Tuberculosis

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Tuberculosis History Pathogenesis Presentation Diagnosis Treatment Prognosis

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By: Amitchandradeva (30 month(s) ago)

it was a nice presentation on Pulmonary rehabilitation. congratulation.

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Tuberculosis:

Tuberculosis Professor AKM Mosharraf Hossain MBBS, FCCP, FCPS, PhD Respiratory Medicine Unit, BSMMU Drmosharraf_hossain@yahoo.com www.authorstream.com

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Robert Koch in 1882 discovered M.tuberculosis .

Koch’s Pastulate-1890:

Koch’s Pastulate-1890 The nobel prize was awarded for this in 1905. The postulates consist of four criteria to establisha causal relationship between a causative microbe and a disease: The organism must be found in all animals suffering from the disease, but not in healthy animals The organism must be isolated from a diseased animal and grown in pure culture The cultured organism should cause disease when introduced into a healthy animal The organism must be re-isolated from the experimentally infected animal.

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 TB was documented in Egypt, India, and China as early as 5,000, 3,300, and 2,300 years ago. Typical skeletal abnormalities, including Pott’s deformities, were found in Egyptian and Andean mummies and were also depicted in early Egyptian and pre-colombian art .  Clinical features of Pulmonary tuberculosis were well described by Hipocrates in about 400 BC.  The TB epidemic in Europe, later known as the “Great White Plague”, probably started at the beginning of the 17th century and continued for the next 200 years. HISTORY OF TB

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When, in 1820, the poet John Keats (1795-1821) coughed a spot of bright red blood, he told a friend, "It is arterial blood. I cannot be deceived. That drop of blood is my death warrant. I must die". He died within a year, at just 25 years of age. Poet John Keats

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MUMMY OF A TB SPINE AND CT SHOWING LESION T10/T11

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WOMEN WITH POTT’S DISEASE IN MOMIL CULTURE

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Hermann Brehmer (1826-1889) a Silesian botany student suffering from TB, was instructed by his doctor to seek out a healthier climate. He traveled to the Himalayas where he studied the mountain’s flora. He returned home cured and began to study medicine. In 1854, he presented his medical dissertation Tuberculosis is a Curable Disease. Brehmer then opened an in-patient hospital in Gorbersdorf, where patients received good nutrition and fresh air SANATORIUM AND INITIAL THERAPY

Brhemers Sanatorium Gorbersdorf in late 1870:

Brhemers Sanatorium Gorbersdorf in late 1870

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Bed rest, fresh air and good nutrtion

Ancient TB Treatment:

• The Italian physician Carlo Forlanini (1847-1918) discovered that the collapse of the affected lung tended to have a favorable impact on the outcome of the disease. He proposed to reduce the lung volume by artificial pneumothorax methods that were applied worldwide after 1913. • Artificial pneumothorax - pleural cavities were filled with gas or filtered air • Bilateral pneumothorax - only parts of the lungs were collapsed in such a way that the patient could still live a relatively normal live. Ancient TB Treatment

Ancient TB Treatment:

• Thoracoplasty - ribs from one side of the thorax were removed in order to collapse the infected portion of the lung permanently. • Gold Therapy - Holger Mollgaard (1885-1973) from Copenhagen introduced the compound sanocrysin in 1925, which is a double thiosulphate of gold and sodium. But it was too toxic even in low doses. Ancient TB Treatment

Defintion:

Defintion Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (MTB) complex. MTB complex includes M. tuberculosis, M. bovis (reservoir cattle), M. africanum (reservoir human),M. canettii and M. microti .

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Epidemiology-Global Nearly one-third of the global population, i.e. two billion people, is infected with Mycobacterium tuberculosis and at risk of developing the disease. > 8 million people develop active tuberculosis (TB) every year, and about two million die . > 90% of global TB cases and deaths occur in the developing world, 75% of cases are in the most economically productive age group (15-54 years).

