Tuberculosis disease is caused by an infection with organisms of the Mycobacterium tuberculosis complex. Most infections caused by the M. tuberculosis complex in children and adolescents are asymptomatic. When pulmonary tuberculosis occurs, clinical manifestations appear most frequently 1 to 6 months after infection and include fever, weight loss or poor weight gain, growth retardation, cough, night sweats, and chills. Chest radiographic findings are rarely specific for tuberculosis and include lymphadenopathy of the hilar, subcarinal, paratracheal, or mediastinal nodes; atelectasis or infiltration of a segment or lobe; pleural effusion that can hide small interstitial lesions; interstitial cavities; or infiltrators of a military pattern.
In selected cases, CT or MRI of the chest can clarify indistinct radiographic findings, but these methods are not necessary for routine diagnosis. Although cavitation is common in reactivation “adult” tuberculosis, cavitation is rare in childhood tuberculosis. Necrosis and cavitation can be the result of a progressive primary focus in very young or immunosuppressed patients and in the context of lymphobronchial disease. Extrapulmonary manifestations include meningitis and granulomatous inflammation of the lymph nodes, bones, joints, skin, middle ear, and mastoids. Tuberculosis of the gastrointestinal tract can mimic inflammatory bowel disease. Renal tuberculosis and progression to latent M. tuberculosis infection (“adult-type pulmonary tuberculosis”) are unusual in younger children, but can occur in adolescents. In addition, chronic abdominal pain with peritonitis and intermittent partial intestinal obstruction may be present in Mycobacterium bovis disease.
Congenital tuberculosis can mimic neonatal sepsis, or the baby can seek medical attention in the first 90 days of life with bronchopneumonia and hepatosplenomegaly. Clinical findings in patients with drug-resistant tuberculosis disease are indistinguishable from manifestations in patients with the drug-susceptible disease.
Table of Contents
Cause of Tuberculosis
The causative agent is M tuberculosis complex, a group of closely related acid-fast bacilli, which routinely includes the human pathogens M tuberculosis, M bovis, Mycobacterium africanum, and a few additional species infrequently associated with human infection. M africanum is rare in the United States, so clinical laboratories do not distinguish it routinely, and treatment recommendations are the same as for M tuberculosis. M bovis can be distinguished from M tuberculosis in reference laboratories, and although the spectrum of illness caused by M bovis is similar to that of M tuberculosis, the epidemiology, treatment, and prevention are different.
Definitions:
Positive tuberculin skin test (TST):
A positive TST result (Table 154.1) indicates possible infection with M tuberculosis complex. Tuberculin reactivity appears 2 to 10 weeks after initial infection; the median interval is 3 to 4 weeks. Bacille CalmetteGuérin (BCG) immunization can produce a positive TST result.A positive TST result (Table 154.1) indicates possible infection with M tuberculosis complex. Tuberculin reactivity appears 2 to 10 weeks after initial infection; the median interval is 3 to 4 weeks. Bacille CalmetteGuérin (BCG) immunization can produce a positive TST result.
Positive interferon-gamma release assay (IGRA):
A positive IGRA result indicates probable infection with M tuberculosis complex. IGRAs measure ex vivo interferongamma production from T lymphocytes in response to stimulation with antigens specific to M tuberculosis complex, including M tuberculosis and M bovis.
Exposed person:
Exposed person is a person who has had recent (eg, within 3 months) contact with another person with suspected or confirmed contagious tuberculosis disease (ie, pulmonary, laryngeal, tracheal, or endobronchial disease) and who has a negative TST or IGRA result, normal physical examination findings, and chest radiographic findings that are normal or not compatible with tuberculosis.
Some exposed people are or become infected (and subsequently develop a positive TST or IGRA result), and others do not become infected after exposure; the 2 groups cannot be distinguished initially.
Source case:
Source case is the person who has transmitted infection with M tuberculosis complex to another person who subsequently develops infection not yet clinically apparent (especially a young child) or develops established latent M tuberculosis infection (LTBI) or tuberculosis disease.
LTBI:
LTBI is M tuberculosis complex infection in a person who has a positive TST or IGRA result, no physical findings of disease, and chest radiograph findings that are normal or reveal evidence of healed infection (eg, calcification in the lung, the hilar lymph nodes, or both). Hilar adenopathy is evidence of tuberculous disease, not LTBI.
