><ul><li>Bx </li></ul>
  23. 25. MILIARY OR DISSEMINATED TB <ul><li>Pathogenesis: hematogenous spread </li></ul><ul><li>Consequence of primary infxn in child’n. </li></ul><ul><li>Recent infxn or reactivation of old disseminated foci in adult. </li></ul><ul><li>S/Sx: fever, night sweats, anorexia, weakness, wt. loss, respiratory & abdominal Sx. </li></ul><ul><li>Choroidal tubercle – pathognomonic, 30% </li></ul>
  24. 26. <ul><li>CXR: miliary reticulonodular pattern </li></ul><ul><li>Sputum smear: 80% negative </li></ul><ul><li>Hematologic abnormalities: anemia w/ leukopenia, lymphopenia, neutrophilic leukocytosis & leukomoid rxn, and polycythemia. </li></ul><ul><li>Bronchoalveolar lavage & transbronchial Bx – provide bacteriologic confirmation. </li></ul><ul><li>Bone marrow Bx – granuloma (+) </li></ul><ul><li>Glucocortecoid – not proven beneficial </li></ul>
  25. 27. <ul><li>Cryptic miliary TB – rare, chronic type characterize by mild intermittent fever, anemia meningeal involvement death. </li></ul><ul><li>Nonreactive miliary TB – very rarely, due to massive hematogenous dissemination </li></ul>
  26. 28. Less Common Extrapulmonary TB <ul><li>Tuberculous otitis – hearing loss, otorrhea, tympanic membrane perforation </li></ul><ul><li>Adrenal TB – Mx of disseminated dse, manifest as adrenal insufficiency. </li></ul><ul><li>Congenital TB – transplacental spread or from ingestion of contaminated amniotic fluid. </li></ul>
  27. 29. HIV-ASSOCIATED TUBERCULOSIS <ul><li>One of the most common diseases among HIV-infected person worldwide. </li></ul><ul><li>HIV w/ TST (+) = 3-13% annual risk of developing active TB. </li></ul><ul><li>A new TB infxn acquired by an infected HIV individual may evolve to active dse in a matter of wks. </li></ul><ul><li>It appear in any stage of HIV and it varies the presentation. </li></ul>
  28. 30. <ul><li>Late stage of HIV: a primary TB-like pattern, w/ diffuse interstitial or miliary infiltrates, little or no cavitation, & intrathoracic lymphadenopathy, is more common. </li></ul><ul><li>Mycobacteremia & meningitis are also frequent. </li></ul><ul><li>Sputum smear negativ 40% </li></ul>
  29. 31. DIAGNOSIS OF TB <ul><li>AFB Smear </li></ul><ul><li>Mycobacterial culture </li></ul><ul><li>Nucleic acid amplification </li></ul><ul><li>Drug susceptibility testing </li></ul><ul><li>Radiographic procedures </li></ul><ul><li>Tuberculin skin testing </li></ul><ul><li>IFN-y Release assay (IGRAs) </li></ul>
  30. 32. AFB Microscopy <ul><li>Used as presumptive Dx. </li></ul><ul><li>40-60% sensitivity </li></ul><ul><li>Traditional method: light microscopy of specimens stained w/ Kinyoun or Ziehl-Neelsen basic fuchsin dyes. </li></ul><ul><li>Modern method: auramine-rhodamine staining & fluorescence microscopy. </li></ul><ul><li>Early morning collection w/ no formaldehyde. </li></ul>
  31. 33. MYCOBACTERIAL CULTURE <ul><li>Definitive diagnosis. </li></ul><ul><li>Specimen inoculated into egg or agar-based medium (L Öwenstein-Jensen or Middlebrook 7H10) & incubated @ 37C (under 5% CO2 for Middlebrook medium. </li></ul><ul><li>M. tuberculosis grow slowly for 4-8 wks. </li></ul><ul><li>The use of broth-based culture for isolation & speciation by molecular methods or high-pressure liquid chromatography of mycolic acids to decreased the time required for bacteriologic confirmation to 2-3 wks. </li></ul>
