Tuberculosis (TB)

Clinical Description

Identification

A mycobacterial disease with over nine million new infections and 1.7 million deaths (including 230 000 among HIVassociated tuberculosis cases) every year, tuberculosis (TB) is a major global cause of disability and death, especially in developing countries. The disease begins, in virtually all cases, with exposure to an infectious human source, and subsequent infection that usually goes un-noticed. This can be detected through tuberculin skin testing (TST) sensitivity and/or one of the newer interferon-gamma release assays (IGRA). These tests become positive after 2–6 weeks.

Initial infection generally causes no outward clinical manifestations. This latent infection state is characterized by small microscopic lesions in the lungs that commonly heal, leaving no residual changes other than occasional small pulmonary or tracheo-bronchial lymph node calcifications. Less than 10% of those otherwise healthy persons infected will eventually develop active disease during their lifetime. Among persons who develop active disease, half will develop disease within the first 2 years following infection; over 90% of infected individuals will never develop active TB. Appropriate treatment of latent TB infection can reduce the lifetime risk of TB disease.

In some individuals, initial TB infection may progress rapidly to active tuberculosis; this is called primary TB disease. Rapid clinical progression is more common among infants, in whom the disease is often disseminated (e.g. miliary) or meningeal, and in the immunosuppressed, such as HIV-infected persons. Treatment of latent TB infection in these individuals and other susceptible populations is highly effective in preventing development of TB disease.

Active pulmonary TB may arise from endogenous reactivation of a latent focus originating from the initial sub-clinical infection or from exogenous re-infection. Demonstration of acid-fast bacilli (AFB) in stained smears from sputum or other body fluids in a clinical and epidemiological situation suggestive of TB allows a presumptive diagnosis of active TB disease, and justifies initiation of anti-tuberculosis treatment. Fluorescent microscopy enhances sensitivity compared to standard microscopy by about 10%. Isolation of organisms of Mycobacterium tuberculosis complex on culture confirms diagnosis and also permits determination of drug susceptibility of the infecting organism. Traditional egg- or agar-based media for culturing mycobacteria include Löwenstein-Jensen and Middlebrook 7H10. In modern laboratories, liquid culture media for isolation and nucleic acid probes for speciation accelerate timing of diagnosis confirmation to 2–3 weeks. In the absence of bacteriological confirmation, active disease can be presumed if clinical, histological or radiological evidence is suggestive of TB and other likely diseases can be ruled out. Diagnosis of TB among persons living with HIV/AIDS is further complicated by frequent atypical presentations and a tendency to smear-negative disease.

Extrapulmonary TB occurs less commonly than pulmonary TB, but in up to one third of all cases. Children and persons with immunodeficiencies, such as those with HIV infection and AIDS, have a higher risk of extrapulmonary TB, but pulmonary disease remains the most common type worldwide, even in these more susceptible groups, and often occurs simultaneously with extrapulmonary diseases. TB may affect any organ or tissue; in order of frequency, TB tends to affect lymph nodes, pleura, the genito-urinary tract, bones and joints, meninges, the gastro-intestinal tract and peritoneum, and the pericardium.

Cough, fatigue, fever, night sweats, weight loss, and pleuritic pain are common signs and symptoms associated with pulmonary TB disease. Localizing symptoms, including hemoptysis, and hoarseness (which can be associated with laryngeal TB), can become prominent in advanced stages. Globally, the classification of pulmonary TB for treatment purposes is based primarily on the presence or absence of acid-fast bacilli (AFB) in the sputum. A smear positive for AFB is indicative of high infectiousness. Non-specific signs and symptoms, such as fever, night sweats, weight loss and fatigue, may occur early. In most cases, cough appears, initially non-productive and later accompanied by purulent sputum. In some cases, hemoptysis ensues as a result of the rupture of small vessels inside a growing cavity. Chest radiography most commonly reveals pulmonary infiltrates and cavitations in the upper segments of the lung lobes. In prolonged disease, fibrotic changes with volume loss can be seen. Approximately 65% of patients with untreated sputum smear-positive pulmonary TB will die within 5 years of diagnosis.

Infectious Agents

Mycobacterium tuberculosis complex. This includes M. tuberculosis, M. bovis (the “bovine tubercle bacillus”, historically an important cause of TB transmitted from infected cows through unpasteurized milk), M. africanum, and M. canettii (the latter two responsible for a small number of cases in Africa). Occasionally, M. microti, M. caprae and M. pinnipedii have also caused human disease. Other mycobacteria occasionally produce disease clinically indistinguishable from tuberculosis; the causal agents can be identified only through culture and speciation. M. tuberculosis is a thin aerobic organism, usually neutral on Gram's stain, but acid-fast (it cannot be decolorized by acid alcohol once stained). Its genome has been fully sequenced, and contains over 4 000 genes.


Diagnosis

Immunocompetent persons who have been infected with Mycobacterium tuberculosis complex usually have a delayed-type (cellular) hypersensitivity reaction to 5 IUs of purified protein derivative (PPD) tuberculin. Among persons with active TB disease, up to 25% may have no reaction to PPD tuberculin. Therefore, a negative tuberculin skin test (TST) result does not exclude TB disease in a person with signs and symptoms consistent with TB. Persons suspected to have TB disease should have a full diagnostic evaluation, including a chest radiograph and three sputum specimens collected for AFB smear and culture. Sputum specimens should be collected at least 8 hours apart, and at least one should be an early morning specimen.

