Pregnancy and the Newborn

Pulmonary and particularly extrapulmonary tuberculosis other than lymphadenitis in a pregnant woman is associated with increased risk for prematurity, fetal growth retardation, low birthweight, and perinatal mortality. Congenital tuberculosis is rare because the most common result of female genital tract tuberculosis is infertility. Congenital transmission usually occurs from a lesion in the placenta through the umbilical vein. Primary infection in the mother just before or during pregnancy is more likely to cause congenital infection than is reactivation of a previous infection. The tubercle bacilli first reach the fetal liver, where a primary focus with periportal lymph node involvement can occur. Organisms pass through the liver into the main fetal circulation and infect many organs. The bacilli in the lung usually remain dormant until after birth, when oxygenation and pulmonary circulation increase significantly. Congenital tuberculosis can also be caused by aspiration or ingestion of infected amniotic fluid. However, the most common route of infection for the neonate is postnatal airborne transmission from an adult with infectious pulmonary tuberculosis.

Immunity

Conditions that adversely affect cell-mediated immunity predispose to progression from tuberculosis infection to disease. Rare specific genetic defects associated with deficient cell-mediated immunity in response to mycobacteria include interleukin (IL)-12 receptor B1 deficiency and complete and partial interferon-γ (IFN-γ) receptor 1 chain deficiencies. Tuberculosis infection is associated with a humoral antibody response, which appears to play little role in host defense. Shortly after infection, tubercle bacilli replicate in both free alveolar spaces and within inactivated alveolar macrophages. Sulfatides in the mycobacterial cell wall inhibit fusion of the macrophage phagosome and lysosomes, allowing the organisms to escape destruction by intracellular enzymes. Cell-mediated immunity develops 2-12 wk after infection, along with tissue hypersensitivity (see Fig. 207-6). After bacilli enter macrophages, lymphocytes that recognize mycobacterial antigens proliferate and secrete lymphokines and other mediators that attract other lymphocytes and macrophages to the area. Certain lymphokines activate macrophages, causing them to develop high concentrations of lytic enzymes that enhance their mycobactericidal capacity. A discrete subset of regulator helper and suppressor lymphocytes modulates the immune response. Development of specific cellular immunity prevents progression of the initial infection in most persons.

The pathologic events in the initial tuberculosis infection seem to depend on the balance among the mycobacterial antigen load; cell-mediated immunity, which enhances intracellular killing; and tissue hypersensitivity, which promotes extracellular killing. When the antigen load is small and the degree of tissue sensitivity is high, granuloma formation results from the organization of lymphocytes, macrophages, and fibroblasts. When both antigen load and the degree of sensitivity are high, granuloma formation is less organized. Tissue necrosis is incomplete, resulting in formation of caseous material. When the degree of tissue sensitivity is low, as is often the case in infants or immunocompromised persons, the reaction is diffuse and the infection is not well contained, leading to dissemination and local tissue destruction. Tumor necrosis factor (TNF) and other cytokines released by specific lymphocytes promote cellular destruction and tissue damage in susceptible persons.

Tuberculin Skin Testing

The development of delayed-type hypersensitivity (DTH) in most persons infected with the tubercle bacillus makes the TST a useful diagnostic tool. The Mantoux TST is the intradermal injection of 0.1 mL purified protein derivative (PPD) stabilized with Tween 80. T cells sensitized by prior infection are recruited to the skin, where they release lymphokines that induce induration through local vasodilatation, edema, fibrin deposition, and recruitment of other inflammatory cells to the area. The amount of induration in response to the test should be measured by a trained person 48-72 hr after administration. In some patients the onset of induration is >72 hr after placement; this is also a positive result. Immediate hypersensitivity reactions to tuberculin or other constituents of the preparation are short lived (<24 hr) and not considered a positive result. Tuberculin sensitivity develops 3 wk to 3 mo (most often in 4-8 wk) after inhalation of organisms.

Host-related factors can depress the skin test reaction in a child infected with M. tuberculosis, including very young age, malnutrition, immunosuppression by disease or drugs, viral infections (measles, mumps, varicella, influenza), vaccination with live-virus vaccines, and overwhelming tuberculosis. Corticosteroid therapy can decrease the reaction to tuberculin, but the effect is variable. TST done at the time of initiating corticosteroid therapy is usually reliable. Approximately 10% of immunocompetent children with tuberculosis disease (up to 50% of those with meningitis or disseminated disease) do not react initially to PPD; most become reactive after several months of antituberculosis therapy. Nonreactivity may be specific to tuberculin or more global to a variety of antigens, so positive “control” skin tests with a negative tuberculin test never rule out tuberculosis. The other common reasons for a false-negative skin test are poor technique and misreading of the results.

False-positive reactions to tuberculin can be caused by cross sensitization to antigens of nontuberculous mycobacteria (NTM), which generally are more prevalent in the environment as one approaches the equator. These cross reactions are usually transient over months to years and produce less than 10-12 mm of induration. Previous vaccination with bacille Calmette-Guérin (BCG) also can cause a reaction to a TST, especially if 2 or more BCG vaccinations have been given. Approximately 50% of the infants who receive a BCG vaccine never develop a reactive TST, and the reactivity usually wanes in 2-3 yr in those with initially positive skin test results. Older children and adults who receive a BCG vaccine are more likely to develop tuberculin reactivity, but most lose the reactivity by 5-10 yr after vaccination. When skin test reactivity is present, it usually causes <10 mm of induration, although larger reactions occur in some persons. In general in the USA, a tuberculin skin reaction of ≥10 mm in a BCG-vaccinated child or adult is considered positive and necessitates further diagnostic evaluation and treatment, although many such patients do not have LTBI. Prior vaccination with BCG is never a contraindication to tuberculin testing.

The appropriate size of induration indicating a positive Mantoux TST result varies with related epidemiologic and risk factors. In children with no risk factors for tuberculosis, skin test reactions are usually false-positive results. The American Academy of Pediatrics (AAP) and Centers for Disease Control and Prevention (CDC) discourage routine testing of children and recommend targeted tuberculin testing of children at risk identified through periodic screening surveys conducted by the primary care provider (Table 207-2). Possible exposure to an adult with or at high risk for infectious pulmonary tuberculosis is the most crucial risk factor for children. Reaction size limits for determining a positive tuberculin test result vary with the person’s risk for infection (Table 207-3). For adults and children at the highest risk for having infection progress to disease (those with recent contact with infectious persons, clinical illnesses consistent with tuberculosis, or HIV infection or other immunosuppression), a reactive area of ≥5 mm is classified as a positive result, indicating infection with M. tuberculosis. For other high-risk groups, a reactive area of ≥10 mm is considered positive. For low-risk persons, especially those residing in communities where the prevalence of tuberculosis is low, the cutoff point for a positive reaction is ≥15 mm. An increase of induration of ≥10 mm within a 2-yr period is considered a TST conversion at any age.

