Tuberculosis in Infancy in the 1990s

UPDATE ON NEONATOLOGY

0031-3955/93 $0.00 + .20

TUBERCULOSIS IN INFANCY IN THE 19908 Elaine A. Rosenfeld, MO, Joseph R. Hageman, MO, and Ram Yogev, MO

EPIDEMIOLOGY

In 1990, 25,701 cases of tuberculosis (TB) were reported in the United States, an increase of 9.4% over 1989 and the largest annual increase since 1953. The majority of these cases occurred in minority groups: 36% African-American, 27% Hispanic, 13% Asian/Pacific Islander, and 4% Native American, with only 20% occurring in Caucasians.71 Children <15 years of age accounted for 1596 new cases. Although the greatest percentage increase since 1985 was in the 25- to 44-year-old age group (44%), the next highest increase (39.8%) was in the 5- to 14-year-old age group. An increase of 18.6% was reported in children less than 5 years old (this comprised 9730, 660, and 936 cases, respectively).16 The resurgence of TB in children can be attributed to several factors. Probably the most important factor is the HIV epidemic, which has contributed to the increase in TB particularly in young urban adults. The incidence of TB in patients with AIDS is almost 500 times the incidence in the general population,59 and the risk of active TB among HIV-infected persons with a positive tuberculin skin test is approximately 8% per year. 67 Outbreaks of multidrug-resistant strains of Mycobacterium tuberculosis in HIV-infected patients increase the likelihood of systematic spread of the disease. 15 The recent rapid increase in HIV-infected women, especially during the child-bearing years, and the increase in the rate of TB in non-white women (20 in 100,000), suggest that many more preg-

From the Division of Infectious Diseases, Children's Memorial Hospital, Chicago (EAR, RY); Department of Pediatrics, Northwestern University Medical School (JH, RY), Chicago; and Division of Neonatology, Evanston Hospital, Evanston (JH), Illinois

PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 40 • NUMBER 5 • OCTOBER 1993

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nant young women are likely to be infected with TB (without showing symptoms of the disease) and transmit the infection to their offspring. Poverty, overcrowding, poor nutrition, and poor access to health care have hindered the diagnosis and treatment of TB, thus increasing the pool of infected patients. Recent immigration from areas with high prevalence of TB has enlarged the pool of TB-infected persons in the United States. In 1989 the estimated TB case rate for foreign-born persons arriving in the United States was 13 times greater than the overall US rate. Although the majority of children with TB are US born, the proportion of foreign-born children is increasing. In addition, TB infection and disease are common in foreign-born adopted children?5 Of 873 Korean adoptees studied between 1985 and 1988 in Baltimore, overall tuberculin reactivity or active TB was documented in 9. This reactivity rate is 50 times greater than that of age-matched US-born children. 4o Certain environments with high incidence rates of TB promote transmission of the infection. Homeless persons, especially persons residing in shelters, have TB case rates 40 times higher than the general population. 53 Migrant farm workers have a very high incidence of TB and are difficult to treat because of their transient living situations. 18 Residents of nursing homes and correctional facilities have a disproportionately increased prevalence of TB.12 Health care professionals are also at increased risk for TB.28

PERINATALLV ACQUIRED TUBERCULOSIS

Perina tally acquired TB occurs rarely. There are four modes of transmission of the tubercle bacilli to the fetus or the newborn: (1) tuberculous bacillemia can spread the bacteria to the placenta and then to the fetus, which may lead to fetal death secondary to severe placental involvement; (2) placental TB can spread to the fetus via the umbilical vein to the liver and lymph nodes of the porta hepatis or via rupture of a placental tubercle, causing amnionitis and subsequent fetal aspiration; this results in primary disease in the liver, gastrointestinal tract, and mesenteric lymph nodes; (3) endocervical TB can spread to the newborn by aspiration during the birth process, leading to primary pulmonary disease; and (4) early postnatal exposure can occur secondary to care by the infected mother, another infected family member, or an infected health-care worker with active pulmonary TB.50 The differentiation between congenital and early neonatal infection may be important for epidemiologic purposes, but both have almost the same mode of presentation, treatment, and prognosis. Thus, the term perinatal TB is used in the current discussion. In 1980 Hageman et apo reviewed 26 cases of congenital TB reported in the English literature since the introduction of isoniazid in 1952. Since then more cases have been published and many of them from developing countries. * This *References 1, 5-7, 9, 10, 23, 35, 42, 44, 45, 49, 52, 55, 60, 65, 78, 81, 83.

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increased number of reported cases emphasizes the importance of having a high index of suspicion for this disease, which has clinical manifestations that cannot be distinguished from other neonatal infections or persistent pulmonary disease. Early reviews of perinatal TB demonstrated that the affected newborns were usually born prematurely. The onset of symptoms varies from the first few days of life to a few months of age, with an average of 2 to 4 weeks. Signs and symptoms commonly included prolonged fever, a paucity of auscultatory findings despite extensive radiograph changes, failure to thrive, lymphadenopathy, splenomegaly, biliary obstruction, and calcification of the liver and spleen. Purified protein derivative (PPD) skin test reactivity was usually absent, but bacilli were often found in gastric aspirate smears. Death ensues within weeks to months without treatment. 33,62, 79 Hageman et apo reported markedly different clinical findings. Respiratory distress was the most common presenting manifestation (found in 75% of the cases). Fever and hepatic (with or without splenic) enlargement were found in two thirds of the cases. Irritability, poor feeding, and lethargy were reported in one half of the patients, whereas lymphadenopathy was noted in one third of the cases. Failure to thrive, jaundice, abdominal distention, skin lesions, ear discharge, and central nervous system (eNS) involvement were less common presenting manifestations.30 Very rarely, ear discharge may be the only presenting symptom of a localized perinatal TB.s2 This unusual presentation may be the result of infected amniotic fluid reaching the ear canal in utero, without aspiration or transplacental transmission. The skin manifestations are also rare and initially appear as small erythematous papules with a central crusted area. These lesions may represent a hypersensitivity reaction resembling papulonecrotic tuberculid or embolic spread of the mycobacteria (for example, tuberculosis cutis miliaris disseminata). The characteristic morphologic appearance of such lesions suggests that a skin biopsy may be helpful in the diagnosis. 46 The survival rate (54% in Hageman review) was not influenced by specific signs or symptoms, the nature or severity of maternal disease, or by whether diagnosis of maternal TB was established before or after the infant's diagnosis. 30 CLINICAL PRESENTATION IN IMMUNOCOMPETENT INFANTS