Interpretation of the TST induration size is important because it determines the need to start treatment for latent TB infection (also referred to as chemoprophylaxis or preventive therapy). In the USA, a positive TST result is defined as an induration with a transverse diameter of 5, 10, or 15 mm based on the person's risk of exposure to TB disease and risk of progression from latent TB infection to disease. An induration of ≥5 mm is considered positive among persons who are HIV-infected; are recent contacts of a person with TB disease; have fibrotic changes on chest radiograph consistent with old TB disease; or are immunosuppressed. An induration of ≥10 mm is considered positive among persons who are recent arrivals (<5 years) from high-prevalence countries; injecting drug users; residents and employees of high-risk congregate settings (e.g., prisons, institutions, homeless shelters); and persons with high-risk clinical conditions (e.g., silicosis, diabetes mellitus, chronic renal failure or hemodialysis, gastrectomy, or carcinoma of the head or neck). Any reaction of 15 mm or more should be considered positive among low-risk persons. Generally, testing is not recommended for persons at low risk.

Skin tests for anergy (i.e., control antigens) are no longer recommended, even for high-risk patients. In many industrialized low-incidence TB countries, including the USA, routine skin testing of all children for TB is no longer recommended; children to be tested include those suspected of having active TB disease and those exposed to an infectious case. If treatment for latent TB infection will be initiated, targeted tuberculin skin testing can be provided to immigrants, including children, from highincidence countries, as well as other high-risk groups such as incarcerated, homeless, or HIV-infected persons.

In some persons with latent TB infection, delayed-type hypersensitivity to PPD tuberculin may wane with time. When persons are tested many years after initial TB infection, they may show a negative reaction (i.e. negative TST result); however, the skin test can “boost” their ability to react subsequently to tuberculin PPD, causing a positive reaction to subsequent tests. This boosting phenomenon can persist for up to several years and might be incorrectly interpreted as recent infection. Boosting has also been reported in persons who have received the Bacille Calmette-Guérin (BCG) vaccine. To prevent misinterpretation, a two-step skin testing procedure can distinguish between reactions due to new boosting and those due to recent TB infection. If the reaction to the first TST is classified as negative, a positive reaction to a second test 1–3 weeks later probably represents a boosted reaction. On the basis of this second result, the person should be classified as previously infected and treated for latent TB infection as indicated. If the second test is also negative, the person should be classified as uninfected with TB. Two-step skin testing should be used for initial skin testing of adults who will be retested periodically (e.g. health care workers), who are not known to have a prior positive TST result, and who have not had a documented TST result in the previous year or so. Treatment for latent TB infection generally does not change future TST results; therefore, persons with positive TST results should not have repeat skin testing. Persons with prior positive TST results and subsequent exposure to a person with infectious TB disease should have a clinical evaluation to exclude active TB disease.

In the last few years, two in vitro interferon-gamma release assays (IGRAs) have become available: QuantiFERON-TB Gold ® (Cellestis ltd, Carnegie, Australia), done on whole blood, and T-SPOT.TB ® (Offord Immunotec, Oxford, UK) done on purified blood cells. These tests measure the release of interferon-gamma by T lymphocytes in response to stimulation with TB-specific antigens. They are highly specific, with reduced cross-reactivity with BCG and other mycobacteria, and at least as sensitive as TST in detecting active disease and latent infection.

In addition, IGRAs do not trigger a boosting effect because the tests do not expose persons to antigens. In direct comparisons, the 80% sensitivity of IGRAs has been statistically similar to that of the TST for detecting infection in persons with untreated culture-confirmed TB as a surrogate for latent TB infection. However, their true sensitivity for latent TB infection, particularly in certain populations (e.g. children and immunocompromised persons) has not been determined. IGRAs, as with the TST, cannot differentiate TB infection from TB disease. A diagnosis of latent TB infection requires that active TB disease be excluded.

Similar to the TST, impaired immune function can decrease the sensitivity of IGRAs. Consequently, the performance of IGRAs might be decreased and the rate of indeterminate results increased for persons with HIV infection, undernourishment, immunosuppression, hematologic disorders (e.g., leukemia, lymphoma), specific malignances, diabetes, silicosis, and chronic renal failure. As with a negative TST result, a negative or indeterminate IGRA result alone might not be sufficient to exclude M. tuberculosis infection in these persons.

IGRAs are being integrated into routine clinical and public health practice in many regions of the world. In the USA, IGRAs have been recommended for use in all circumstances in which the TST is currently used, including contact investigations, evaluation of recent immigrants, and sequential testing surveillance programs for infection control (e.g., healthcare workers). IGRAs can be used in place of the TST, but are not recommended for use in addition to the TST (simultaneously or sequentially).

When the epidemiological and clinical evidence suggests TB disease, demonstration of AFB in smears from sputum or other body fluids is a presumptive diagnosis of TB disease and justifies initiation of anti-TB treatment. Isolation and identification of M. tuberculosis by culture confirms the diagnosis and permits determination of drug-susceptibility patterns. In the absence of bacteriological culture confirmation, TB disease can be diagnosed if clinical, histological, or radiological evidence is suggestive of TB disease and other likely disease processes have been excluded.


Epidemiology

Mode of Transmission

Exposure to tubercle bacilli in airborne, aerosolized droplet nuclei, that measure 1–5 microns in diameter, and are produced by persons with pulmonary or high respiratory tract tuberculosis (e.g. laryngeal) during forceful expiratory efforts (e.g. coughing, singing or sneezing). The droplet nuclei are inhaled by a vulnerable contact into the pulmonary alveoli. Here, the aerosolized particles containing M. tuberculosis are ingested by alveolar macrophages, initiating a new infection.