Interferon-γ Release Assays

Two blood tests (T-SPOT.TB and QuantiFERON-TB) detect IFN-γ generation by the patient’s T cells in response to specific M. tuberculosis antigens (ESAT-6, CFP-10, and TB7.7). The QuantiFERON-TB test measures whole blood concentrations of IFN-γ, and the T-SPOT.TB test measures the number of lymphocytes producing IFN-γ. The test antigens are not present on M. bovis–BCG and M. avium complex, the major groups of environmental mycobacteria, so one would expect fewer false-positive results. Both tests have internal positive and negative controls. These tests have several theoretical and practical advantages over the TST, including the need for only one patient encounter, lack of cross reaction with BCG vaccination and most other mycobacteria, and absence of boosting (increasing reaction to the TST with serial testing).

When specificity is important, such as in persons who received a BCG vaccination, the IFN-γ release assays (IGRAs) are the preferred test. However, IGRAs should be interpreted with caution when used for children <5 yr of age and immunocompromised patients owing to the relative lack of data and the increased propensity for indeterminate results (mostly owing to failure of the positive control) in these groups.

Primary Pulmonary Disease

The primary complex includes the parenchymal pulmonary focus and the regional lymph nodes. About 70% of lung foci are subpleural, and localized pleurisy is common. The initial parenchymal inflammation usually is not visible on chest radiograph, but a localized, nonspecific infiltrate may be seen before the development of tissue hypersensitivity. All lobar segments of the lung are at equal risk for initial infection. Two or more primary foci are present in 25% of cases. The hallmark of primary tuberculosis in the lung is the relatively large size of the regional lymphadenitis compared with the relatively small size of the initial lung focus (see Figs. 207-6 to 207-9). As DTH develops, the hilar lymph nodes continue to enlarge in some children, especially infants, compressing the regional bronchus and causing obstruction. The usual sequence is hilar lymphadenopathy, focal hyperinflation, and then atelectasis. The resulting radiographic shadows have been called collapse-consolidation or segmental tuberculosis (see Fig. 207-9). Rarely, inflamed caseous nodes attach to the endobronchial wall and erode through it, causing endobronchial tuberculosis or a fistula tract. The caseum causes complete obstruction of the bronchus, resulting in extensive infiltrate and collapse. Enlargement of the subcarinal lymph nodes can cause compression of the esophagus and, rarely, a bronchoesophageal fistula.

Most cases of tuberculous bronchial obstruction in children resolve fully with appropriate treatment. Occasionally, there is residual calcification of the primary focus or regional lymph nodes. The appearance of calcification implies that the lesion has been present for at least 6-12 mo. Healing of the segment can be complicated by scarring or contraction associated with cylindrical bronchiectasis, but this is rare.

Children can have lobar pneumonia without impressive hilar lymphadenopathy. If the primary infection is progressively destructive, liquefaction of the lung parenchyma can lead to formation of a thin-walled primary tuberculosis cavity. Rarely, bullous tuberculous lesions occur in the lungs and lead to pneumothorax if they rupture. Erosion of a parenchymal focus of tuberculosis into a blood or lymphatic vessel can result in dissemination of the bacilli and a miliary pattern, with small nodules evenly distributed on the chest radiograph (Fig. 207-10).

Figure 207-10 Posteroanterior (A) and lateral (B) chest radiographs of an infant with miliary tuberculosis. The child’s mother had failed to complete treatment for pulmonary tuberculosis twice within 3 yr of this child’s birth.

The symptoms and physical signs of primary pulmonary tuberculosis in children are surprisingly meager considering the degree of radiographic changes often seen. When active case finding is performed, up to 50% of infants and children with radiographically moderate to severe pulmonary tuberculosis have no physical findings. Infants are more likely to experience signs and symptoms. Nonproductive cough and mild dyspnea are the most common symptoms. Systemic complaints such as fever, night sweats, anorexia, and decreased activity occur less often. Some infants have difficulty gaining weight or develop a true failure-to-thrive syndrome that often does not improve significantly until several months of effective treatment have been taken. Pulmonary signs are even less common. Some infants and young children with bronchial obstruction have localized wheezing or decreased breath sounds that may be accompanied by tachypnea or, rarely, respiratory distress. These pulmonary symptoms and signs are occasionally alleviated by antibiotics, suggesting bacterial superinfection.

The most specific confirmation of pulmonary tuberculosis is isolation of M. tuberculosis. Sputum specimens for culture should be collected from adolescents and older children who are able to expectorate. Induced sputum with a jet nebulizer and chest percussion followed by nasopharyngeal suctioning is effective in children as young as 1 mo. Sputum induction provides samples for both culture and smear staining, whereas gastric aspirates are usually cultured. The traditional culture specimen in young children is the early morning gastric acid obtained before the child has arisen and peristalsis has emptied the stomach of the pooled secretions that have been swallowed overnight. However, even under optimal conditions, 3 consecutive morning gastric aspirates yield the organisms in <50% of cases. The culture yield from bronchoscopy is even lower, but this procedure can demonstrate the presence of endobronchial disease or a fistula. Negative cultures never exclude the diagnosis of tuberculosis in a child. The presence of a positive TST or IGRA, an abnormal chest radiograph consistent with tuberculosis, and history of exposure to an adult with infectious tuberculosis is adequate proof that the disease is present. Drug susceptibility test results of the isolate from the adult source can be used to determine the best therapeutic regimen for the child. Cultures should be obtained from the child whenever the source case is unknown or the source case has possible drug-resistant tuberculosis.

Progressive Primary Pulmonary Disease

A rare but serious complication of tuberculosis in a child occurs when the primary focus enlarges steadily and develops a large caseous center. Liquefaction can cause formation of a primary cavity associated with large numbers of tubercle bacilli. The enlarging focus can slough necrotic debris into the adjacent bronchus, leading to further intrapulmonary dissemination. Significant signs or symptoms are common in locally progressive disease in children. High fever, severe cough with sputum production, weight loss, and night sweats are common. Physical signs include diminished breath sounds, rales, and dullness or egophony over the cavity. The prognosis for full but usually slow recovery is excellent with appropriate therapy.

Reactivation Tuberculosis

Pulmonary tuberculosis in adults usually represents endogenous reactivation of a site of tuberculosis infection established previously in the body. This form of tuberculosis is rare in childhood but can occur in adolescence. Children with a healed tuberculosis infection acquired at <2 yr of age rarely develop chronic reactivation pulmonary disease, which is more common in those who acquire the initial infection at >7 yr of age. The most common pulmonary sites are the original parenchymal focus, lymph nodes, or the apical seedings (Simon foci) established during the hematogenous phase of the early infection. This form of disease usually remains localized to the lungs, because the established immune response prevents further extrapulmonary spread. The most common radiographic presentations of this type of tuberculosis are extensive infiltrates or thick-walled cavities in the upper lobes.

