From Seminars in Respiratory and Critical Care Medicine

Tuberculosis in Children
Posted 08/27/2004

Jeffrey R. Starke, M.D.

Abstract and Introduction

Abstract

The natural history and clinical expression of infection due to Mycobacterium tuberculosis
differ substantially in children compared with adults. The natural history depends upon the
age at infection and the host immune status. Children infected prior to age 4 have a very high
rate of developing immediate clinical or radiographic manifestations or both, but are unlikely
to develop reactivation disease in adulthood. In contrast, children infected in preadolescence
or adolescence are more prone to developing more severe adult-type pulmonary tuberculosis
soon after infection or in adulthood. It is difficult to confirm the diagnosis of tuberculosis by
current microbiological methods. Even in industrialized countries, the triad of a positive
tuberculin skin test, radiographic and/or clinical manifestations consistent with tuberculosis,
and establishing a recent link to a known infectious case of tuberculosis is the "gold standard"
for diagnosis. Children with tuberculosis respond well to and tolerate the same basic
treatment regimens as used for adults. Some prevention of childhood tuberculosis can be
achieved by the use of the bacille Calmette-Gurin (BCG) vaccines, but the use of
chemotherapy to treat recent tuberculosis infection, discovered via contact tracing, is of
paramount importance even when BCG vaccines are used.

Introduction

Tuberculosis remains one of the major diseases afflicting children throughout the world.
Although the exact number of annual cases of childhood tuberculosis is unknown, the World
Health Organization (WHO) has estimated approximately 1 million new cases and 400,000
deaths per year in children due to tuberculosis.[1] Many of these cases go undiagnosed and
untreated and many of these children could be salvaged if there were improvements in
diagnosis and treatment available for children.

Many experts in childhood tuberculosis feel that children have been neglected in the
worldwide effort to control tuberculosis. There are many reasons for this including the fact that
most children with tuberculosis are not infectious and therefore not considered to be as
important as adults with contagious tuberculosis, the frustration at the difficulty in establishing
a microbiological diagnosis of tuberculosis in children, and the relative neglect of pediatricians
and researchers in studying childhood tuberculosis.[2] In fact, there is a rich scientific literature
about childhood tuberculosis supporting simple practices, which, if adequately put into place,
would greatly improve the ability to diagnose and treat children with tuberculosis.

A comprehensive description of childhood tuberculosis is beyond the scope of this article.

Instead, this article concentrates on the special aspects of tuberculosis diagnosis, treatment,
and control that are particularly salient to the study of childhood tuberculosis.

Natural History and Pathophysiology

Virtually all transmission of Mycobacterium tuberculosis is from person to person, usually by

mucous droplets that become airborne when the ill individual coughs, sneezes, laughs, sings,
or even breathes.[3] Infectiousness is related to certain characteristics of the person with
tuberculosis and to specific environmental factors such as poor circulation of air. The exact
number of organisms required to infect a child is unknown but is probably small, based on
animal experiments. Unlike adults, the vast majority of children with tuberculosis are not
infectious to others.[4] In the early 1900s, several studies from European orphanages showed
that when an adult in the orphanage had tuberculosis, many of the children developed
tuberculosis as well; however, when only a child had tuberculosis, none of the other children
developed the disease.[5] Subsequent studies from children's hospitals and other
environments where children are separated from the adult from whom they acquired the
organism have shown that most children with the classic forms of childhood tuberculosis are
not infectious to others.[6-8] However, those children who develop the adult type of tuberculosis,
including upper lobe infiltrates or cavities, and, particularly, having a positive acid-fast smear
of the sputum, can be infectious to others.[9] The age of the child is not relevant; it is the type
of disease the child develops that is important. It is rare for children < 10 years of age to
develop the adult type of tuberculosis, but those children of any age with extensive infiltrates,
sputum production, or cavity on chest x-ray should be isolated when in health care facilities
until it can be determined that they are not infectious. [10,11] Because most children who develop
tuberculosis disease do so within a few months of acquiring the infection, one should be sure
that the adults accompanying the child are not the source of the child's infection by
performing chest radiographs on them.[4,12]

It is commonly asked why young children with the childhood type of tuberculosis are not
infectious. Many children with tuberculosis do not have significant cough. When cough is
present children rarely produce sputum. Even when sputum is produced, organisms are
sparse because they are in low concentration in the endobronchial secretions of children. In
addition, young children lack tussive force necessary to suspend infectious particles of the
correct size in the air.