The balance between number and virulence of the microorganisms and the bactericidal activity of the macrophages determines the capacity to contain the infection. The risk of exposure and subsequent infection is linked with the intimacy and duration of the contact, the ventilation in the shared environment, and the degree of contagiousness of the index case. Health care workers are at high risk of exposure during aerosolizing procedures such as bronchoscopy, intubation, and autopsy. Laryngeal TB disease is highly contagious, but rare. Direct invasion through mucous membranes or breaks in the skin can occur but are extremely rare. Bovine tuberculosis, also a rare event, results from exposure to tuberculous cattle; exposure to M. bovis usually occurs through ingestion of unpasteurized contaminated milk or dairy products, and sometimes through airborne spread from cattle to farmers and animal handlers. Except for rare situations where there is a draining sinus, extrapulmonary tuberculosis (other than laryngeal) is generally not communicable.

Incubation Period

Two to 10 weeks from infection to demonstrable primary lesion or significant TST reaction and positivity of IGRA. IGRAs are expected to be positive by 10 weeks from infection, but the actual time from infection to IGRA conversion has not been adequately studied. Less than 10% of infected persons will develop TB disease in their lifetimes; half of those will develop TB disease within 2 years after initial infection. Latent TB infection can persist for a lifetime. HIV infection and other immunosuppressive conditions increase the subsequent risk of progressive pulmonary or extrapulmonary TB and shorten the interval for the development of TB disease following infection.

Period of Communicability

Theoretically, as long as viable tubercle bacilli are discharged in the sputum. Effective antimicrobial chemotherapy usually eliminates communicability within 2–4 weeks, although M. tuberculosis can still be cultured from sputum. Some untreated or inadequately treated patients (e.g. “chronic cases”) with TB disease can be intermittently AFB sputum-positive, and therefore contagious, for years. Studies from the United States and Canada suggest that persons with smear-negative, culture-positive pulmonary TB can be contagious and can transmit infection to other persons. Children with primary TB generally are not contagious.

The degree of communicability depends on intimacy and duration of the exposure, the number of bacilli discharged, infectivity of the bacilli, adequacy of ventilation, exposure of bacilli to sun or ultraviolet light, and opportunities for aerosolization through coughing, sneezing, talking or singing—or, for health care workers, during aerosolizing procedures.

Reservoir

Primarily humans, rarely other primates; except for M. bovis, which is found in cattle and a variety of other mammals.

Susceptibility

The risk of infection with the tubercle bacillus is directly related to the degree of exposure and less to genetic or other host factors. However, HIV-infected persons may have a higher risk of infection following exposure. The first 12–24 months after infection constitute the period of greatest risk for the development of clinical TB disease. The risk of developing disease is highest in children under 3, lowest in school-aged children, and high again among adolescents and young adults, the very old and the immunocompromised. Population groups not previously exposed to TB appear to have greater susceptibility to new infection and disease. Reactivation of long-latent infection accounts for a large proportion of TB disease cases in older people. Among infected persons, susceptibility to reactivation and TB disease is markedly increased by HIV infection and other forms of immunosuppression, and among the underweight or undernourished, people with a debilitating disorder (e.g. diabetes, chronic renal failure, some forms of cancer, silicosis, or gastrectomy), and substance users. Tobacco smokers and alcoholics are also at increased risk of TB morbidity and mortality.

For adults co-infected with HIV and latent TB, the lifetime risk of developing active TB disease rises from an estimated 10% to up to 50%. This phenomenon has resulted in a parallel pandemic of HIV/AIDS and TB disease where HIV prevalence is high: in some sub-Saharan African areas, where 10%–15% of the adult population are co-infected with both HIV and TB, annual TB disease rates have increased 5- to 10-fold between the start of the HIV/AIDS pandemic in the 1980s and today. In some countries in eastern and southern Africa, the HIV seroprevalence among TB cases may be as high as 70–80%.


Occurrence

Worldwide, all countries are affected; 9.15 million new infections occurred in 2006, of which some 61% were officially reported. Over 95% of infections are in developing countries, where TB remains a dominant cause of morbidity and mortality. The highest rates per capita are in Africa, especially the eastern and southern sub-regions (up to 1 000 per 100 000 population), but the highest numbers are reported in Asia (nearly 60% of all cases). In high incidence settings, morbidity is highest among adult males. In most industrialized countries, downward trends of mortality and morbidity in place for nearly a century reversed in the mid-1980s, when incidence of TB stagnated or began to increase. This phenomenon, still observed today in some northern European countries, is due to a number of factors, including immigration from high incidence areas, HIV infection, and deteriorated socio-economic conditions among the poorest segments of the population, besides dismantling of TB control services. In regions with declining TB incidence, TB mortality and morbidity rates increase with age. Morbidity and mortality rates are also higher among impoverished, disadvantaged, and minority populations, and are usually higher in urban areas.

The global estimated incidence of TB peaked around 2004–2005, and estimated incidence is now stable or decreasing in six of nine WHO epidemiological regions. The 22 highest-burden TB countries account for approximately 80% of the estimated number of new TB cases arising each year; for these 22 countries, the estimated case rate was 174 cases per 100 000 persons in 2005.

The prevalence of latent TB infection, detected by TST, increases with age. It is estimated that one third of the human population is infected today. The incidence of infection, expressed as annual risk of infection, in industrialized countries has declined rapidly in recent decades; in the USA, the annual risk of new infection is estimated to average about 10/100 000 people at most, although segments of the population in the USA and other industrialized countries may have a relatively high annual risk of new infection. In areas where human infections with non-tuberculous mycobacteria are prevalent, cross-reactions can complicate interpretation of the TST reaction.