Most infants less than 1 year of age have nonspecific symptoms such as low grade fever and mild cough. Weight loss and night sweats may occur as pulmonary inflammation progresses. Abnormal physical findings are rare even when extensive lesions are seen on the chest radiograph. In the early stage of bronchial involvement, infants may have a harsh expiratory cough, with wheezing and rhonchi. The clinical picture may be indistinguishable from that seen in laryngotracheobronchitis.73 Miliary TB is commonly encountered in infants less than 1 year of age. It usually presents with cough, fever, loss of appetite and weight, hepato-

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splenomegaly, lymphadenopathy, respiratory distress, and anemia. A classic miliary pattern in the lungs can be seen on chest radiograph in >90% of cases. Meningitis is reported in 19% to 35% of cases. Anergy to PPD is reported in as many as 62% of cases. 34 Patients with associated meningeal TB do less well than those without CNS involvement.66 Diagnosis is often quite difficult to make because most diagnostic measures are nonspecific. Pleural effusion is not commonly seen in patients less than 2 years of age. When present, it usually develops within 6 months of the onset of primary disease. Effusion may occur as an extension from a subpleural primary focus or from hematogenous spread of the tubercle bacilli to the pleura. Pleural effusion usually presents abruptly with fever and chest pain. Fever remains for a few weeks until treatment has been established. Definitive diagnosis is made by recovery of the organism from pleural biopsy or histologic evaluation of the biopsy specimen. Culture of the pleural fluid is positive for M. tuberculosis in approximately 50% of cases. Therapeutic thoracentesis is not recommended, as the fluid resolves with treatment. 43 Superficial lymph node infection is also uncommon in infants and represents extension from para tracheal lymph nodes and supraclavicular lymph nodes that are accompanied by a primary pulmonary lesion in the upper lung fields. The involved nodes are usually firm, nontender, and multiple. The overlying skin may be erythematous or develop a purple hue. There is no sinus tract formation. This presentation may be similar to that of cat scratch disease or atypical mycobacteriallymphadenitis.21, 38, 39 Although CNS involvement is rare, it is the most severe life-threatening form of TB in infants. The mortality rate has been estimated to vary from 15% to 32%, and neurologic sequelae are common. The most frequent presenting clinical signs and symptoms of patients with CNS TB include fever, vomiting, lethargy, seizures, and anorexia. Early in the course of CNS TB, the clinical presentation is nonspecific and resembles that seen in many childhood illnesses. With further advancement of the illness, signs of increased intracranial pressure and meningeal irritation develop and patients may present with cranial nerve palsies, hemiparesis, obtundation, stupor, papilledema, or coma. 19 PPD skin tests are > 10 mm in only 50% of patients with CNS TB. Chest radiograph findings are noted in approximately 40% of patients with CNS TB.82 Cranial CT demonstrates ischemic infarction in 30% to 40% of children with CNS TBY Cerebrospinal fluid (CSF) examination reveals increased opening pressure, a moderate degree of pleocytosis (mostly lymphocytosis), protein between 100 and 500 mg/dL, and glucose <40 mg/ dL. Often the initial CSF examination is not diagnostic, and repeated lumbar puncture is important. 48 Early diagnosis is often hampered by the low sensitivity of the acid-fast bacilli smear (37%) and the CSF culture (50%).36 The earlier tuberculous meningitis is diagnosed and treatment is initiated, the better is the prognosis.54 Very rare manifestations of TB in infants include cutaneous TB, conjunctival and corneal involvement, tuberculous dactylitis, TB of the middle ear and mastoid, and peritonitis.

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CLINICAL PRESENTATION IN HIV-INFECTED CHILDREN

There have been few reported cases of children with coexisting TB and HIV infection. Children with HIV infection are likely to be in contact with HIV-infected adults who are at high risk for TB. Moss et a151 reported five HIV-infected children with TB. They ranged in age from 6 to 94 months of age. The clinical manifestations ranged from asymptomatic pulmonary infection to fatal· tuberculous meningitis. Four of the five children had cultures from various sites that grew M. tuberculosis. Pulmonary infection was diagnosed by tracheal aspiration, bronchoscopy, and lung biopsy. One child had a positive skin test and characteristic radiographic findings. Three of the four patients with pulmonary TB had upper lobe infiltrates. One patient had radiographic findings consistent with lymphocytic interstitial pneumonitis. CD4 counts ranged from 135 to 1764/mm3 • Three of four children with pulmonary TB responded to antituberculous therapy and had clinical resolution of their symptoms. The child with tuberculous meningitis died. 51 Extrapulmonary TB occurs in more than 70% of adults with TB and AIDS but only in 25% to 45% of patients with TB and less advanced HIV infection. Of 48,712 cases of AIDS reviewed by Braun et al,12 2.5% had extrapulmonary TB, yet only 1 in 497 AIDS patients under 10 years of age had extrapulmonary disease. Extrapulmonary disease appears more common in patients with more severe HIV-inducedimmunosuppression. The most frequently involved organs are lymph nodes, bone marrow, the genitourinary tract, and the CNS. Patients with lymphadenitis and HIV infection have tender adenopathy, fever, and weight loss. Biopsy of the lymph node reveals acid-fast bacilli in 67% to 90% of patients.47 Neurologic signs and symptoms are common in patients with CNS involvement and include altered mental status, headache, stiff neck, focal neurologic deficit, and seizures.68 Tuberculous abscesses and tuberculomas in brain parenchyma are frequent abnormalities. CT scan reveals ring-enhancing or hypodense mass lesions. CSF may be normal. Chest radiograph is rtormal in 70% of cases with CNS involvement, and in most cases a definite diagnosis requires brain biopsy with demonstration of acid-fast bacilli on smearY DIAGNOSiS