Older children and adolescents with reactivation tuberculosis are more likely to experience fever, anorexia, malaise, weight loss, night sweats, productive cough, hemoptysis, and chest pain than children with primary pulmonary tuberculosis. However, physical examination findings usually are minor or absent, even when cavities or large infiltrates are present. Most signs and symptoms improve within several weeks of starting effective treatment, although the cough can last for several months. This form of tuberculosis may be highly contagious if there is significant sputum production and cough. The prognosis for full recovery is excellent when patients are given appropriate therapy.

Pleural Effusion

Tuberculous pleural effusions, which can be local or general, originate in the discharge of bacilli into the pleural space from a subpleural pulmonary focus or caseated lymph node. Asymptomatic local pleural effusion is so common in primary tuberculosis that it is basically a component of the primary complex. Larger and clinically significant effusions occur months to years after the primary infection. Tuberculous pleural effusion is uncommon in children <6 yr of age and rare in children <2 yr of age. Effusions are usually unilateral but can be bilateral. They are rarely associated with a segmental pulmonary lesion and are uncommon in disseminated tuberculosis. Often the radiographic abnormality is more extensive than would be suggested by physical findings or symptoms (Fig. 207-11).

Figure 207-11 Pleural tuberculosis in a 16 yr old girl.

Clinical onset of tuberculous pleurisy is often sudden, characterized by low to high fever, shortness of breath, chest pain on deep inspiration, and diminished breath sounds. The fever and other symptoms can last for several weeks after the start of antituberculosis chemotherapy. The TST is positive in only 70-80% of cases. The prognosis is excellent, but radiographic resolution often takes months. Scoliosis is a rare complication from a long-standing effusion.

Examination of pleural fluid and the pleural membrane is important to establish the diagnosis of tuberculous pleurisy. The pleural fluid is usually yellow and only occasionally tinged with blood. The specific gravity is usually 1.012-1.025, the protein level is usually 2-4 g/dL, and the glucose concentration may be low, although it is usually in the low-normal range (20-40 mg/dL). Typically there are several hundred to several thousand white blood cells per cubic millimeter, with an early predominance of polymorphonuclear cells followed by a high percentage of lymphocytes. Acid-fast smears of the pleural fluid are rarely positive. Cultures of the fluid are positive in <30% of cases. Biopsy of the pleural membrane is more likely to yield a positive acid-fast stain or culture, and granuloma formation usually can be demonstrated.

Pericardial Disease

The most common form of cardiac tuberculosis is pericarditis. It is rare, occurring in 0.5-4% of tuberculosis cases in children. Pericarditis usually arises from direct invasion or lymphatic drainage from subcarinal lymph nodes. The presenting symptoms are nonspecific, including low-grade fever, malaise, and weight loss. Chest pain is unusual in children. A pericardial friction rub or distant heart sounds with pulsus paradoxus may be present. The pericardial fluid is typically serofibrinous or hemorrhagic. Acid-fast smear of the fluid rarely reveals the organism, but cultures are positive in 30-70% of cases. The culture yield from pericardial biopsy may be higher, and the presence of granulomas often suggests the diagnosis. Partial or complete pericardiectomy may be required when constrictive pericarditis develops.

Lymphohematogenous (Disseminated) Disease

Tubercle bacilli are disseminated to distant sites, including liver, spleen, skin, and lung apices, in all cases of tuberculosis infection. The clinical picture produced by lymphohematogenous dissemination depends on the quantity of organisms released from the primary focus and the adequacy of the host’s immune response. Lymphohematogenous spread is usually asymptomatic. Rare patients experience protracted hematogenous tuberculosis caused by the intermittent release of tubercle bacilli as a caseous focus erodes through the wall of a blood vessel in the lung. Although the clinical picture may be acute, more often it is indolent and prolonged, with spiking fever accompanying the release of organisms into the bloodstream. Multiple organ involvement is common, leading to hepatomegaly, splenomegaly, lymphadenitis in superficial or deep nodes, and papulonecrotic tuberculids appearing on the skin. Bones and joints or kidneys also can become involved. Meningitis occurs only late in the course of the disease. Early pulmonary involvement is surprisingly mild, but diffuse involvement becomes apparent with prolonged infection.

The most clinically significant form of disseminated tuberculosis is miliary disease, which occurs when massive numbers of tubercle bacilli are released into the bloodstream, causing disease in 2 or more organs. Miliary tuberculosis usually complicates the primary infection, occurring within 2-6 mo of the initial infection. Although this form of disease is most common in infants and young children, it is also found in adolescents and older adults, resulting from the breakdown of a previously healed primary pulmonary lesion. The clinical manifestations of miliary tuberculosis are protean, depending on the load of organisms that disseminate and where they lodge. Lesions are often larger and more numerous in the lungs, spleen, liver, and bone marrow than other tissues. Because this form of tuberculosis is most common in infants and malnourished or immunosuppressed patients, the host’s immune incompetence probably also plays a role in pathogenesis.

The onset of miliary tuberculosis is sometimes explosive, and the patient can become gravely ill in several days. More often, the onset is insidious, with early systemic signs, including anorexia, weight loss, and low-grade fever. At this time, abnormal physical signs are usually absent. Generalized lymphadenopathy and hepatosplenomegaly develop within several weeks in about 50% of cases. The fever can then become higher and more sustained, although the chest radiograph usually is normal and respiratory symptoms are minor or absent. Within several more weeks, the lungs can become filled with tubercles, and dyspnea, cough, rales, or wheezing occur. The lesions of miliary tuberculosis are usually smaller than 2-3 mm in diameter when first visible on chest radiograph (see Fig. 207-10). The smaller lesions coalesce to form larger lesions and sometimes extensive infiltrates. As the pulmonary disease progresses, an alveolar-air block syndrome can result in frank respiratory distress, hypoxia, and pneumothorax, or pneumomediastinum. Signs or symptoms of meningitis or peritonitis are found in 20-40% of patients with advanced disease. Chronic or recurrent headache in a patient with miliary tuberculosis usually indicates the presence of meningitis, whereas the onset of abdominal pain or tenderness is a sign of tuberculous peritonitis. Cutaneous lesions include papulonecrotic tuberculids, nodules, or purpura. Choroid tubercles occur in 13-87% of patients and are highly specific for the diagnosis of miliary tuberculosis. Unfortunately, the TST is nonreactive in up to 40% of patients with disseminated tuberculosis.

Diagnosis of disseminated tuberculosis can be difficult, and a high index of suspicion by the clinician is required. Often the patient presents with fever of unknown origin. Early sputum or gastric aspirate cultures have a low sensitivity. Biopsy of the liver or bone marrow with appropriate bacteriologic and histologic examinations more often yields an early diagnosis. The most important clue is usually history of recent exposure to an adult with infectious tuberculosis.