The portal of entry for M. tuberculosis for almost all children is the respiratory tract. Ingestion
of milk laden with bovine tuberculosis can lead to a gastrointestinal primary lesion. Rarely,
infection of the skin or mucous membrane can occur through an abrasion, cut, or insect bite.

The tubercle bacilli multiply initially within the alveoli and alveolar ducts. Some of the bacilli
are ingested but not killed by macrophages that carry the organisms through lymphatic
channels to the regional lymph nodes. The major groups of lymph nodes involved in children
are in the hilar region, although paratracheal and subcarinal nodes also may be involved,
depending upon where the organisms lodge in the lung. [13]

As with adults, the incubation period between the time the tubercle bacilli are inhaled and the
development of delayed hypersensitivity is usually between 3 and 12 weeks, most often, 4 to
8 weeks. Some children experience a febrile illness that lasts from 1 to 3 weeks when
hypersensitivity first develops. These children may have mild cough and other respiratory
symptoms. The primary complex of tuberculosis consists of local reaction in the parenchyma
of the lung where the organisms lodge and the inflammatory reaction of the associated lymph
nodes.[14] In most cases, the parenchymal portion of the primary complex heals completely by
fibrosis and is of no clinical significance. Occasionally, the parenchymal lesion continues to
enlarge resulting in focal pneumonitis and thickening of the overlying pleura. The foci in the
regional lymph nodes develop some fibrosis but healing is usually less complete than in the
parenchymal lesion. M. tuberculosis may persist for decades after fibrosis or calcification of
the lymph nodes.

In most cases of initial tuberculosis infection, the child develops a positive tuberculin skin test,
but the lymph nodes remain normal in size, the lung parenchymal lesion is not visible on
chest x-ray, and the child has no symptoms and no complications. This stage is called
tuberculosis infection and most children have a normal chest radiograph. Occasionally, the
child will have evidence of fibrosis or calcification in the parenchyma or lymph node foci or
both. However, in some children, the lymph nodes become enlarged by the host inflammatory
reaction. These lymph nodes then encroach on the regional bronchus. Partial obstruction
caused by external compression may lead at first to hyperinflation in the distal lung segment.
This compression occasionally causes complete obstruction of the bronchus resulting in
atelectasis of the lung segment. More often, inflamed caseous nodes attach to the bronchial
wall and erode through it, leading to endobronchial tuberculosis and a fistulous tract. [15] The
extrusion of infected caseous material into the bronchus transmits infection to the lung
parenchyma causing bronchial obstruction and further atelectasis. The resulting lesion, which
is a combination of the pneumonitis and atelectasis, is often referred to as a collapse-
consolidation or segmental lesion. If the subcarinal nodes are involved, the enlargement may
cause invasion of adjacent structures such as the pericardium or esophagus, resulting in
pericarditis or a tracheoesophageal fistula, respectively.

During the development of the parenchymal and lymph node lesions, tubercle bacilli from the
primary complex spread via the bloodstream and lymphatics to many parts of the body. Sites
that are most commonly seeded are the apices of the lungs, liver, spleen, meninges,
peritoneum, lymph nodes, pleura, and bone. This dissemination can involve either large
numbers of bacilli, which leads to disseminated tuberculosis, or small numbers of bacilli that
create microscopic tuberculous foci scattered in the tissues. Initially, these metastatic foci are
clinically inapparent but they can be the origin of both extrapulmonary tuberculosis or
reactivation pulmonary tuberculosis in later life.

The fairly predictable time table for the events and complications of primary tuberculosis
infection in infants and children is shown in Figure 1. [16] Massive lymphohematogenous
dissemination leading to miliary or disseminated disease occurs in only 0.5 to 2% of infected
children but occurs early after the initial infection. Clinically significant lymph node or lung
tuberculosis usually appears within 3 to 9 months. However, lesions in bones and joints and
kidneys take much longer to develop, often several years after the infection first occurs. In
summary, the vast majority of cases of tuberculosis in children occur within 1 year of the
infection, meaning that tuberculosis disease in a child is a marker of the recent transmission
of the organism.

