Tuberculosis and epidemiology

1. Tuberculosis and epidemiology Dr. Barati

2. History 3000 سال پيش از ميلاد: آثار سل ستون مهره در موميائي هاي مصري مشاهده شد.اشاره به بيماري سل در قانون مانو در هند به عنوان يكي از علل منع ازدواج با دختري كه در اجدادش بيماري به سل وجود داشته است. اشاره در طب قديم چين به بيماري سل تحت عنوان كائوپينگاشاره به مصر به عنوان مركز معالجه مسلولان در گزارش هرودت مورخ يوناني2000سال قبل از ميلاد: اشاره به بيماري سل در قانون حمورابي 700سال قبل از ميلاد: اشاره در آئين زرتشت پيامبر به انتقال بيماري از طريق دفع خلط 500سال قبل از ميلاد: تشريح كامل و ذكر مسائل بهداشتي و عوارض بيماري سل توسط بقراط پزشك بزرگ يوناني 300سال قبل از ميلاد: اشاره ارسطو به بيماري سل قرن اول ميلادي: جالينوس پدر طب تجربي در رابطه با سل توضيح داده و داروهايي را نيز جهت درمان به كار برده است . او معتقد بود كه جهت جلوگيري از سرايت بيماري , بيماران مسلول بايد از افراد سالم جدا شوند.  قرن ششم تا هشتم ميلادي: توضيح هارون اسكندواني (سال622م) و حنين ابن اسحاق (873-809م) در رابطه با بيماري سل قرن نهم ميلادي: تشريح بيماري سل توسط ابوبكر محمدبن زكرياي رازي در كتاب الحاوي)وي اولين پزشكي است كه در رابطه با سل استخوان اندام ها بحث مي كند.(

3. Etiology • Mycobacteria belong to the family Mycobacteriaceae and the order Actinomycetales. • M. tuberculosis complex: M. Bovis , M. Caprae , M. Africanum , M. microti, M. pinnipedii, and M. Canetti • tuberculosis is a rod-shaped, nonspore-forming, thin aerobic bacterium • Acid fastness is due mainly to the organisms' high content of mycolic acids, long-chain cross-linked fatty acids, and other cell-wall lipids. • acid fastness : Nocardia, Rhodococcus, Legionella micdadei, Isospora and Cryptosporidium.

4. وضعیت بروز سل در جهان-1 از هر سه نفر جمعيت جهان، يك نفر به باسيل سل آلوده بوده و درهر ثانيه يك نفر به تعداد آنان افزوده مي شود.درحال حاضر 12 ميليون نفر درجهان به بيماري سل مبتلا هستند كه بيش از 80% اين موارد، تنها مربوط به 22 كشور درحال توسعه جهان است.در سال 2012 میلادی، حدود 8.6 ميليون نفر جدید به سل فعال مبتلا شده که برآورد میشود حدود 1.3 ميليون نفر در اثر اين بيماري جان مي سپارند. بيش از 90% موارد بيماري و مرگ ناشي از سل در كشورهاي در حال توسعه رخ مي دهد، كشورهايي كه 75% موارد بيماري در آنها به فعال ترين گروه سني به لحاظ اقتصادي )يعني 15 تا 54 سالگي( تعلق دارد.

5. وضعیت بروز سل در جهان-2 1- آلودگي همزمان به ويروس ايدز خطر ابتلا به بيماري سل را به طور معناداري افزايش مي دهد. کشورهای با شیوع بالای ایدز)افريقاي زير صحرا(، شاهد افزايش چشمگير تعداد بيماران مبتلا به سل بوده و در سال 2012، میزان شیوع عفونت اچ آی وی در میان بیماران مبتلا به سل در جهان 13% تخمین زده شده است. 2- مقاومت چند دارويي، كه نتيجه مديريت ضعيف درمان سل است مشكلي جدي و روبه فزوني در بسياري از كشورهاي جهان مي باشد.بيماري سل كه بزرگترين علت مرگ ناشي از بيماري هاي عفوني تك عاملي در جهان است )حتي بيشتر از ايدز، مالاريا و سرخك(، داراي مرتبه دهم در بار جهاني بيماري هاست و پيش بيني مي شود تا سال 2020 همچنان جايگاه كنوني خود را حفظ كند و یا تا رتبه هفتم بالا رود.

