144: Tuberculosis

Tuberculosis (TB) is an infection caused by the organism Mycobacterium tuberculosis. TB is a global disease that has important implications for affected neonates who can acquire the disease in either the postnatal period or, more rarely, through congenital transmission from an infected mother.

The World Health Organization (WHO) estimates that there were 9.4 million incident and 14 million prevalent cases of TB in 2009. A total of 3.3 million (35%) of the new cases in 2009 occurred in women. The majority of incident cases in 2009 occurred in Asia (55%) and Africa (30%). An estimated 1.1 million (12%) of cases occurred in human immunodeficiency virus (HIV)–positive individuals. Approximately 1.7 million people died of TB in 2009. The Centers for Disease Control and Prevention (CDC) reports 11,545 incident cases of TB in the United States in 2009, with 59% of cases occurring in foreign-born individuals. Although the exact incidence of neonatal cases is unknown, <200 cases of congenital TB have been reported in the English literature.

M. tuberculosis is transmitted via inhalation of airborne droplet nuclei. Alveolar macrophages engulf M. tuberculosis, which then spreads through the lymphatic system to hilar lymph nodes. The infection can either be contained or lead to primary progressive TB. Granulomas containing the mycobacterium form via cell-mediated immunity within 2–8 weeks in most individuals. Infected macrophages interact with T lymphocytes to release cytokines that promote phagocytosis of M. tuberculosis and granuloma formation. Children under the age of 5 years and immunosuppressed individuals lack host immunity and therefore develop active primary progressive disease in the lung parenchyma and hilar lymph nodes. In these individuals, the characteristic fibrous granuloma capsule is disrupted, and liquefactive necrosis of the central caseous material occurs. The necrotic material can then flow into adjacent vasculature and disseminate systemically or to adjacent bronchi and spread externally via respiratory droplets. Immunosuppression and malnutrition are risk factors for reactivation of latent infection.

Vertical transmission to the fetus can occur hematogenously or transplacentally. Hematogenous spread results in lesions in the liver and periportal lymph nodes or lungs. The increase in oxygenation and circulation in the postnatal period activate the replication of the bacilli. M. tuberculosis has been identified in amniotic fluid, and transmission of TB can occur via aspiration of infected fluid.

The highest risk of transmission to newborns occurs via respiratory transmission from untreated mothers during the postnatal period. Maternal extrapulmonary TB, such as miliary TB or tuberculous endometritis, increases the risk of congenital infection. Maternal treatment for 2–3 weeks in the antenatal period reduces the risk of postnatal infection. HIV is a risk factor for maternal TB, which in turn increases the risk of mother to child transmission of HIV. Living in endemic areas or crowded conditions also increases the risk of TB.

1. Pregnancy. Pregnant women with TB tend to have fewer of the typical symptoms associated with TB. Active TB symptoms and signs include fever, cough, night sweats, anorexia, weight loss, general malaise, and weakness. Extrapulmonary TB can affect the genitourinary tract, bones and joints, meninges, lymph nodes, pleural lining, and peritoneum. Extrapulmonary TB is more common when there is coinfection with HIV. The natural history of TB is thought to be unaffected by pregnancy. Maternal TB, especially extrapulmonary disease, does increase pregnancy and perinatal complications such as preeclampsia, vaginal bleeding, early pregnancy loss, preterm labor, and low birthweight.

2. Neonatal period. Neonates with congenital infection can present with symptoms at any time from birth up to 4 months of age but usually present by the second or third week of life. As neonates tend to present with atypical signs, the diagnosis of TB must be considered in the differential diagnosis of other congenital infections (eg, syphilis, cytomegalovirus, toxoplasmosis) or neonatal sepsis. Congenital TB can present with hepatosplenomegaly, respiratory distress, fever, lymphadenopathy, abdominal distention, lethargy or irritability, ear discharge, and papular skin lesions. Less common symptoms and signs include vomiting, apnea, cyanosis, jaundice, seizures, and petechiae. The clinical presentation of infants <3 months with either congenital or postnatal acquired TB include respiratory signs such as cough, wheezing, tachypnea, stridor, and crepitations and are thought to result from obstruction of bronchi by enlarged hilar lymph nodes. Other signs include failure to thrive, hepatosplenomegaly, prolonged jaundice, meningitis, and cervical lymphadenopathy. Young infants are at increased risk for disseminated or miliary TB due to their immature immune systems. They are also at increased risk for meningeal presentations including meningoencephalitis, basal arachnoiditis, and intracranial tuberculomas. TB of the spine (Pott disease) has also been described in congenital infection. Clinical signs of congenital or postnatally acquired TB are typically occult and delayed in presentation because of the immaturity of the newborn and infant immune system. Only M. tuberculosis meningitis is known to present clinically as early as 2 weeks of age.