Diagnosis of perinatal TB is often difficult and delayed. The disease in the mother is often overlooked or misdiagnosed. The signs and symptoms in the neonate may also be overlooked as they are nonspecific. Once the diagnosis is suspected, diagnostic procedures should be carried out rapidly and treatment initiated. Chest radiographs must be obtained, and cultures should be sought from gastric aspirates, urine, and CSF. Hageman et apo reported that 20 of 24 patients with perinatal TB had abnormal chest radiographs. The tuberculin skin test initially was posi-

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tive in only 2 of 14 infants, but 7 infants subsequently developed positive tests. Twenty of 26 patients had at least one positive culture for M. tuberculosis. Nine of 12 patients had gastric aspirates positive for M. tuberculosis. Liver biopsy and skin biopsy revealed the diagnosis in both patients in whom these procedures were performed. Usually tuberculin skin test reactivity appears approximately 2 to 10 weeks after infection. Once acquired, it often remains reactive for life despite medical treatment. Although three techniques of applying the tuberculin test are currently available (the multiple puncture test [MPT], the Monovac, and the Mantoux), the MPT and the Monovac tests should not be used routinely because the exact dose of administered antigen cannot be well standardized, and there is a high rate of false-negative and false-positive results. Therefore, any reaction to an MPT or Monovac (for example, palpable induration) must be followed with a Mantoux test,75 The Mantoux test contains five tuberculin units of PPD in 0.1 mL of solution. The antigen solution should be injected intradermally and read at 48 to 72 hours. Only the margins of the induration should be palpated and measured. Approximately 10% of children with culture-proven TB will not react initially to standard PPD. False.:.negative Mantoux results may also occur if the test is performed during an infection (particularly viral), coincident with a vaccination with live virus such as measlesmumps-rubella (MMR), poor nutrition, lymphoproliferative disease (for example, Hodgkin's), immunosuppression by drugs (for example, corticosteroids), overwhelming tuberculous infection, atopic dermatitis, or HIV infection (especially in advanced stages). Improper storage or dilution of the PPD or improper administration of the skin test and its interpretation may also result in a false-negative test,7° Usually lO-mm induration is considered positive. Unfortunately, the frequency of positive skin tests (2:10 mm) in HIV-infected patients with TB is only 70% in cases in which TB occurred more than 2 years before the diagnosis of AIDS and it declines to 33% in cases occurring with or after the diagnosis of AIDSP Anergy in cases of HIV infection identified prospectively ranges from 20% to 50%.58,77 Thus, induration of >5 mm in an HIVinfected child is considered an evidence of infection with M. tuberculosis. As mentioned before in perinatal TB, a false-negative test is the rule rather than the exception. In persons already sensitized to mycobacterial antigens, a false-positive Mantoux test may result. This may result from repetitive testing (for example, Monovac or MPT followed by a Mantoux) done lO days to 12 months apart. Cross-reactivity due to exposure to nontuberculous mycobacteria also can result in a false-positive test. This very rarely occurs with the Mantoux test. Prior BCG administration can also cause a falsepositive result. This usually produces an induration < 12 mm. Thus, at any time a PPD reaction> 15 mm is not likely to be due to BCG. The skin test reactivity tends to diminish with time, and by 10 years after BCG vaccination, most recipients do not have a significant reaction. The critical piece of information for interpreting the size of the induration in response to a standard 5 tuberculin units (TU) PPD is

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whether or not the child is likely to have been exposed to an adult with TB. High-risk children are defined as those who have had contact with TB-infected cases, have an abnormal chest radiograph, are HIV-infected, or are otherwise immunosuppressed. Induration measuring ~5 mm is considered positive in this group. Moderate-risk children are defined as those who are foreign-born from high prevalence areas; are from a lowincome population; live in shelters for the homeless; or have medical risk factors that may predispose them to the development of TB, such as Hodgkin's, diabetes, or chronic renal failure. Induration of ~10 mm is considered positive in this group. In patients with no risk factors, a reaction of ~15 mm is considered positive.3 There are no pathognomonic roentgenographic features in primary pulmonary TB. TB can produce almost any form of pulmonary radiograph abnormality. The roentgenographic changes represent the perifocal exudative reaction to the presence of tubercle bacilli in the primary focus, the draining lymph nodes, and/or the adjacent pleura. As a result of the inflammatory response, the primary pulmonary focus can be seen on chest radiographs as increased density of variable size and shape. Additionally, linear shadows connecting the pulmonary focus and the enlarged draining nodes can be observed. Most infants with perinatal TB have abnormal chest radiographs. 3D Because hematogenous spread of TB is the most common mode of primary involvement of the lungs in perinatal TB, it is characterized by diffuse finely nodular uniformly distributed ("miliary") lesions on the chest radiograph. Cavitation of the primary focus is unusual in childhood TB. Unilateral, or rarely, bilateral pleural effusions are usually the only radiographic abnormality evident with pleural TB.3 As healing takes place, there is gradual clearing of the pulmonary and pleural exudates and reaeration of the atelectatic alveoli. Necrotic foci heal by fibrous hyalinization and calcification. Calciferous lesions may be gradually reabsorbed or may persist unchanged for years. Lymph node changes tend to persist longer than parenchymal shadows. 69 In many instances the radiograph findings in primary TB do not appear until the child's skin test is positive; therefore chest radiographs are not an appropriate screening method to detect exposure to TB. Findings on chest radiographs also do not aid in the evaluation of clinical progress because the changes seen may not represent active inflammatory pulmonary disease. The most useful aspect of chest radiography is following the course of children with recent conversion of their PPD skin test and for the early identification of miliary TB.69 Radiographic findings in adult patients coinfected with TB and HIV may differ from those in non-HIV-infected patients. Among HIV-infected patients with relatively well-preserved immune function, the chest radiograph findings are often similar to those of TB in immunocompetent patients (for example, reactivation of a previous focus). They include cavitation in the upper lobes (45%), mediastinal adenopathy (25%), and lower lobe infiltration without cavitation (20%).17,77 In contrast, severely immunocompromised adults with HIV infection have chest radiographic findings that are typical for primary TB in immunocompetent patients