Epidemiology

Between 1953 and 1980, childhood tuberculosis rates in the United States declined ~8% per
year.[17] Between 1980 and 1987, the case rates remained flat but they began to increase in
1988. Between 1988 and 1993 there was a 40% increase in the reported cases of
tuberculosis in children < 15 years of age.[18] In general, pediatric tuberculosis case rates tend
to mirror case rates in adults because children develop disease soon after acquiring the
infection. Many experts point to four major causes of the so-called resurgence of tuberculosis
in the United States in the late 1980s and early 1990s: (1) increase in human
immunodeficiency virus (HIV) infection with associated tuberculosis, [19] (2) increase in legal
immigration with a subsequent increase in the pool of infected individuals and cases of
tuberculosis disease,[20] (3) increased rates of tuberculosis in congregate settings, [21,22] and (4)
poor tuberculosis control efforts due mostly to diminished health department budgets. [23,24] Of
these four, the problems in tuberculosis control had the greatest impact on the increase of
childhood tuberculosis case rates in the United States.

Age is an important aspect of the epidemiology of childhood tuberculosis. About 60% of

tuberculosis cases in children in the United States occur in infants and children < 5 years of
age.[25] Between 5 and 14 years has often been called the "favored age" because children in
this range have the lowest rates of tuberculosis disease in virtually every population. The
rates of tuberculosis disease begin to increase again in late childhood and adolescence,
particularly for girls. The gender ratio for tuberculosis in children is ~1:1 in contrast to adults in
whom males predominate.

Childhood tuberculosis case rates in the United States are strikingly higher among ethnic and
racial minority groups and the foreign born than in U.S.-born whites. [18] Approximately 85% of
childhood tuberculosis occurs in African American, Hispanic, Asian, and Native American
children, reflecting the risk of transmission within the living conditions of these children. As
with adults, the proportion of childhood tuberculosis cases in the United States occurring
among foreign born children is increasing, but the rates are about half those noted for adults.
[20]

Most children are infected with M. tuberculosis in the home, but outbreaks of childhood
tuberculosis centered in elementary and high schools, nursery schools, family daycare
homes, and churches still occur.[9,26-28] In most cases, a high risk adult working in the area has
been the source of the outbreak. The recent epidemic of HIV infection has had a profound
affect on the epidemiology of tuberculosis among children as a result of two mechanisms: [29,30]
(1) HIV-infected adults with tuberculosis may transmit M. tuberculosis to children, some of
whom will develop tuberculosis disease, (2) children with HIV infection may be at increased
risk of progressing from tuberculosis infection to disease. In the United States, the former
mechanism is the most important,[31] but in areas of the world where HIV infection is rampant,
such as sub-Saharan Africa, the second mechanism is at least as important. Tuberculosis
may be underdiagnosed among HIV-infected children because of its similarity in clinical
presentation to other opportunistic infections common in acquired immunodeficiency
syndrome (AIDS) and the difficulty confirming the diagnosis with positive cultures. One recent
study from Africa showed tuberculosis to be the second most common pulmonary finding in
autopsies of children who died during hospitalization.

In developing countries, tuberculosis infection rates among the young population can average
20% to 50%. In most children in the United States, the rate of tuberculosis infection is < 1%,
but in some urban populations the risk is much higher. One 1990 study of Boston public
schools showed that 5.1% of seventh graders and 8.9% of tenth graders had a positive
tuberculin skin test.[32] Several other surveys in large American cities have consistently shown
tuberculosis infection rates of 2 to 5% in elementary schoolchildren.

There is little accurate information about the epidemiology of childhood tuberculosis in most
parts of the world, particularly in developing nations where tuberculosis rates are the highest.
In most of these countries, the major method of diagnosing tuberculosis in adults is by sputum
microscopy; however, very few children and almost no infants produce sputum in which
organisms can be viewed. As a result, tuberculosis in children is vastly underreported and
many children die without being diagnosed or treated.

Clinical, Radiographic, and Laboratory Findings

The majority of children with tuberculosis infection develop no signs nor symptoms at any
time. Occasionally, the initiation of the infection is marked by several days of low grade fever
and mild cough. Rarely, the child experiences a clinically significant disease with high fever,
cough, malaise, and flulike symptoms that resolve within a week. Most children who develop
tuberculosis disease experience pulmonary manifestations, but ~25 to 35 percent of children
have an extrapulmonary presentation.[18] The most common extrapulmonary form of
tuberculosis is lymphatic disease accounting for about two thirds of cases of extrapulmonary
tuberculosis. However, the second most common form is meningeal disease occurring in 13%
of patients and, historically, occurring in three out of a thousand untreated tuberculosis
infections in children < 5 years of age.

