TBC

TUBERCULOSIS

Etiologic agent

Mycobacteria belong to the family Mycobacteriaceae and the order actinomycetales. M. tuberculosis is a rod-shaped, non-spore forming, thin aerobic bacterium measuring 0.5um by 3um. Mycobateria are often neutral on gram staining. However, once stained, the bacilli cannot be decolorized by acid alcohol; this characteristic justifies their classification as acid fast bacilli. Acid fastness is due mainly to the organisms’ high content of mycolic acids, long chain cross-linked fatty acids and other cell wall lipids. In the mycobacterial cell wall, lipids are linked to underlying arabinogalactan and peptidoglycan. This structure confers very low permeability of the cell wall, thus reducing the effectiveness of most antibiotics. Another molecule in the mycobacterial cell wall, lipoarabinimannan is involved in the pathogen-host interactionand facilitates the survival of M. tuberculosis within macrophages.

From exposure to infection

M. tuberculosis is most commonly transmitted from a person with infectious pulmonary tuberculosis to others by droplet nuclei, which are aerosolized by coughing, sneezing or speaking. The tiny droplets dry rapidly and may remain suspended in the air for several hours and may reach the terminal air passages when inhaled.

The probability of contact with a person who has an infectious form of tuberculosis, 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. Severeal studies on close contact situations have clearly demonstrated that tuberculosis patients whose sputum contains AFB visibly by microscopy are the most likely to transmit the infection. The most infectious patients have cavitary pulmonary disease or much less common, laryngeal tuberculosis and produce sputum containing as many as 10^5-10^7 AFB/mL. Patients with sputum smear-negative/culture positive TB are less infectious and those with culture-negative pulmonary disease and extrapulmonary TB are essentially non-infectious.

From infection to disease

The risk of developing disease after being infected depends largely on endogenous factors, such as the individual’s innate immunologic and nonimmunologic defenses and level of function of cell-mediated immunity (CMI). Clinical illnesses directly following infection is classified as primary tuberculosis and is common among children up to 4 years of age and among immunocompromised persons. When infection is acquired later in life, the chance is greater that the mature immune system will contain it at least temporarily. The majority of infected individuals take time about 1-2 years before they ultimately develop the disease.

Among the infected persons, the incidence of TB is highest during late adolescence and early adulthood; with unclear reasons. The incidence among women peaks at 25-34 years old.

A variety of disease and conditions favor the development of active TB. The most potent factor for TB among infected person is clearly HIV co-infection, which suppresses cellular immunity.

Pathogenesis & Immunity

Infection & Macrophage Invasion

The interaction of M. TB with the human host begins when droplet nuclei containing microorganisms from infectious patients are inhaled. The majority of inhaled bacilli trapped in the upper airways and expelled by ciliated mucosal cells, and a fraction (<10%) reach the alveoli. Alveolar macrophages that have not yet been activated phagocytize the bacilli.  Invasion of macrophages by mycobacteria results largely from binding of the bacterial cell wall with a variety of macrophage cell-surface molecules, including complement receptors, mannose receptors, immunoglobulin receptor and type-A scavenger receptors. Phagocytosis is enhanced by complement activation leading to opsonization of bacilli with C3 activation products, such as C3b. After the phagosome forms, the survival of M.TB within it seems to depend on reduced acidification due to lack of accumulation of vesicular proton-adenosine triphosphatase. A complex series of events is probably generated by the bacterial cell-wall glycolipid lipoarabinomannan (LAM). LAM inhibits the intracellular increase of Ca2+. Thus the Ca2+/calmodulin pathway is impaired, and the bacilli may survive within the phagosome.

*** (impair in Ca2+/calmodulin pathway disrupt the maturation process of phagosome)

Host response

In the initial stage of host-bacterium interaction, either fusion between phagosome and lysosomes occurs, preventing bacillary survival, or the bacilli begin to multiply, ultimately killing the macrophage. A variety of chemoattractants that are released after cell lysis recruit additional immature monocyte-derived macrophages, including dendritic cells, which migrate to the draining lymph nodes and present mycobacterial antigens to T-lymphocytes. At this point, the development of CMI and humoral immunity begins.