Tuberculosis disease:
Tuberculosis disease is an illness in a person with infection in whom symptoms, signs, or radiographic manifestations caused by M tuberculosis complex are apparent; disease can be pulmonary, extrapulmonary, or both.
Directly observed therapy (DOT):
Directly observed therapy (DOT) is an intervention by which medications are administered directly to the patient by a health care professional or trained third party (not a relative or friend) who observes and documents that the patient ingests each dose of medication and assesses for possible adverse drug effects.
Multidrug-resistant tuberculosis:
Multidrug-resistant tuberculosis is an infection or disease caused by a strain of M tuberculosis complex that is resistant to at least isoniazid and rifampin.
Extensively drug-resistant tuberculosis:
Extensively drug-resistant tuberculosis is an infection or disease caused by a strain of M tuberculosis complex that is resistant to isoniazid and rifampin, at least 1 fluoroquinolone, and at least 1 of the following parenteral drugs: amikacin, kanamycin, or capreomycin.
Bacille Calmette-Guérin (BCG):
Bacille Calmette-Guérin (BCG) is a live attenuated vaccine strain of M bovis. BCG vaccine rarely is administered to children in the United States but is one of the most widely used vaccines in the world. An isolate of BCG can be distinguished from wild-type M bovis only in a reference laboratory.
Epidemiology:
Case rates of tuberculosis in all ages are higher in urban, low-income areas and in nonwhite racial and ethnic groups; more than 80% of reported cases in the United States occur in Hispanic and nonwhite people. In recent years, more than 65% of all US cases have been in people born outside the United States. Almost 80% of childhood TB disease is associated with some form of foreign contact of the child, parent, or a household member.
Specific groups with greater LTBI and disease rates include immigrants, international adoptees, refugees from or travelers to high-prevalence regions (eg, Asia, Africa, Latin America, and countries of the former Soviet Union), homeless people, people who use alcohol excessively or illicit drugs, and residents of certain correctional facilities and other congregate settings. Secondhand smoke exposure increases the risk of TB disease in infected children.
Infants and postpubertal adolescents are at increased risk of progression of LTBI to tuberculosis disease. Other predictive factors for development of disease include recent infection (within the past 2 years); immunodeficiency, especially from HIV infection; use of immunosuppressive drugs, such as prolonged or highdose corticosteroid therapy or chemotherapy; intravenous drug use; and certain diseases or medical conditions, including Hodgkin disease, lymphoma, diabetes mellitus, chronic renal failure, and malnutrition. Tuberculosis disease has occurred in adolescents and adults being treated with tumor necrosis factor-alpha (TNF-alpha) antagonists or blocking agents, such as infliximab.
A positive TST or IGRA result should be accepted as indicative of infection in individuals receiving or soon to receive these medications, and the patient should be evaluated and treated accordingly.
A diagnosis of LTBI or tuberculosis disease in a young child is a public health sentinel event often representing recent transmission. Transmission of M tuberculosis complex is airborne, with inhalation of droplet nuclei usually produced by an adult or adolescent with contagious pulmonary, endobronchial, or laryngeal tuberculosis disease.
Although contagiousness usually lasts only a few days to weeks after initiation of effective drug therapy, it can last longer, especially when the adult patient has a positive acid-fast sputum smear, significant productive cough, pulmonary cavities, does not adhere to medical therapy, or is infected with a drug-resistant strain. If the sputum smear becomes negative for acid-fast bacilli (AFB) on 3 separate specimens at least 8 hours apart after treatment is started and the patient has improved clinically with resolution of cough, the treated person can be considered at low risk of transmitting M tuberculosis.
Children younger than 10 years with only adenopathy in the chest or small pulmonary lesions (paucibacillary disease) and nonproductive cough rarely are contagious. Unusual cases of adultform pulmonary disease in young children, particularly with lung cavities and positive sputum-smear microscopy for AFB, and cases of congenital tuberculosis can be contagious. M bovis is transmitted most often by unpasteurized dairy products, but airborne humanto-human transmission can occur. The incubation period from infection to development of a positive TST or IGRA result is 2 to 10 weeks. Many years can elapse between initial M tuberculosis infection and subsequent disease.