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such as hilar adenopathy (25%), focal consolidation (35%), and diffuse pulmonary infiltrate (60%). Data for chest radiographic findings in HIVinfected infants and children with TB are not available, but from the adult data one should expect a variety of findings related to the severity of the TB infection and the competency of the immune system. LABORATORY DIAGNOSIS

The demonstration of acid-fast bacilli in stained smears of gastric aspirate, or, less commonly, urine, CSF, pleural fluid, or bronchial washing, is the first bacteriologic evidence of the presence of mycobacterium. In general, the yield of the acid-fast stain is very low because the lowest concentration of organisms detectable by microscopic examination is 10/ mL of sputum, which is higher than the usual load of bacteria in perinatal TB.3 It is important to note that the yield of acid-fast smears in HIVinfected patients with TB is even lower than in immunocompetent patients. 37 Mycobacterial culture is therefore of great importance for confirmation of the diagnosis. It is very difficult to obtain sputum from children less than 10 years of age; thus, gastric aspiration is necessary in younger patients. The yield of gastric lavage is higher if it is performed in the morning, when the patient has had nothing to eat or drink. The yield on culture of gastric aspirates in perinatal TB or children with pulmonary TB is 75% and 40%, respectively.3,30 Bronchoscopy may be necessary with bronchial washing, bronchiolar lavage, and/or transbronchial biopsy. Bronchoscopy yield varies from 13% to 62%.24 When noninvasive techniques have not provided the diagnosis, tissue biopsy should be obtained for histologic evaluation and culture. Liver biopsy, especially in patients with perinatal TB who present with hepatomegaly, has a very good yield. Other tissues such as lymph nodes or bone marrow should be considered, and previous reports suggest that the yield is good. 30 Traditional culture methods utilizing 5% to 10% CO2 take 4 to 6 weeks for isolation of organisms and another 2 to 4 weeks for susceptibility testing. The most widely used radiometric method to detect early growth of mycobacterium in culture (the BACTEC system) takes only 7 to 10 days to produce culture and susceptibility results. In addition, it is more sensitive for sputum than the traditional medium. 32 Other more sophisticated but not yet widely used methods to identify TB include the use of DNA probes, which can be completed in 2 to 8 hours with a sensitivity and a specificity approaching 100%63; polymerase chain reaction (PCR), in which results are available in 72 hours14,25, 26; and ELISA and RIA, which offer species-specific mycobacterial identification. 22 Currently serologic diagnosis of TB is not widely available, and under optimal circumstances the ELISA method for detection of IgG antibody to mycobacterial antigens has the same yield as the sputum smear. Further study is needed for development of accurate and reliable serodiagnosis tests. 2,64

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THERAPY It is of great importance to identify pregnant women who are infected with TB so as to minimize the risk of transmission to the fetus. Pregnancy does not appear to change the clinical symptoms of the disease. Most pregnant women are asymptomatic, and therefore a careful history for exposure, especially in high-risk groups, is important. Skin testing should be done on all pregnant women who are (1) suspected to be exposed to a person with TB; (2) have increased susceptibility to acquire TB such as HIV infection, diabetes, or gastrectomy; (3) living in a high prevalence area (for example, low socioeconomic population, new immigrant, and so on); or (4) working in a profession with a high probability for exposure (for example, hospital, prison, agency for the homeless, nursing home).31, 73 Pregnancy does not affect the response to a tuberculin skin test, and there have been no adverse effects on women or their babies from tuberculin testing. Chest radiography is helpful in defining the extent of the disease, but it exposes the fetus to radiation and is not reliable in identification of extrapulmonary disease. Only if the tuberculin skin test is positive should a chest radiograph be obtained to determine if there is active disease. Shielding of the abdomen during the procedure to minimize exposure of the fetus is important. If active TB disease is diagnosed during pregnancy, a 9-month regimen of isoniazid (INH) and rifampin is recommended. There is no evidence that INH causes any risk to the fetus, despite the fact that it crosses the placenta. Also, there is no increase in incidence of congenital defects in offsprings of women who received rifampin during pregnancy. The safety of other anti-TB drugs is less well known. Ethambutol, which has a teratogenic effect in experimental animals, was found to be safe in humans. Ethionamide was reported as causing an increase in anomalies in the newborns. Streptomycin and other aminoglycosides should be avoided because of ototoxicity to the fetus. When INH resistance is a possibility, ethambutol should be added to the regimen. Pyrazinamide should be avoided because very little is known about its safety during pregnancy. Pyridoxine should always be given with INH because of the increased requirements for this vitamin in pregnancy. When sensitivity of the bacteria is known, one of the drugs may be discontinued after 1 or 2 months. If rifampin or INH is discontinued, treatment should be continued for 18 months; if ethambutol is discontinued, treatment can continue for a total of only 9 months. If the bacteria is multidrug-resistant, other drugs with unknown side effects or contraindications have to be used. The potential toxicity to the fetus should be discussed with the pregnant woman and other options (for example, abortion) should be considered. Following delivery, the management of the newborn depends on the maternal course. If the mother has completed a course of therapy during pregnancy and has no evidence of disease, there is a minimal risk to the newborn and no antituberculous therapy is needed. If the mother or other household contacts are PPD positive without evidence of disease,