In the low incidence areas of USA and many other industrialized countries, most TB disease in adults results from reactivation of latent foci remaining from an initial infection. However, in some large urban areas, about one-third of TB disease cases may result from recent infection. Micro-epidemics have been reported in closed spaces, such as nursing homes, shelters for the homeless, hospitals, schools, prisons, and during long-haul-flights.

From 1989 to the early 1990s, outbreaks of multidrug-resistant TB (MDR-TB), defined as resistance to at least isoniazid and rifampicin, have been recognized in settings where HIV-infected persons are congregated (hospitals, prisons, drug treatment clinics and HIV residences). These outbreaks were associated with high fatality rates and transmission of M. tuberculosis to other patients and health care workers. Strict enforcement of infection control guidelines, proactive case finding, intensive contact investigations, and ensuring completion of appropriate treatment regimens have been effective in stopping and preventing MDR TB outbreaks. In a 2008 report, WHO estimated that 4.8% of all TB cases worldwide were due to MDR strains; in some countries, particularly those in Eastern Europe and Central Asia, up to 20% of new cases and 60% of previously treated cases were MDR TB. Three countries—China, India, and Russia—accounted for 57% of the overall estimated incidence of MDR TB.

Recently, extensively resistant forms of TB (XDR-TB) have emerged, especially in settings where the use of second-line drugs has been widespread and poorly managed, and where the capacity to diagnose drug resistance exists. XDR-TB is defined as MDR-TB plus resistance to any fluoroquinolone and any of the three injectable drugs, amikacin, kanamycin and capreomycin. In a 2005–2006 outbreak of XDR TB in KwaZulu Natal, South Africa, 52 of 53 (98%) patients died, and median survival was 16 days from date of diagnosis. In a laboratory study published in 2007, over 6% of all MDR TB isolates worldwide met the definition for XDR TB.

HIV-associated TB (TB/HIV) is frequent in Africa and a few other settings. Worldwide, more than 700 000 TB cases a year were estimated to be due to HIV in 2006, with over 230 000 deaths a year. For HIV-infected persons, the annual risk of TB disease has been estimated at 2%–13%, based on CD4 cell count, and the cumulative risk is well over 50%.

Human infection with M. bovis, the bovine tubercle bacillus, continues to be a problem in areas where the disease in cattle is poorly controlled, and unpasteurized milk or dairy products are consumed raw. In some industrialized countries, TB disease caused by M. bovis accounts for approximately 1% of all reported TB cases.


Prevention and Control

1)    Preventive measures:

a)    The best prevention of TB is prompt diagnosis and treatment, especially of infectious sputum smear-positive cases, as patients are rendered non-infectious within 2–4 weeks after starting an effective regimen. Establishment of active casefinding through contact investigations, and provision of adequate treatment facilities for infectious cases, are key to reducing transmission. This normally requires a well-functioning and coordinated TB program operating at the lowest health administrative authority level (e.g., district level), under the guidance of national program norms and standards, providing training and supervision, and monitoring performance.

b)    Ensure clinical, laboratory, and radiology facilities for prompt identification of suspects and examination of patients and contacts. Ensure provision of the four essential anti-TB drugs (see below) and medical facilities for early and complete treatment of cases and people at high risk of infection, including beds for those needing hospitalization due to severe, advanced disease.

Among persons presenting with signs and symptoms consistent with TB disease in high-incidence countries, direct microscopy sputum examination for AFB can detect as much as 50%–65% of infectious pulmonary TB. In most situations, direct microscopy is the most cost-effective method of case finding, and this is the first priority in developing countries. However, culture, especially using liquid media to accelerate detection, is today recommended to identify TB among HIV-infected people and MDR-TB. In fact, due to the emergence of MDR-TB in most countries, ideally all initial isolates should be submitted to drug susceptibility testing. In countries currently with limited resources and laboratory capacity, drug susceptibility testing should be performed at least among cases needing re-treatment, such as treatment failures and defaulters of previous treatment. In countries with adequate resources, all cases should have culture confirmation and drug susceptibility testing. To face the management challenge of MDR-TB more effectively, WHO has recently recommended the use of molecular, PCR-based methods for rapid detection of isoniazid and rifampicin resistance. These methods, called “line-probe assays” (LPSa), can be used directly on the sputum produced by sputum-smear positive cases and reveal the presence of MDR-TB within a few hours, thus shortening time to diagnosis and start of proper treatment.

c)    Educate the public regarding mode of spread, methods of control, and importance of early diagnosis and continued adherence to treatment.

d)    Reduce or eliminate social conditions that increase the risk of infection and progression to disease.

e)    Establish and maintain effective TB infection control programs in institutional settings where healthcare is provided and where immunocompromised patients (e.g., HIV-infected persons) congregate (including hospitals, drug treatment programs, prisons, nursing homes, and homeless shelters).

f)    Treating latent TB infections (TLTBI, also called preventive chemotherapy or chemoprophylaxis) with isoniazid (INH) for 6–9 months has been effective in preventing the progression of latent TB infection to TB disease in up to 90% of adherent individuals. Studies in adults with HIV infection have shown the effectiveness of alternative regimens including 4 months of daily rifampicin and 3 months of isoniazid and rifampicin. A shorter course (2 months) of rifampicin and pyrazinamide has been associated with severe and even fatal hepatotoxicity, and is not currently recommended for general use. It is essential to rule out active TB disease before starting treatment for latent TB infection, especially in immunocompromised persons such as HIV-infected individuals, in order to avoid inadvertently treating active disease with a 1- or 2-drug regimen that would encourage the development of drug resistance. Because of the risk of isoniazid-associated hepatitis, isoniazid is not routinely advised for persons with active liver disease.