1. Clinical criteria. Congenital infection is diagnosed if the infant has the primary criteria and meets one of the secondary criteria for congenital TB (also known as Cantwell's criteria). Otherwise, postnatally acquired TB is diagnosed on the basis of known exposure and a proven tuberculous lesion as per Cantwell's secondary criteria.

   1. Primary criteria. The infant must have proven tuberculous lesions.

   2. Secondary criteria

      1. Lesions in the first week of life.

      2. A primary hepatic complex or caseating hepatic granulomas.

      3. Tuberculous infection of the placenta or the maternal genital tract.

      4. Exclusion of the possibility of postnatal transmission by a thorough investigation of contacts, including the infant's hospital attendants, and by adherence to existing recommendations for treating infants exposed to tuberculosis.

2. Acid-fast bacillus (AFB) smear and culture. M. tuberculosis can be identified by culture from the following specimens: gastric aspirates, sputum, bronchial washings, pleural fluid, cerebrospinal fluid (CSF), urine, or other body fluids. A biopsy specimen can also be obtained from lymph node, pleura, mesentery, liver, bone marrow, or other tissues. The best specimen in neonates and infants who may have an absent or nonproductive cough is an early-morning gastric aspirate, obtained by a nasogastric tube before feeding. Aspirates should be collected on 3 separate days. Gastric aspirates usually yield negative AFB smears, with an overall diagnostic yield of <50%. Fluorescent staining methods increase the sensitivity of gastric aspirates. The presence of nontuberculous mycobacteria can result in a false-positive smear. Liquid media culture facilitates growth of M. tuberculosis, which can take between 3 and 6 weeks to grow.

3. Polymerase chain reaction (PCR). PCR assays are currently available for AFB-positive respiratory tract specimens as well as any respiratory tract specimen, but they have low sensitivity with gastric aspirates, CSF, and tissue specimens. False-positive and false-negative results have also been reported.

4. Tuberculin skin testing (TST). A negative TST result should be considered unreliable in infants <3 months of age. The definition of a positive Mantoux skin test is as follows:

   1. Reaction ≥5 mm

      1. Infants in close contact with known or suspected infectious cases of TB

      2. Infants suspected to have TB disease based on clinical evidence or abnormal chest radiograph

      3. Infants with an immunosuppressive condition, including HIV or receiving immunosuppressive therapy

   2. Reaction ≥10 mm

      1. Age <4 years

      2. Medical risk factors such as chronic renal failure or malnutrition

      3. Increased environmental exposure

5. Chest radiograph. Although chest imaging may be normal early in the course of disease, most infants present with abnormal imaging findings, including miliary TB, multiple pulmonary nodules, lobar pneumonia, bronchopneumonia, interstitial pneumonia, and mediastinal adenopathy. The upper lobes and posterior lung segments are thought to be the most common sites for TB in infants.

6. Imaging. Other imaging modalities include abdominal sonography for hepatic involvement and thoracic computed tomography (CT) for adenopathies. Central nervous system (CNS) imaging includes ultrasonography, CT, and magnetic resonance imaging (MRI).

7. Laboratory markers. Increased blood leukocyte count with neutrophil predominance and elevation of C-reactive protein has been reported in congenital TB due to the inflammatory response associated with M. tuberculosis. Thrombocytopenia has also been observed, although it is a nonspecific finding.

8. CSF. A lumbar puncture should promptly be performed when congenital or postnatally acquired TB is suspected. CSF findings can include lymphocytic pleocytosis, increased protein levels, and decreased CSF/serum glucose ratio.

9. HIV testing. All individuals with TB should be evaluated for HIV infection due to the increased incidence of TB coinfection.

10. Placental pathology. The placenta may demonstrate evidence of granulomas, and an AFB smear and culture should be sent from a specimen of suspected congenital tuberculosis.

1. Antimicrobial therapy during pregnancy

   1. Latent infection. The CDC recommends deferring treatment of pregnant women with latent infection until the postpartum period except in high-risk situations. Isoniazid therapy for 9 months should be considered for latent TB (positive TST and normal chest radiographic findings) in pregnant women with HIV, recent contagious contact, and skin test conversion within the prior 2 years. Pyridoxine supplementation should be administered for the duration of pregnancy and breast-feeding.

   2. Active infection. The CDC recommends an initial treatment regimen with isoniazid, rifampin, and ethambutol for 2 months, followed by isoniazid and rifampin for a total of 9 months. Isoniazid, rifampin, and ethambutol are considered relatively safe for the fetus. Streptomycin should not be administered to the mother due to ototoxic effects in the fetus. Although pyrazinamide is used in some regiments, its safety during pregnancy has not been established.