Diagnosis & Tests:
Testing for M tuberculosis Infection The Tuberculin Skin Test (TST) The TST is an indirect method for detecting M tuberculosis infection. It is one of 2 methods for diagnosing LTBI, the other method being IGRA. Both methods rely on specific cellular sensitization after infection. Conditions that decrease lymphocyte numbers or function can reduce the sensitivity of these tests. The routine (ie, Mantoux) technique of administering the skin test consists of 5 tuberculin units of purified protein derivative (PPD; 0.1 mL).
injected intradermally using a 27-gauge needle and a 1.0-mL syringe into the volar aspect of the forearm. Creation of a palpable wheal 6 to 10 mm in diameter is crucial to accurate testing. Administration of TSTs and interpretation of results should be performed by trained and experienced health care personnel, because administration and interpretation by unskilled people and family members are unreliable. The standardized time for assessing the TST result is 48 to 72 hours after administration. The diameter of induration, in millimeters, is measured transversely to the long axis of the forearm and should be recorded as the result. Positive TST results, as defined in Table 154.1, can persist for several weeks. Lack of reaction to a TST does not exclude LTBI or tuberculosis disease. Approximately 10% to 40% of immunocompetent children with culture-documented tuberculosis disease do not react initially to a TST.
Host factors, such as young age, poor nutrition, immunosuppression, viral infections (especially measles, varicella, and influenza), recent M tuberculosis infection, and disseminated tuberculosis disease, can decrease TST reactivity. Classification of TST results is based on epidemiologic and clinical factors. Interpretation of the size of induration (mm) as a positive result varies with the person’s risk of LTBI and likelihood of progression to tuberculosis disease. Current guidelines from the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP) recommend interpretation of TST findings on the basis of an individual’s risk stratification. Prompt clinical and radiographic evaluation of all children and adolescents with a positive TST result is recommended. Generally, interpretation of TST results in BCG recipients who are known contacts of a person with tuberculosis disease or who are at high risk of tuberculosis disease is the same as for people who have not received BCG vaccine.
After BCG immunization, distinguishing between a positive TST result caused by M tuberculosis complex infection and that caused by BCG is difficult. Reactivity of the TST after receipt of BCG vaccine does not occur in some patients. The size of the TST reaction (ie, mm of induration) attributable to BCG immunization depends on many factors, including age at BCG immunization, quality and strain of BCG vaccine used, number of doses of BCG vaccine received, nutritional and immunologic status of the vaccine recipient, frequency of TST administration, and time lapse between immunization and TST. Evidence that increases the probability that a positive TST result is attributable to LTBI includes known contact with a person with contagious tuberculosis, a family history of tuberculosis disease, more than 5 years since neonatal BCG immunization, and a TST reaction 15 mm or greater.
Blood-Based Testing With InterferonGamma Release Assays (IGRAs) QuantiFERON-TB Gold In-Tube (QIAGEN, Germantown, MD) and T-SPOT.TB (Oxford Immunotec Inc, Marlborough, MA) are blood tests that measure ex vivo interferon-gamma production from T lymphocytes in response to stimulation with antigens specific to M tuberculosis complex, which includes M tuberculosis and M bovis. However, the IGRA antigens used are not found in BCG. As with TSTs, IGRAs cannot distinguish between latent infection and disease, and a negative result from these tests cannot exclude the possibility of tuberculosis disease in a patient with suggestive clinical findings (Table 154.2).
The sensitivity of IGRA tests is similar to that of TSTs for detecting infection in adults and children who have untreated culture-confirmed tuberculosis. In many clinical settings, the specificity of IGRAs is higher than that for the TST, because the antigens used are not found in BCG or most pathogenic nontuberculous mycobacteria (eg, are not found in M avium complex, but are found in M kansasii, M szulgai, and M marinum). IGRAs consistently perform well in children 2 years and older, and some data support their use for even younger children. The negative predictive value of IGRAs is not clear, but in general, if the IGRA result is negative and the TST result is positive in an asymptomatic, unexposed child, the diagnosis of LTBI is unlikely, especially if the child has received a BCG vaccine. A negative result for either a TST or an IGRA should be considered as especially unreliable in infants younger than 3 months.
TST Versus IGRA For children younger than 2 years, TST is the preferred method for detection of M tuberculosis infection. For children 2 years and older, either TST or IGRA can be used, but in people previously vaccinated with BCG IGRA is preferred to avoid a false-positive TST result. If a BCG-vaccinated child who is 2 years and older has a positive TST, IGRA can be performed to help determine whether it is attributable to LTBI or to the previous BCG vaccine. Lowgrade, false-positive IGRA results occur in some individuals. However,
• Children with a positive IGRA should be considered infected with M tuberculosis complex. However, a negative IGRA result cannot absolutely exclude infection.
