Tuberculosis

Dr.Abdulla ALfarttoosi

To recognize the characteristics and Transmission of Mycobacterium tuberculosis. To describe the pathogenesis of M. tuberculosis. To determine Factors increasing the risk of Tuberculosis. To judge the types and Clinical Features of tuberculosis. To assess the Chronic complications of pulmonary TB . To define the characteristics of Extrapulmonary tuberculosis . To assess the clinical and lab. methods to diagnose a case of TB. To demonstrate the importance of Tuberculin skin test. To illustrate drugs and methods of treatment of TB. To recognize the problem of MDR and predisposing factors .

Tuberculosis (TB) is a serious global problem. It remains the number one killer infectious disease in developing countries. The clinical manifestations of TB could be either Pulmonary or Extra pulmonary (EPTB). It is estimated that around one-third of the world's population has latent TB

CHARACTERISTICS OF MYCOBACTERIUM TUBERCULOSIS

Acid fast, intracellular parasites, have slow rates of growth , are obligate aerobes, and in normal hosts induce a granulomatous response in tissue .Tuberculosis is caused by any one of three mycobacterial pathogens that form part of the M. tuberculosis complex: M. tuberculosis, Mycobacterium bovis, and Mycobacterium africanum.

Regarding TB bacilli: A.it is extracellular micro-organism. B. it is obligate anaerobic C.it is uncommon infection in Iraq D. It has slow rate of growth E.ALL of the above

EPIDEMIOLOGY

The World Health Organization (WHO) estimates that nearly one third (1.9 billion people) of all the people in the world are infected with M. tuberculosis . The reasons for the resurgence of tuberculosis in the late 1980s and early 1990s in the United States, as well as in western Europe, are complex but revolve largely around two major factors: the epidemic of infection with HIV and the deterioration of public health systems

M. tuberculosis is spread by the inhalation of aerosolised droplet nuclei from other infected patients Once inhaled, the organisms lodge in the alveoli and initiate the recruitment of macrophages and lymphocytes. Macrophages undergo transformation into epithelioid and Langhans cells which aggregate with the lymphocytes to form the classical tuberculous granuloma.


Numerous granulomas aggregate to form a primary lesion or 'Ghon focus' (a pale yellow, caseous nodule, usually a few mm to 1-2 cm in diameter), which is characteristically situated in the periphery of the lung. Spread of organisms to the hilar lymph nodes is followed by a similar pathological reaction; the combination of a primary lesion and regional lymph nodes is referred to as the 'primary complex of Ranke‘ .

Reparative processes encase the primary complex in a fibrous capsule limiting the spread of bacilli: so-called latent TB. If no further complications ensue, this lesion eventually calcifies and is clearly seen on a chest X-ray. However, lymphatic or haematogenous spread may occur before immunity is established, seeding secondary foci in other organs including lymph nodes, serous membranes, meninges, bones, liver, kidneys and lungs, which may lie dormant for years.

The only clue that infection has occurred may be the appearance of a cell-mediated, delayed-type hypersensitivity reaction to tuberculin, demonstrated by tuberculin skin testing. If these reparative processes fail, primary progressive disease ensues .The estimated lifetime risk of developing disease after primary infection is 10%, with roughly half of this risk occurring in the first 2 years after infection

Factors increasing the risk of TB

Patient-related Age (children > young adults < elderly) First-generation immigrants from high-prevalence countries Close contacts of patients with smear-positive pulmonary TB Overcrowding Chest radiographic evidence of self-healed TB Primary infection < 1 year previously Smoking

Associated diseases

Immunosuppression: HIV, anti-TNF therapy, high-dose corticosteroids, cytotoxic agents Malignancy (especially lymphoma and leukaemia) Type 1 diabetes mellitus Chronic renal failure Silicosis Gastrointestinal disease associated with malnutrition (gastrectomy, jejuno-ileal bypass, cancer of the pancreas, malabsorption) Deficiency of vitamin D or A Recent measles: increases risk of child contracting TB

Clinical Features

Primary pulmonary TB Primary TB refers to the infection of a previously uninfected (tuberculin-negative) individual. A few patients develop a self-limiting febrile illness but clinical disease only occurs if there is a hypersensitivity reaction or progressive infection . Progressive primary disease may appear during the course of the initial illness or after a latent period of weeks or months.