Pulmonary Disease

The symptoms and physical signs of intrathoracic tuberculosis in children are often
surprisingly meager considering the degree of radiographic changes observed. [33] The physical
manifestations of disease tend to differ by the age of onset. Young infants and adolescents
are more likely to have significant signs or symptoms, whereas school-age children often
have clinically silent disease.[34,35] More than one half of infants and young children with
radiographically moderate to severe pulmonary tuberculosis have no symptoms nor physical
findings and, in the United States, are discovered mainly by contact tracing of an adult with
pulmonary tuberculosis.[36] Infants are more likely to experience signs and symptoms, probably
because of their small airway diameters relative to the parenchymal and lymph node
changes. 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 failure-to-thrive presentation that may
not improve significantly until after several months of treatment. Pulmonary signs are even
less common. Some infants and young children with bronchial obstruction show signs of air
trapping, such as localized wheezing or decreased breath sounds that may be accompanied
by tachypnea or, rarely, respiratory distress. Occasionally, these nonspecific symptoms and
signs are alleviated by antibiotics, suggesting that bacterial superinfection distal to the focus
of tuberculosis contributed to the clinical presentation.

In childhood pulmonary tuberculosis, the radiographic hallmark is the relatively large size and
importance of lymphadenopathy compared with the less significant size of the parenchymal
focus.[13,15] Adenopathy is invariably present with childhood tuberculosis but may not be
discerned by a plain radiograph when other pulmonary findings are present. [37] In most cases
of pulmonary tuberculosis in children, the mild parenchymal infiltrate and lymphadenopathy
resolve spontaneously, the chest radiograph remains normal, and the child is asymptomatic.
In some children, the hilar and mediastinal lymph nodes continue to enlarge and are readily
visible on chest radiograph. Partial bronchial obstruction caused by external compression
from the enlarging nodes can cause air trapping, hyperinflation, and even emphysema. As the
nodes attach to and infiltrate the bronchial wall, caseum fills the lumen causing complete
obstruction. This results in atelectasis that usually involves the lobar segment distal to the
obstructed lumen. The resulting radiographic shadows are usually called collapse-
consolidation or segmental lesions (Fig. 2). These findings are similar to those caused by
aspiration of a foreign body; in essence, the lymph node is acting as the foreign body. Multiple
segmental lesions in different lobes may be apparent in 25% of children. [38]
Other radiographic findings occur in some patients. Occasionally, children have a picture of
lobar pneumonia without impressive lymphadenopathy. If the infection is progressively
destructive, liquefaction of the lung parenchyma leads to formation of a thin-walled primary
tuberculous cavity.[39] Rarely, bullous lesions occur in the lungs leading to pneumothorax. [40]
Enlargement of the subcarinal lymph nodes causes compression of the esophagus, and
rarely, bronchoesophageal fistula. A sign of subcarinal tuberculosis is horizontal splaying of
the mainstem bronchi.

Older children and adolescents can develop the more typical adult type reactivation
tuberculosis.[41-43] They are more likely to experience the classic symptoms of fever, anorexia,
malaise, weight loss, night sweats, productive cough, chest pain, and hemoptysis than
younger children. However, findings on physical examination are usually minor or absent
even when cavities or large infiltrates are present. Most signs and symptoms improve within
several weeks of starting effective treatment although cough may last for several months. In
these cases, the chest radiograph appearance is that typically seen in adults with a
predominance of upper lobe infiltrates with or without cavitation. Some adolescents get a
somewhat peculiar form of tuberculosis resulting in necrotizing pneumonitis. In these cases, it
can be difficult to establish the diagnosis of tuberculosis because the sputum is often devoid
of organisms; in my experience, open lung biopsy has been required in several cases to
establish the correct diagnosis.

Extrapulmonary Tuberculosis

A complete review of extrapulmonary tuberculosis in children is beyond the scope of this

monograph. For most forms of extrapulmonary tuberculosis, the clinical presentation is similar
in children to that in adults. However, there are two forms of extrapulmonary tuberculosis that
are common in children and merit special attention. The first is lymphohematogenous
disease.[44] Tubercle bacilli are disseminated to distant sites in all cases of tuberculosis
infection. This dissemination is clinically silent in most cases but can be the origin of miliary
tuberculosis or extrapulmonary tuberculosis in the immediate or distant future. Other patients
experience protracted hematogenous tuberculosis caused by an 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 fevers accompanying the release of organisms into the bloodstream. Multiple organ
involvement is common leading to hepatomegaly, splenomegaly, and lymphadenitis in
superficial or deep nodes. Early pulmonary involvement is surprisingly mild, but diffuse lung
involvement becomes apparent if treatment is not given promptly. Culture confirmation of this
form of tuberculosis can be difficult, often requiring sampling of the bone marrow or liver
biopsy with the appropriate stains and cultures.