• Indeterminate or invalid IGRA results have several possible causes that could be related to the patient, the assay, or the assay’s
performance. These results do not exclude M tuberculosis infection and may necessitate repeat testing, possibly with a different test. Specific recommendations for TST and IGRA use are provided in Figure 154.1.
Use of Tests for M tuberculosis Infection
The most reliable strategies for identifying LTBI and preventing tuberculosis disease in children are based on thorough and expedient contact investigations. Contact investigations are public health interventions that should be coordinated through the local public health department. Universal testing with TST or IGRA, including programs based at schools, child care centers, and camps that include populations at low risk, is discouraged because it results in either a low yield of positive results or a large proportion of false-positive results.
However, using a questionnaire to determine risk factors for LTBI can be effective in health care settings. Simple questionnaires can identify children with risk factors for LTBI (Table 154.3) who then should have a TST or IGRA performed. Risk assessment for tuberculosis should be performed at the first encounter of a child with a health care provider, and then annually if possible. Household investigation of children for tuberculosis is indicated whenever a TST or IGRA result of a household member converts from a negative to a positive result (indicating recent infection).
HIV Infection:
Children with HIV infection are considered at high risk for tuberculosis and should be tested annually beginning at 3 through 12 months of age if perinatally infected or at the time of HIV diagnosis in older children or adolescents. Conversely, children who have tuberculosis disease should be tested for HIV infection. The clinical manifestations and radiographic appearance of tuberculosis disease in children with HIV infection tend to be similar to those in immunocompetent children, but manifestations in these children can be more severe and unusual and more often include extrapulmonary involvement. In HIV-infected patients, a TST induration of ≥5 mm is considered a positive result (see Table 154.1); however, a false-negative TST or IGRA result attributable to HIV-related immunosuppression also can occur. Specimens for culture and, if available, PCR should be obtained from all HIV-infected children with suspected tuberculosis.
Organ Transplant Patients:
The risk of tuberculosis in organ transplant patients is several-fold greater than in the general population. A careful history of previous exposure to tuberculosis should be taken from all transplant candidates, including details about previous TST results and exposure to individuals with active TB.
All transplant candidates should undergo evaluation by TST or IGRA for LTBI before the initiation of immunosuppressive therapy. A positive result of either test should be taken as evidence of M tuberculosis infection.
Patients Receiving Immunosuppressive Therapies Including Biologic Response Modifiers
Patients should be questioned for risk factors for M tuberculosis complex infection. In the presence or absence of tuberculosis risk factors, a TST or IGRA should be performed before the initiation of therapy with high-dose systemic corticosteroids, antimetabolite agents, and tumor necrosis factor antagonists or blockers (eg, infliximab and etanercept).
Other Considerations
Testing for tuberculosis at any age is not required before the administration of live-virus vaccines. Measles vaccine temporarily can suppress tuberculin reactivity for at least 4 to 6 weeks, but the effect of varicella, yellow fever, and live attenuated influenza vaccines on TST reactivity and IGRA results is not known. If indicated, a TST can be applied or blood drawn for an IGRA at the same visit during which these vaccines are administered. The effects of live-virus vaccination on IGRA characteristics have not been determined; the same precautions as for TST should be followed.
There is no evidence that inactivated vaccines, polysaccharide vaccines, or recombinant or subunit vaccines or toxoids interfere with clinical interpretation of TST or IGRAs. Sensitivity to PPD tuberculin antigen persists for years in most instances, even after effective treatment. The durability of positive IGRA results has not been determined. Repeat testing with either TST or IGRA has no known clinical utility for assessing the effectiveness of treatment or for diagnosing newly acquired infection in patients who previously were infected with M tuberculosis.
Assessing for M tuberculosis Disease
Although both IGRA and TST testing provide evidence for infection with M tuberculosis, they cannot distinguish active infection from LTBI. Patients with positive IGRA or TST results should be evaluated for tuberculous disease before initiating any therapeutic intervention. This assessment should include: (1) query for symptoms of active tuberculosis disease, (2) physical examination for signs of active disease, and (3) chest radiograph. If radiographic signs of active tuberculosis (eg, airspace opacities, pleural effusions, cavities, or changes on serial radiographs) are found, sputum or gastric aspirate samples should be obtained. Children younger than 12 months who are suspected of having pulmonary or extrapulmonary tuberculosis disease (eg, have a positive TST and clinical or physical examination signs, or chest radiograph abnormalities consistent with
tuberculosis disease), with or without neurologic symptoms, should have a lumbar puncture. Some experts also recommend performing a lumbar puncture in children 12 through 23 months of age with tuberculosis disease, with or without neurologic symptoms or signs. Children 24 months of age and older with tuberculosis disease require a lumbar puncture only if they have neurologic symptoms or signs. Laboratory isolation of M tuberculosis complex by culture from a specimen of sputum, gastric aspirate, bronchial washing, pleural fluid, cerebrospinal fluid (CSF), urine, or other body fluid or a tissue biopsy specimen confirms the diagnosis of tuberculosis disease.