About 2-4wks after infection, two hosts responses o M.TB develop; a macrophage-activating CMI response and a tissue-damaging response. The macrophage activating response is a T cell mediated phenomenon resulting in the activation of macrophages that are capable of killing and digesting tubercle bacilli. The tissue-damaging response is the result of a delayed-type hypersensitivity (DTH) reaction to various bacillary antigens; it destroys unactivated macrophages that contain multiply bacilli but also causes caseous necrosis of the involved tissues. Although both of these responses can inhibit mycobacterial growth, it is the balance between the two that determines the form of TB that will develop subsequently.

Granuloma formation

With the development of specific immunity and the accumulation of large numbers of activated macrophages at the site of the primary lesion, granulomatous lesions are formed. This lesion consists of accumulations of lymphocytes and activated macrophages that evolve towards epithelioid and giant cell morphologies. Initially, the tissue damaging response can limit mycobacterial growth within macrophages. As stated, this response mediated by various bacterial products, produces early solid necrosis in the center of the tubercle. Although the M.TB can survive, its growth is inhibited by low oxygen tension and low pH. At this point, some lesions may heal by fibrosis, with subsequent calcification, whereas inflammation and necrosis occur in other lesions.

The macrophage-activating response

CMI is critical at this early stage. In majority infected individuals, local macrophages are activated when bacillary antigens (processed by macrophages) stimulate T lymphocytes to release a variety of lymphokines. These activated macrophages aggregates around the lesion’s center and effectively neutralize tubercle bacilli without causing further tissue destruction. In the central part of the lesion, the necrotic material resembles soft cheese (caseous necrosis) a phenomenon that may also observed in other conditions such as neoplasms. Even when healing takes place, viable bacilli may remain dormant within macrophages or in the necrotic material for many years. These healed lesions in the lung parenchyma and hilar lymph nodes may later undergo calcification.

The Delayed-Type Hypersensitive Reaction

In a minority of cases, the macrophage-activating response is weak, and mycobacterial growth can be inhibited only by intensified DTH reactions, which lead to lung tissue destruction.  The lesion tends to enlarge further, and the surrounding tissue is progressively damaged. At the center of lesion, the caseous material liquefies. Bronchial walls as well as blood vessels are invaded and destroyed, and cavities are formed. The liquefied caseous material containing large numbers of bacilli is drained through bronchi. Within the cavity, tubercle bacilli multiply, spill into airways and are discharged into environment through expiratory maneuvers such as talking and coughing.

In the early stages of infection, bacilli are usually transported by macrophages to regional lymph nodes, from which they gain access to the bloodstream and disseminate widely throughout the body. The resulting lesions may undergo the same evolution as those in the lungs, although most tend to heal. In young children with poor natural immunity, hematogenous dissemination may result in fatal military TB or tuberculous meningitis.

Role of Macrophages and Monocytes

While CMI confers partial protection against M.TB, humoral immunity plays a less well-defined role in protection. In the case of CMI, 2 types of cells are essential; macrophages (which directly phagocytize tubercle bacilli) and –cells (which induce protection through the production of cytokines, especially IFN-gamma.

After infection, alveolar macrophages secrete various cytokines responsible for a number of events as well as systemic effects. Monocytes & macrophages attracted to the site are key components of immune response. Their primary mechanism is probably related to production of nitric oxide, which has antimycobacterial activity and increases synthesis of cytokines such as TNF-alpha and IL-1, which in turn regulate release of reactive nitrogen intermediates. In addition, macrophages can undergo apoptosis, a defensive mechanism to prevent release of cytokines and bacilli via their sequestration in the apoptotic cell.

CLINICAL MANIFESTATIONS

(1)    Pulmonary tuberculosis

Pulmonary tuberculosis can be categorized as primary or post-primary (secondary)

Primary disease

Primary pulmonary TB occurs soon after the initial infection with tubercle bacilli. This form of disease often seen in children who live in areas with high TB transmission. The middle and lower lung zones are the areas that most commonly involved in primary TB as the air is distributed here. The lesion forming after infection is usually peripheral and accompanied in more than half of cases by hilar and paratracheal lymphadenopathy, which may not detectable on CXR. In majority cases, the lesions heals spontaneously and may later be evident as a small calcified nodule (Ghon lesion)

In children and in persons with impaired immunity, the primary pulmonary TB may progress rapidly to clinical illness. The initial lesion increased in size and can evolve indifferent ways. Pleural effusion results from the penetration of bacilli into pleural space from an adjacent subpleural focus. In severe cases, the primary site rapidly enlarges, its central portion undergoes necrosis and cavitation develops. TB in young children is almost invariably accompanied by hilar or mediastinal lymphadenopathy due to spread of bacilli from the lung parenchyma through lymphatic vessels. Enlarged lymph nodes may compress bronchi, causing obstruction and subsequent segmental or lobar collapse. Partial obstruction may cause obstructive emphysema, and bronchiectasis may also develop. Hematogenous dissemination which is common and often asymptomatic may result in the most severe manifestations of primary M.TB infection. Bacilli reach the bloodstream from the pulmonary lesion or the lymph nodes and disseminate into various organs, where they may produce granulomatous lesions. Immunocompromised persons may develop military TB and /or tuberculous meningitis.