TB Incidence Prevalence Mortality:

TB Incidence Prevalence Mortality

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Epidemiology- Bangladesh 60 % of adult population are infected in BD Annual rate of infection (ARI) 2.2% in BD Incidence of smear positive cases is 0.5 % (6 lac) 70,000 deaths in 2005 in BD (WHO)

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Developed countries: Immigration from high-prevalence areas Human immunodeficiency virus (HIV) Increasing proportion of elderly Drug resistance Developing countries: Ineffective control programmes Lack of access to health care Poverty, civil unrest HIV Population increase Drug resistance FACTORS FOR INCREASED INCIDENCE OF TB

Case Definitions:

Case Definitions Tuberculosis suspect. Any person who presents with symptoms or signs suggestive of TB, in particular cough of long duration (> 2 weeks) Case of tuberculosis. A patient in whom TB has been bacteriologically confirmed or diagnosed by a clinician. Definite case of tuberculosis. A patient with positive culture for the Mycobacterium tuberculosis complex. In countries where culture is not routinely available, a patient with two sputum smears positive for acid-fast bacilli (AFB) is also considered a "definite" case.

Case Definitions:

Case Definitions Pulmonary tuberculosis (PTB) refers to disease involving the lung parenchyma. Therefore tuberculous intrathoracic lymphadenopathy (mediastinal and/or hilar) or tuberculous pleural effusion, without radiographic abnormalities in the lungs, constitutes a case of extrapulmonary TB. A patient with both pulmonary and extrapulmonary TB should be classified as a case of pulmonary TB. Extrapulmonary tuberculosis (EPTB) refers to tuberculosis of organs other than the lungs, e.g. pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and bones, meninges. The case definition of an extrapulmonary TB case with several sites affected depends on the site representing the most severe form of disease.

Case Definitions:

Case Definitions Smear-positive (PTB+) a. two or more initial sputum smear examinations positive for AFB, or b. one sputum smear examination positive for AFB plus radiographic abnormalities consistent with active PTB as determined by a clinician, or c. one sputum smear positive for AFB plus sputum culture positive for M. tuberculosis. Smear-negative (PTB-): a. at least three sputum specimens negative for AFB, and b. radiographic abnormalities consistent with active PTB, and c. no response to a course of broad-spectrum TB antibiotics, and d. decision by a clinician to treat with a full course of antituberculosis chemotherapy.

Case Definitions:

Case Definitions New: A patient who has never had treatment for TB or who has taken antituberculosis drugs for < 1 month. Relapse: A patient previously treated for TB who has been declared cured or treatment completed, and is diagnosed with bacteriologically positive (smear or culture) tuberculosis. Failure: smear +ve or have become +ve after 5 months or more after the start of treatment or smear +ve at 2 months in a previously – ve patient.

Case Definitions:

Case Definitions Treatment after failure: A patient who is started on a re-treatment regimen after having failed previous treatment. Treatment after default. A patient who returns to treatment, positive bacteriologically, following interruption of treatment for 2 months or more. Transfer in: A patient who has been transferred from another TB register to continue treatment. Chronic case: a patient who is sputum-positive at the end of a re-treatment regimen.

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Classification of Mycobacteria There are 55 recognized species of Mycobacteria. They include  Typical or Strict pathogen Non tuberculous  Opportunistic pathogen Mycobacteria (NTM)  Saprophytes Classification: Typical Mycobacteria M.tuberculosis or M.bovis Mycobacterium tuberculosis M.africanum Complex M.microti M.caprae M. canettii M. pinnipedii

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Opportunistic mycobacteria III. Nonphotochromgen SLOW GROWERS M. avium intracellulare M. malmoense I. Photochromogen M. kansasi M. marinum M. simiae RAPID GROWERS M. asiaticum M. fortuitum M. gordonae M. chelonei II. Scotochromogen Saprophytic mycobacteria M. scrofulaceum M. flavescence M.shulgai M. fallax M. xenopi M. gastri M. gordonae M. smegmatis M. terrae M. triviale

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Mycobacterium tuberculosis It is the most important mycobacteria that causes Tuberculosis Man is the only known reservoir Morphology: They are slightly curved or straight rod Rigid cell wall contain abundant mycolic acid Non sporing Non capsulated Staining characteristics: Gram positive Acid Fast

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Composition of cell wall Lipid Mycolic acid*, Phospholipid, Wax, Glycolipid, Sulphatid Protein Purified protein derivative(PPD) CHO Polysaccharide Lipid constitutes about 60% of dry weight of cell wall

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Cultural characteristics Obligate aerobe Generation time of M.tuberculosis is about 15-20 hour Growth is enhanced by CO2 Glycerol is used as carbon source in most culture They produce dry, rough surfaced colony