immunization status
Children older than 2 years and adolescents frequently can produce sputum spontaneously or by induction with aerosolized hypertonic saline. Studies have demonstrated successful collections of induced sputum from infants with pulmonary tuberculosis, but this requires special expertise. The best specimen for diagnosis of pulmonary tuberculosis in any child or adolescent in whom cough is absent or nonproductive and sputum cannot be induced is an early-morning gastric aspirate. Gastric aspirate specimens should be obtained with a nasogastric tube on awakening the child and before ambulation or feeding.
Aspirates collected on 3 separate mornings should be submitted for testing by staining and culture. Fluorescent staining methods for specimen smears are more sensitive than the traditional Kinyoun acid fast smears and are preferred. The overall diagnostic yield of microscopy of gastric aspirates and induced sputum is low in children with clinically suspected pulmonary tuberculosis, and false-positive smear results caused by the presence of nontuberculous mycobacteria occur rarely. Histologic examination for and demonstration of AFB and granulomas in biopsy specimens from lymph node, pleura, mesentery, liver, bone marrow, or other tissues can be useful, but M tuberculosis complex organisms cannot be distinguished reliably from other mycobacteria in stained specimens. Regardless of results of the AFB smears, each specimen should be cultured. Because M tuberculosis complex organisms are slow-growing, detection of these organisms may take as long as 10 weeks using solid media.
For a child with clinically suspected tuberculosis disease, finding the source case supports the child’s presumptive diagnosis and provides the likely drug susceptibility of the child’s organism. Culture material should be collected from children with evidence of tuberculosis disease, especially when (1) an isolate from a source case is not available; (2) the presumed source case has drug-resistant tuberculosis; (3) the child is immunocompromised or ill enough to require hospital admission; or (4) the child has the extrapulmonary disease.
Traditional methods of determining drug susceptibility require bacterial isolation. Several new molecular methods of rapidly determining drug resistance directly from clinical samples now are available. Two NAATs are available for the detection of M tuberculosis complex organisms from smear-positive and smear-negative sputum specimens. One system, Xpert MTB-RIF (Cepheid, Sunnyvale, CA), also can detect the genetic marker for rifampin resistance in specimens within 2 hours. For children, Xpert MTB-RIF is more sensitive than microscopy but is not as sensitive as, and does not replace, culture. It is widely available in countries with a high prevalence of tuberculosis and is increasingly available in the United States. The CDC recommends NAAT testing on at least 1 respiratory tract specimen in the patient with suspected tuberculosis.
TREATMENT
Specific Drugs Antituberculosis drugs kill or inhibit the multiplication of M tuberculosis complex organisms, thereby arresting the progression of infection and preventing most complications. Chemotherapy does not cause a rapid disappearance of already caseous or granulomatous lesions (eg, mediastinal lymphadenitis). For the treatment of tuberculosis disease, these drugs always must be used in recommended combination and dosage to minimize the emergence of drug-resistant strains. Use of nonstandard regimens for any reason (eg, drug allergy, drug resistance) should be undertaken only by an expert in treating tuberculosis.
Isoniazid is bactericidal, rapidly absorbed, and well-tolerated, and penetrates into body fluids, including CSF. Isoniazid is metabolized in the liver and excreted primarily through the kidneys. Hepatotoxic effects are rare in children but can be life-threatening. In children and adolescents who receive recommended doses, peripheral neuritis or seizures caused by inhibition of pyridoxine metabolism are rare, and most do not need pyridoxine supplements. Pyridoxine supplementation is recommended for exclusively breastfed infants and for children and adolescents who have meat- and milk deficient diets; children with nutritional deficiencies, including all symptomatic HIV-infected children; and pregnant adolescents and women. For infants and young children, isoniazid tablets can be pulverized or compounded by some pharmacies.