6. DRUG-RESISTANT TB • Primary: strain infecting a patient who has not previously been treated. • Acquired: during treatment with an inappropriate regimen • MDR-TB: • XDR-TB: MDR strains that are resistant to all fluoroquinolones and to at least one of three second-line injectable agents (amikacin, kanamycin, and capreomycin). . management of patients with MDR- and XDR-TB is y provided in specialized centers.

7. وضعیت سل مقاوم به چند دارو در جهان . سازمان جهانی بهداشت تعداد موارد جدید MDR-TB را در سال 2011 ، 310000 مورد براورد کرده استسل مقاوم به دارو اساساً یک پدیده ساخته دست بشر است.عوامل مرتبط با بیمار : 1- تمکین ضعیف بیماران 2- نا آگاهی بیماران 3- عدم دسترسی / عدم اطلاع از وجود درمان ضدسل رایگان 4- مشکلات موجود برای ایاب و ذهاب بیماران به مرکز بهداشتی درمانی 5- نگرش منفی جامعه نسبت به بیماری 6- ابتلا به سوءجذب 7- اعتیاد / سوء مصرف مواد عوامل مرتبط با دارو: 1- کیفیت نامناسب دارو 2- نامنظمی در تأمین برخی داروهای ضد سل 3- نامناسب بودن شرایط ذخیره سازی دارو 4- تجویز دوز غلط یا ترکیب نامناسب دارویی عوامل مرتبط با ارائه کنندگان خدمات درمانی : 1- عدم وجود دستورالعمل مناسب و جامع کشوری 2- عدم تبعیت پزشکان از دستورالعمل کشوری 3- آموزش ناکافی پزشکان و کارکنان بهداشتی- درمانی مرتبط 4- عدم پایش صحیح درمان بیماران 5- ضعف ساختاری یا اعتباری برنامه کنترل سل 6- عدم آموزش بیماران و خانواده آن ها 7- ضعف در اطلاع رسانی به مردم در زمینه رایگان بودن درمان ضد سل مهمترین راه پیشگیری از بروز M(X)DR-TB: اجرای کامل استراتژیدرمان صحیح و موثر بیماران مبتلا به سل با دوز، ترکیب، طول مدت مناسب و کافی تحت نظارت مستقیم روزانه

8. وضعیت بروز سل در ایران روند نزولي ميزان بروز بيماري سل در طول 47 سال گذشته )از 142 مورد در يكصد هزار نفر جمعيت در سال 1343 به 14.4 در يكصد هزار نفر جمعيت در سال 1391 – حدود 10 برابر كاهش ( از تعداد 10987 مورد مبتلا به سل گزارش شده کشور در سال 1390، 50% موارد را زنان بیمار و 12% موارد را بیماران غیر ایرانی )اغلب افغانی(تشکیل می دهند و بیشترین میزان بروز سل مربوط به گروه سنی 65 سال به بالا بوده است درمیان استانها سیستان و بلوچستان و گلستان بیشترین میزانهای بروز و شیوع را در کشور دارا هستند. همسايگي ايران با دو كشور افغانستان و پاكستان كه در زمره 22 كشور High Burden دنیا هستند ـ وهمچنين عراق )با بحران هاي چند ساله اخير آن( و كشور هاي تازه استقلال يافته شمال كشور )با شيوع بالاي سل مقاوم به چند دارو)(ضرورت توجه بيش از پيش ما را به اين بيماري متذكر مي كند.

9. طول مدت تاخير در تشخيص و درمان بيماران مبتلا به سل سال 1382 ميانه تاخير كلي تشخيص و درمان بيماران مبتلا به سل ريوي خلط مثبت درايران 92 روز ) با ميانگين 10+ 120 روز (بوده و ميانه تاخير بيمار و پزشك در تشخيص به ترتيب )20 باميانگين 6+44 روز(و 46 روز ) با ميانگين 8+ 76روز)بوده

10. Acquired Infection: exogenous factors • droplet nuclei: coughing, sneezing, or speaking. • Other routes ( through the skin or the placenta), an abrasion occurs in pathologists and laboratory personnel (prosector’s wart), and venereal transmission • M. bovis infection from ingestion of contaminated milk • The probability of contact with a person who has an infectious form of TB, the intimacy and duration of that contact, the degree of infectiousness of the case, and the shared environment in which the contact takes place are all important determinants of the likelihood of transmission. • sputum smear positive > sputum smear negative / culture positive> culture negative / extrapulmonary • HIV co-infection • Crowding in poorly ventilated rooms is one of the most important factors in the transmission of tubercle bacilli, since it increases the intensity of contact with a case.