Post-primary disease

Also called adult-type, reactivation or secondary tuberculosis, post-primary disease results from endogenous reactivation of latent infection and is usually localized to the apical and posterior segments of upper lobes, where the substantially higher mean oxygen tension favors mycobacterial growth. In addition, the superior segments of the lower lobes frequently involved. The extent of lung parenchymal involvement varies greatly, from small infiltrates to extensive cavitary disease. With cavity formation, liquefied necrotic contents are ultimately discharged into the airways, resulting in satellite lesions within the lungs that may in turn undergo cavitation. Massive involvement of pulmonary segments or lobes with coalescence of lesions produces tuberculous pneumonia.

Early in the course of disease, symptoms and signs are often nonspecific and insidious, consisting mainly of fever and night sweats, weight loss, anorexia, general malaise and weakness. However, in majority cases, cough eventually develops – often initially nonproductive and subsequently accompanied by the production of purulent sputum, sometimes with blood streaking. Massive hemoptysis may ensue as a consequence of the erosion of a blood vessel in the wall of cavity. Hemoptysis, however may also resukt from rupture of a dilated vessel in a cavity (Rasmussen’s aneurysm) or from aspergilloma formation in an old cavity. Pleuritic chest pain sometimes develops in patients with subpleural parenchymal lesions.

Physical findings are of limited use in pulmonary tuberculosis. Many patients have no abnormalities detectable by chest examination, whereas others have detectable rales in the involved areas during inspiration, especially after coughing. Occasionally, shonchi due to partial bronchial obstruction and classic amphoric breath sounds in areas with large cavities may be heard. Systemic features include fever in up to 80% of cases and wasting. Absence of fever, however does not exclude TB. The most common hematologic findings are mild anemia and leukocytosis. Hyponatremia due to SIADH has also been reported.

(2)    Extrapulmonary TB

The extrapulmonary sites most commonly involved in TB are the lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum and pericardium.

Lymph node TB (Tuberculous Lymphadenitis)

The most common presentation of extrapulmonary TB is particularly frequent among HIV-infected patients. Once caused mainly by M. bovis, tuberculous lymphadenitis is due to M.TB. the disease presents as painless swelling of the lymph nodes, most commonly at posterior cervical and supraclavicular sites. Lymph nodes usually discrete and nontender in early disease but may be inflamed and have a fistulous ract draining caseous material. Associated pulmonary disease is seen in >40% of cases. Systemic symptoms are usually limited to HIV-infected patients. The diagnosis is established only by fine-needle aspiration or surgical biopsy.

Pleural TB

This is common in primary TB and may result from either contiguous spread of parenchymal inflammation or, as in many cases of pleurisy accompanying postprimary disease, actual penetration by tubercle bacilli into pleural space. The effusion may be small, remain unnoticed, and resolve sponatenously or may be sufficiently large to cause symptoms such as fever, peluritic chest pain, and dyspnea.

Physical findings are those of pleural effusion (dullness to percussion & absence of breath sound). A CXR reveals the effusion and, in up to 1/3 of cases, also shows a parenchymal lesion. Thoracocentesis is acquired to ascertain the nature of effusion and to differentiate it from manifestations of other etiologies. The fluid is straw colored and at times hemorrhagic. Neutrophils may predominate in the early stage while mononuclear cells are the typical finding later. Mesothelial cells are generally rare or absent. Needle biopsy of plerua often required for diagnosis and reveals granulomas and/or yields a positive culture in up to 80% of cases. This form of pleural TB responds well to chemotherapy and may resolve sponatenously.

Tuberculous empyema is a less common complication of pulmonary TB. It is usually the result of the rupture cavity with spillage of a large number or organisms into pleural spaces. This process may create a bronchoplerual fistula with evident air in the pleural space. A CXR shows hydropneumothroax with an air-fluid level. The pleural fluid is purulent and thick and contains large numbers of lymphocytes. Acid-fast smears and mycobacterial cultures are often positive. Surgical drainage is required as an adjunct to chemotherapy.