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Mode of Transmission  By droplet nuclei which are aerosolized by coughing, sneezing or speaking. There may be as many as 3000 infectious nuclei per cough. Each nuclei contain 3 – 4 Mycobacteria. Patient with sputum positive, are more infectious Sputum negative but culture positive cases are less infectious Extrapulmonary tuberculosis cases are non infectious Sputum of Positive case may contain as many as 10 5 M.tuberculosis/ml Each positive cases infect at least 3 persons before detection  By ingestion of raw milk (Intestinal tuberculosis)*

Pathogenesis of TB infection (Droplet infection)…:

Pathogenesis of TB infection (Droplet infection)… Once inhaled, most tubercle bacilli are trapped in the mucosa of the upper respiratory tract, trachea and bronchi, especially when inhaled in clumps, and are eliminated by the mucocilliary defense mechanisms. Tiny particles or droplet nuclei smaller than 5 µm behave as a gas and overcome this barrier and reach the inferior respiratory tract, especially inside the alveoli, where they are readily phagocytosed by alveolar macrophages. M. tuberculosis enters macrophages by endocytosis .

Pathogenesis of TB infection (Primary tuberculosis)…:

Pathogenesis of TB infection (Primary tuberculosis)… Once inside the macrophage, M. tuberculosis replicates within the phagosome by blocking fusion of the phagosome and lysosome. This is an active process as live mycobacteria block phagolysosome formation. Thus the earliest stage of primary tuberculosis (<3 weeks) in the nonsensitized individual is characterized by proliferation of bacteria in the pulmonary alveolar macrophages and airspaces, with resulting bacteremia and seeding of multiple sites. Despite the bacteremia, most patients at this stage are asymptomatic or have a mild flulike illness.

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Figure 19.35 Primary pulmonary TB. (1) Spread from the primary focus to hilar and mediastinal lymph glands to form the 'primary complex', which in most cases heals spontaneously. (2) Direct extension of the primary focus-'progressive pulmonary tuberculosis'. (3) Spread to the pleura-tuberculous pleurisy and pleural effusion. (4) Blood-borne spread: few bacilli-pulmonary, skeletal, renal, genitourinary infection often months or years later; massive spread-miliary tuberculosis and meningitis.

Sequence of TB infection (Genetic defect)…:

Sequence of TB infection (Genetic defect)… The genetic make-up of the host may influence the course of the disease. In some people with polymorphisms in the NRAMP1 gene, the disease may progress from this point without development of an effective immune response. NRAMP1 protein is a transmembrane protein found in endosomes and lysosomes that may have role in generation of anti-microbial oxygen radicals.

Sequence of TB infection…:

Sequence of TB infection… Tubercle bacilli can disseminate by the lymphatic route to regional lymph nodes, constituting the tuberculous primary complex of Ranke , composed by the original granuloma at the inoculation site (Gohn’s nodule), the lymphangitis and the hilar lymph node enlargement. Although in some cases these lesions may become evident on chest X-ray, most cases of primary tuberculous infection are clinically and radiologically unapparent, with a positive TST being the only indication of the occurrence of the infection.

Chest X-ray showing a calcified peripheral nodule in the lower right lung, lymphangitis (encircled in b) and hilar involvement (Ranke’s complex) :

Chest X-ray showing a calcified peripheral nodule in the lower right lung, lymphangitis (encircled in b) and hilar involvement (Ranke’s complex)

Sequence of TB infection…:

Sequence of TB infection… From the hilar lymph nodes, tubercle bacilli disseminate to tracheal and vertebral lymph nodes. Through the thoracic duct, they reach the blood stream, spreading to the upper areas of the lungs or to different organs, such as kidney, brain, and bones. At these sites, they find a favorable atmosphere for implantation that combines a satisfactory oxygen tension and a low local perfusion- this is an ideal association that hinders the access of defense cells.

Sequence of TB infection (Granuloma formation)…:

Sequence of TB infection (Granuloma formation)… After 3 weeks, with the development of specific cellular immune response and production of interferon-gamma (IFN-γ), a mature stable granuloma is formed, which is responsible for the immune containment of the pathogen. Mature granulomas present neovascularization, epithelioid and giant multinucleated cells. An extensive fibrotic capsule develops and infected macrophages trapped inside granulomas eventually die.