  32. 34. NUCLEIC ACID AMPLIFICATION <ul><li>Definitive Dx: identification of specific sequences of DNA. </li></ul><ul><li>it takes few hrs only with high specificity & sensitivity. </li></ul><ul><li>Most useful than culture & for those AFB-negative. </li></ul>
  33. 35. DRUG SUSCEPTIBILITY TESTING <ul><li>Initial Isolate: INH, rifampin, ethambutol </li></ul><ul><li>Expanded susceptibility testing is mandatory when resistance to 1 or more of these drugs or either patient fails to respond to initial therapy or has a relapse after the completion Tx. </li></ul><ul><li>Conducted directly (w/ clinical specimens) or indirectly (w/ mycobacterial cultures). </li></ul><ul><li>Direct testing on liquid medium – 3 wks </li></ul><ul><li>Direct testing on solid medium - ≥8 wks. </li></ul>
  34. 36. <ul><li>CLASSIC PICTURE: (+) infiltrates & cavities on the upper lobe. </li></ul><ul><li>AIDS Pt have no radiographic pattern that can be pathognomonic. </li></ul><ul><li>CT-scan may be useful in interpreting questionable CXR & to diagnose extrapulmonary TB. </li></ul><ul><li>MRI is useful in the Dx of intracranial TB. </li></ul>RADIOGRAPHIC PROCEDURES
  35. 37. Tuberculin Rxn Size ≥ 10 Recently infected person ( ≤ 2yrs) ≥ 5 Persons w/ fibrotic lesions on CXR ≥ 5 a Close contacts of TB pt. ≥ 5 HIV-infected person or persons receiving immunosupressive Tx TUBERCULIN Rxn SIZE, mm RISK GROUP
  36. 38. ≥ 15 Low risk persons c ≥ 10 Persons w/ high-risk medical conditions b TUBERCULIN Rxn SIZE, mm RISK GROUP
  37. 39. <ul><li>a- Tuberculin-negative contacts, esp. child. Should receive prohylaxis for 2-3 months after contact ends & should then be retested w/ PPD. Those whose result remain negative should discontinue prophylaxis. </li></ul><ul><li>HIV infected contacts should receive a full course of Tx regardsless of PPD results. </li></ul>
  38. 40. ANTI-TB TREATMENT
  39. 41. FIRST-LINE AGENTS <ul><li>RIFAMPIN- Most important & potent anti-TB agent. </li></ul><ul><li>- 600mg/d. </li></ul><ul><li>- distributes well throughout the body tissues including inflamed meninges. </li></ul><ul><li>- cause GI upset & hepatitis because it is a potent inducer of hepatic microsomal Enz. </li></ul><ul><li>Rifabutin – closely related to Rifampin agent w/c have fewer side effects. </li></ul>
  40. 42. ISONIAZIDE (INH) <ul><li>Best agent 2 nd to Rifampin. </li></ul><ul><li>300 mg/d or 900mg 2 or 3x per wk. </li></ul><ul><li>Distributed well throughout the body, infected tissues, CSF & caseous granuloma. </li></ul><ul><li>Hepatotoxicity & peripheral neuropathy. </li></ul><ul><li>Pyridoxine 25-50mg/d </li></ul>
  41. 43. <ul><li>PYRAZINAMIDE (PZA) </li></ul><ul><li>25mg/kg daily </li></ul><ul><li>Less hepatotoxic, hyperuricemia </li></ul><ul><li>ETHAMBUTOL </li></ul><ul><li>Less potent </li></ul><ul><li>15mg/kg/day </li></ul><ul><li>At higher doses – retrobulbar optic neuritis causing central scotoma & impairing both visual acuity & ability to see reen. </li></ul>