Features of primary TB

Infection(4-8weeks) Influenza-like illness Skin test conversion Primary complex

Disease

Lymphadenopathy: hilar (often unilateral), paratracheal or mediastinal Collapse (especially right middle lobe) Consolidation (especially right middle lobe) Obstructive emphysema Cavitation (rare) Pleural effusion Endobronchial Miliary Meningitis Pericarditis


Hypersensitivity
Erythema nodosum Phlyctenular conjunctivitis Dactylitis

Post-primary pulmonary TB

Post-primary disease refers to exogenous ('new' infection) or endogenous (reactivation of a dormant primary lesion) infection in a person who has been sensitised by earlier exposure. It is most frequently pulmonary and characteristically occurs in the apex of an upper lobe where the oxygen tension favours survival of the strictly aerobic organism. The onset is usually insidious, developing slowly over several weeks.

Systemic symptoms include fever, night sweats, malaise, and loss of appetite and weight, and are accompanied by progressive pulmonary symptoms Radiological changes include ill-defined opacification in one or both of the upper lobes, and as progression occurs, consolidation, collapse and cavitation develop to varying degrees .


It is often difficult to distinguish active from quiescent disease on radiological criteria alone, but the presence of a miliary pattern or cavitation favours active disease. In extensive disease, collapse may be marked and result in significant displacement of the trachea and mediastinum. Occasionally, a caseous lymph node may drain into an adjoining bronchus resulting in tuberculous pneumonia

Clinical presentations of pulmonary TB

Chronic cough, often with haemoptysis Pyrexia of unknown origin Unresolved pneumonia Exudative pleural effusion Asymptomatic (diagnosis on chest X-ray) Weight loss, general debility Spontaneous pneumothorax

The TST may be negative in up to half of case but reactivity may be restored during chemotherapy Bronchoelveolar lavage and transbronchial biopsy are more likely to provide bacteriologic confirmation， and granulomas are evident in liver or bone-marrow biopsy specimens from many patients. If it goes unrecognized， miliary TB is lethal; with proper early treatment， however， it is amenable to cure. Glucocorticoid therapy has not proved beneficial.. 'Cryptic' miliary TB is an unusual presentation sometimes seen in old age .

A rare presentation seen in the elderly， cryptic miliary TB has a chronic course characterized by mild intermittent fever， anemia， and ultimately- meningeal involvement preceding death. An acute septicemic form， nonreactive miliary TB， occurs very rarely and is due to massive hematogenous dissemination of tubercle bacilli. Pancytopenia is common in this form of disease， which is rapidly fatal. At postmortem examination， multiple necrotic but nongranulomatous "nonreactive") lesions are detected.

Chronic complications of pulmonary TB 

Pulmonary Massive haemoptysis Cor pulmonale Fibrosis/emphysema Atypical mycobacterial infection Aspergilloma Lung/pleural calcification Obstructive airways disease Bronchiectasis Bronchopleural fistula


Non-pulmonary Empyema necessitans Laryngitis Enteritis*

Anorectal disease* Amyloidosis Poncet's polyarthritis

Non-pulmonary
Empyema necessitans Laryngitis Enteritis Anorectal disease Amyloidosis Poncet's polyarthritis

Extrapulmonary TB

Extrapulmonary tuberculosis presents more of a diagnostic and therapeutic problem than does pulmonary tuberculosis. In part this relates to its being less common and therefore less familiar to most clinicians and Microscopy with the auramine or Ziehl-Neelsen (ZN) stain is frequently negative in cases of extrapulmonary tuberculosis In addition, extrapulmonary tuberculosis involves relatively inaccessible sites, and often, because of the vulnerability of the areas involved, much greater damage can be caused by fewer bacilli.

The combination of small numbers of bacilli in inaccessible sites causes bacteriologic confirmation of a diagnosis to be more difficult, and invasive procedures are frequently necessary to establish a diagnosis. In addition to the need for invasive diagnostic procedures, surgery may be an important component of management.