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the infant should be skin tested with PPD at 4 to 6 weeks of age and then again at 3 to 4 months of age. INH should be administered to the infant until exposure to active disease can be ruled out. If the mother is being treated for TB at delivery, the newborn needs careful evaluation. If no signs of congenital infection are present, the newborn should be treated with INH until the mother has a negative sputum smear and is known to be complying with therapy. The infant should be skin tested at birth and again at 3-month intervals. If after 3 months the mother is smear and culture negative and the infant's skin test is negative, INH prophylaxis may be discontinued. Infants whose tuberculin skin test is >5 mm at 3 months of age should be investigated thoroughly for pulmonary and extrapulmonary disease and prophylactic INH continued. At 6 months of age the skin test should be repeated. If the skin test is positive, the INH must be continued for a total of 12 months. Temporary separation of the infant and mother is necessary only in cases in which the mother is highly infectious at the time of delivery. The infant and mother can be reunited when the mother is noninfectious as evidenced by a negative sputum smear. BCG vaccination of the newborn should be considered in this situation because it has been shown to have some protective effect. BCG should also be considered if the newborn is going to be living in a home with a high risk for TB (see below). Early therapy of perinatal TB can result in complete response; therefore, if the newborn is suspected to have perinatal TB prompt antituberculous therapy is recommended (Table 1). It is important to note that TB in newborns and infants differs from adult disease in several ways that affect treatment. Children develop TB as an immediate complication of the primary infection typically involving closed caseous lesions with a small burden of bacteria. Because drug resistance is proportional to the size of the population of mycobacteria, children are less likely than adults to develop drug resistance during therapy unless they acquired a drug-resistant bacterium from their mother or other infectious contacts?4 Children have a higher propensity to develop extrapulmonary forms of Table 1. ANTITUBERCULOSIS DRUGS FOR PERINATAL INFECTION Drug

Activity

Dosage (mg/d)

Side Effects Peripheral neuritis, convulsions, hepatotoxic Orange coloration of body fluids, hepatotoxic, nausea, vomiting Hepatotoxic Ototoxic, nephrotoxic Optic neuritis Hepatotoxic CNS manifestations Gastrointestinal, hepatotoxic, allergic reactions Ototoxic, nephrotoxic, pain at the site of injection

INH

Bactericidal

10-15

Rifampin

Bactericidal

10-20

Pyrazinamide Streptomycin Ethambutol Ethionamide' Cycloserine' Para-amino' salicylic acid Capreomycin'

Bactericidal Bactericidal Bacteriostatic Bacteriostatic Bacteriostatic Bacteriostatic

30-40 20-40 15-25 15-20 15-20 150

Bacteriostatic

15-30

'Should be used only for therapy of multidrug-resistant strains.

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TB, especially meningitis and miliary TB. Therefore, it is important that anti-TB drugs penetrate a variety of tissues. INH, rifampin, and pyrazinamide cross-inflamed and uninflamed meninges, whereas streptomycin crosses only when inflammation is present; even then its CSF level will be low,?4 In comparison with adults, children tolerate higher doses (per kilogram of body weight) of the regular antituberculous medications and have fewer side effects. Children with severe disease, however, experience more significant hepatotoxicity than children with less severe disease when given the same treatment,74 Administration of TB medications to children is sometimes difficult because of the lack of a pediatric formulation for some drugs. Crushing and resuspending pills cause delays and interruption of treatment; thus compliance becomes a tremendous problem. In a recently reported 30year study of TB in children less than 10 years of age, only a 62% compliance rate with therapy was found. 56 Nine months of therapy with INH and rifampin (see Table 1 for dosage and side effects) cures virtually 100% of children with drugsusceptible pulmonary TB. Because of problems of compliance with taking daily medications and treatment cost, shorter treatment regimens have been developed. Most trials used INH, rifampin, and pyrazinamide in the initial 2 months, followed by INH and rifampin for the remaining 4 months. Rates of adverse reactions were quite low as was the number of relapses. Addition of streptomycin did not change the outcome, and thus it should not be routinely used. Giving directly observed medications twice weekly (double the dose in Table 1) during the continuation phase was as effective and safe as daily administration. The overall success rate was >95% for complete cure and 99% for significant improvement at 2-year follow-up,?4 Treatment of the infant suspected of having perinatal TB should be started before culture results are reported. Treatment should initially include INH, rifampin, and pyrazinamide until the drug susceptibility of the infant's or the mother's isolate is known. If there is a possibility that the organism is drug resistant (prior therapy to the mother, parents are recent immigrants, high prevalence of such bacteria in the region, and so on), four drugs should be given and streptomycin should be added. If there is no evidence of drug resistance, treatment should be continued with two bactericidal drugs (for example, INH and rifampin) for 9 months. In infants it is best to avoid ethambutol or streptomycin because of the inability to check visual acuity and ototoxicity, respectively. Primary resistance to INH and streptomycin is most commonly found. Resistance to pyrazinamide and rifampin is still rare. Unfortunately, there has been a rise in INH and rifampin resistance, especially in patients coinfected with HIV and TB. Infections with multidrug-resistant organisms are often diagnosed late after ineffective therapy has been attempted, and therefore the mortality rate is extremely high.27 Regimens for drug-resistant TB must include two bactericidal drugs (see Table 1) to which the isolate is sensitive. If either INH or rifampin resistance is present, a fourth drug such as streptomycin, ethionamide, or ethambutol should be added to the initial regimen and the length of