Sequence of TB infection (Caseation necrosis)…:

Sequence of TB infection (Caseation necrosis)… Tubercle bacilli tend to locate in the center of the granuloma, but bacteria and antigens are also associated with macrophages in the peripheral infiltrate . The necrotic material present in the center of TB lesions contains high amounts of fat representing the lipids liberated from bacillary catabolism. This material, which has a soft, dry and cottage cheese texture, is known as caseous necrosis. On microscopy, large amounts of epithelioid and giant multinucleated cells can be observed in the granulomas, located mainly around the caseous material .

Sequence of TB infection (Immune response)…. :

Sequence of TB infection (Immune response)…. About 3 weeks after infection, a TH1 response against M. tuberculosis is mounted that activates macrophages to become bactericidal. Differentiation of TH1 cells depends on the presence of IL-12, which is produced by antigen presenting cells that have encountered the mycobacteria.

Sequence of TB infection (IFN)…:

Sequence of TB infection (IFN)… Mature TH1 cells, both in lymph nodes and in the lung, produce IFN-γ. IFN-γ is the critical mediator which drives macrophages to become competent to contain the M. tuberculosis infection. IFN-γ stimulates formation of the phagolysosome in infected macrophages, exposing the bacteria to an inhospitable acidic environment. IFN-γ also stimulates expression of inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO). NO generates reactive nitrogen intermediates and other free radicals capable of oxidative destruction of several mycobacterial constituents, from cell wall to DNA.

Sequence of TB infection (Caseation or cavitation)…:

Sequence of TB infection (Caseation or cavitation)… In addition to stimulating macrophages to kill mycobacteria, the TH1 response orchestrates the formation of granulomas and caseous necrosis. Activated macrophages, stimulated by IFN-γ, produce TNF, which recruits monocytes. These monocytes differentiate into the "epithelioid histiocytes" that characterize the granulomatous response. In many people, this response contains the bacteria and doesn't cause significant tissue destruction or illness. In other people, the infection progresses due to age or immunosuppression, and the ongoing immune response results in tissue destruction due to caseation and cavitation.

Sequence of TB infection(TNF)…:

Sequence of TB infection(TNF)… The importance of TNF in this response is underscored by the fact that patients with rheumatoid arthritis who are treated with a TNF antagonist have an increased risk of tuberculosis reactivation. However, it is clear that TH1 cells have a central role in this process as defects in any of the steps in generating a TH1 response results in absence of resistance and disease progression.

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Stages in Pathogenesis of Tuberculosis 3-4% of infected individual leads to disease progression and only few reaches last of pathogenesis. Host usually control disease progression at any stage of disease. * Stage I : Onset Inhaled TB into alveolus  Alveolar MQ ingest and destroy the bacilli Stage II : Symbiosis If original alveolar MQ fails to destroy or inhibit the inhaled bacilli, the bacilli multiply  Ultimately MQ bursts Bacillary load are ingested by other alveolar MQ* A symbiosis phase may last between 7 to 21 days

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Stage III : Initial caseous necrosis  The third stage of disease begins when logarithmic bacillary multiplication stops.  At that time (2 to 3 week after inhalation) the host become tuberculin positive and the lesion undergo caseous necrosis in the centre. Patient develop CMI* The host locally destroys its own tissues to control the uninhibited intracellular multiplication of bacilli (anoxic condition, reduced pH and presence of inhibitory fatty acid)

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Stage IV: Liquefaction and Cavity formation If the disease is not contained at stage III there occur liquefaction and cavity formation Excellent environment for growth of Mycobacteria, for the first time the bacterial multiply extracellularly Erosion of blood vessels may lead to haemoptysis or milliary tuberculosis In any stage Antibody don’t play role in pathogenesis or protection

Time Table of TB:

Time Table of TB Time from infection Diseases 3-8 weeks Primary TB, +ve TST 3-6 mons Meningeal, miliary and pleural disease Upto 3 yrs GI, Bone & Joint and Lymphnode diseases Around 8 yrs Renal tract diseases From 3 yrs onwards Post-primary diseases due to reactivation/reinfection

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Site of involvement Percentage Pulmonary tuberculosis 86 Extra pulmonary tuberculosis 14 Lymphatic 27 Pleural 21 Genitourinary 16 Milliary 9 Bone and Joint 8 Meningial 4 Peritoneal 4 Others 1 Distribution sites of Tuberculosis

Clinical Presentations:

Clinical Presentations Chronic cough, often with haemoptysis PUO Unresolved pneumonia Exudative pleural effusion Asymptomatic , incidentally diagnosed with CXR Wt loss, general debility Spontaneous pneumothorax

