Tuberculosis ד"ר מנדל גלזר מנהל מכון רוקח ומלש"ח ירושלים שירותי בריאות כללית, מחוז ירושלים מסונף לאוניברסיטה העברית מכון הריאה ב"ח הדסה ע"כ

מלש"ח – מרכז לאבחון וטיפול בשחפת 9 מלש"חים בארץ לשכות הבריאות האזוריות ירושלים – מרכז רוקח

מרכז רפואי על שם ד"ר י.ל. רוקח

מלש"ח מרפאות קהילה מלש"חים אחרים לשכת הבריאות משרד הבריאות בתי חולים כלליים מלש"ח צה"ל בי"ח ספציפיים מרכז קליטה מבוטחי כל הקופות עובדים זרים

History Terms Consumption Phthisis [ Greek ] Phthisis Pulmonalis Scropula Tabes Mesenterica Koch’s Disease

TB History 1020 – Ibn Sina [ Avicena ] described in first as contagious disease 1839 - Senabsin - name Tuberculosis 1859 – First sanatorium in Germany 1882 – R.Koch found bacilli 1905 – Nobel Price 1906 – A. Galmette and Camele Gurien – first immunisation

TB History 1907 – National TB Association founded in US and Canada 1921 – First human vaccination used in France 1946 – Streptomycin was developed 80’s – Drug resistance appeared The 20th _ TB kill’s more than 100 million people

Incidence 8,8 million new cases and 1,4 million died in 2010. 19-43% of the world`s population are infected by M.Tuberculosis. >95% of cases occur in developing countries.

TB - USA

Tuberculosis . Infectious disease caused by Mycobacterium Tuberculosis Transmitted from a person with active lung disease Airborne transmission Exposure time, host susceptibility dependant

MT COMPLEX . Mycobacterium Tuberculosis Mycobacterium Bovis Mycobacterium Africanum M.Microti, M.Pinnipedii, M.Carpae

MTB Small rod-like bacillus Aerobic Divides every 16-20 hours Can identify under regular microscopy Ziehl-Neelsen stain Fluorescent microscopy Rhodamine, Ahramine stain

Mycobacterium TB

Sputum ZN Stained

TB

Tuberculosis Active Disease Latent [ LTI ]

Tuberculosis MDR [ Multi drug resistance ]- Rifampicin, Isoniazid XDR [ Extensive drug resistance ] – Rif., Ison., Fluoroqinolones, Aminoglicosides HIV

Lung TB

TB Diagnostics Sputum Bronchoscopes Gastric Aspiration Histopathology [ Biopsy ]

Rapid TB Tests NAA [ Nucleic Acid Amplification ] Gen-Probe MTD Enhanced MTD Amplicor MT Test

TB in Children Under 5year triad of close contact, positive TST, suggestive findings on the x-ray [ primary complex, opacification with hilar or subcarinal lymphadenopathy ] or physical examination are useful for diagnosis for active TB Gastric aspiration

Relative Risk for TB AIDS 110- 170 HIV 50 - 110 Transplant 20 - 74 CA Head/Neck 16 TNF Inhibitor 1,7 – 9 Solitary Granuloma 2 Apical Fibronodules 6 - 19 Resent TB Inf [ under 2 years ] 15

Relative Risk for TB CRF – Hemodialysis 10-25 Silicosis 30 Anti – TNF 1,7 - 9 Young age [under 5 ] 2,2 - 5 Glucocorticoids 4,9 DM all types 2 – 3,6 Smoker 1 p/d 2 – 3 Underweight [ 85% ] 2 - 3

Close Contact - Disease Risk Under 1 year old 50% 1 - 2 years 12% – 25% 2 – 5 years 5% 5 – 10 years 2% Adolescent , young adults 10% - 20% Other adults 3% - 5%

LTI Diagnosis TST Interferon-Gamma release assay [IGRA ]: Enzyme-linked immunosorbent assay - Quantiferon e.g. Elisa Enzyme-linked immunospot assay – Elipsot e.g. T-Spot TB assay.

Tuberculin test (Mantoux) Intradermal injection of 5 TU (tuberculin units) of purified protein derivative (PPD). Induration measured after 48-72 hours. Booster [ two step testing ] Conversion: an increase of 6-10mm to >10mm.