2. Antimicrobial therapy during the neonatal period

   1. Active maternal and congenital or neonatal acquired infection. In cases in which the maternal physical examination and chest radiographic findings are diagnostic of active TB, the infant should be treated promptly with isoniazid, rifampin, pyrazinamide, and an aminoglycoside such as amikacin. Pyridoxine supplementation in infants receiving isoniazid therapy is recommended in the following instances: exclusively breast-fed infants, malnourished infants, and those with symptomatic HIV infection. Hepatotoxic effects of isoniazid therapy are rare but can be life-threatening.

   2. Active maternal infection without congenital infection. If the mother has active TB disease but the neonate is not affected, isoniazid should be given until 3 or 4 months of age. If a negative TST result is obtained at the end of therapy and the mother demonstrates successful response to therapy, the infant's isoniazid can be discontinued. A positive TST at 3–4 months of age necessitates a reevaluation for TB disease in the infant and continued isoniazid therapy for a total of 9 months with monthly evaluation.

   3. Latent maternal infection. Neonatal evaluation and therapy are not required in cases where the mother is asymptomatic and is diagnosed with latent TB infection.

   4. Postnatal TB infection. For infants with pulmonary disease, pulmonary disease with hilar adenopathy, and hilar adenopathy disease, a 6-month 4-drug regimen is recommended as follows: isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months followed by isoniazid and rifampin for 4 months. The duration of therapy is extended to 9 months if there is evidence of cavitary pulmonary lesions or sputum culture remains positive after 2 months of therapy. The risks and benefits of using ethambutol in infants need to be considered due to a dose and duration dependent risk of optic neuritis. An infectious disease consultation is essential for managing infants who are coinfected with HIV due to drug interactions and overlapping drug toxicities, especially between antiretrovirals and rifampin.

   5. Extrapulmonary TB. For tuberculous meningitis, treatment is initiated with isoniazid, rifampin, pyrazinamide, and ethambutol/aminoglycoside. Pyrazinamide is given for a total of 2 months, and isoniazid and rifampin are given for a total of 9–12 months. Ethambutol or aminoglycoside is discontinued after drug susceptibility is established. Corticosteroids should be added in confirmed cases of TB meningitis as they reduce mortality rates and long-term neurologic impairment. A regimen of isoniazid, rifampin, pyrazinamide, and streptomycin for 1–2 months, followed by isoniazid and rifampin for another 10 months, is recommended for skeletal and miliary TB. Corticosteroids can also be considered for pleural and pericardial effusions, severe miliary disease, endobronchial disease, and abdominal tuberculosis. Surgical therapy for lymphadenitis, bone and joint abscesses, and hydrocephalus complicating CNS disease may be indicated.

3. Isolation precautions/breast-feeding

   1. Maternal latent infection. No separation or restrictions on breast-feeding are required.

   2. Maternal active disease. In suspected or proven cases of maternal TB, the mother and infant should be separated pending evaluation and appropriate maternal and infant therapy. Separation is not necessary once the infant begins isoniazid; the mother adheres to treatment, wears a mask, and follows infection control measures. In cases of multidrug-resistant TB or maternal nonadherence to therapy, the infant should be separated, and bacille Calmette-Guerin (BCG) vaccine should be considered in consultation with an infectious disease specialist. Breast-feeding restrictions can be removed after the mother has been treated appropriately for ≥2 weeks and is not considered contagious.

4. Hospital control measures. Restriction to an airborne infection isolation room is indicated in the following cases: neonates with congenital or acquired TB undergoing manipulation of the oropharyngeal airway, infants with cavitary lesions, positive sputum AFB smears, and laryngeal or extensive pulmonary involvement. Nosocomial transmission from infants to health care workers and between infants via contaminated respiratory equipment has been reported.

5. Prevention. The BCG vaccine contains a live attenuated strain of Mycobacterium bovis. The WHO recommends that a single dose of BCG vaccine should be given to all infants soon after birth in countries with a high TB burden. BCG vaccine should not be given to symptomatic HIV-positive or immunosuppressed infants. If the neonate is exposed to smear-positive pulmonary TB shortly after birth, BCG vaccine should be delayed pending completion of isoniazid therapy. The CDC does not recommend routine use of BCG vaccine in the United States due to the low burden of disease and interference of the vaccine with TST reactivity.

Information on prognostic factors are not well defined for infants of either congenital or acquired disease. Survival rate is not influenced by the following factors: specific signs or symptoms, birthweight, the nature or severity of maternal disease, timing of maternal diagnosis, prematurity, hepatic dysfunction, or thrombocytopenia. An improved survival rate was seen in all infants with the following: presentation of symptoms after 3 weeks of age, no CNS TB disease, appropriate anti-TB therapy, higher leukocyte count, absence of a military pattern on chest radiographs, and multiple pulmonary nodules on chest radiograph.