The resolution of miliary tuberculosis is slow, even with proper therapy. Fever usually declines within 2-3 wk of starting chemotherapy, but the chest radiographic abnormalities might not resolve for many months. Occasionally, corticosteroids hasten symptomatic relief, especially when air block, peritonitis, or meningitis is present. The prognosis is excellent if the diagnosis is made early and adequate chemotherapy is given.

Upper Respiratory Tract Disease

Tuberculosis of the upper respiratory tract is rare in developed countries but is still observed in developing countries. Children with laryngeal tuberculosis have a croup-like cough, sore throat, hoarseness, and dysphagia. Most children with laryngeal tuberculosis have extensive upper lobe pulmonary disease, but occasional patients have primary laryngeal disease with a normal chest radiograph. Tuberculosis of the middle ear results from aspiration of infected pulmonary secretions into the middle ear or from hematogenous dissemination in older children. The most common signs and symptoms are painless unilateral otorrhea, tinnitus, decreased hearing, facial paralysis, and a perforated tympanic membrane. Enlargement of lymph nodes in the preauricular or anterior cervical chains can accompany this infection. Diagnosis is difficult, because stains and cultures of ear fluid are often negative, and histology of the affected tissue often shows a nonspecific acute and chronic inflammation without granuloma formation.

Lymph Node Disease

Tuberculosis of the superficial lymph nodes, often referred to as scrofula, is the most common form of extrapulmonary tuberculosis in children (Fig. 207-12). Historically, scrofula was usually caused by drinking unpasteurized cow’s milk laden with M. bovis. Most current cases occur within 6-9 mo of initial infection by M. tuberculosis, although some cases appear years later. The tonsillar, anterior cervical, submandibular, and supraclavicular nodes become involved secondary to extension of a primary lesion of the upper lung fields or abdomen. Infected nodes in the inguinal, epitrochlear, or axillary regions result from regional lymphadenitis associated with tuberculosis of the skin or skeletal system. The nodes usually enlarge gradually in the early stages of lymph node disease. They are discrete, nontender, and firm but not hard. The nodes often feel fixed to underlying or overlying tissue. Disease is most often unilateral, but bilateral involvement can occur because of the crossover drainage patterns of lymphatic vessels in the chest and lower neck. As infection progresses, multiple nodes are infected, resulting in a mass of matted nodes. Systemic signs and symptoms other than a low-grade fever are usually absent. The TST is usually reactive, but the chest radiograph is normal in 70% of cases. The onset of illness is occasionally more acute, with rapid enlargement, tenderness, and fluctuance of lymph nodes and with high fever. The initial presentation is rarely a fluctuant mass with overlying cellulitis or skin discoloration.

Figure 207-12 Axial CT image of the neck in an 8 yr old boy shows calcified right cervical lymphadenopathy (black arrow) with tonsillar swelling (white arrow).

(From Lighter J, Rigaud M: Diagnosing childhood tuberculosis: traditional and innovative modalities, Curr Prob Pediatr Adolesc Health Care 39:55–88, 2009.)

Lymph node tuberculosis can resolve if left untreated but more often progresses to caseation and necrosis. The capsule of the node breaks down, resulting in the spread of infection to adjacent nodes. Rupture of the node usually results in a draining sinus tract that can require surgical removal. Tuberculous lymphadenitis can usually be diagnosed by fine-needle aspiration of the node and responds well to antituberculosis therapy, although the lymph nodes do not return to normal size for months or even years. Surgical removal is not usually necessary and must be combined with antituberculous medication because the lymph node disease is only one part of a systemic infection.

A definitive diagnosis of tuberculous adenitis usually requires histologic or bacteriologic confirmation, which is best accomplished by fine-needle aspiration for culture, stain, and histology. If fine-needle aspiration is not successful in establishing a diagnosis, excisional biopsy of the involved node is indicated. Culture of lymph node tissue yields the organism in only about 50% of cases. Many other conditions can be confused with tuberculous adenitis, including infection due to NTM, cat scratch disease (Bartonella henselae), tularemia, brucellosis, toxoplasmosis, tumor, branchial cleft cyst, cystic hygroma, and pyogenic infection. The most common problem is distinguishing infection due to M. tuberculosis from lymphadenitis caused by NTM in geographic areas where NTM are common. Both conditions are usually associated with a normal chest radiograph and a reactive TST. An important clue to the diagnosis of tuberculous adenitis is an epidemiologic link to an adult with infectious tuberculosis. In areas where both diseases are common, the only way to distinguish them may be culture of the involved tissue.

Central Nervous System Disease

Tuberculosis of the central nervous system (CNS) is the most serious complication in children and is fatal without prompt and appropriate treatment. Tuberculous meningitis usually arises from the formation of a metastatic caseous lesion in the cerebral cortex or meninges that develops during the lymphohematogenous dissemination of the primary infection. This initial lesion increases in size and discharges small numbers of tubercle bacilli into the subarachnoid space. The resulting gelatinous exudate infiltrates the corticomeningeal blood vessels, producing inflammation, obstruction, and subsequent infarction of cerebral cortex. The brain stem is often the site of greatest involvement, which accounts for the commonly associated dysfunction of cranial nerves III, VI, and VII. The exudate also interferes with the normal flow of cerebrospinal fluid (CSF) in and out of the ventricular system at the level of the basilar cisterns, leading to a communicating hydrocephalus. The combination of vasculitis, infarction, cerebral edema, and hydrocephalus results in the severe damage that can occur gradually or rapidly. Profound abnormalities in electrolyte metabolism due to salt wasting or the syndrome of inappropriate antidiuretic hormone secretion also contribute to the pathophysiology of tuberculous meningitis.

Tuberculous meningitis complicates about 0.3% of untreated tuberculosis infections in children. It is most common in children between 6 mo and 4 yr of age. Occasionally, tuberculous meningitis occurs many years after the infection, when rupture of 1 or more of the subependymal tubercles discharges tubercle bacilli into the subarachnoid space. The clinical progression of tuberculous meningitis may be rapid or gradual. Rapid progression tends to occur more often in infants and young children, who can experience symptoms for only several days before the onset of acute hydrocephalus, seizures, and cerebral edema. More commonly, the signs and symptoms progress slowly over several weeks and can be divided into 3 stages.

The 1st stage typically lasts 1-2 wk and is characterized by nonspecific symptoms such as fever, headache, irritability, drowsiness, and malaise. Focal neurologic signs are absent, but infants can experience a stagnation or loss of developmental milestones. The 2nd stage usually begins more abruptly. The most common features are lethargy, nuchal rigidity, seizures, positive Kernig and Brudzinski signs, hypertonia, vomiting, cranial nerve palsies, and other focal neurologic signs. The accelerating clinical illness usually correlates with the development of hydrocephalus, increased intracranial pressure, and vasculitis. Some children have no evidence of meningeal irritation but can have signs of encephalitis, such as disorientation, movement disorders, or speech impairment. The 3rd stage is marked by coma, hemiplegia or paraplegia, hypertension, decerebrate posturing, deterioration of vital signs, and eventually death.