In the USA, 9 months of daily INH (twice weekly if directly observed therapy is available) is the recommended treatment for all persons with latent TB infection without contraindications; 4 months of daily rifampin (RIF) is an acceptable alternative. RIF is contraindicated in HIV-infected persons being treated with certain combinations of antiretroviral drugs (protease inhibitors or non-nucleoside reverse transcriptase inhibitors [NNRTI]). WHO and UNAIDS recommend a preventive treatment with 6 months of daily isoniazid for all HIV-infected individuals after careful exclusion of active disease.

Persons started on TLTBI must be informed of possible adverse effects (e.g. hepatitis, drug fever or severe rash), reminded of these possibilities, and checked for symptoms monthly, prior to prescription refills; they should be advised to discontinue treatment and seek medical advice if suggestive symptoms develop. Baseline liver function tests are important in patients with signs, symptoms or history of liver disease, and in those who abuse alcohol. Avoiding or discontinuing isoniazid generally is advised for persons with serum aspartate aminotransferase levels more than 5 times the upper limit of normal values (3 times if symptoms suggest hepatic dysfunction). Supervised treatment should be used when possible (e.g. prisons, drug treatment programs, schools). Not more than 1 month's supply of medication should be given at any one time, and patients should be queried at least monthly about adverse effects. Among persons taking INH, 10%–20% can have asymptomatic elevation of serum liver enzymes and 0.1%–0.15% can develop clinical hepatitis. Factors that can increase the rate or severity include alcohol consumption, underlying liver disease, or concurrent use of liver-metabolized medications. Peripheral neuropathy occurs in less than 0.2% of persons and is more likely in the presence of other conditions associated with neuropathy (e.g., diabetes, HIV infection, renal failure, and alcohol abuse). Pyridoxine (vitamin B6) supplementation is recommended to prevent peripheral neuropathy in persons at increased risk for this complication.

Among persons taking RIF, 0.6% can have hepatotoxicity, as evidenced by transient asymptomatic hyperbilirubinemia, and 6% can have cutaneous reactions, such as pruritis with or without a rash. Orange discoloration of body fluids is expected and harmless; soft contact lenses can be permanently stained. RIF interacts with a number of drugs and accelerates hepatic metabolism; as a result, RIF reduces the concentrations of methadone, warfarin, oral contraceptives, and phenytoin.

Baseline hepatic transaminases are important in persons with a known or suspected history of liver disease, alcohol abuse, HIV infection, or pregnancy. Routine periodic laboratory tests are recommended for persons who had abnormal initial results or who are at high risk for hepatic disease. Laboratory testing is recommended for any persons on treatment who have symptoms suggestive of hepatitis (e.g., fatigue, weakness, malaise, anorexia, nausea, vomiting, abdominal pain, pale stools, dark urine, chills) or who have signs of jaundice. At the start of treatment and at each monthly visit for medication refills, persons should be advised not to wait until a clinic visit to stop treatment, and to seek medical attention immediately if symptoms of hepatitis develop.

During pregnancy, it may be wise to postpone treatment for latent TB infection until after delivery, except in high-risk individuals, where it should be administered with caution. If INH treatment is prescribed for pregnant women or in the immediate post-partum period, monthly routine hepatic transaminases should be monitored. INH daily or twice weekly (using directly observed therapy) is the preferred regimen supplementation with 50 mg of pyridoxine (vitamin B6) is recommended. Breastfeeding is not contraindicated.

Mass TLTBI is unsuitable in most communities unless there is a well-organized program to supervise and encourage adherence to treatment and unless a high rate of cure can be achieved among patients with active TB disease. However, vulnerable groups, such as the HIV-infected, may be targeted for selective, large-scale treatment. Infants and children under 5 years of age with latent TB infection have been recently infected and are therefore at high risk for progression to disease. Risk of INH-related hepatitis in infants, children, and adolescents is minimal and routine monitoring of liver enzymes is not necessary. If resources allow, directly observed therapy should be considered.

Treating latent TB infection in contacts (especially in pediatric and HIV-infected contacts) is the highest public health priority after finding and curing active TB cases. Mass treatment for latent TB infection is unrealistic and unsuitable in most communities unless (a) high detection and cure rates are first being achieved among persons with TB disease; (b) contact investigations are thorough, with recently infected persons routinely completing treatment; and (c) there is a well-organized program to supervise and ensure adherence to treatment.

g)    Persons infected with HIV should be screened for TB at the time their HIV infection is identified; they should start TLTBI if they have been tested positive with TST or IGRA and if active TB disease has been carefully ruled out through proper medical history and examination, including chest radiography. Conversely, all people with evidence of TB disease should be counseled and tested for HIV infection, and offered the option of antiretroviral treatment and all other support measures for HIV-infected persons.

h)    In industrialized countries where BCG immunization is not routinely carried out, selective TST and TLTBI may be considered for groups at high risk of TB infection and/or HIV infection, including health care workers and groups such as prison inmates and injecting drug users; this may also be considered for foreign-born persons from areas of high tuberculosis prevalence, and possibly for travelers to and from high-prevalence areas. Prior BCG immunization may complicate interpretation of a positive skin test in a child or recently immunized adult. Since skin test reactions from BCG wane over time, strongly positive reactions or significant increases in reactivity should be considered indicative of TB infection. Targeted testing, standard interpretation of TST, and TLTBI are recommended regardless of prior history of BCG vaccination.