In 2007 in the United States, 20% of newly reported cases of tuberculosis involved extrapulmonary sites only. In order of frequency, the extrapulmonary sites most commonly involved in TB are the lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum, and pericardium. However, virtually all organ systems may be affected.

Diagnosis of pulmonary TB

Unexplained cough for more than 2-3 weeks. typical chest X-ray changes Direct microscopy of sputum is the most important first step. A positive smear is sufficient for the presumptive diagnosis of TB but definitive diagnosis requires culture. Smear-negative sputum should also be cultured, as only 10-100 viable organisms are required for sputum to be culture-positive. A diagnosis of smear-negative TB may be made in advance of culture if the chest X-ray appearances are typical of TB and there is no response to a broad-spectrum antibiotic


Aspergilloma developing in an old tuberculosis cavity. A, Front chest radiograph in a patient with tuberculosis shows bilateral upper lobe fibronodular changes with a right apical cavity (arrow). B, Frontal chest radiograph several years after (A) when the patient complained of hemoptysis shows development of an opacity within the right apical cavity (arrowheads) representing aspergilloma. C-E, Focused axial chest CT confirms the presence of aspergilloma.



Tuberculin Skin Testing
Skin testing with tuberculin-PPD( tuberculin purified protein derivative) (TST) is most widely used in screening for latent M. tuberculosis infection . The test is of limited value in the diagnosis of active tuberculosis because of its relatively low sensitivity and specificity and its inability to discriminate between latent infection and active disease.


For example, a reaction of 5 mm in a child who is a contact of a person with smear-positive tuberculosis would probably indicate tuberculous infection and be considered positive. Likewise, a 5-mm reaction in a person with known HIV infection should be considered positive. There are several reasons why the tuberculin reaction may be interpreted as negative in the presence of tuberculous infection.Two INF-γ release assays are currently approved for marketing .

Treatment

The two aims of tuberculosis treatment are to interrupt tuberculosis transmission by rendering patients noninfectious and to prevent morbidity and death by curing patients with tuberculosis.

Drugs

Four major drugs are considered the first-line agents for the treatment of tuberculosis: isoniazid, rifampin, pyrazinamide, and ethambutol. These drugs are well absorbed after oral administration, with peak serum levels at 2–4 h and nearly complete elimination within 24 h. These agents are recommended on the basis of their bactericidal activity (i.e., their ability to rapidly reduce the number of viable organisms and render patients noninfectious), their sterilizing activity (i.e., their ability to kill all bacilli and thus sterilize the affected tissues, measured in terms of the ability to prevent relapses), and their low rate of induction of drug resistance.

Dosage

Drug
Daily Dose

Isoniazid

5 mg/kg, max 300 mg
15 mg/kg, max 900 mg
Rifampin
10 mg/kg, max 600 mg
10 mg/kg, max 600 mg
Pyrazinamide
20–25 mg/kg, max 2 g 30–40 mg/kg, max 3 g
15–20 mg/kg 25–30 mg/kg


Because of a lower degree of efficacy and a higher degree of intolerability and toxicity, six classes of second-line drugs are generally used only for the treatment of patients with tuberculosis resistant to first-line drugs. Included in this group are the injectable aminoglycosides streptomycin (formerly a first-line agent), kanamycin, and amikacin; the injectable polypeptide capreomycin; the oral agents ethionamide, cycloserine, and PAS; and the fluoroquinolone antibiotics. Of the quinolones, third-generation agents are preferred: levofloxacin.

Regimens

Standard short-course regimens are divided into an initial, or bactericidal, phase and a continuation, or sterilizing, phase. During the initial phase, the majority of the tubercle bacilli are killed, symptoms resolve, and usually the patient becomes noninfectious. The continuation phase is required to eliminate persisting mycobacteria and prevent relapse.


The treatment regimen of choice for virtually all forms of tuberculosis in both adults and children consists of a 2-month initial phase of isoniazid, rifampin, pyrazinamide, and ethambutol followed by a 4-month continuation phase of isoniazid and rifampin. Treatment may be given daily throughout the course or intermittently (either three times weekly throughout the course or twice weekly after an initial phase of daily therapy, although the twice-weekly option is not recommended by the WHO. Intermittent treatment is especially useful for patients whose therapy is being directly observed..