The prognosis of tuberculous meningitis correlates most closely with the clinical stage of illness at the time treatment is initiated. The majority of patients in the 1st stage have an excellent outcome, whereas most patients in the 3rd stage who survive have permanent disabilities, including blindness, deafness, paraplegia, diabetes insipidus, or mental retardation. The prognosis for young infants is generally worse than for older children. It is imperative that antituberculosis treatment be considered for any child who develops basilar meningitis and hydrocephalus, cranial nerve palsy, or stroke with no other apparent etiology. Often the key to the correct diagnosis is identifying an adult who has infectious tuberculosis and is in contact with the child. Because of the short incubation period of tuberculous meningitis, the illness has not yet been diagnosed in the adult in many cases.

The diagnosis of tuberculous meningitis can be difficult early in its course, requiring a high degree of suspicion on the part of the clinician. The TST is nonreactive in up to 50% of cases, and 20-50% of children have a normal chest radiograph. The most important laboratory test for the diagnosis of tuberculous meningitis is examination and culture of the lumbar CSF. The CSF leukocyte count usually ranges from 10 to 500 cells/mm³. Polymorphonuclear leukocytes may be present initially, but lymphocytes predominate in the majority of cases. The CSF glucose is typically <40mg/dL but rarely <20mg/dL. The protein level is elevated and may be markedly high (400-5,000mg/dL) secondary to hydrocephalus and spinal block. Although the lumbar CSF is grossly abnormal, ventricular CSF can have normal chemistries and cell counts because this fluid is obtained from a site proximal to the inflammation and obstruction. During early stage I, the CSF can resemble that of viral aseptic meningitis only to progress to the more-severe CSF profile over several weeks. The success of the microscopic examination of acid-fast-stained CSF and mycobacterial culture is related directly to the volume of the CSF sample. Examinations or culture of small amounts of CSF are unlikely to demonstrate M. tuberculosis. When 5-10 mL of lumbar CSF can be obtained, the acid-fast stain of the CSF sediment is positive in up to 30% of cases and the culture is positive in 50-70% of cases. Cultures of other fluids, such as gastric aspirates or urine, can help confirm the diagnosis.

Radiographic studies can aid in the diagnosis of tuberculous meningitis. CT or MRI of the brain of patients with tuberculous meningitis may be normal during early stages of the disease. As disease progresses, basilar enhancement and communicating hydrocephalus with signs of cerebral edema or early focal ischemia are the most common findings. Some small children with tuberculous meningitis can have one or several clinically silent tuberculomas, occurring most often in the cerebral cortex or thalamic regions.

Another manifestation of CNS tuberculosis is the tuberculoma, a tumor-like mass resulting from aggregation of caseous tubercles that usually manifests clinically as a brain tumor. Tuberculomas account for up to 40% of brain tumors in some areas of the world but are rare in North America. In adults tuberculomas are most often supratentorial, but in children they are often infratentorial, located at the base of the brain near the cerebellum. Lesions are most often singular but may be multiple. The most common symptoms are headache, fever, and convulsions. The TST is usually reactive, but the chest radiograph is usually normal. Surgical excision is sometimes necessary to distinguish tuberculoma from other causes of brain tumor. However, surgical removal is not necessary because most tuberculomas resolve with medical management. Corticosteroids are usually administered during the 1st few weeks of treatment or in the immediate postoperative period to decrease cerebral edema. On CT or MRI of the brain, tuberculomas usually appear as discrete lesions with a significant amount of surrounding edema. Contrast medium enhancement is often impressive and can result in a ringlike lesion. Since the advent of CT, the paradoxical development of tuberculomas in patients with tuberculous meningitis who are receiving ultimately effective chemotherapy has been recognized. The cause and nature of these tuberculomas are poorly understood, but they do not represent failure of antimicrobial treatment. This phenomenon should be considered whenever a child with tuberculous meningitis deteriorates or develops focal neurologic findings while on treatment. Corticosteroids can help alleviate the occasionally severe clinical signs and symptoms that occur. These lesions can persist for months or even years.

Cutaneous Disease

Cutaneous tuberculosis is rare in the USA but occurs worldwide and accounts for 1-2% of tuberculosis (Chapter 657).

Bone and Joint Disease

Bone and joint infection complicating tuberculosis is most likely to involve the vertebrae. The classic manifestation of tuberculous spondylitis is progression to Pott disease, in which destruction of the vertebral bodies leads to gibbus deformity and kyphosis (Chapter 671.4). Skeletal tuberculosis is a late complication of tuberculosis and has become a rare entity since the availability of antituberculosis therapy but is more likely to occur in children than in adults. Tuberculous bone lesions can resemble pyogenic and fungal infections or bone tumors. Multifocal bone involvement can occur. A bone biopsy is essential to confirm the diagnosis.

Abdominal and Gastrointestinal Disease

Tuberculosis of the oral cavity or pharynx is quite unusual. The most common lesion is a painless ulcer on the mucosa, palate, or tonsil with enlargement of the regional lymph nodes. Tuberculosis of the parotid gland has been reported rarely in endemic countries. Tuberculosis of the esophagus is rare in children but may be associated with a tracheoesophageal fistula in infants. These forms of tuberculosis are usually associated with extensive pulmonary disease and swallowing of infectious respiratory secretions. However, they can occur in the absence of pulmonary disease, presumably by spread from mediastinal or peritoneal lymph nodes.

Tuberculous peritonitis occurs most often in young men and is uncommon in adolescents and rare in children. Generalized peritonitis can arise from subclinical or miliary hematogenous dissemination. Localized peritonitis is caused by direct extension from an abdominal lymph node, intestinal focus, or genitourinary tuberculosis. Rarely, the lymph nodes, omentum, and peritoneum become matted and can be palpated as a doughy irregular nontender mass. Abdominal pain or tenderness, ascites, anorexia, and low-grade fever are typical manifestations. The TST is usually reactive. The diagnosis can be confirmed by paracentesis with appropriate stains and cultures, but this procedure must be performed carefully to avoid entering a bowel that is intertwined with the matted omentum.

Tuberculous enteritis is caused by hematogenous dissemination or by swallowing tubercle bacilli discharged from the patient’s own lungs. The jejunum and ileum near Peyer patches and the appendix are the most common sites of involvement. The typical findings are shallow ulcers that cause pain, diarrhea or constipation, weight loss, and low-grade fever. Mesenteric adenitis usually complicates the infection. The enlarged nodes can cause intestinal obstruction or erode through the omentum to cause generalized peritonitis. The clinical presentation of tuberculous enteritis is nonspecific, mimicking other infections and conditions that cause diarrhea. The disease should be suspected in any child with chronic GI complaints and a reactive TST or positive IGRA. Biopsy, acid-fast stain, and culture of the lesions are usually necessary to confirm the diagnosis.