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treatment extended to at least 9 to 12 months.72 It is important to note that the drug susceptibility patterns of isolates from children and their adult contacts are often similar. Greater than 90% of the susceptibility patterns are identical in these two groups. Therefore, the drug susceptibility pattern of isolates obtained from the mother generally can serve as a useful guide in planning initial drug treatment for the perinatally infected infant.76 If the infant is suspected or proven to have tuberculous meningitis, therapy should continue for 12 months using daily treatment with INH, rifampin, pyrazinamide, and streptomycin (for dosage see Table 1) for 2 months, followed by INH and rifampin daily or twice weekly under direct observation for 10 months if the organism is sensitive. Some clinicians recommend that four drugs be used initially even if drug resistance is not suspected. Dexamethasone should be considered as adjunctive treatment for tuberculous meningitis. By reducing inflammation, vasculitis and intracranial pressure, steroids may decrease mortality and long-term neurologic sequelae.29 Treatment regimens for TB in the HIV-infected child have not yet been well defined. Adults with HIV and TB that is not drug-resistant tend to respond well to standard regimens, although they may require longer total duration of treatment. Thus, in pediatric patients initial treatment should include INH, rifampin, and pyrazinamide. If there is any suspicion of drug resistance, ethambutol or streptomycin must be added. In patients with drug susceptible organisms, INH, rifampin, and pyrazinamide should be continued for 2 months and then only INH and rifampin for 7 months longer. If INH resistance or intolerance is present, rifampin and ethambutol must be given for 18 months or for 12 months after cultures are negative, whichever is longer. Some clinicians would also add pyrazinamide to this regimen. There is no accepted regimen to treat cases with rifampin intolerance or resistance. Some clinicians recommend use of INH, pyrazinamide, and ethambutol for 18 to 24 months or for at least 12 months after cultures are negative, whichever is longer. For extrapulmonary TB in HIV-infected patients with sensitive bacteria, the standard treatment regimen is recommended for at least 9 to 12 months.8 Limited data suggest that the combination of zidovudine and antituberculous medications is well tolerated. Fluconazole and ketoconazole have a complex interaction with INH and rifampin, either of which may reduce serum ketoconazole and/or fluconazole concentrations, rendering the antifungal therapy ineffective. In addition, ketoconazole inhibits the absorption of rifampin if the drugs are taken together, which can result in the failure of the TB therapy.8 Monitoring for clinical and if possible bacteriologic response to therapy as well as adverse effects of chemotherapy is mandatory. Compliance with treatment is a major problem with the expensive long-term therapeutic regimens required for TB. If there is any question as to the patient's adherence to the treatment regimen, direct observation of twice weekly medication must be arranged. Any interruption in the treatment regimen necessitates a lengthening of the overall length of therapy. Be-

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cause it is almost impossible in infants to follow the bacteriologic response to therapy by examination of sputum, their response to treatment should be documented by chest radiographs.4 It should be noted that radiographic changes of recovering pulmonary T8 occur very slowly; thus it is recommended to obtain a baseline chest radiograph at diagnosis and 1 month after initiation of treatment. A third chest radiograph should not be repeated until therapy is discontinued (approximately 6 months later). The decision to discontinue antituberculous therapy should not be based on the expectation that the patient will have a normal chest radiograph, because pulmonary infiltrates may clear only after 14 months and hilar adenopathy may not resolve radiographically for 2 to 3 years. A follow-up chest radiograph, 3 to 6 months after discontinuation of therapy, is recommended to assure cure.72 Monthly clinical evaluations for the first 3 months of therapy and every 3 months thereafter to evaluate the patient's progress and to monitor for signs or symptoms of adverse side effects of the drugs are appropriate. Some clinicians prefer routine evaluation every 4 to 6 weeks throughout treatment. Because adverse reactions to antituberculous medications in children are low, routine monitoring of liver function tests, blood counts, and serum uric acid is not indicated. In cases of disseminated disease or tuberculous meningitis, INH toxicity is increased, and therefore liver function tests should be monitored during the first few months of therapy. Liver function tests are also recommended if the patient has concomitant liver disease, clinical evidence of hepatotoxicity, or is taking high daily doses of INH and rifampin. 57,80

PREVENTION

To prevent TB in infants and children, screening and treatment of the adult population are important because children acquire their infection from adults. The optimal method of prevention is minimizing exposure. High-risk environments in which the child may be exposed to TB should be identified. These include urban dwelling, homelessness, poverty, contact with HIV-infected persons, relation to migrant workers, recent immigration, and being a foreign-born adoptee. The increased risk of TB in the HIV-infected population incurs an additional risk of transmission of TB to household members and nonintimate contacts. Approximately 30% of close contacts of HIV-infected persons with newly identified TB infection have positive skin test reactions indicative of infection, presumably acquired from the HIV-infected patient.20 Thus, emphasis must be placed on aggressive therapeutic intervention and INH prophylaxis in HIV-infected persons with latent tuberculous infection so as to prevent progression to tuberculous disease. 67 Chemoprophylaxis should also be considered for selected anergic HIVinfected patients who are at high risk to develop TB (that is, history of tuberculin skin positivity without previous therapy, chest radiograph