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Primary pulmonary TB : 1. A few patients develop a self-limiting febrile illness 2. Progressive primary disease may appear during the course of the initial illness or after a latent period of weeks or months. Clinical Manifestations

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1 . present acutely but more frequently is characterised by 2-3 weeks of fever, night sweats, anorexia, weight loss and a dry cough. 2. Hepatosplenomegaly may be present and the presence of a headache may indicate co-existent tuberculous meningitis. 3. Auscultation of the chest is frequently normal, although with more advanced disease widespread crackles are evident. 4. Fundoscopy may show choroidal tubercles. 5 . The classical appearances on chest X-ray are those of fine 1-2 mm lesions ('millet seed') distributed throughout the lung fields, although occasionally the appearances are coarser. 6. Anaemia and leucopenia may be present. Clinical Manifestations-Miliary TB

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1. Pulmonary TB is the most frequent form 2.The onset is typically insidious and develops slowly over several weeks. 3. Systemic symptoms include fever, night sweats, malaise, loss of appetite and weight, and are accompanied by progressive pulmonary symptoms 4.Very occasionally this form of TB may present with one of the complications 5. The earliest radiographical change is typically an ill-defined opacity situated in one of the upper lobes. Disease often involves two or more areas of lung and may be bilateral. As disease progresses, consolidation, collapse and cavitation develop to varying degrees . 6. Occasionally, a caseous lymph node may drain into an adjoining bronchus, resulting in tuberculous pneumonia. Post Primary TB

Phlyctenular conjunctivitis:

Phlyctenular conjunctivitis

Erythema nodosum (a) and erythema induratum of Bazin (b). :

Erythema nodosum ( a ) and erythema induratum of Bazin ( b ).

Diagnostic Methods:

Diagnostic Methods AFB smear staining:  Easiest and most rapid diagnosis  It is less sensitive than culture (50‑80%)  To be positive need 5000 - 10000 bacilli/ml(10-100 bacilli/ml for culture)  A tubercle bacilli is not found as commensal or carrier. Presence of AFB is virtually diagnostic Sputum: Rinse mouth with water before collection. Collect only exudative material brought up from lung after a deep productive cough. On an average 3 consecutive sputum sample should be collected Pulmonary specimen : Sputum*, Tracheal aspirate, Gastric levage, BAL . Extra pulmonary specimen : CSF, Aspirated fluid in case of Bone and Joint infection, Body fluids, Urine, Aspirated or draining pus, Surgically excised tissue, Endometrial tissue etc.

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Reporting of AFB

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Multiple specimens recommended to maximize chances for positive microscopy/culture

Typical AFB- Ziehl Neelsen stain:

Typical AFB- Ziehl Neelsen stain

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Figure 19.36 Chest X-ray: major manifestations and differential diagnosis of pulmonary TB. Less common manifestations include pneumothorax, ARDS (p. 187), cor pulmonale and localised emphysema. Downloaded from: StudentConsult (on 5 May 2008 07:39 AM) © 2005 Elsevier

TB histopathology:

TB histopathology The morphologic spectrum of tuberculosis. A characteristic tubercle at low magnification ( A ) and in detail ( B ) illustrates central caseation surrounded by epithelioid and multinucleated giant cells. This is the usual response seen in patients who have developed cell mediated immunity to the organism. Occasionally, even in immunocompetent individuals, tubercular granulomas might not show central caseation ( C ); hence, irrespective of the presence or absence of caseous necrosis, special stains for acid-fast organisms need to be performed when granulomas are present in histologic section. In immunosuppressed individuals, tuberculosis may not elicit a granulomatous response (" nonreactive tuberculosis"); instead, sheets of foamy histiocytes are seen, packed with mycobacteria that are demonstrable with acid-fast stains

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Granuloma

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Diagram of a Granuloma A fibrin layer develops around granuloma (fibrosis) , further “walling off” the lesion. Typical progression in pulmonary TB involves caseation , calcification and cavity formation .

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Eight Week Growth of Mycobacterium tuberculosis on Lowenstein-Jensen Agar

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Tuberculin skin test*:  The test is based on the fact that persons infected with tubercle bacilli develop hypersensitivity to the proteins of the organism. Reagents in tuberculin test:  Purified Protein Derivatives (PPD): It is a purified preparation of tuberculoprotein.