Genitourinary Disease

Renal tuberculosis is rare in children, because the incubation period is several years or longer. Tubercle bacilli usually reach the kidney during lymphohematogenous dissemination. The organisms often can be recovered from the urine in cases of miliary tuberculosis and in some patients with pulmonary tuberculosis in the absence of renal parenchymal disease. In true renal tuberculosis, small caseous foci develop in the renal parenchyma and release M. tuberculosis into the tubules. A large mass develops near the renal cortex that discharges bacteria through a fistula into the renal pelvis. Infection then spreads locally to the ureters, prostate, or epididymis. Renal tuberculosis is often clinically silent in its early stages, marked only by sterile pyuria and microscopic hematuria. Dysuria, flank or abdominal pain, and gross hematuria develop as the disease progresses. Superinfection by other bacteria is common and can delay recognition of the underlying tuberculosis. Hydronephrosis or ureteral strictures can complicate the disease. Urine cultures for M. tuberculosis are positive in 80-90% of cases, and acid-fast stains of large volumes of urine sediment are positive in 50-70% of cases. The TST is nonreactive in up to 20% of patients. An intravenous pyelogram or CT scan often reveals mass lesions, dilatation of the proximal ureters, multiple small filling defects, and hydronephrosis if ureteral stricture is present. Disease is most often unilateral.

Tuberculosis of the genital tract is uncommon in both boys and girls before puberty. This condition usually originates from lymphohematogenous spread, although it can be caused by direct spread from the intestinal tract or bone. Adolescent girls can develop genital tract tuberculosis during the primary infection. The fallopian tubes are most often involved (90-100% of cases), followed by the endometrium (50%), ovaries (25%), and cervix (5%). The most common symptoms are lower abdominal pain and dysmenorrhea or amenorrhea. Systemic manifestations are usually absent, and the chest radiograph is normal in the majority of cases. The TST is usually reactive. Genital tuberculosis in adolescent boys causes epididymitis or orchitis. The condition usually manifests as a unilateral nodular painless swelling of the scrotum. Involvement of the glans penis is extremely rare. Genital abnormalities and a positive TST in an adolescent boy or girl suggests genital tract tuberculosis.

Disease in HIV-Infected Children

Most cases of tuberculosis in HIV-infected children are seen in developing countries. The rate of tuberculosis disease in HIV-infected children is 30 times higher than in non–HIV-infected children in the USA. Establishing the diagnosis of tuberculosis in an HIV-infected child may be difficult, because skin test reactivity can be absent (with a negative IGRA), culture confirmation is difficult, and the clinical features of tuberculosis are similar to many other HIV-related infections and conditions. Tuberculosis in HIV-infected children is often more severe, progressive, and likely to occur in extrapulmonary sites. Radiographic findings are similar to those in children with normal immune systems, but lobar disease and lung cavitation are more common. Nonspecific respiratory symptoms, fever, and weight loss are the most common complaints. Rates of drug-resistant tuberculosis tend to be higher in HIV-infected adults and probably are also higher in HIV-infected children.

The mortality rate of HIV-infected children with tuberculosis is high, especially as the CD4 lymphocyte numbers decrease. In adults, the host immune response to tuberculosis infection appears to enhance HIV replication and accelerate the immune suppression caused by HIV. Increased mortality rates are attributed to progressive HIV infection rather than tuberculosis. Therefore, HIV-infected children with potential exposures and/or recent infection should be promptly evaluated and treated for tuberculosis. Conversely, all children with tuberculosis disease should be tested for HIV co-infection, because of the potential benefits of early diagnosis and treatment of HIV infection and because the presence of HIV can necessitate a longer duration of treatment.

Perinatal Disease

Symptoms of congenital tuberculosis may be present at birth but more commonly begin by the 2nd or 3rd wk of life. The most common signs and symptoms are respiratory distress, fever, hepatic or splenic enlargement, poor feeding, lethargy or irritability, lymphadenopathy, abdominal distention, failure to thrive, ear drainage, and skin lesions. The clinical manifestations vary in relation to the site and size of the caseous lesions. Many infants have an abnormal chest radiograph, most often with a miliary pattern. Some infants with no pulmonary findings early in the course of the disease later develop profound radiographic and clinical abnormalities. Hilar and mediastinal lymphadenopathy and lung infiltrates are common. Generalized lymphadenopathy and meningitis occur in 30-50% of patients.

The clinical presentation of tuberculosis in newborns is similar to that caused by bacterial sepsis and other congenital infections, such as syphilis, toxoplasmosis, and cytomegalovirus. The diagnosis should be suspected in an infant with signs and symptoms of bacterial or congenital infection whose response to antibiotic and supportive therapy is poor and in whom evaluation for other infections is unrevealing. The most important clue for rapid diagnosis of congenital tuberculosis is a maternal or family history of tuberculosis. Often, the mother’s disease is discovered only after the neonate’s diagnosis is suspected. The infant’s TST is negative initially but can become positive in 1-3 mo. A positive acid-fast stain of an early morning gastric aspirate from a newborn usually indicates tuberculosis. Direct acid-fast stains on middle-ear discharge, bone marrow, tracheal aspirate, or biopsy tissue (especially liver) can be useful. The CSF should be examined and cultured, although the yield for isolating M. tuberculosis is low. The mortality rate of congenital tuberculosis remains very high because of delayed diagnosis; many children have a complete recovery if the diagnosis is made promptly and adequate chemotherapy is started.

Drug-Resistant Tuberculosis

The incidence of drug-resistant tuberculosis is increasing in many areas of the world, including North America. There are two major types of drug resistance. Primary resistance occurs when a person is infected with M. tuberculosis that is already resistant to a particular drug. Secondary resistance occurs when drug-resistant organisms emerge as the dominant population during treatment. The major causes of secondary drug resistance are poor adherence to the medication by the patient or inadequate treatment regimens prescribed by the physician. Nonadherence to one drug is more likely to lead to secondary resistance than is failure to take all drugs. Secondary resistance is rare in children because of the small size of their mycobacterial population. Therefore, most drug resistance in children is primary, and patterns of drug resistance among children tend to mirror those found among adults in the same population. The main predictors of drug-resistant tuberculosis among adults are history of previous antituberculosis treatment, co-infection with HIV, and exposure to another adult with infectious drug-resistant tuberculosis.