Patients with cavitary pulmonary tuberculosis and delayed sputum-culture conversion (i.e., those who remain culture-positive at 2 months) should have the continuation phase extended by 3 months, for a total course of 9 months. To prevent isoniazid-related neuropathy, pyridoxine (10–25 mg/d) should be added to the regimen given to persons at high risk of vitamin B6 deficiency

Monitoring Treatment Response and Drug Toxicity

Bacteriologic evaluation is the preferred method of monitoring the response to treatment for tuberculosis. Patients with pulmonary disease should have their sputum examined monthly until cultures become negative. With the recommended regimen, >80% of patients will have negative sputum cultures at the end of the second month of treatment. By the end of the third month, virtually all patients should be culture-negative.

patients with cavitary disease who do not achieve sputum culture conversion by 2 months require extended treatment. When a patient's sputum cultures remain positive at 3 months, treatment failure and drug resistance or poor adherence with the regimen should be suspected A sputum specimen should be collected by the end of treatment to document cure.

Monitoring of the response to treatment during chemotherapy by serial chest radiographs is not recommended, as radiographic changes may lag behind bacteriologic response and are not highly sensitive. After the completion of treatment, neither sputum examination nor chest radiography is recommended for routine follow-up purposes. However, a chest radiograph obtained at the end of treatment may be useful for comparative purposes should the patient develop symptoms of recurrent tuberculosis months or years later.

drug toxicity

Hepatitis: common, baseline assessment of liver function Up to 20% of patients have small increases in aspartate aminotransferase (up to three times the upper limit of normal) that are not accompanied by symptoms and are of no consequence. For patients with symptomatic hepatitis and those with marked (five- to sixfold) elevations in serum levels of aspartate aminotransferase, treatment should be stopped and drugs reintroduced one at a time after liver function has returned to normal.


Hypersensitivity reactions usually require the discontinuation of all drugs and rechallenge to determine which agent is the culprit Hyperuricemia and arthralgia caused by pyrazinamide should be stopped if the patient develops gouty arthritis. Individuals who develop autoimmune thrombocytopenia secondary to rifampin therapy should not receive the drug thereafter. Similarly, the occurrence of optic neuritis with ethambutol is an indication for permanent discontinuation of this drug.

Main adverse reactions of first-line antituberculous drugs

Isoniazid
Rifampicin
Pyrazinamide
Streptomycin
Ethambutol
Mode of action
Cell wall synthesis
DNA transcription
Unknown
Protein synthesis
Cell wall synthesis
Major adverse reactions
Peripheral neuropathy1Hepatitis2Rash
Febrile reactionsHepatitisRashGastrointestinal disturbance
HepatitisGastrointestinal disturbanceHyperuricaemia
8th nerve damageRash
Retrobulbar neuritis3Arthralgia
Less common adverse reactions
Lupoid reactionsSeizuresPsychoses
Interstitial nephritisThrombocytopeniaHaemolytic anaemia
RashPhotosensitisationGout
NephrotoxicityAgranulocytosis
Peripheral neuropathyRash

Drug-resistant TB

Drug-resistant TB is defined by the presence of resistance to any first-line agent. Multidrug-resistant (MDR) TB is defined by resistance to at least rifampicin and isoniazid, with or without other drug resistance. Extensively drug-resistant (XDR) TB is defined by resistance to at least rifampicin and isoniazid, in addition to any quinolone and at least one injectable second-line agent.

The prevalence of MDR-TB is rising It is more common in those with a prior history of TB, particularly if treatment has been inadequate, and those with HIV infection Diagnosis is challenging, especially in developing countries, and although cure may be possible, it requires prolonged treatment with less effective, more toxic and more expensive therapies. Mortality rate from MDR-TB is high and that from XDR-TB higher still.

Factors contributing to emergence of drug-resistant TB

Drug shortages Poor-quality drugs Lack of appropriate supervision Transmission of drug-resistant strains Prior anti-tuberculosis treatment Treatment failure (smear-positive at 5 months)

Vaccines