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Method: Mantoux test It is usually performed by intracutaneous injection of 0.1 ml (5TU) of PPD on the flexor aspect of the fore arm. 1 TU contain .00002 mg of PPD.  Interpretation of Skin test  Reading is taken 48 to 72 hours after injection  Reading is based on induration  Diameter of induration is measured transversely to the long axis of the fore arm and recorded in mm

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Results: a. An induration more than 10 mm indicate positive test Opinion: These person has been exposed to M.tuberculosis or NTM and has been sensitized. It may not indicate active disease. b. An induration between 5 to 10 mm is doubtful reaction Opinion: 1. BCG vaccination 2. NTM infection 3. Old tuberculous infection c. An induration less than 5 mm is considered negative Opinion: The person is not exposed to M.tuberculosis Such result are repeated with 10 to 25 TU dose

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 Causes of false negative skin test Injection of PPD in the deeper layer 2. Improper storage and handling of PPD reagent 3. Acute viral infection 4. Immunosuppression by disease (Sarcoidosis, lymphoma, AIDs- if CD4 count < 200 cells/ml) or Drugs 5. Severe TB (25% of cases negative) 6. Newborn and elderly 7. Malnutrition  Causes of false positive skin test 1. Hypersensitivity to NTM 2. During convalescence from measles and influenzae 3. BCG vaccination

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TUBERCULIN SKIN TEST

Immunological diagnosis:

 IgG antibody titre is high in active infection IgM and IgA appear early in infection and disappear or present in low titre, later On subsequent exposure again IgM appear for a short period Mycobacteria posses many nonpathogenic species that are antigenically closely related  BCG vaccination gives false positivity  Minimum or no value in area of high prevalence``` Immunological diagnosis

Other Diagnostic Methods:

Other Diagnostic Methods PCR: A useful support in some cases, to speed up the diagnosis of TB. Culture, supported by microscopy, still remains the gold standard, and molecular methods. IFN- γ : IFN-γ can be detected by the extremely sensitive ELISPOT

Other Diagnostic Methods:

Other Diagnostic Methods ADA: ADA determination in body fluids (spinal, pleural, ascitic, pericardial) for the diagnosis of tuberculous meningitis , tuberculous pleurisy peritoneal TB and pericardial TB has a high positive predictive value, especially in high endemic countries. Pleural fluid elevated adenosine deaminase (ADA) concentrations > 45 to 60 U/L is 100 percent sensitive and 95 to 97 percent for TBPE. Specificity is increased when the lymphocyte to neutrophil ratio is greater than 0.75. High ADA levels occasionally occur in other conditions, including rheumatoid effusion, empyema, mesothelioma, lung cancer, parapneumonic effusion, and hematologic malignancies. pleural effusions with an ADA level <40 U/L are rarely caused by TB.

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Cough ≥ 3 wks

Drug History:

Drug History 1944 - streptomycin (SM) and paraaminosalicylic (PAS) were discovered 1950 - the first trial was performed by SM & PAS as Mono/combined therapy. 1952- isoniazid (INH), was added to the previous combination for 18-24 months. 1960- ethambutol (EMB) substituted PAS, and the treatment course was reduced to 18 months. 1970-the introduction of rifampicin (RIF) into the combination treatment was shortened to 9 months. 1980- pyrazinamide (PZA) was introduced into the antituberculosis treatment, reduced to 6 months.

Rationale of anti-TB combination Drugs:

Rationale of anti-TB combination Drugs First-line drugs are: INH, RIF, PZA, EMB, and SM. Second-line drugs are aminoglycosides kanamycin and amikacin, the polypeptide capreomycin, PAS, cycloserine, the thioamides ethionamide and prothionamide and several fluoroquinolones such as moxifloxacin, levofloxacin and gatifloxacin

Principles of Combination Therapy:

Principles of Combination Therapy

Rationale of anti-TB combination Drugs:

Rationale of anti-TB combination Drugs Two main objectives - First, to rapidly kill those bacilli living extracellularly in lung cavities, to attain the negativization of sputum and prevent further transmission of the disease. Second, it is necessary to achieve complete sterilization and elimination of those bacilli replicating less actively and to kill semi-dormant bacilli living intracellularly in other host tissues, to prevent subsequent TB relapses. INH is the drug with the highest activity against rapidly dividing bacilli, whereas RIF and PZA have the greatest sterilizing activity against bacteria that are not dividing.