Treatment of drug-resistant tuberculosis is successful only when at least 2 bactericidal drugs are given to which the infecting strain of M. tuberculosis is susceptible. When a child has possible drug-resistant tuberculosis, usually 4 or 5 drugs should be administered initially until the susceptibility pattern is determined and a more-specific regimen can be designed. The specific treatment plan must be individualized for each patient according to the results of susceptibility testing on the isolates from the child or the adult source case. Treatment duration of 9 mo with rifampin, pyrazinamide, and ethambutol is usually adequate for isoniazid-resistant tuberculosis in children. When resistance to isoniazid and rifampin is present, the total duration of therapy often must be extended to 12-18 mo, and twice-a-week regimens should not be used. The prognosis of single- or multidrug-resistant tuberculosis in children is usually good if the drug resistance is identified early in the treatment, appropriate drugs are administered under directly observed therapy, adverse reactions from the drugs do not occur, and the child and family are in a supportive environment. The treatment of drug-resistant tuberculosis in children always should be undertaken by a clinician with specific expertise in the treatment of tuberculosis.

Extensively drug resistant (XDR) TB with resistance to isoniazid, rifampicin, any fluoroquinolone, and any one of capreomycin, kanamycin, or amikacin is a growing problem, particularly in developing countries and patients with HIV.

Corticosteroids

Corticosteroids are useful in treating some children with tuberculosis disease. They are most beneficial when the host inflammatory reaction contributes significantly to tissue damage or impairment of organ function. There is convincing evidence that corticosteroids decrease mortality rates and long-term neurologic sequelae in some patients with tuberculous meningitis by reducing vasculitis, inflammation, and, ultimately, intracranial pressure. Lowering the intracranial pressure limits tissue damage and favors circulation of antituberculosis drugs through the brain and meninges. Short courses of corticosteroids also may be effective for children with endobronchial tuberculosis that causes respiratory distress, localized emphysema, or segmental pulmonary lesions. Several randomized clinical trials have shown that corticosteroids can help relieve symptoms and constriction associated with acute tuberculous pericardial effusion. Corticosteroids can cause dramatic improvement in symptoms in some patients with tuberculous pleural effusion and shift of the mediastinum. However, the long-term course of disease is probably unaffected. Some children with severe miliary tuberculosis have dramatic improvement with corticosteroid therapy if the inflammatory reaction is so severe that alveolocapillary block is present. There is no convincing evidence that 1 corticosteroid preparation is better than another. The most commonly prescribed regimen is prednisone, 1-2 mg/kg/day in 1-2 divided doses orally for 4-6 wk, followed by gradual tapering.

Supportive Care

Children receiving treatment should be followed carefully to promote adherence to therapy, to monitor for toxic reactions to medications, and to ensure that the tuberculosis is being adequately treated. Adequate nutrition is important. Patients should be seen at monthly intervals and should be given just enough medication to last until the next visit. Anticipatory guidance with regard to the administration of medications to children is crucial. The physician should foresee difficulties that the family might have in introducing several new medications in inconvenient dosage forms to a young child. The clinician must report all cases of suspected tuberculosis in a child to the local health department to be sure that the child and family receive appropriate care and evaluation.

Nonadherence to treatment is the major problem in tuberculosis therapy. The patient and family must know what is expected of them through verbal and written instructions in their primary language. About 30-50% of patients taking long-term treatment are significantly nonadherent with self-administered medications, and clinicians are usually not able to determine in advance which patients will be nonadherent. Preferably, directly observed therapy should be instituted with the help of the local health department.

Latent Mycobacterium tuberculosis Infection (LTBI)

The following aspects of the natural history and treatment of LTBI in children must be considered in the formulation of recommendations about therapy: (1) infants and children <5 yr of age with LTBI have been infected recently; (2) the risk for progression to disease is high; (3) untreated infants with LTBI have up to a 40% chance of development of tuberculosis disease; (4) the risk for progression decreases gradually through childhood; (5) infants and young children are more likely to have life-threatening forms of tuberculosis, including meningitis and disseminated disease; and (6) children with LTBI have more years at risk for development of disease than adults. Because of these factors, and the excellent safety profile of isoniazid in children, there is a tendency to err on the side of overtreatment in infants and young children.

Isoniazid therapy for LTBI appears to be more effective for children than adults, with several large clinical trials demonstrating risk reduction of 70-90%. The risk of isoniazid-related hepatitis is minimal in infants, children, and adolescents, who generally tolerate the drug better than adults.

The recommended regimen for treatment of LTBI in children is a 9-mo course of isoniazid as self-administered daily therapy or by twice-weekly directly observed therapy (DOT). Analysis of data from several studies has demonstrated that the efficacy decreased significantly if isoniazid was taken for <9 mo. Isoniazid given twice weekly has been used extensively to treat LTBI in children, especially schoolchildren and close contacts of case patients. DOT should be considered when it is unlikely that the child and family will adhere to daily self-administration, or if the child is at increased risk for rapid development of disease (newborns and infants, recent contacts, immunocompromised children). For healthy children taking isoniazid but no other potentially hepatotoxic drugs, routine biochemical monitoring and supplementation with pyridoxine are not necessary. A 3-mo regimen of rifampin and isoniazid has been used in England, with programmatic data suggesting that the regimen is effective, but this regimen is not recommended in the USA. Rifampin alone for 6 mo has been used for the treatment of LTBI in infants, children, and adolescents when isoniazid could not be tolerated or the child has had contact with a case patient infected with an isoniazid-resistant but rifamycin-susceptible organism. However, no controlled clinical trials have been conducted. For children with multidrug-resistant tuberculosis infection, the regimen will depend on the drug susceptibility profile of the contract case’s organism; usually an expert in tuberculosis should be consulted in such cases.

No controlled studies have been published regarding the efficacy of any form of treatment for LTBI in HIV-infected children. A 9-mo course of daily isoniazid is recommended. Most experts recommend that routine monitoring of serum hepatic enzyme concentrations be performed and pyridoxine be given when HIV-infected children are treated with isoniazid. The optimal duration of rifampin therapy in children with LTBI is not known, but many experts recommend at least a 6-mo course.

Isoniazid should be given to young children who have negative skin test or IGRA results but who have known recent exposure to an adult with contagious tuberculosis disease. This practice is often referred to as window prophylaxis. By the time delayed hypersensitivity develops (2-3 mo), an untreated child already may have developed severe tuberculosis. For these children, tuberculin skin or IGRA testing is repeated 3 mo after contact with the source case for tuberculosis has been broken (broken contact is defined as physical separation or adequate initial treatment of the source case). If the second test result is positive, isoniazid therapy is continued for the full 9-mo duration, but if the result of the second test is negative, treatment can be stopped.

Bacille Calmette-Guérin Vaccination

The only available vaccine against tuberculosis is the BCG, named for the 2 French investigators responsible for its development. The original vaccine organism was a strain of M. bovis attenuated by subculture every 3 wk for 13 yr. This strain was distributed to dozens of laboratories that continued to subculture the organism on different media under various conditions. The result has been production of many BCG vaccines that differ widely in morphology, growth characteristics, sensitizing potency, and animal virulence.