i)    For contacts with TB infection from infectious cases with known drug-resistant strains, treatment regimens have been based on in vitro data, extrapolation from treatment of active TB disease, and expert opinion rather than controlled clinical trials. None of the potential regimens has been fully evaluated for efficacy. For persons who are likely to be infected with drug-resistant strains and are at high risk of developing TB disease, treatment regimens that include at least 2 drugs to which the mycobacteria from the source patient are known to be susceptible should be considered for 6–12 months duration. Clinical evaluations and chest radiographs every 3–6 months for the first 2 years is an alternative strategy to treatment with unproven drug regimens.

j)    Provide public health nursing and outreach services to patients; ensure each patient receives directly observed therapy for TB disease; ensure contact investigations are conducted to identify and treat latent TB infection among contacts.

k)    Persons with HIV infection should have tuberculin skin testing or an IGRA at their first clinical evaluation; HIV-infected persons with a positive TST result (≥5 mm induration) or IGRA should start treatment for latent TB infection as soon as active TB disease has been excluded. In the USA, 9 months of INH is the recommended treatment for HIV-infected persons with latent TB infection; RIF is generally contraindicated in persons who are taking protease inhibitors and NNRTIs. Conversely, all persons with TB infection or disease should receive HIV counseling and testing where available.

l)    Case-control and contact studies consistently show that BCG is protective against TB meningitis and disseminated disease in children under 5. Some controlled trials indicate that protection may persist for as long as 20 years in high incidence situations; others have shown no protection at all. Meta-analyses on BCG effectiveness provide conflicting results. Ongoing efforts to develop a vaccine more effective than BCG have identified candidate vaccines that are currently undergoing testing in humans for safety and immunogenicity. Because the risk of infection is low in many industrialized countries, BCG is not used routinely in these settings; BCG may be considered for children with a negative PPD skin test who cannot be placed on preventive therapy but have continuous exposure to people with untreated or ineffectively treated active disease, or are continuously and irremovably exposed to patients infected by organisms resistant to isoniazid and rifampicin. In countries with high TB prevalence, WHO recommends BCG vaccination for newborns as part of the routine immunization program. A live-attenuated vaccine, BCG is contraindicated in persons with immunodeficiency disorders, including infants and children with symptomatic HIV infection, because of the risk of disseminated BCG disease. In settings where HIV services for mothers and infants are limited, BCG vaccine should continue to be given at birth to all infants regardless of HIV exposure. WHO recommends close follow-up of infants known to be born to HIV-infected mothers and who receive BCG at birth, in order to identify and treat BCG-related complications. In settings with adequate HIV services that could allow for early identification and administration of antiretroviral therapy to HIV-infected infants, consideration should be given to delaying BCG vaccination in infants born to mothers known to be HIV-infected until the infants are confirmed to be HIV negative. Re-vaccination at older ages is regarded as an intervention for which evidence of efficacy is controversial, and WHO does not recommend it.

BCG immunization of uninfected (TST-negative) people induces tuberculin reactivity in approximately half of those vaccinated. Tuberculin reactivity and protection vary. Protection varies markedly in different field trials, and is probably related to immunological characteristics of population, quality of vaccine, BCG strain, and prevalence of environmental mycobacteria.


m)    Eliminate bovine tuberculosis among dairy cattle, through tuberculin testing and slaughtering of positive reactors; pasteurize or boil milk and dairy products for human consumption.

n)    A number of social and economic conditions and their consequences have been associated with a high risk of developing TB among those infected; these include malnutrition, silicosis among those working in industrial plants and mines, indoor air pollution, smoking and alcohol abuse. Interventions aiming at reducing the prevalence of such conditions will also benefit TB control.

2)    Control of patient, contacts and the immediate environment:

a)    Report to local public health authorities when diagnosis is suspected: obligatory case report in most countries, Class 2. Case reports must state whether the case is bacteriologically confirmed (AFB smear positive or culture positive) or if diagnosis was based on clinical and/or radiographic findings, and whether the case was previously treated. Public health authorities must maintain a register of cases requiring treatment, and must be actively involved with planning and monitoring the course of treatment.

b)    Isolation: For pulmonary tuberculosis, control of infectivity is most efficiently achieved through prompt specific drug treatment, usually leading to disappearance of vital organisms in the sputum in 2–4 weeks and full sputum clearance within 4–8 weeks. Hospitalization is necessary only for patients with severe illness requiring hospital-level care, and for those whose medical or social circumstances make treatment at home impossible. Where available, adult patients with sputum smear-positive pulmonary TB who reside in congregate settings should be placed in an airborne infection isolation room with negative pressure ventilation, with at least six air exchanges per hour. Patients should be taught to cover both mouth and nose when coughing or sneezing. Face masks, such as the cloth or paper surgical masks, prevent spread of bacilli from the wearer to others by capturing the large wet particles expelled, but do not protect the wearer from inhaling infectious droplets nuclei in the air. Persons entering rooms where TB patients reside should wear personal respiratory protective devices capable of filtering particles of less than a micron in diameter, such as N95 face respirators. Patients whose sputum is bacteriologically negative, who do not cough, and who are known to be on adequate chemotherapy (known or probable drug susceptibility and clear clinical response to treatment) do not require isolation, nor do children with active TB disease with negative sputum smears and no cough, as they are not contagious. For patients with MDR TB, sputum culture conversion to negative is generally recommended for discontinuing isolation precautions.