Tuberculous of upper airways

Nearly always a complication of advanced cavitary pulmonary Tb may involve the larynx, pharynx and epiglottis. Symptoms include hoarseness, dysphonia, and dysphagia in addition to chronic productive cough. Ulcerations may be seen on laryngoscopy. Acid-fast smear of the sputum is often positive but biopsy may be necessary in some cases to establish the diagnosis. Carcinoma of the larynx may have similar features but is usually painless.

Skeletal tuberculosis

In bone & joint disease, pathogenesis is related to reactivation of hematogenous foci or to spread from adjacent paravertebral lymph nodes. Weight bearing joints are most commonly affected. Spinal TB often involves two or more adjacent vertebral bodies. While the upper thoracic spine is the most common site of spinal TB in children, the lower thoracic and upper lumbar vertebrae are usually affected in adults. From the anterior superior or inferior angle of the vertebral body, the lesion slowly reaches the adjacent body, later affecting the intervertebral disk. With advanced of disease, collapse of vertebral bodies results in kyphosis (gibbus). A paravertebral cold abscess may also form. In the upper spine, this abscess may track to and penetrate chest wall, presenting as a soft tissue mass, in the lower spine it may reach the inguinal ligaments or present as psoas abscess.

Aspiration of the abscess or bone biopsy confirms the tuberculous etiology, as cultures are usually positive and histologic findings highly typical. TB of hip joints usually involving the head of femur, causes pain; TB of knee produces pain & swelling. If the disease goes unrecognized, the joints may be destroyed. Diagnosis requires examination of the synovial fluid, which is thick in appearance, with a high protein concentration and a variable cell count. Synovial biopsy and tissue culture may be necessary to establish the diagnosis.

Tuberculous Meningitis and Tuberculoma

It is seen most often in young children but also develop in adults, especially those infected with HIV. Tuberculous meningitis results from the Hematogenous spread of primary or postprimary pulmonary disease or from the rupture of a subependymal tubercle into the subarachnoid space. In more than half cases, evidence of old pulmonary lesions or a military pattern is found on chest radiography. The disease often presents subtly as headache and slight mental changes after a prodrome of weeks of low grade fever, malaise, anorexia and irritability. If not recognized, tuberculous meningitis may evolve acutely with severe headache, confusion, lethargy altered sensorium and neck rigidity. Typically, the disease evolves over 1-2 weeks, a course longer than that of bacterial meningitis. Paresis of cranial nerves is a frequent finding and the involvement of cerebral arteries may produce focal ischemia.

Lumbar puncture is the cornerstone of diagnosis. CSF reveals a high leukocyte counts, usually with predominance of lymphocytes but sometomes with a presdominance of neutrophils in the early stage; a protein content of 1-8g/L; and a low glucose concentration. Culture of CSF is diagnostic in up to 80% of cases and remains the gold standard. Imaging studies (CT and MRI) may show hydrocephalus and abnormal enhancement of basal cisterns or ependyma.

Gastrointestinal tuberculosis

GI TB is uncommon. Various pathogenetic mechanism are involved: swallowing of sputum with direct seeding, Hematogenous spread or ingestion of milk from cows affected by bovine TB. The terminal ileum and the cecum are the most commonly involved. Abdominal pain and swelling, obstruction, hematochezia and a palpable mass in the abdomen are common findings at presentation. Fever, weight loss, anorexia and night sweats are also common. With intestinal wall involvement, ulceration and fistulae may stimulate Crohn’s disease.

Tuberculous peritonitis follows either the direct spread of tubercle bacilli from ruptured lymph nodes and intraabdominal organs or hematogenous seeding. Nonspecific abdominal pain, fever and ascites should raise the suspicion of tuberculous peritonitis. Paracentesis reveals an exudative fluid with a high protein content and leukocytosis that is usually lymphocytic. Peritoneal biopsy is often needed to establish the diagnosis.

Pericardial Tuberculosis

The onset may be subacute, although an acute presentation with dyspnea, fever, dull retrosternal pain and a pericardial friction rub is possible. An effusion eventually develops in many cases; cardiovascular symptoms and signs of cardiac tamponade may ultimately appear. A definitive diagnosis can be obtained by pericardiocentesis under echocardiographic guidance. The effusion is exudative in nature, with a high count of leukocytes. Hemorrhagic effusion is frequent. Culture of pericardial fluid reveals M.TB in up 2/3 cases while pericardial biopsy has a higher yield.