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abnormalities suggestive of previously untreated TB, and close contact with patients with TB).67 Tuberculin skin testing is the most effective means of identifying those at risk of TB. Routine tuberculin skin testing of children in low-risk groups is not recommended. They should be tested at age 12 to 15 months (before or at the time of MMR immunization), before school entry (4 to 6 years of age), and in adolescence (14 to 16 years of age). Children in high-risk populations such as lower socioeconomic groups; neighborhoods where the case rate is above the national average; children where parents have immigrated from high-risk areas of Asia, Africa, the Middle East, Latin America, or the Caribbean; children in households with cases of TB; and children with immunodeficiency, Hodgkin's lymphoma, diabetes mellitus, chronic renal failure, malnutrition, or drug-induced immunosuppression should be tested annually. Preventative treatment with INH is recommended for household contacts with an active TB case, infants and children with impaired immunity, and newborns whose mothers are newly diagnosed with TB but judged to be noncontagious. Preventative therapy with INH (10 mg/kg daily) alone should be given for 9 months. The exception is an HIV-infected person, for whom 12 months is recommended. Twice-weekly dosage (20 mg/kg with a maximum of 600 mg), directly observed, should be considered when compliance with daily treatment is in question. When INH resistance is a factor, rifampin should be given in addition to INH until sensitivities are obtained. If the organism from the source case is INH resistant, rifampin (10 to 15 mg/kg/ d) alone for 9 months is recommended. If partial INH resistance is demonstrated, both INH and rifampin should be given for 9 months. Although BCG vaccination has a variable efficacy in newborns and children, it should be considered in tuberculin-negative infants and children who are (1) in an intimate and prolonged exposure to persistently untreated or ineffectively treated adults with infectious pulmonary TB and cannot be placed on long-term preventative therapy, (2) continuously exposed to people with TB caused by bacteria resistant to INH and rifampin, and (3) living in a group that has a TB rate exceeding 1% per year and for whom the usual surveillance and treatment programs are not effective. Complications of BCG vaccination are relatively rare but are more prevalent in the immunodeficient population such as hypogammaglobulinemia, severe combined immunodeficiency, chronic granulomatous disease, cellular immunodeficiency, or HIV infection. At least 35 cases of fatal disseminated BCG infection have been reported, mainly in children less than 1 year of age. This is of particular concern given the increasing incidence of HIV in the population. The current recommendations of the World Health Organization are that BCG not be given to any symptomatic HIV-infected child. BCG should also not be given to asymptomatic HIV-infected children who reside in areas where the risk of TB is low. In areas where the risk of TB is high, however, BCG vaccination should be considered for asymptomatic HIV-infected children, because the risk

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from TB is greater than the risk of potential complications of BCG vaccination. 61 In the United States, where the risk of TB is still low, it is not recommended to vaccinate routinely asymptomatic HIV-infected children with BCG. References 1. Airede KI: Congenital miliary tuberculosis. Ann Trop Pediatr 10:363,1990 2. Aide SLM, Pinasco HM, Pelosi FR, et al: Evaluation of an enzyme-linked immunosorbent assay using an IgG antibody to Mycobacterium tuberculosis antigens in the diagnosis of active tuberculosis in children. Am Rev Respir Dis 139:748, 1989 3. American Thoracic Society: Pragnostic standards and classification of tuberculosis. Am Rev Respir Dis 142:725, 1990 4. American Thoracic Society: Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis 134:355, 1986 5. Andres Martin A, Gomez de Terreros I, Rodenas Luque G, et al: Congenital tuberculosis. An Esp Pediatr 32:357,1990 6. Anuntaseree W, Suntornlohanakul S, Mitarnun W: Disseminated tuberculosis in a 2month-old infant. Pediatr Pulmonol13:255, 1992 7. Arrizaga N, Burgos R, Gutierrez M: Congenital tuberculosis. Rev Chil Pediatr 60:290, 1989 8. Barnes PI, Block AB, Davidson PT, et al: Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 324:1644, 1991 9. Bate TW, Sinclair RE, Robinson MJ: Neonatal tuberculosis. Arch Dis Child 61:512,1986 10. Baumgartner W, van Calker H, Eisenberg W: Congenital tuberculosis. Monatsschr Kinderheilk 128:563,1980 11. Bishburg E, Sunderam G, Reichman LB, et al: Central nervous system tuberculosis with the acquired immunodeficiency syndrome and its related complex. Ann Intern Med 105:210, 1986 12. Braun MM, Byers RH, Heyward WL, et al: Acquired immunodeficiency syndrome and extrapulmonary tuberculosis in the United States. Arch Intern Med 150:1913, 1990 13. Braun MM, Truman BI, Maguire B, et al: Increasing incidence of tuberculosis in a prison inmate population. JAMA 261:393,1989 14. Brisson-Noel A, Gicquel B, Leossier D, et al: Rapid diagnosis of tuberculosis by amplification of mycobacterial DNA in clinical samples. Lancet 2:1069, 1989 15. CDC surveillance summaries. MMWR 40:585,1991 16. CDC surveillance summaries. MMWR 40:26, 1992 17. Chaisson RE, Slutkin G: Tuberculosis and human immunodeficiency virus infection. J Infect Dis 159:96, 1989 18. Ciesielski SD, Seed JR, Esposito DH, et al: The epidemiology of tuberculosis among North Carolina migrant farm workers. JAMA 265:1715,1991 19. Curless KG, Mitchell CD: Central nervous system tuberculosis in children. Pediatr Neurol 7:270,1991 20. Daley CL, Small PM, Schecter GF, et al: An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. N Engl J Med 326:231,1992 21. Dandapat Me, Mishra BM, Dash SP, et al: Peripheral lymph node tuberculosis: Review of 80 cases. Br J Surg 77:911,1990 22. Daniel TM, Debanne SM: The serodiagnosis of tuberculosis and other mycobacterial diseases by enzyme-linked immunosorbent assay. Am Rev Respir Dis 135:1137, 1987 23. De Angelis P, Gullace R, Antonelli P, et al: Congenital tuberculosis in twins. Pediatria 89:401,1981 24. de Blic J, Azevedo I, Burren CP, et al: The value of flexible bronchoscopy in childhood pulmonary tuberculosis. Chest 100:688, 1991 25. Eisenach KD, Cave MD, Bates JH, et al: Polymerase chain reaction amplification of a repetitive DNA sequence specific for Mycobacterium tuberculosis. J Infect Dis 161:977, 1990