The most common 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 two or more organs.[45-47] Miliary tuberculosis usually occurs early after the
infection, within the first 2 to 6 months. The clinical manifestations of miliary tuberculosis are
protean, depending on the load of organisms and where they lodge. Lesions are usually
larger and more numerous in the lungs, spleen, and bone marrow than other organs. This
form of tuberculosis is most common in infants and in malnourished or immunosuppressed
patients. The onset of clinical disease is sometimes explosive and the patient may become
gravely ill in several days. More often, the onset is insidious; the patient may not be able to
pinpoint accurately the time of onset of the initial symptoms. Early systemic signs include
malaise, anorexia, weight loss, and low grade fever. Within several weeks
hepatosplenomegaly and generalized lymphadenopathy develop in about one half of cases.
About this time, the fever may become higher and more sustained although the chest
radiograph usually remains normal and respiratory symptoms are few. Within several weeks,
the lungs become filled with tubercles, and dyspnea, cough, rales, or wheezing occur. [48] As
the pulmonary disease progresses, an alveolar air block syndrome may result in respiratory
distress, hypoxia, and pneumothorax or pneumomediastinum. Signs or symptoms of
meningitis or peritonitis are found in 20 to 40% of patients with advanced disease. Cutaneous
lesions such as papulonecrotic tuberculosis often appear in crops. [49] Choroid tubercles occur
in 13% to 87% of patients and are highly specific for tuberculosis.

The second form of extrapulmonary tuberculosis that is particularly common among children
is tuberculosis of the central nervous system, most commonly meningitis. [50-54] Tuberculous
meningitis is the most serious complication in children and is uniformly fatal without treatment.
The brain stem is the most common focus; cranial nerves III, VI, and VII are frequently
involved.[55] The condition arises from the formation of a metastatic caseous lesion in the
cerebral cortex or meninges that develops during the occult dissemination of the primary
infection. This lesion, called a Rich focus, increases in size and discharges small numbers of
tubercle bacilli into the subarachnoid space.[55] The resulting gelatinous exudate may infiltrate
the cortical or meningeal blood vessels producing inflammation, obstruction, and infarction of
the cerebral cortex. The exudate also interferes with the normal flow of cerebrospinal fluid
(CSF) in and out of the ventricular system at the level of the basal cisterns leading to a
communicating hydrocephalus. The combination of vasculitis, infarction, cerebral edema, and
hydrocephalus results in this severe damage that can occur gradually or rapidly.

The clinical progression of tuberculous meningitis may be rapid or gradual. Rapid progression
tends to occur more often in infants who may experience symptoms for only several days
before the onset of acute hydrocephalus, seizures, or cerebral edema. More often, the signs
and symptoms progress slowly over several weeks and can be divided into three general
stages. The first stage, which typically lasts 1 to 2 weeks, is characterized by nonspecific
symptoms such as fever, headache, irritability, drowsiness, and malaise. Focal neurological
signs are absent but infants may experience stagnation or loss of developmental milestones.
The second stage often begins abruptly with lethargy, nuchal rigidity, and Kernig's or
Brudzinski's signs, seizures, hypertonia, vomiting, cranial nerve palsies, and other focal
neurological signs. This clinical picture usually correlates with the development of
hydrocephalus, increased intracranial pressure, and vasculitis. The third stage is marked by
coma, hemiplegia or paraplegia, hypertension, decerebrate posturing, deterioration in vital
signs, and, eventually, death. The prognosis of tuberculous meningitits correlates most closely
with the clinical stage of illness at the time antituberculosis chemotherapy begins. [56] The
majority of patients in the first stage have an excellent outcome, whereas most patients in the
third stage who survive have permanent disabilities including blindness, deafness, paraplegia,
and mental retardation.[57]