11. Development of Disease:endogenous factors • 1- Age: infancy, ages15 to 25 years, and old age. The incidence among women peaks at 25-34 years of age. • 2- approximately 3% to 4% of infected individuals acquire active tuberculosis during the first year after tuberculin conversion, and a total of 5% to 15% do so thereafter. • 3- HIV co-infection, tuberculin skin test (TST)–positive persons, this risk varied from 2.6 to 13.3 cases per 100 person-years and increased as the CD4+ T cell count decreased. • 4- intensity and duration of exposure. The degree of tuberculin positivity has some predictive value. • 5- Malnutrition, alcoholism, homelessness, incarceration, immunosuppression, Silicosis, Chronic renal failure/hemodialysis , Diabetes, IV drug use, Immunosuppressive treatment, Gastrectomy, Jejunoileal bypass, Posttransplantation period (renal, cardiac),Tobacco smoking, severe underweight • 6- Host genetic factors: • 7- Fibrotic lesions (spontaneously healed) • Noninfectious: cough subsides, concentration of organisms in sputum decreases 2 weeks in patients with drug-sensitive tuberculosis • Hospitalized HIV-positive patients with respiratory symptoms should be admitted to negative-pressure isolation rooms, six air changes per hour, Procedures that stimulate coughing, such as sputum induction, bronchoscopy, and aerosolized pentamidine treatment, should be carried out in negative-pressure rooms or special booths, use of particulate respirator masks, Ultraviolet radiation of the air

12. Natural History of Disease • untreated TB is often fatal. • About one-third of patients died within 1 year after diagnosis, and more than 50% died within 5 years. The 5-year mortality rate among sputum smear–positive cases was 65%. Of the survivors at 5 years, 60% had undergone spontaneous remission, while the remainder were still excreting tubercle bacilli. • With effective, timely, and proper chemotherapy, patients have a very high chance of being cured. However, improper use of anti-TB drugswhile reducing mortality rates, may also result in large numbers of chronic infectious cases, often with drug-resistant bacilli.

13. Pathogenesis • Airborne droplet nuclei -----subpleural and in the midlung zone (the lower parts of the upper lobes and the upper parts of the lower and middle lobes, nonpulmonary initial foci will involve abraded skin, the intestine, the oropharynx, or the genitalia, all associated with foci in regional lymph nodes)------ingested by alveolar macrophages, destroying the macrophage. • Blood-borne lymphocytes and monocytes ------differentiating into macrophages (pneumonitis slowly develops). Infected macrophages are carried by lymphatics to regional (hilar, mediastinal, and sometimes supraclavicular or retroperitoneal) lymph nodes and spread hematogenously throughout the body. • lymph nodes, kidneys, epiphyses of the long bones, vertebral bodies, and juxtaependymal meningeal areas adjacent to the subarachnoid space, apical posterior areas of the lungs. • Before the development of hypersensitivity (tuberculin reactivity), microbial growth is uninhibited, both in the initial focus and in metastatic foci, providing a nidus for subsequent progressive disease in the lung apices and in extrapulmonary sites, either promptly or after a variable period of latency • Tuberculin positivity appears 3 to 8 weeks after infection: 1- positive skin test 2- the Ghon focusو, 3- Ranke complex , 4- Simon’s foci, 5- erythema nodosum, 6- phlyctenular keratoconjunctivitis 7- large hilar or mediastinal lymph nodes may produce bronchial collapse with distal atelectasis or may erode into a bronchus and spread infection distally, 8- advancing pneumonia ( progressive primary) , 9- miliary tuberculosis ( primary complex or wall of a pulmonary vein (Weigart focus),10- meningitis, 11- serofibrinous pleurisy with effusion, 12- seeding of the apical posterior areas of the lung, • Apical Localization: hyperoxic environment /deficient lymphatic flow • Endogenous versus Exogenous Reinfection: new inocula are destroyed before significant multiplication occurs, Repeated inhalational exposures to tubercle bacilli maintain high degrees of tissue hypersensitivity and cellular immunity, making superinfection more difficult; however, when the airborne inoculum is large, or in immunocompromised hosts, superinfection may occur..