Adolescents should be managed as adults. The need to adhere to the prescribed chemotherapeutic regimen must be emphasized repeatedly to all patients. Proper patient education, counseling and support must be provided to ensure that drug regimens are taken as prescribed. Supervision of drug administration through a health care worker or a recognized community worker to ensure that daily doses are taken as prescribed, including directly observed therapy, is essential for all patients. In resource-limited settings, directly observed therapy should be prioritized for persons with suspected drug resistance, a previous history of poor adherence to treatment, or who live in conditions where relapse would result in exposure of many other susceptible persons.

c)    Concurrent disinfection: Hand-washing and good housekeeping practices must be maintained according to policy. Because TB has an airborne mode of transmission, no special precautions are necessary for handling fomites. Decontamination of air is achieved by ventilation; this may be supplemented by filtration and ultraviolet light.

d)    Quarantine: Recently, the emergence of highly drug-resistant forms of TB (MDR-TB, XDR-TB) has raised the issue of application of quarantine measures to enforce isolation. WHO strongly recommends that governments ensure, as their top priority, that every patient has access to high quality TB diagnosis and treatment for TB and drug-resistant forms of TB. It also fully supports the rights and responsibilities of TB patients as recommended in the Patients' Charter for TB Care. In this regard, if a patient willfully refuses treatment and is a danger to the public as a result, the serious threat posed by XDR-TB (and MDR-TB) means that limiting that individual's human rights may be necessary to protect the wider public. Therefore, interference with freedom of movement when instituting quarantine or isolation for a communicable disease such as MDR-TB and XDR-TB may be necessary for the public good, and could be considered legitimate under international human rights law. This must be viewed as a last resort, and justified only after all voluntary measures to isolate such a patient have failed.

A key factor in determining if the necessary protections exist when rights are restricted is that each one of the five criteria of the Siracusa Principles must be met (but these should be of a limited duration, and subject to review and appeal). The Siracusa principles are as follows:

(1)    The restriction is provided for and carried out in accordance with the law.

(2)    The restriction is in the interest of a legitimate objective of general interest.

(3)    The restriction is strictly necessary in a democratic society to achieve the objective.

(4)    There are no less intrusive and restrictive means available to reach the same objective.

(5)    The restriction is based on scientific evidence and not drafted or imposed arbitrarily, i.e. in an unreasonable or otherwise discriminatory manner.

e)    Management and investigation of contacts and source of infection: Investigation of potentially exposed contacts is recommended at the time of diagnosis. TST or IGRA tests for all household members and other close contacts are recommended. If the initial TST or IGRA result is negative, a repeat TST or IGRA should be performed at least 8–10 weeks after exposure to the person with TB disease has ended or they are no longer considered contagious. Clinical evaluation and a chest radiograph should be obtained for contacts with a positive TST (≥5 mm induration) or IGRA result to exclude TB disease. Treatment of latent TB infection is indicated (see 9.A.6.) for contacts with positive TST or IGRA results. In addition, close contacts at high risk of developing TB disease (i.e., children younger than 5 years and persons with HIV infection) should be started on presumptive treatment (i.e., “window prophylaxis”) until the post-exposure TST or IGRA result is available. In many developing countries, investigation of household contacts is limited to sputum microscopy of those contacts who have symptoms suggestive of TB disease.

f)    Specific treatment: principles of case management are included in the WHO's Stop TB Strategy. Its first component, “Pursue DOTS expansion” (where “DOTS” is the WHO-recommended 5-element package for TB control), explicitly describes adequate approaches to diagnosis, treatment, and patient monitoring. Such approaches should be implemented by all care providers, regardless of whether they work in governmental facilities or in the non-state sector (e.g. non-governmental organizations, faith-based organizations, academic institutions, private practice, etc.). They are also described in the International Standards of TB Care. Community participation is also integral part of this strategy, as it supports adherence to treatment and, possibly, early detection of suspects, cases and contacts.

Adequate patient support to ensure that all drugs are taken as prescribed, including directly observed therapy, is highly effective in achieving cure and is recommended for treatment of TB disease worldwide. Patients with TB disease must be promptly treated with an appropriate combination of antimicrobial drugs. In pulmonary TB cases, sputum smears and cultures must be monitored at regular intervals.

For all TB cases, WHO and the International Standards of TB Care recommend a treatment regimen of 2 months of daily doses of INH, RIF, pyrazinamide (PZA), and ethambutol (EMB), followed by 4 months of daily or intermittent (three times a week) INH and RIF. All treatment should be supervised or directly observed to ensure medication ingestion by the patient; this regimen is known as short-course chemotherapy. If treatment cannot be directly observed in the continuation phase, 6 months of INH and EMB can be substituted in place of 4 months of INH and RIF. However, this regimen is a weaker alternative as it increases chances of relapse and failure.

Some recommend that treatment could be extended to 9 months for patients with cavitary lung disease or who remain sputum smear or culture positive after 3 months on appropriate therapy. After drug susceptibility results become available, a specific drug regimen can be selected if the patient has a drug-resistant strain.

In HIV-infected patients, concomitant treatment for TB and antiretroviral therapy has several challenges, including adherence to multiple medications, overlapping medication side effects, immune reconstitution inflammatory syndrome (IRIS), and drug-drug interactions. The key interactions are those between the rifamycin antibiotics and four classes of antiretroviral drugs: protease inhibitors, NNRTIs, CCR5-receptor antagonists, and integrase inhibitors. Two of the antiretroviral drug classes, the nucleoside analogues (excluding zidovudine) and enfuvirtide (a parenteral entry inhibitor) do not have significant interactions with the rifamycins. Because of the complexity of treating TB and HIV concomitantly, these patients should be treated by or in close consultation with a clinician with expertise in management of both TB and HIV.