Laboratory Evaluation

General laboratory tests such as a complete blood count and cell differential are usually
normal in children with tuberculosis. When pleural tuberculosis is present, pleural fluid is
usually yellow and occasionally tinged with blood.[58,59] The chemistry results are indicative of a
mild exudate; specific gravity is usually 1.012 to 1.025, the protein level is usually 2 to 4 g/dL,
and the glucose may be low, although it is often in the low-normal range (20-40 mg/dL). Most
typically, there are several hundred to several thousand white blood cells/mm 3 with an early
predominance of polymorphonuclear cells followed by a high proportion of lymphocytes. Acid-
fast smears of the fluid are usually negative because of the relative paucity of organisms.
Cultures are positive in only 30 to 70% of cases.[60] Biopsy of the pleura is more likely to yield
a positive acid-fast stain or culture, and evidence of granuloma formation can be
demonstrated.

In cases of tuberculous meningitis, the CSF leukocyte count usually ranges from 10 to 500
cells/mm3 but occasionally is higher.[50] Lymphocytes usually predominate but there may be
more leukocytes initially. The CSF glucose level is typically < 40 mg/dL but rarely goes below
20 mg/dL. The protein level is elevated and may be markedly high (400-5000 mg/dL)
secondary to hydrocephalus and spinal block. The success of microscopic examination of an
acid-fast stain of CSF and mycobacterial culture is directly related to the amount of CSF
sampled. When 5 to 10 mL of lumbar CSF is obtained, the acid-fast stain of the CSF sediment
is positive in up to 30% of cases and the culture is positive in 70%.

The most important laboratory test for the diagnosis and management of tuberculosis in
adults is the acid-fast stain and culture of sputum.[61] The best culture specimen for pulmonary
tuberculosis in the child is the early morning gastric aspirate obtained before the child has
arisen and peristalsis has emptied the stomach of the pooled secretions that have been
swallowed overnight.[62] Unfortunately, even under optimum conditions, three gastric aspirates
yield M. tuberculosis in < 50% of cases; negative cultures never exclude the diagnosis of
tuberculosis in a child. The yield from flexible bronchoscopy is less than from properly
obtained gastric aspirates. Unfortunately, the acid-fast stain of either sputum or gastric
contents in small children is positive in < 10% of cases. Bronchial secretions obtained by
stimulating cough with an aerosol solution can be used for culture in older children. [63,64]
Fortunately, the need for culture confirmation is usually low. If the child has a positive
tuberculin skin test, clinical or radiographic findings suggestive of tuberculosis, and known
contact with an adult case of tuberculosis, the child should be treated for tuberculosis
disease. The drug susceptibility test results from the adult case can be used to determine the
best therapeutic regimen for the child. Although the polymerase chain reaction (PCR) to
amplify DNA sequences specificfor M. tuberculosis has been applied to children, the yield is
not much greater than from culture and the specificity is low enough that false-positive results
do occur.[65-68] In general, PCR may be an aid in the diagnosis of extrapulmonary tuberculosis.
[69-71]

Treatment

The same general principles that apply to the treatment of tuberculosis in adults also apply to
children (Table 1). However, children, in general, have smaller mycobacterial loads than
adults and the risk of developing secondary drug resistance is less in children. Of course,
children or adolescents who develop the adult type of pulmonary tuberculosis, with a cavity or
extensive infiltrate in the upper lobes, have a large burden of organisms and a higher
propensity to develop drug resistance while on treatment.

Historically, recommendations for treating children with tuberculosis have been extrapolated
from clinical trials of adults with pulmonary tuberculosis. [72] However, over the past 2 decades,
over a dozen studies and clinical trials of treatment of tuberculosis in children have been
published.[73-86] These trials have shown that the basic regimen of 6 months of isoniazid and
rifampin, supplemented during the first 2 months with pyrazinamide, cures over 99% of cases
of drug-susceptible pulmonary tuberculosis in children, with an incidence of clinically
significant adverse reactions of < 2%. Although a short period of daily administration of
medications (the first 2-6 weeks) may be desirable, several studies have shown that giving
two or three times per week intermittent treatment from the very beginning is effective in the
vast majority of cases of pulmonary tuberculosis in children. [78,81,83] Several studies have shown
that regimens containing only isoniazid and rifampin for 6 to 9 months are effective in some of
the milder forms of pulmonary tuberculosis in children,[85,86] but most experts feel that the
additional use of pyrazinamide in the initial phase is warranted in case the child absconds
from treatment early. Many adults with tuberculosis are routinely given four drugs as initial
therapy, with ethambutol being the most common fourth drug. However, in small children,
addition of extra drugs leads to problems with tolerance, especially because there are few
pediatric dosage forms available, and treatment involves the crushing of pills or creation of
suspensions that are difficult to administer. Because of this, most experts in the United States
initially start three drugs in children and add a fourth drug only if there is increased risk of drug
resistance because of epidemiologic characteristics of the child or the adult source case, or if
the child has a life-threatening form of tuberculosis such as meningitis or disseminated
disease. There are a few case series of treatment of tuberculous meningitis in children; most
experts recommend a minimum of 6 months of treatment but many extend treatment to 9 or
even 12 months.[87,88] Currently, the recommendations for treatment of HIV-infected children
with tuberculosis are the same as those for children without HIV infection, but some experts
always extend treatment to at least 9 months in HIV-infected children. There are no published
clinical trials comparing one regimen or one length of therapy to another in HIV-infected
children.