The administration route and dosing schedule for the BCG vaccines are important variables for efficacy. The preferred route of administration is intradermal injection with a syringe and needle, because it is the only method that permits accurate measurement of an individual dose.

The BCG vaccines are extremely safe in immunocompetent hosts. Local ulceration and regional suppurative adenitis occur in 0.1-1% of vaccine recipients. Local lesions do not suggest underlying host immune defects and do not affect the level of protection afforded by the vaccine. Most reactions are mild and usually resolve spontaneously, but chemotherapy is needed occasionally. Surgical excision of a suppurative draining node is rarely necessary and should be avoided if possible. Osteitis is a rare complication of BCG vaccination that appears to be related to certain strains of the vaccine that are no longer in wide use. Systemic complaints such as fever, convulsions, loss of appetite, and irritability are extraordinarily rare after BCG vaccination. Profoundly immunocompromised patients can develop disseminated BCG infection after vaccination. Children with HIV infection appear to have rates of local adverse reactions to BCG vaccines that are comparable with rates in immunocompetent children. However, the incidence in these children of disseminated infection months to years after vaccination is currently unknown.

Recommended vaccine schedules vary widely among countries. The official recommendation of the World Heath Organization is a single dose administered during infancy, in populations where the risk for tuberculosis is high. However, infants with known HIV infection should not receive a BCG vaccination. In some countries repeat vaccination is universal, though no clinical trials support this practice. In others it is based on either TST or the absence of a typical scar. The optimal age for administration and dosing schedule are unknown because adequate comparative trials have not been performed.

Although dozens of BCG trials have been reported in various human populations, the most useful data have come from several controlled trials. The results of these studies have been disparate. Some demonstrated a great deal of protection from BCG vaccines, but others showed no efficacy at all. A recent meta-analysis of published BCG vaccination trials suggested that BCG is 50% effective in preventing pulmonary tuberculosis in adults and children. The protective effect for disseminated and meningeal tuberculosis appears to be slightly higher, with BCG preventing 50-80% of cases. A variety of explanations for the varied responses to BCG vaccines have been proposed, including methodologic and statistical variations within the trials, interaction with NTM that either enhances or decreases the protection afforded by BCG, different potencies among the various BCG vaccines, and genetic factors for BCG response within the study populations. BCG vaccination administered during infancy has little effect on the ultimate incidence of tuberculosis in adults, suggesting that the effect of the vaccine is time limited.

BCG vaccination has worked well in some situations but poorly in others. Clearly, BCG vaccination has had little effect on the ultimate control of tuberculosis throughout the world, because more than 5 billion doses have been administered but tuberculosis remains epidemic in most regions. BCG vaccination does not substantially influence the chain of transmission, because cases of contagious pulmonary tuberculosis in adults that can be prevented by BCG vaccination constitute a small fraction of the sources of infection in a population. The best use of BCG vaccination appears to be prevention of life-threatening forms of tuberculosis in infants and young children.

BCG vaccination has never been adopted as part of the strategy for the control of tuberculosis in the USA. Widespread use of the vaccine would render subsequent TST less useful. However, BCG vaccination can contribute to tuberculosis control in selected population groups. BCG is recommended for TST-negative infants and children who are at high risk for intimate and prolonged exposure to persistently untreated or ineffectively treated adults with infectious pulmonary tuberculosis and cannot be removed from the source of infection or placed on long-term preventive therapy, and it is recommended for those who are continuously exposed to persons with tuberculosis who have bacilli that are resistant to isoniazid and rifampin. Any child receiving BCG vaccination should have a documented negative TST before receiving the vaccine. After receiving the vaccine, the child should be separated from the possible sources of infection until it can be demonstrated that the child has had a vaccine response, demonstrated by tuberculin reactivity, which usually develops within 1-3 mo.

Active research to develop new tuberculosis vaccines has led to the creation and preliminary testing of several vaccine candidates based on attenuated strains of mycobacteria, subunit proteins, or DNA. The genome of M. tuberculosis has been sequenced, allowing researchers to further study and better understand the pathogenesis and host immune responses to tuberculosis.

Perinatal Tuberculosis

The most effective way of preventing tuberculosis infection and disease in the neonate or young infant is through appropriate testing and treatment of the mother and other family members. High-risk pregnant women should be tested with a TST or IGRA, and those with a positive test result should receive a chest radiograph with appropriate abdominal shielding. If the mother has a negative chest radiograph and is clinically well, no separation of the infant and mother is needed after delivery. The child needs no special evaluation or treatment if he or she remains asymptomatic. Other household members should undergo testing for tuberculosis infection and further evaluation as indicated.

If the mother has suspected tuberculosis at the time of delivery, the newborn should be separated from the mother until the chest radiograph is obtained. If the mother’s chest radiograph is abnormal, separation should be maintained until the mother has been evaluated thoroughly, including examination of the sputum. If the mother’s chest radiograph is abnormal but the history, physical examination, sputum examination, and evaluation of the radiograph show no evidence of current active tuberculosis, it is reasonable to assume that the infant is at low risk for infection. The mother should receive appropriate treatment, and she and her infant should receive careful follow-up care. In addition, all household members should be evaluated for tuberculosis.

If the mother’s chest radiograph or acid-fast sputum smear shows evidence of current tuberculosis disease, additional steps are necessary to protect the infant. Isoniazid therapy for newborns has been so effective that separation of the mother and infant is no longer considered mandatory. Separation should occur only if the mother is ill enough to require hospitalization, has been or is expected to become nonadherent to treatment, or has suspected drug-resistant tuberculosis. Isoniazid treatment for the infant should be continued until the mother has been shown to be sputum culture negative for ≥3 mo. At that time, a Mantoux TST should be placed on the child. If the test is positive, isoniazid is continued for a total duration of 9-12 mo; if the test is negative, isoniazid can be discontinued. If isoniazid resistance is suspected or the mother’s adherence to medication is in question, separation of the infant from the mother should be considered. The duration of separation must be at least as long as is necessary to render the mother noninfectious. An expert in tuberculosis should be consulted if the young infant has potential exposure to the mother or another adult with tuberculosis disease caused by an isoniazid-resistant strain of M. tuberculosis.

Although isoniazid is not thought to be teratogenic, the treatment of pregnant women who have asymptomatic tuberculosis infection is often deferred until after delivery. However, symptomatic pregnant women or those with radiographic evidence of tuberculosis disease should be appropriately evaluated. Because pulmonary tuberculosis is harmful to both the mother and the fetus and represents a great danger to the infant after delivery, tuberculosis in pregnant women always should be treated. The most common regimen for drug-susceptible tuberculosis is isoniazid, rifampin, and ethambutol. The aminoglycosides and ethionamide should be avoided because of their teratogenic effect. The safety of pyrazinamide in pregnancy has not been established.