  42. 44. HRE e 2 mos. pregnant HRZE a 2 mos. New culture(-) HRZE a,b 2 mos. New smear or culture (+) DRUGS DURATION (month) INDICATION INITIAL PHASE
  43. 45. ZEQ + S 18-24 mos. Resistance to H + R RZE g Throughout 6 mos. Resistance or intolerance to H Failure & relapse f DRUGS DURATION (month) INDICATION INITIAL PHASE
  44. 46. HRZES i 3 mos. Standardized re-tx (susceptibility testing unavailable) 1 IV h + 3 of these 4: ethionamide, cycloserine, Q, PAS 24 mos. Resistance to all 1 st -line drugs DRUGS DURATION (month) INDICATION INITIAL PHASE
  45. 47. HRE 2 mos. Drug intolerance to Z HZE 12 mos. Drug intolerance to R DRUGS DURATION (month) INDICATION INITIAL PHASE
  46. 48. HR 7 mos. Pregnant Failure & relapse f New culture(-) New smear or culture (+) INDICATION HR a 2 mos. HR a,c,d 4 mos. DRUGS DURATION (months) CONTINUATION PHASE
  47. 49. HR 7 mos. Drug intolerance to Z HRE 5 mos. Standardized re-tx (susceptibility testing unavailable) DRUGS DURATION (months) INDICATION CONTINUATION PHASE
  48. 50. Footnotes: <ul><li>b- striptomycin can be used in place of Ethambutol </li></ul><ul><li>c- continuation phase should be extended to 7 mos.for pt.w/ cavitary lesion who remain sputum culture (+) after the initial phase of tx. </li></ul><ul><li>d - HIV-negative pt.w/ noncavitary lesion & AFB sputum (-) after initial phase of tx can be given weekly Rifapentine/INH in the continuation phase. </li></ul>
  49. 51. <ul><li>e- PZA is safe to pregnant for 6 mos. If PZA is not included in the initial tx regimen, the minimum duration of therapy is 9 mos. </li></ul><ul><li>f- regimen is tailored according to the results of susceptibility tests. </li></ul><ul><li>g- Q ( Fluoroquinolone) may strengthen the regimen for pt w/ extensive dse. </li></ul><ul><li>h- Amikacin, kanamycin or capreomycin should be d/c after 2-6 mos. </li></ul><ul><li>i- Streptomycin should be d/c after 2 mos. Because it is less effective for tx failure. </li></ul>
  50. 52. <ul><li>j- Streptomycin for initial 2 mos.or a Fluroquinolone might strengthen the regimen for extensive dse. </li></ul><ul><li>PAS – para-aminosalicylic acid. </li></ul><ul><li>Fluroquinolones : Levofloxacin, ciprofloxacin, moxifloxacin, gatifloxacin have a good, broad antimycobacterial activity. </li></ul>
  51. 53. 25-30mg/kg 15-20mg/kg Ethambutol 30-40mg/kg, max 3G 20-25mg/kg, max 2G PZA 10mg/kg, max 600mg 10mg/kg, max 600mg Rifampin 15mg/kg, max 900mg 5mg/kg, max 300mg INH TRICE-WKLY DAILY DOSE DRUG DOSAGE RECOMMENDED DOSAGE FOR INITIAL Rx OF TB IN ADULT
  52. 54. <ul><li>Streptomycin – usual adult dose is 0.5-1.0g IM OD or 5x per wk. </li></ul><ul><li>- less nephrotoxic; ototoxic </li></ul><ul><li>Bacteriologic evaluation is the prefereed method of monitoring response to tx. </li></ul><ul><li>All pts. Have negative sputum culture by the end of 2-3 mos.of tx. </li></ul><ul><li>If the culture remains (+), tx failure & drug resistance should be suspected. </li></ul>
  53. 55. Drug Resistance <ul><li>Primary – infection caused by a strain resistant prior to therapy. </li></ul><ul><li>Acquired – resistance arising during tx because of an inadequate regimen. </li></ul><ul><li>Noncompliance. </li></ul>

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