Tuberculosis

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Tuberculosis.

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Mycobacteria. Microbiology: >20 species – human tuberculosis caused by 2 species M. tuberculosis (Mtb) and M. bovis “Acid-fast bacilli” (AFB) based on Ziehl-Nielsen (ZN) stain or Kinyoun stain generally do not stain on gram-stain Mtb grows slowly (generation time 15 - 20 hrs); colonies take 4-6 wks to appear.

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Spread during the 19 th century.

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467 Onondaga Sanitorium, Hopper's Glen, Syracuse, N. Y..

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Canadian Rates. Eigure I Reported new active and relapsed tuberculosis incidence rate per 100.000 1924-1998 140 120 100 80 60 40 20 1928 1938 — Canada: 1998 1948 1958 1968 Year of diagnosis 1978 1988.

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Spread during the 21 st century.

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Mycobacterium tuberculosis. Epidemiology: infects 1.7 billion people worldwide; 3 million deaths per year spread is favoured by crowded living conditions concentrated in urban poor, alcoholics, IVDU, homeless, prisons, AIDS, immigrants, aboriginals, elderly.

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Mycobacterium tuberculosis. Epidemiology: major risk group is HIV-infected patients: incidence 400 x general population 5-10% of general adult population infected Canada: 2,000 new cases per year.

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Mycobacterium tuberculosis. Transmission: inhalation of droplet nuclei (Mtb) ingestion of unpasteurized milk (now uncommon) ( M. bovis ) humans are the only reservoir of Mtb other mycobacteria are free-living with no significant person-to-person spread prolonged, and multiple exposures required.

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Mycobacterium tuberculosis. Transmission: most important determinants are: closeness of contact infectiousness of the source (smear positive >> smear negative) ventilation in contact area.

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Mycobacterium tuberculosis. Transmission: infectiousness decreased substantially within 2 wks of therapy 3 to 4% of infected patients will develop active Tb during 1st year after tuberculin converson; 5 - 15% will do so thereafter.

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Immunologic Features of Tuberculosis. good antibody response - no role in host defense cell mediated immunity - major factor in controlling infection: activated lymphocytes able to recognize Mtb antigen presented by macrophages takes 3 - 9 weeks to develop basis of cutaneous reactivity to tuberculin may wane over time (8% will revert to negative when retested 1 year later).

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Pathogenesis of Tuberculosis. Inhalation of droplet nuclei  midlung infection ( 1 0 focus )  macrophages ingest mycobacteria (continue to multiply unimpeded)  infected macrophages carried to regional lymph nodes  spread throughout body via blood ( 2 0 foci )  initially growth is uninhibited  lymphocytes and monocytes arrive (3-9 wks)  tubercle formation, caseous necrosis.

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Pulmonary Tuberculosis - Primary Infection. Multiple outcomes are possible: most instances - rapid destruction of bacteria leads to resolution and only skin test positivity some heal by fibrosis and organisms slowly die; may calcify minority of cases may progress to pneumonia (eg. children, AIDS, elderly), or other disease in some patients, organisms remain viable at 2 0 focus - may reactivate months / years later.

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Pulmonary Tuberculosis - Adult or Reactivation Tuberculosis.

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Mycobacterium tuberculosis. Clinical Manifestations: 1) Pulmonary (85%) - primary infection - adult or reactivation Extrapulmonary (15%) Can be anywhere (meningitis, peritoneal, bone, chest, lymph nodes) Take home point: TB can present in many ways.

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Mycobacterium tuberculosis. Clinical Manifestations - 1 0 infection: most are asymptomatic may manifest as mild “flu-like” illness CXR - enlarged hilar lymph nodes and pulmonary infiltrates in mid-lung zones.

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Mycobacterium tuberculosis. Reactivation tuberculosis: occurs in 5-15% of those recovering from 1 0 infection nonspecific symptoms: anorexia, fatigue, weight loss, fever, chills, night sweats - gradual onset cough productive of sputum, hemoptysis CXR: infiltrate in apical posterior area of upper lobes;  cavities,  nodules,  calcifications.