Without treatment, pericardial TB is usually fatal. Even with treatment, complications may develop, including chronic constrictive pericarditis with thickening of the pericardium, fibrosis and sometimes calcification which may be visible on CXR. A course of glucocorticoid treatment (prednisone 20-60mg/d for up to 6wks) is useful in the management of acute disease, reducing effusion, facilitating hemodynamic recovery and thus decreasing mortality rates.

Miliary or Disseminated Tuberculosis

This is due to hematogenous spread of tubercle bacillia. In children is is often the consequence of primary infection, in adults it may be due to either recent infection or reactivation of old disseminated foci. The lesions are usually yellowish granulomas 1-2mm in diameter that resemble millet seeds.

Clinical manifestations are nonspecific and protean, depending on the predominant site of involvement. Fever, night sweats, anorexia, weakness and weight loss are presenting symptoms in the majority cases. At times, patient has cough and other respiratory symptoms due to pulmonary involvement as well as abdominal symptoms. Physical findings include hepatomegaly, splenomegaly and lymohadenopathy. Eye examination may reveal choroidal tubercles, which are pathognomonic of military TB.

CXR reveals a military reticulonodular pattern, although no radiographic abnormality may be evident early in the course and among HIV-infected patients. Other radiologic findings include large infiltrates, interstitial infiltrates and pleural effusion. Sputum smear microscopy is negative in 80% of cases.

Various hematologic abnormalities may be seen, including anemia with leukopenia, lymphopenia, neutrophilic leukocytosis and leukemoid reactions, and polycythemia. Disseminated intravascular coagulation has been reported. Elevation of alkaline phosphatase levels and other abnormal values in liver function tests are detected in patients with severe hepatic involvement. The TST may be negative in up to half of cases, but reactivity may be restored during chemotherapy. Bronchoalveolar 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 tuberculosis is lethal; with proper early treatment, however, it is amenable to cure. Glucocorticoid therapy has not proved beneficial.

A rare presentation seen in the elderly is cryptic miliary tuberculosis, which has a chronic course characterized by mild intermittent fever, anemia, and—ultimately—meningeal involvement preceding death. An acute septicemic form, nonreactive miliary tuberculosis, 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.

DIAGNOSIS

AFB microscopy

Although rapid and inexpensive, AFB microscopy  has a relatively low sensitivity in confirmed cases of pulmonary TB. Most modern laboratories processing large numbers of diagnostic specimens use auramine-rhodamine staining and fluorescence microscopy. The more traditional method—light microscopy of specimens stained with Kinyoun or Ziehl-Neelsen basic fuchsin dyes—is satisfactory, although more time-consuming. For patients with suspected pulmonary tuberculosis, three sputum specimens, preferably collected early in the morning, should be submitted to the laboratory for AFB smear and mycobacterial culture. If tissue is obtained, it is critical that the portion of the specimen intended for culture not be put in formaldehyde. The use of AFB microscopy on urine or gastric lavage fluid is limited by the presence of commensal mycobacteria that can cause false-positive results.

Mycobacterial Culture

Specimens may be inoculated onto egg- or agar-based medium (e.g., Löwenstein-Jensen or Middlebrook 7H10) and incubated at 37°C (under 5% CO2 for Middlebrook medium). Because most species of mycobacteria, including M. tuberculosis, grow slowly, 4–8 weeks may be required before growth is detected. Although M. tuberculosis may be presumptively identified on the basis of growth time and colony pigmentation and morphology, a variety of biochemical tests have traditionally been used to speciate mycobacterial isolates.

Nucleic acid amplification

These systems permit the diagnosis of tuberculosis in as little as several hours, with high specificity and sensitivity approaching that of culture. These tests are most useful for the rapid confirmation of tuberculosis in persons with AFB-positive specimens but also have utility for the diagnosis of AFB-negative pulmonary and extrapulmonary tuberculosis.

Drug susceptibility testing

In general, the initial isolate of M. tuberculosis should be tested for susceptibility to isoniazid, rifampin, and ethambutol. In addition, expanded susceptibility testing is mandatory when resistance to one or more of these drugs is found or the patient either fails to respond to initial therapy or has a relapse after the completion of treatment.