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26. Eisenstein BJ: The polymerase chain reaction: A new method of using molecular genetics for medical diagnosis. N Engl J Med 322:178,1990 27. Fischl MA, Daikos GL, Hamchandani RB, et al: Clinical presentation and outcome of patients with HIV infection and tuberculosis caused by multiple-drug-resistant bacilli. Ann Intern Med 117:184, 1992 28. Geiseler pJ, Nelson KE, Crispen RG, et al: Tuberculosis in physicians: A continuing problem. Am Rev Respir Dis 133:773, 1986 29. Girgis NI, Farid Z, Kilpatrick ME, et al: Dexamethasone adjunctive treatment for tuberculosis meningitis. Pediatr Infect Dis J 10:179, 1991 30. Hageman J, Shulman S, Schreiber M, et al: Congenital tuberculosis: Critical reappraisal of clinical findings and diagnostic procedures. Pediatrics 66:980,1980 31. Hamadeh MA, Glassroth J: Tuberculosis and pregnancy. Chest 101:114, 1992 32. Heifets LB: Rapid automated methods (BACTEC system) in clinical microbiology. Semin Respir Infect 1:242,1986 33. Hudson FP: Clinical aspects of congenital tuberculosis. Arch Dis Child 31:136,1956 34. Hussey G, Chisholm T, KibeI M: Miliary tuberculosis in children: A review of 94 cases. Pediatr Infect Dis J 10:832, 1991 35. Kang GH, Chi JG: Congenital tuberculosis-report of an autopsy case. J Korean Med Sci 5:59,1990 36. Kennedy DH, Fallon RJ: Tuberculosis meningitis. JAMA 241:264, 1979 37. Klein NC, Duncanson FC, Lenox TH, et al: Use of mycobacterial smears in the diagnosis of pulmonary tuberculosis in AIDS/ARC patients. Chest 95:1190,1989 38. Lai KK, Stottmeier KD, Sherman IH, et al: Mycobacterial cervical lymphadenopathy: Relation of etiologic agents to age. JAMA 251:1286, 1984 39. Lake AM, Oski FA: Peripheral lymphadenopathy in childhood: Ten-year experience with excisional biopsy. Am J Dis Child 132:357, 1978 40. Lange WR, Warnock-Eckhart E, Bean ME: Mycobacterium tuberculosis infection in foreign born adoptees. Pediatr Infect Dis J 8:625, 1989 41. Leiguarda R, Berthier M, Starkstein S, et al: Ischemic infarction in 25 children with tuberculous meningitis. Stroke 19:200, 1988 42. Li CK, Chan YF, Har CM: Congenital tuberculosis. Aust Paediatr J 25:366,1989 43. Lincoln EM, Davis PA, Bovornkitti S: Tuberculous pleurisy with effusion in children. Am Rev Tuberc 77:271, 1958 44. Machin GA, Honore LH, Fanning EA, et al: Perina tally acquired neonatal tuberculosis: Report of two cases. Pediatr PathoI12:707, 1992 45. Majewska-Zalewska H, Kopytko E, Rudnik I: Seven-year follow-up of a child with the diagnosis of congenital tuberculosis. Pediatri Pol 58:895, 1983 46. McCray M, Esterly NB: Cutaneous eruptions in congenital tuberculosis. Arch Dermatol 117:460, 1981 47. Modilevsky T, Sattler FR, Barres PF: Mycobacterial disease in patients with human immunodeficiency virus infection. Arch Intern Med 149:2201, 1989 48. Molavi A, LeFrock JL: Tuberculous meningitis. Med Clin North Am 69:315, 1985 49. Moltesen B, Albertsen P, Viskum K, et al: Congenital tuberculosis. Ugeskr Laeger 154:2503, 1992 50. Morley JF: Congenital tuberculosis. Arch Dis Child 27:107,1952 51. Moss WJ, Dedyo T, Suarez M, et al: Tuberculosis in children infected with human immunodeficiency virus: A report of 5 cases. Pediatr Infect Dis J 11:114, 1992 52. Naranbhai RC, Mathiassen W, Malan AF: Congenital tuberculosis localized to the ear. Arch Dis Child 64:738, 1989 53. Nardell E, McInnis B, Thomas B, et al: Exogenous reinfection with tuberculosis in a shelter for the homeless. N Engl J Med 315:1570, 1986 54. Naughton E, Weindling AM, Newton R, et al: Tuberculosis meningitis in children. Lancet 2:973,1981 55. Nemir RL, O'Hare D: Congenital tuberculosis. Am J Dis Child 139:284, 1985 56. Nemir RL, O'Hare D: Tuberculosis in children 10 years of age and younger: Three decades of experience during the chemotherapeutic era. Pediatrics 88:236,1991 57. O'Brien RJ, Long MW, Cross FS, et al: Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis. Pediatrics 72:491, 1983 58. Pitchenik AE, Burr J, Suarez M, et al: Human T-celllymphotropic virus-III (HTLV-III)

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Address reprint requests to Elaine A. Rosenfeld, MD Division of Infectious Diseases Children's Memorial Hospital 2300 Children's Plaza Chicago, IL 60614