Rifampin is a bactericidal agent in the rifamycin class of drugs that is absorbed rapidly and penetrates into body fluids, including CSF. Other drugs in the rifamycin class approved for treating tuberculosis are rifabutin and rifapentine. Rifampin is metabolized by the liver and can alter the pharmacokinetics and serum concentrations of many other drugs. Rare adverse effects include hepatotoxicity, influenza-like symptoms, pruritus, and thrombocytopenia. Rifampin is excreted in bile and urine and can cause orange urine, sweat, and tears, with discoloration of soft contact lenses. Rifampin can make oral contraceptives ineffective, so nonhormonal birth-control methods should be adopted when rifampin is administered to sexually active female adolescents and adults. For infants and young children, the contents of the capsules can be suspended in flavored syrup or sprinkled on semisoft foods (eg, pudding).
Rifabutin is a suitable alternative to rifampin in HIV-infected children receiving antiretroviral therapy that restricts the use of rifampin because of drug interactions; however, experience in children is limited, and there is no commercially available pediatric formulation.
Rifapentine is a long-acting rifamycin that permits weekly dosing in selected adults and adolescents with tuberculosis disease and is used for short-course multidrug treatment for LTBI.
Pyrazinamide attains therapeutic CSF concentrations, is detectable in macrophages, is administered orally, and is metabolized by the liver. Administration of pyrazinamide for the first 2 months with isoniazid and rifampin allows for 6-month regimens in immunocompetent patients with drug-susceptible tuberculosis. Almost all isolates of M bovis are resistant to pyrazinamide.
Ethambutol is well absorbed after oral administration, diffuses well into tissues, and is excreted in urine. Ethambutol is bacteriostatic, and its primary therapeutic role is to prevent the emergence of drug resistance. Ethambutol can cause reversible or irreversible optic neuritis but reports in children with normal renal function are rare.
Occasionally, a patient cannot tolerate oral medications. Isoniazid, rifampin, kanamycin and related drugs, linezolid, and fluoroquinolones can be administered parenterally.
Treatment Regimens for LTBI Several regimens are available. Any of these options is considered adequate, depending on the circumstances for individual patients. When indicated for LTBI, doses are the same as for treatment of tuberculosis.
Isoniazid-Rifapentine Therapy for LTBI Based on a large clinical trial (which included children 2–11 years of age), the CDC recommended in 2011 a 12-week, once-weekly dose of isoniazid and rifapentine for treatment of LTBI. This regimen was shown to be safe, well-tolerated, and at least as efficacious as 9 months of isoniazid given daily by self-supervision. Most experts consider isoniazid-rifapentine to be the preferred regimen for treatment of LTBI for children 5 years and older, and some experts prefer isoniazid-rifapentine therapy for LTBI in children 2 years and older. Isoniazidrifapentine should not be used in children younger than 2 years because of a lack of pharmacokinetic data.
Rifampin Therapy for LTBI:
Rifampin given daily for 4 months also is an acceptable regimen for the treatment of LTBI. Most of the data supporting the efficacy of this regimen come from case control studies in adults and a few trials that included children. The regimen has been as effective as 9 months of daily isoniazid, rates of adverse effects have been low, and therapy completion rates have been much higher than for 9 months of isoniazid.
Isoniazid Therapy for LTBI A 9-month course of daily isoniazid therapy in children has an efficacy that approaches 100% if adherence to therapy is high. Unfortunately, many studies have shown the adherence and completion rates to be 50% to 75% over 9 months when families administer isoniazid on their own. Isoniazid should not be used if the child received antituberculosis therapy previously or if resistance to isoniazid is suspected or proven in the source case. Additionally, immigrants who received isoniazid in countries with high rates of isoniazid-resistant tuberculosis may not have been treated adequately. For infants, children, and adolescents, including those with HIV infection or other immunocompromising conditions, the recommended duration of isoniazid therapy in the United States is 9 months.
The World Health Organization recommends a 6-month course of isoniazid, but modeling studies have shown that the efficacy of 6 months of treatment is approximately 30% less than that of a 9-month course. Many experts accept 6 months of uninterrupted treatment as adequate. When adherence with daily therapy with isoniazid cannot be ensured, twice-a-week DOT can be considered, but each dose must be observed directly. Determination of serum transaminase concentrations before or during therapy is not indicated except in patients with underlying liver or biliary disease or during pregnancy or the first 12 weeks postpartum, with concurrent use of other potentially hepatotoxic drugs (eg, anticonvulsant or HIV agents).
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