14. Late hematogenous tuberculosis • Chronic tuberculosis + aging or compromise cellular immunity • General stress, poor health, malnutrition , pregnancy ( early postpartum period), corticosteroids, other immunosuppressive agents, hematopoieticreticuloendothelial diseases, particularly malignancies. Infliximab • The postgastrectomy state, jejunal-ileal bypass surgery, end-stage renal disease , Viral illnesses, Destructive local pulmonary processes such as lung abscess, carcinoma, cavitary histoplasmosis, and pulmonary resection,bone and joint tuberculosis after physical injury, tuberculous peritonitis after tubal insufflation, progressive hematogenous tuberculosis after curettage of a tuberculous endometrium, and late generalized hematogenous tuberculosis after major trauma • nearly all tuberculin-positive patients with HIV infection eventually develop active tuberculosis unless either HIV or the tuberculous infection, or both, are effectively treated, or another fatal complication of AIDS occurs.

15. CLINICAL MANIFESTATIONS • Pulmonary : primary, post primary • Extrapulmonary: lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum, and pericardium, miliary • Both.

16. DIAGNOSIS: 1- AFB Microscopy smear of expectorated sputum / tissue (e.g., a lymph node biopsy): 1- inexpensive 2- low sensitivity (40–60%) : 10,000 /ml ( culture : 10-100/ml) Ziehl-Neelsen basic fuchsin Kinyoun ( modified, without heat( auramine-rhodamine staining and fluorescence microscopy.(Less expensive light-emitting diode (LED) fluorescence microscopes) two or three sputum specimens, preferably collected early in the morning(two specimens collected on the same visit ) AFB microscopy on urine or gastric lavage fluid is limited by the presence of commensal mycobacteria that can cause false-positive results.

17. DIAGNOSIS: 2- Culture, NAA • Definitive diagnosis : 1-isolation and identification of M. tuberculosis from a clinical specimen 2- identification of specific sequences of DNA in a nucleic acid amplification test . Culture: 3-8W solid egg based: Lowenstein Jensen Solid agar based: Middlebrook 7H11 1-3 W Liquid broth: Middlebrook 7H12 BACTEC • Lysis-centrifugation culture method: intracellular organism( blood culture( • Nucleic acid amplification: in smear positive, sens. and spec. more than 95% in smear negative, sens. 40-77% and spec. more than 95%

18. Diagnosis: 4- Radiographic Procedures • upper-lobe disease with infiltrates and cavities • any radiographic pattern: from a normal film or a solitary pulmonary nodule to diffuse alveolar infiltrates in a patient with adult respiratory distress syndrome • AIDS, no radiographic pattern can be considered pathognomonic. • CT : 1- questionable findings on plain chest , 2- extrapulmonary TB (e.g., Pott's disease). • MRI : intracranial TB.

19. Additional Diagnostic Procedures • Sputum induction: ultrasonic nebulization of hypertonic saline • fiberoptic bronchoscopy with bronchial brushings and endobronchial or transbronchial biopsy of the lesion. Bronchoalveolar lavage of a lung segment containing an abnormality • early-morning gastric lavage • extrapulmonary TB: specimens from involved sites (CSF, pleural fluid and biopsy samples , biopsy and culture of bone marrow and liver tissue , blood culture), epidemiologic evidence ( history of close contact with an infectious patient), a positive TST or IFN- release assay , and a compatible clinical and radiographic response to treatment.

20. Diagnosis of Latent M. Tuberculosis Infection: 1- TUBERCULIN SKIN TESTING • Koch’s tuberculin (old tuberculin) was an extract of a boiled culture of tubercle bacilli. In 1934, Siebert made a simple protein precipitate (purified protein derivative [PPD]) of old tuberculin. A 5-tuberculin unit , 250-TU dose, 1-unit • multiple puncture techniques (Heaf and Tine tests ) • tuberculin purified protein derivative (PPD). Limitation: 1- lack of mycobacterial species specificity ( large number of proteins in this product that are highly conserved in the various species). 2- subjectivity of the skin-reaction interpretation, 3- deterioration of the product, 4- batch-to-batch variation. • tuberculin testing: 1- only of persons at high risk for developing tuberculosis without treatment of latent infection, and for whom treatment will be prescribed if the test is positive. 2- Initial testing for persons whose activities will place them at increased risk of exposure • 90%of persons with 10 mm of induration and virtually all with greater than 15 mm of induration to 5 TU are infected with M. tuberculosis