Booster Response, Conversion Booster – 10mm or more and has increased by 6mm since the previous in the absence of exposure. Lover risk than initial positive TST Conversion – 10mm or more and has increased by 6mm since the previous up to 8weks after initial negative TST in the setting of recent exposure Reaction 10 and more mm should be referred for medical evaluation to exclude active TB

TST

התפלגות תוצאות PPD אצל ילידי ישראל

Close Contact PPD Negative – Second test should undergo 8 – 12 weeks later

Potential causes of false negative Tuberculin test : Technical - correctible Tuberculin material : improper storage [ exposure to light, heat ], contamination, improper dilution, chemical denaturation Administration: injection of too little tuberculin, or too deeply, or more than 20 minutes after drawing up into the syringe Reading: inexperienced or biased reader, error in recording

Potential causes of false negative tuberculin tests: Biologic – not correctible Infections: Active TB [ especially if advanced ], bacterial infections [ typhoid fever, brucellosis, typhus, leprosy, pertussis ]. HIV inf [ especially if CD count less than 200 ], viral infection [ measles, mumps, varicella ], fungal infection [ blastomycosis ] Live virus vaccination : measles, mumps, polio Immunosuppressive drugs : corticosteroids, TNF inhibit, others Metabolic disease: CRF, severe malnutrition, stress [ surgery, burns ] Diseases of lymphoid organs: Lymphoma, CLL, Sarcoidosis Age under 6 months, elderly

LTI Diagnosis IGRAs Specificity 95%, Sensitivity 80-90% TST - Specificity 97% in non BCG, and 60% in BCG administered, Sensitivity -80% IGRAs sensitivity is diminished in HIV with lower CD4 [ TSPOT is less affected ] M.Kansasii, M.Marinum affect

LTI Diagnosis USA – IGRAs used, but not in addition to TST Canada – IGRAs is appropriated in the setting of negative TST UK – TST is the first-line test. If positive – may be considered IGRA depending of BCG status

TB - TREATMENT DOT [ Direct Observed Therapy ]

TB Treatment First Line [ INH, RIF, ETH, PZM, Rifabutin] Second Line [ Cycloserine, Ethionamide, Streptomycin, Amikacin, Kanamycin, Capreomycin, PAS, Levofloxacin, Moxyfloxcin ] New drugs [ Interferon, Linezolid ] Surgery

Active TB - Treatment Prolonged Treatment in cavitary , miliary TB In pericarditis, meningitis – corticosteroids Treatment failure – positive sputum culture after 4months treatment - continue 4 drug regimen

Rifampicin 4 months; children 6 months. Treatment Regimes for LTBI Isoniazid 6 to 9 months. Rifampicin 4 months; children 6 months. Rifampicin + Isoniazid 3 months. Liver and kidney functions monitoring.

Risk of Isoniazid-Induced Hepatitis More than 65 years - more than 5% 50 – 65 years - 3-5% Less 50 years – less than 3% Less than 35years – less than 1%

BCG Benefits: diminished risk of TB meningitis Reaction 3-19mm in the first 3 months, after less than 10mm Should not be administrated in individuals with immune compromise

BCG לילודים ולילדים ממשפחות עולים חדשים ותושבים שאינם אזרחי ישראל המגיעים מארצות בהן שכיחות TB גבוה מייד אחרי לידה ועד גיל 4 [ שלא חוסן או שאין עדות על החיסון וכשHIV נשלל ]

BCG Adverse Events - 5% Fever - 2,9% Signif. Proteinurua - 1% Granulomatous Prostatitis - 0,9% Pneumonitis - 0,7% Granulomatous Hepatitis - 0,7% Artralgia - 0,5% Epididymitis - 0,4% Cystitis

BCG – Adverse Events Sepsis - 0,4% Rash - 0,3% Uretral Obstruction - 0,3% Contracted Bladder - 0,2% Renal Abscess - 0,1% Cytopenia - 0,1% Osteomyelitis

NTM Infection MAC M. Kansasii Rapidly Growing – M.Fortuitum, M.Abscessus, M.Chelonae

תודה