WHO Anti-TB Regimen:

WHO Anti-TB Regimen Category of TB Initial phase Continuation phase New smear+ PTB Severe smear- PTB Severe extrapulmonary TB Severe concomitant HIV 2m HRZE 4m HR Previously Treated smear+ PTB Relapse, Failure Treatment after default 2m HRZES 1m HREZ 5m HRE New case smear- PTB Less severe extra-pulmonary TB 2m HREZ 4m HR

Dose Range:

Dose Range Drug Daily dose mg/kg 3 times weekly dose mg/kg H 5 10 R 10 10 Z 25 35 E 15 30 S 15 15

Anti-TB Adverse Reactions:

Anti-TB Adverse Reactions I R Z S E Mode of action Cell wall syn DNA transcription Unknown Protein Syn Cell wall syn Major AR Per Neurop Febrile reaction Hepatitis 8 th N damage Retrobulbar N Hepatitis Hepatitis GI disturbence Rash Arthralgia Rash Rash Hyperuricaemia GI disturbence Less common Lupoid reaction Int Nephritis Rash Nephrotoxicity Perip N AR Seizure Thrombocytopenia Photosensation Agranulocyto Rash Psychoses Haemolytic Anae Gout

Approach To AR of Anti-TB Drugs:

Approach To AR of Anti-TB Drugs

Monitoring Treatment Response (smear+ve):

Monitoring Treatment Response (smear+ve)

Monitoring Treatment Response (Smear-ve):

Monitoring Treatment Response (Smear-ve)

Treatment Outome of Smear+ TB patients:

Treatment Outome of Smear+ TB patients

Special Situations:

Special Situations Pregnancy: SM avoid Brestfeeding: baby prophylaxis with INH for 3 months beyond non-infectious period. OC: higher dose (50 μ g) or another method Liver disorders: hepatotoxicity is as Z>I>R. No problem with carrier, past acute hepatitis, alcohol consumption; but increase risk of hepato-toxic effects. In established chr liver diseae the regimen is 2SHRE/6HR, 9RE or 2SHE/10HE. In acute hepatitis defer treatment or 3SE/6HR or 12SE. Renal Failure: 2HRZ/6HR, thioacetazone is not recommended.

Actions on Anti-TB Interruption:

Actions on Anti-TB Interruption

DOTS:

DOTS Directly observed treatment means that an observer watches the patient swallowing their tablets. The observer may be a health worker or a trained and supervised community member, cured patients may also be successful DOT providers. There may be an incentive of some sort for community members to become observers of TB treatment. The drugs should remain with the treatment observer and be given to the patient only at time. Aims-Directly observed treatment is required to ensure treatment adherence. It helps to reinforce patients' motivation to continue treatment and counters the tendency of some to interrupt treatment. TB programme is organized in such a way that the patient has treatment as close to home (or the workplace) as possible. The fixed-dose combinations and blister packs reduce medication error.

DOTS Strategy components:

DOTS Strategy components

Control and Prevention:

Control and Prevention BCG (the Calmette-Guérin bacillus) is a live attenuated vaccine derived from M. bovis , used to stimulate protective immunity and prevent the dissemination of MTB in an infected host. Reports on the efficacy of BCG are variable (20-60%) but it appears to be most effective in preventing disseminated disease, including tuberculous meningitis, in children.

Control and Prevention:

Control and Prevention Patient should wear a mask or at least cover mouth and nose when coughing or sneezing. Expectorated sputum should be handled carefully and properly disposed. Adequate negative pressure isolation room and use of UV lighting are very effective in reducing the number of infectious particles in the air. Extra care needed when cleaning RT equipment Health care workers should wear personal respiratory protective devices. The most effective measure to control of infectivity of the patient with active TB is early proper chemotherapy

Prognosis:

Prognosis Following successful completion of chemotherapy, cure should be anticipated in the majority of patients. There is a small (< 5%) and unavoidable risk of relapse. Most recurrences occur within 5 months and usually have the same drug susceptibility. In the absence of treatment a patient with smear-positive TB will remain infectious for an average of 2 years; in 1 year, 25% of untreated cases will die. A few patients die unexpectedly soon after commencing therapy and it is possible that some of these individuals have subclinical hypoadrenalism that is unmasked by a rifampicin-induced increase in steroid metabolism. HIV-positive patients have higher mortality rates and a modestly increased risk of relapse.

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