21. PPD-2 • booster effect • False-negative: 20% (general illness and become positive 2-3 weeks after effective treatment ), Protein malnutrition, Sarcoidosis, Intercurrent viral infections, reticuloendothelial disease, and corticosteroid therapy, Intraobserver reliability in reading reactivity may vary by as much as 3 mm, overwhelming TB • false-positive: environmental mycobacterial exposure or BCG vaccination and operator-dependent variability in test placement and reading. • Variant (“Delayed”) Tuberculin Reactivity: among Indochinese immigrants. • PPD conversion: 8.1% of positive reactors reverted to true negative when retested 1 year late • HIV infection: tuberculin reactivity decreases as the CD4 cell count falls

22. Diagnosis of Latent M. Tuberculosis Infection: 2- IFN-γ RELEASE ASSAYS • TB-specific antigens ESAT-6 and CFP-10 stimulate T cell-------- release of IFN- γ: 1- T-SPOT.TB enzyme-linked immunospot (ELISPOT) assay, detects T cell responses to M. tuberculosis antigens. 2- QuantiFERON-TB Gold ( a whole-blood enzyme-linked immunosorbent assay (ELISA) for measurement of IFN-γ, • Specific: less cross-reactivity due to BCG vaccination and nontuberculous mycobacteria. • Sensitivity: lack of a gold standard • Because there is no gold standard for the detection of latent tuberculosis, prospective studies of the new assays are needed to evaluate their predictive value for future development of active tuberculosis. • advantages of IGRAs: fewer patient visits to complete testing, the avoidance of somewhat subjective measurements such as skin induration, and the ability to perform serial testing without inducing the boosting phenomenon . • Different national guidelines: United States, IGRA over the age of 5 years who are being screened for LTBI. for those at high risk of progression to active TB (e.g., HIV-infected persons), either or both In Canada and some European countries, a two-step approach for those with positive TST

23. Treatment • First line: Isoniazid( H) 5 mg/kg ( max 300) Rifampin (R) 10 mg/kg ( max 600) Ethambutol (E) 15 mg/kg Pyrazinamide (Z) 25 mg/kg ( 2 g) • Second line: aminoglycosides (streptomycin, kanamycin, amikacin); capreomycin; ethionamide, cycloserine, PAS; fluoroquinolone (levofloxacin, gatifloxacin, moxifloxacin), amithiozone (thiacetazone). Unproven: clofazimine, amoxicillin/clavulanic acid, clarithromycin, imipenem, and linezolid

24. PREVENTION • diagnose and isolate infectious cases rapidly • appropriate treatment until patients are rendered noninfectious (usually 2-4 weeks) • BCG vaccination • treatment of persons with latent tuberculosis

25. BCG Vaccination • M. bovis • Efficacy: from 80% to 0 • protection of infants and young children from relatively serious forms of TB, such as tuberculous meningitis and miliary TB. • The local tissue response begins 2-3 weeks after vaccination, with scar formation and healing within 3 months. • Side effects: ulceration at the vaccination site and regional lymphadenitis ( 1-10%) , osteomyelitis (1/1000,000), Disseminated BCG infection ("BCGitis“)(1/10,000,000) , although this problem is restricted almost exclusively to persons with impaired immunity, such as children with severe combined immunodeficiency syndrome or adults with HIV infection. induces TST reactivity • recommended for routine use at birth in countries with high TB prevalence • HIV-infected adults and children should not receive BCG vaccine.

26. Treatment: Latent Tuberculosis Infection • HIV-infected persons or persons receiving immunosuppressive therapy: PPD≥ 5 • Close contacts: PPD ≥ 5: children, HIV • Persons with fibrotic lesions on chest radiography: PPD ≥ 5 • Recently infected (≤2 years): PPD ≥10 • high-risk medical conditions: PPD ≥ 10 • Low-risk persons: PPD ≥ 15

27. Isoniazid : Daily for 9 m Twice weekly for 9 m Daily for 6 m. Twice weekly for 6 m. • Rifampin: Daily for 4 m 1- contacts of patients with isoniazid-resistant, rifampin-susceptible tuberculosis • Rifampin plus pyrazinamide: Daily for 2 m Twice weekly for 2–3 months

28. Direct Observed Therapy( DOTS) 1- political commitment with increased and sustained financing; 2- case detection through quality-assured bacteriology (starting with microscopic examination of sputum from patients with cough of >2–3 weeks' duration, culture, and possibly drug susceptibility testing); 3- administration of standardized short-course chemotherapy, with direct supervision and patient support; 4- an effective drug supply and management system; 5- a monitoring and evaluation system, with impact measurement (including assessment of treatment outcomes—e.g., cure, completion of treatment without bacteriologic proof of cure, death, treatment failure, and default—in all cases registered and notified).