If sputum culture fails to become negative after 3 months of standard treatment or reverts to positive after a series of negative results, or if clinical response is poor, examination of the patient's drug adherence and repeat drug-susceptibility testing is indicated. Treatment failure can be due to irregular or interrupted drug regimens, drug malabsorption, the presence of a drug-resistant strain, or a combination of these factors. A change in supervision practices is required if the problem is irregular or interrupted drug regimens. If drug-susceptibility testing is available, at least 2 new drugs to which the organisms are susceptible should be added to the original drug regimen; a single new drug should never be added to a failing regimen. Adding a single new drug to a failing regimen increases the risk of developing resistance to the new drug and can further complicate clinical management. If the organisms are resistant to INH or RIF, treatment should continue for at least 18 months after cultures have become negative to ensure a cure has been obtained. Expert consultation is advised for the proper management of patients with MDR TB and XDR TB.

WHO recommends children receive the same regimens as adults with minor modifications; susceptibility of the causal organism can often be inferred from the drug-susceptibility pattern of the adult source patient's isolate. Children with pulmonary or extrapulmonary TB can be treated with INH, RIF, PZA, and EMB for 2 months, followed by INH and RIF for 4 months. If treatment cannot be directly observed in the continuation phase, 6 months of INH and EMB can be substituted in place of 4 months of INH and RIF. Children with TB meningitis or HIV co-infection should be treated for a minimum of 9 months. In some countries, EMB generally is not used until the child is old enough for color vision to be checked (usually when aged 5 years or more), although it can be added to the regimen of children with more severe disease. A recent review indicates, however, that EMB can be safely added to the regimen of children at a dose of 20 mg/kg daily. Children with meningitis, miliary disease, bone/joint disease or HIV infection should be treated for 9 to 12 months. For further details of case management in children, see Guidance for national tuberculosis programmes on the management of tuberculosis in children, which can be found at: http://whqlibdoc.who.int/hq/2006/WHO_HTM_TB_2006.371_eng.pdf.


All drugs can cause adverse reactions. Thoracic surgery is rarely indicated, but has been used successfully in certain MDR and XDR TB cases with focal pulmonary disease and adequate pulmonary function. Patients in whom surgery is considered should have several months of adequate treatment before resection, and should continue treatment for 12–24 months following surgery. For WHO guidance on details of case management (including MDR- and HIV-associated TB), see Treatment of tuberculosis: Guidelines for national programmes (WHO/CDS/TB/2003.313), which can be found at: http://whqlibdoc.who.int/hq/2003/WHO_CDS_TB_2003.313.pdf

For US-specific case management advice, see Treatment of tuberculosis: American Thoracic Society, CDC, and Infectious Diseases Society of America, which can be found at: http://www.cdc.gov/MMWR/PDF/rr/rr5211.pdf

Monitoring of treatment response necessitates symptom evaluation and in pulmonary cases, sputum-smear microscopy and culture monthly, or at least after 1, 2, 5, and 6 months. In developing countries where smear microscopy is still the only readily available tool, the latter plan is most common. Radiological abnormalities may persist for months after a bacteriological response, often with permanent scarring, and monitoring by serial chest radiographs is thus neither useful nor recommended for evaluation of response. An end-of-treatment chest X-ray in patients with pulmonary or pleural TB may help show new baseline anatomy and will document findings for future comparison.
WHO strongly recommends that cohort analysis of treatment outcomes include all patients registered for treatment. The 6 mutually exclusive categories of treatment results are: bacteriologically proven cure; treatment completion (without bacteriological evidence of cure); failure (smear positive at month 5 after treatment start); default; death; and transfer to other administrative units. Cohort analysis allows proper evaluation of treatment program performance and prompts corrective measures when unacceptable levels of treatment failures, deaths, and defaulting occur.

3)    Epidemic measures:

Prompt diagnosis and treatment of each person with contagious TB disease; active case finding for secondary cases of TB disease among contacts; identification and treatment of TB infections among contacts; in pediatric TB patients, an intensive search for and treatment of the source patient; airborne infection precautions.

4)    Disaster implications:

TB care and control are not a priority in the acute phase of an emergency when mortality rates are high. A TB control program should be considered when there is a high prevalence of TB disease, basic needs are provided for, essential clinical services and supplies are available, and death rates have been reduced to less than 1 per 10 000 persons per day. TB control programs in these settings should be integrated with the national or host country TB control program to ensure acceptable standards and outcomes are met. For WHO guidance, see Tuberculosis care and control in refugee and displaced populations: An interagency field manual, which can be found at: http://whqlibdoc.who.int/publications/2007/9789241595421_eng.pdf.

5)    International measures:

In industrialized countries, a high proportion of new disease cases arise among foreign-born persons, especially those from high prevalence areas. The annual proportion of new cases born abroad has been growing steadily, and today is around 60% in some industrialized countries. Surveillance allows the identification of those at excess risk. Among the at-risk population, screening allows individuals to benefit from curative and preventive interventions. These include:

a)    Adequate notification systems (physician and laboratory reports) to identify populations at risk

b)    Smears, culture and other diagnostic procedures, followed by curative/preventive interventions for symptomatic persons with latent TB infection or TB disease

c)    Provision of culturally and socially sensitive curative and preventive services for persons with TB disease; ensured follow-up of interventions

d)    Ongoing evaluation of the efficiency and efficacy of interventions.

Further information can be found at:
    http://www.who.int/topics/tuberculosis/en/
    http://www.cdc.gov/tb/
    http://www.who.int/gtb/
    http://www.stoptb.org.

Source: Heymann (Ed.). (2008). Control of Communicable Diseases Manual, 19th edition. Washington, DC: American Public Health Association.
 


Available Vaccines

WHO-Prequalified Tuberculosis Vaccines (BCG)

 
Common Disease Taxonomy: