Tuberculosis

1882 March 24– Robert Koch – “one seventh of all human beings die of tuberculosis and… if one considers only the productive middle-age groups, tuberculosis carries away one-third and often more of these…”

M tuberculosis as causative agent for tuberculosis Robert Koch 1886

TB – A Multi-system Infection

Global burden of TB 200 crore infected, i.e. 1 in 3 of global population 90 lakh (139/lakh) new cases in 2013, 80% in 22 high-burden countries 40 lakh new sm+ve PTB (61/lakh) cases in 2008 Global incidence of TB has peaked in 2004 and is declining. 1.5m deaths in 2013, 98% in low-income countries MDR-TB -prevalence in new cases around 3.6% Source of information (2006 report) 06 3

Estimated TB incidence rate, 2007 :Source: WHO Geneva; WHO Report 2009: Global Tuberculosis Control; Surveillance, Planning and Financing

Magnitude of the Problem Global annual incidence = 9.1 million India annual incidence = 1.9 million India is 17th among 22 High Burden Countries (in terms of TB incidence rate) In 2008, there were estimated 9.4 million new cases equivalents to 139 cases per 100,000 population of TB globally. In 2008, out of the estimated global annual incidence of 9.4 million TB cases, 1.98 million were estimated to have occurred in India, of whom 0.87 million were infectious cases, thus catering to a fifth of the global burden of TB. About 40% of Indian population is infected with TB bacillus. The incidence of TB in India is estimated based on findings of the nationwide annual risk of tuberculosis infection (ARTI) study conducted in 2000-2003. The national ARTI being 1.5%, the incidence on smear positive TB cases in the country is estimated as 75 new smear positive cases per 100,000 population Source: WHO Geneva; WHO Report 2008: Global Tuberculosis Control; Surveillance, Planning and Financing Dr. KANUPRIYA CHATURVEDI 4/17/2019

Problem of TB in India Estimated incidence 171 per lakh in 2013 Estimated prevalence of TB disease 211 per lakh in 2013 Estimated mortality 19/lakh in 2013 240,000 deaths due to TB each year Divide into two slides

Natural History of TB Infection Exposure to TB No infection (70-90%) Infection (10-30%) Latent TB (90%) Active TB (10%) Never develop Active disease Untreated Treated Die within 2 years Survive Die Cured

Latent TB vs. Active TB Latent TB (LTBI) (Goal = prevent future active disease) = TB Infection = No Disease = NOT SICK = NOT INFECTIOUS Active TB (Goal = treat to cure, prevent transmission) = TB Infection which has progressed to TB Disease = SICK (usually) = INFECTIOUS if PULMONARY (usually) = NOT INFECTIOUS if not PULMONARY (usually)

Agent-Mycobacterium tuberculosis

TB Invades/Infects the Lung Effective immune response Infection limited to small area of lung Immune response insufficient

Source of infection Human source- Sputum smear positive case can infect 15 person per year if untreated Bovine source- infected milk

Factors associated with TB Host factors Age- affect all ages, but more in productive age group Males are more affected than females Nutrition status Immunity Social factors Poor housing Over crowding Smoking , alcoholism poverty

Classification of tuberculosis Pulmonary – affecting lung or tracheobronchial tree Extra pulmonary- involving Pleura or pericardium Lymphnodes Abdomen Genitourinary tract Skin Joints Bones meninges

Bacteriological confirmed TB and clinical tuberculosis Drug resistant tubeculosis

Pulmonary tuberculosis The most common symptom of PTB is a persistent cough of two weeks or more, with or without expectoration. It may be accompanied by one or more of the following symptoms:- • Fever, night sweats, weight loss • Chest pain, hemoptysis, shortness of breath, tiredness and loss of appetite

Extra pulmonary tuberculosis A person with extra-pulmonary TB may have symptoms related to the organs affected along with constitutional symptoms stated above. Enlarged cervical lymph nodes with or without discharging sinuses (TB Lymphadenitis) Chest pain with or without dyspnoea in pleural TB Pain and swelling of the joints in bone tuberculosis (fever, backache, deformity in spinal TB) Signs of raised intra-cranial tension like irritability, headache, vomiting, fever, stiffness of the neck and mental confusion in TB meningitis Painless haematuria or sterile pyuria in renal tuberculosis and infertility in genito-urinary TB.

Control of tuberculosis Has 2 component Preventive – BCG vaccination, INH prophylaxis for children Curative Case finding and treatment

BCG Vaccination Danish 1331 strain Dose 0.1 ml intra dermal (0.05 ml in < 4 weeks) Effective in reducing pediatric tuberculosis and mortality Contraindicated in those with eczema, immunodeficiency states

Evolution of TB Control in India 1950s-60s Important TB research at TRC and NTI 1962 National TB Programme (NTP) 1992 Programme Review only 30% of patients diagnosed; of these, only 30% treated successfully 1993 RNTCP pilot began 1998 RNTCP scale-up 2001 450 million population covered 2004 >80% of country covered 2006 Entire country covered by RNTCP 4/17/2019

Program performance and evolution of RNTCP Despite a nationwide network of facilities , NTCP failed to yield satisfactory results. The situation did not change much. The case finding efficiency was only 30 of the expected level although the mortality rate decreased to 53/100,00 population Government of India launched the Revised National Tuberculosis Control Program(RNTCP) in 1997 encouraged by the results of Pilot studies were tested in 1993-94 4/17/2019

Case finding tools Sputum microscopy X ray Sputum culture Light microscopy Fluorescent microscopy X ray Sputum culture Genotypic method Phenotypic method

Sputum microscopy Sputum smear microscopy is the most widely used and acceptable testing tool for diagnosing smear positive pulmonary TB. Ziehl-Neelsen staining technique is used in RNTCP. Sputum microscopy has the following advantages:- • Simple, inexpensive, requires minimum training • High specificity • High reliability with low inter-reader variation • Can be used for diagnosis, monitoring and defining cure • Results are available quickly • Feasible at peripheral health institutions • Correlates with infectivity in pulmonary TB cases

X ray Chest x-ray as a diagnostic tool is more sensitive but less specific with higher inter and intra reader variation. It should always be preceded by a repeat sputum smear examination following treatment with It is also useful for diagnosing extra pulmonary TB like pleural effusion,pericardial effusion, mediastinal adenopathy and miliary TB. The following are the limitations of the chest x-ray as a diagnostic tool High inter and intra-reader variation No shadow is characteristic of TB

Diagnostic tools for MDR-TB / XDR TB: Drug resistant TB (MDR/XDR and other types) is a laboratory based diagnosis either phenotypically i.e., growing the bacteria (culture) and demonstrating the ability of bacteria to grow in the presence of the anti-TB drugs (drug sensitivity testing - DST) genotypically by demonstrating the presence of resistance genes using molecular methods.

Culture The conventional and newer rapid tools used for diagnosis are: Solid culture medium - (Egg-based Lowenstein Jensen) or agar based 7H11/10medium Liquid culture medium – Commercial automated MGIT 960

Molecular Assays PCR based technologies resistance genes (rpoβ for rifampicin, katG and inhA for INH etc). Line Probe Assays (LPA) which GeneXpert – a completely closed automated system using real-time PCR which has a sensitivity of 70-90% even for smear negative cases and can also detect the presence of rifampicin resistance

Process of diagnosis of Pulmonary TB Referral of Presumptive TB cases to DMC Collection of 2 sputum samples

Algorithm for case detection

Diagnosis of extra pulmonary tuberculosis (a) Fine Needle Aspiration Cytology (FNAC) and direct smear examination (b) Excision / Biopsy of specimen for histopathological examination (c) Fluid for cytology , biochemical analysis and smear examination (d) X-ray of the involved region (e) Ultra Sonography for Abdominal Tuberculosis (f) Culture for Mycobacterium tuberculosis (M.Tb)

Chemotherapy First line drugs Bacteriocidal Bacteriostatic Rifampicin (R) Isoniazide (H) Pyrazinamide (P) Streptomycin (S) Bacteriostatic Ethambutol (E)

Chemotherapy Second line drugs Fluroquinalones Ethionamide Capreomycin Cycloserine Thioactetazone Para amino salicilic acid Macrolides NEW DRUG- BEUDAQUALINE

Category of treatment in RNTCP

Sputum examination Category 1 2 months - start continuation phase. Repeat sputum at 4 th and 6th month + Continue intensive phase for one more month. If sputum positive in 5th month then considered as failure Category 2 3 months Start continuation phase. Test sputum at 5 months, 6 months and completion of tratment Continue intensive phase for one more month Test sputum at 4 months, if positive send for culture and drug sensitivity

Non-DOTS (ND) treatment regimen under RNTCP Given to Those with adverse reactions to rifampicin and/or pyrazinamide “New” patients who refuse DOTS despite all efforts 12-month duration, comprising 2 months of SHE and 10 months of HE (2SHE / 10HE). Dosages administered per day in the regimen are: Isoniazid - 300 mg Ethambutol - 800 mg Streptomycin - 750 mg (500 mg for those >50 years of age).

Treatment Related Information Importance of DOT Role of rest, special diet and isolation Cough hygiene and sputum disposal Referral for HIV counseling and testing Diabetes screening and control Adherence to follow-up schedules: Sensitization on adverse reactions: Smoking Alcohol abuse Importance of screening symptomatic contacts and children below 6 years

Drug resistant tuberculosis Multi Drug resistant tuberculosis: resistance to isoniazide and rifampicin Poly drug resisitance Resistance to more than one first line drugs (otherthan INH and rifampicin) Extensive drug resistance Resistance to any fluroquinalones and at least one of the second line injectables ( capreomycin, kanamycin,and amikacine)

Drug resistance tuberculosis Drug resistant TB is seen in 2.2 % of new cases and 15 % or retretment cases Diagnosed at intermediate reference laboratory (IRL) by culture, and drug sensitivity test Rapid diagnosis by gene Xpert is avaliable

Multi Drug resistance tuberculosis Treatment is initiated at DOTS plus site Given as single daily dose under DOT Phase Duration drugs Intensive phase 6-9 months Kanamycin Levofloxacin Ethionamide Pyrazinamide Ethambutol cycloserine Continuation phase 18 months Levofloxacine Cycloserine Reserve drugs PAS Capreomycin moxifloxacin

Regimen of XDR TB Phase Duration Intensive phase 6-12 months Capreomycin PAS Moxifloxacin INH high dose Clofazamine Linezolid amoxyclav Continuation phase 18 months Reserve drugs Clarithromycin, thioacetazone

TB in pregnant women IP with Isoniazide, refampicin and ethambutol for 2 months CP with INH and rifampicin for 7 months Ethambutol can be stopped after one month if found sensitive to R and H Vitamin B6 25 mg Od to pevent peripheral neuropathy

TB and HIV All TB cases should be tested for HIV in ICTC All HIV positives should be referred for sputum microscopy

TB and Diabetes Diabetes accounts for 15 % of tuberculosis All tuberculosis cases should be screened for diabetes Blood sugar level of Diabetic TB patients should be checked regularly to asses control

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