Susceptibility testing may be conducted directly (with the clinical specimen) or indirectly (with mycobacterial cultures) on solid or liquid medium. Results are obtained most rapidly by direct susceptibility testing on liquid medium, with an average reporting time of 3 weeks. With indirect testing on solid medium, results may be unavailable for 8 weeks. Molecular methods for the rapid identification of genetic mutations known to be associated with resistance to rifampin and isoniazid have been developed but are not marketed in the United States.

Radiographic Procedures

The initial suspicion of pulmonary tuberculosis is often based on abnormal chest radiographic findings in a patient with respiratory symptoms. Although the "classic" picture is that of upper-lobe disease with infiltrates and cavities, virtually any radiographic pattern—from a normal film or a solitary pulmonary nodule to diffuse alveolar infiltrates in a patient with ARDS—may be seen. MRI is useful in the diagnosis of intracranial tuberculosis.

DIAGNOSIS OF LATENT TB INFECTION

Tuberculin Skin Testing

Skin testing with tuberculin purified protein derivative (PPD) is most widely used in screening for latent M. TB infection. The test is limited value in the diagnosis of active TB because of its relatively low sensitivity & specificity and its inability to discriminate between latent infection and active disease. False-negative reactions are common in immunosuppressed patients and in those with overwhelming TB. False-positive reactions may be caused by infections with nontuberculous mycobacteria and by bacilli Calmette-Guerin vaccination (BCG).

 TREATMENT

Two aims of TB treatment are to interrupt TB transmission and to prevent morbidity and death by curing patients with TB. Randomized clinical trials clearly indicated that the administartaion of streptomysin to patients with chronic TB reduced mortality rates and led to cure in majority cases. With the discovery of para-aminosalicylic acis (PAS) and isoniazid, it became axiomatic that cure of TB require concomitant administration of at least two agents to which the organism was susceptible. Early clinical trials demonstrated that a long period of treatment was required to prevent recurrence.

Drugs

4 major drugs are considered the first-line agents for the treatment of TB: isoniazid, rifampin, pyrazinamide and ethambutol.

These drugs are well absorbed  after oral administration, with peak serum levels at 2-4hrs and nearly complete elimination within 24h. these agents are recommended on the basis of their bactericidal activity, their sterilizing activity and  their low rate of induction of drug resistance.

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 TB 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 (3x/week OR 2x/week after an initial phase of daily therapy). Continuation phase of once-weekly rifapentine and isoniazid is equally effective for HIV-seronegative patients with noncavitary pulmonary tuberculosis who have negative sputum cultures at 2 months. Intermittent treatment is especially useful for patients whose therapy is being directly observed. Patinets with cavitary pulmonary TB and delayed sputum-culture onversion should have the continuation phase extended by 3 months, for a total course of 9months.

For patients with sputum culture–negative pulmonary tuberculosis, the duration of treatment may be reduced to a total of 4 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.

H: isoniazid; R=rifampin; Z=pyrazinamide; E=ethambutol; S=streptomycin; Q=quinolone; PAS=para-aminosalicylic acid

Monitoring Treatment Response & Drug Toxicity

Patients with pulmonary disease should have their sputum examined monthly until cultures become negative. >80% of patients will have negative sputum cultures at the end of second month of treatment. By the end of third month, virtually all patients should be culture-negative. In some patients, especially those with extensive cavitary disease and large numbers of organisms, AFB smear conversion may lag behind culture conversion. This phenomenon is presumably due to the expectoration and microscopic visualization of dead bacilli. As noted above, 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. If mycobacterial cultures are not practical, then monitoring by AFB smear examination should be undertaken at 2, 5, and 6 months. Smears that are positive after 5 months of treatment in a patient known to be adherent are indicative of treatment failure.

The most common adverse reaction of significance is hepatitis. Patients should be carefully educated about the signs and symptoms of drug-induced hepatitis (e.g., dark urine, loss of appetite) and should be instructed to discontinue treatment promptly and see their health care provider should these symptoms occur.

Hypersensitivity reactions usually require the discontinuation of all drugs and rechallenge to determine which agent is the culprit. Hyperuricemia and arthralgia caused by pyrazinamide can usually be managed by the administration of acetylsalicylic acid; however, pyrazinamide treatment 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.

Other common manifestations of drug intolerance, such as pruritus and gastrointestinal upset, can generally be managed without the interruption of therapy.

Ref: Harrison's Principal of Internal Medicine