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Mycobacterium tuberculosis. Diagnosis: Based on clinical suspicion, combined with a skin test, chest Xray, sputum, bronchoscopy culture may take 4 to 6 wks; positive in 85% of cases molecular techniques (PCR, probes) but do produce an isolate for drug testing skin test: false negative in 20% of cases.

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O Sputum liquefaction and inactivation with sample reagent Transfer Of 2 ml material into test cartridge o Sample automatically filtered and washed O Ultrasonic lysis of filter-captured organisms to release DNA o DNA molecules mixed with dry PCR reagents MTB/RIF O Seminested real-time amplification and detection in integrated reaction tube Printable test result Cartridge inserted into MTB-RIF test platform (end of hands-on work) Assay Name MTB-RIF Test Result RIF Resistance NOT DETECTED Time to result, 1 hour 45 minutes.

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Mycobacterium tuberculosis. Treatment: before effective chemotherapy, 50% of patients died within 2 yrs do not wait for culture and sensitivity results 2 or more drugs for up to 6 to 9 months; 95% effective resistance increasing, varies with population.

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Not All TB Drugs are the Same. Agent Early Bactericidal Effect Resistance Prevention Sterilization Isoniazid (INH) Highest High Intermediate Rifampin Intermediate High Highest Pyrazinamide Low Low High Streptomycin Intermediate Intermediate Intermediate Ethambutol Intermediate-High Intermediate Low.

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TB Drugs. Agent Well Tolerated? Adverse Effects Isoniazid Yes Liver toxicity (<1%), peripheral neuropathy, fatigue, headaches, rashes Rifampin Yes! P450 interactions, hepatitis, rashes, diarrhoea, orange urine, headache, fatigue Pyrazinamide No Hepatitis, diarrhoea, rashes, joint pain, gout Ethambutol Yes Dose related optic neuritis (loss of color vision) Amino-glycosides No Renal failure, permanent inner ear damage Quniolones Yes Tendon issues, effective Cycloserine No Mood and cognitive deterioration, psychosis, seizures.

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Standard “short course” therapy for active disease.

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Isoniazid resistance or intolerance. Rifampin + pyrazinamide + ethambutol for 6 to 9 months Require monthly monitoring of colour vision, visual acuity.

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Isoniazid, Rifampin resistance. Pyrazinamide + Ethambutol + Quinolone until 18-24 months after culture conversion Amikacin injections for at least 6-9 months + other drug resistance, treatment becomes very complicated.

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There is a new drug….. Bedaquiline: Inhibits the proton pump necessary for ATP synthase First new class of TB drug in 40 years Drug of choice for highly resistant TB cases CYP3A4 interactions and arrhythmia issues have to be taken into account when using (it has been black boxed).

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The Tuberculin Skin Test (Mantoux test). purified protein derivative (PPD) 5 TU intracutaneous injection - read at 48-72 hrs detects past or current infection: sensitivity - 75 to 90% positive >10 mm of induration (5 mm in certain risk groups) cross reactions with other mycobacteria species and with previous BCG vaccine booster effect (two step test).

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Chemoprophylaxis for Tuberculosis. 2 0 prevention (i.e. those already infected but asymptomatic) to prevent reactivation drug of choice is INH for 1 yr - 60-80% effective must balance risk of reactivation (5-15%) or serious disease vs risk of INH hepatitis based on skin test reaction, age, risk factors (eg. HIV, recent contact, etc.).

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Indications for Chemoprophylaxis. 1. Recent contact with active pulmonary Tb or HIV patients with  5 mm skin test 2. Recent skin converters (  10 mm) within 2 years 3. Patients with abnormal CXR and skin test  10 mm untreated or inadequately treated 4. Children, infants with  10 mm skin test 5. Others with predisposing conditions for active Tb (lymphoma, silicosis, diabetes, etc.).

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Vaccine for Tuberculosis. Bacille Calmette-Guerin (BCG) live attenuated vaccine ( M. bovis ) 60-80% effective in children does not prevent infection; prevents progression to clinical disease and dissemination given only to skin test negative persons only used in high prevalence situations does not alter guidelines for interpretation of skin test.

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Mycobacterium tuberculosis. Prevention: screening for high risk patients adequate ventilation more expensive, tight fitting masks that filter particles 1 - 5  m are costly, uncomfortable routine, yearly skin testing.