There is little information published about the treatment of drug-resistant tuberculosis in

children.[89,90] Again, the principles are similar to those used to treat adults with drug-resistant
tuberculosis. At least two bactericidal drugs must be used and the complete regimen usually
includes at least three drugs for cases of isoniazid-resistant tuberculosis (most commonly
rifampin, pyrazinamide, and ethambutol) and at least four drugs and usually five or six for
cases of multi-drug-resistant tuberculosis. Patterns of drug resistance among children tend to
mirror those found among adults in the same population. [91] However, because the organism is
isolated from, at best, 40% of children with tuberculosis, it is imperative to try to link a child
with tuberculosis to the adult from whom the child acquired the organism so that that adult
isolate's susceptibility tests can be used to correctly treat the child.

Corticosteroids are useful in the treatment of some children with tuberculosis under the cover
of effective antituberculosis drugs and probably are used more commonly for children than
adults with tuberculosis.[92] The most commonly prescribed regimen is prednisone 1 to 2
mg/kg/day for 4 to 6 weeks with gradual tapering. Corticosteroids are beneficial when the host
inflammatory reaction contributes significantly to tissue damage or impairment of organ
function. Evidence is convincing that corticosteroids decrease mortality rates and long-term
neurological sequelae in patients with tuberculous meningitis. [93,94] Short courses of
corticosteroids also may be effective for children with enlarged hilar lymph nodes that
compress the tracheal bronchial tree causing respiratory distress, localized emphysema, or
severe segmental pulmonary disease.[95] Several clinical trials have shown that corticosteroids
can help relieve symptoms and tamponade associated with tuberculous pericardial effusion in
children.[96-98]

The treatment of children with asymptomatic tuberculosis infection to prevent the

development of tuberculosis disease is an established practice. [99-101] During the 1950s, the
U.S. Public Health Service conducted placebo-controlled trials of 1 year daily isoniazid
therapy with more than 125,000 subjects, many of whom were children. These trials
demonstrated a reduction in the incidence of subsequent tuberculosis in children with good
adherence of more than 90%. The effectiveness of isoniazid therapy in children has
approached 100% and lasted for at least 30 years in other studies. [100] Isoniazid therapy is
clearly indicated for children with tuberculosis infection with no clinical or radiographic
evidence of disease. A chest radiograph that shows only a granuloma or a small fibrotic lesion
constitutes infection and the child should be treated accordingly. The currently recommended
length of therapy for children is 9 months and the isoniazid can be given either daily under
self-supervision or twice weekly under directly observed therapy (DOT). DOT may be
particularly indicated for children with high risk infections, such as infants and newborns,
immunocompromised children, and children who are contacts of cases of recently diagnosed
pulmonary tuberculosis.

A special category that applies to children < 5 years old is often referred to as tuberculosis
exposure. These children have had significant contact with a recently diagnosed case of
pulmonary tuberculosis, but their skin tests are negative and chest radiographs and physical
examinations are normal. Some of these children may be infected because it takes up to 3
months for the skin test to turn positive in some small children. However, small children also
can develop severe tuberculosis in < 3 months, before the skin test turns positive in some
cases. As a result, all children < 5 years of age who are close contacts to adults with
suspected or proven pulmonary tuberculosis should be started on treatmenteven if their
tuberculin skin test is negativeas if they are infected. These children should receive the
second tuberculin skin test 3 months after contact with the known case has been broken
either by separation or successful treatment of the case. At the end of 3 months, if the child's
tuberculin skin test is negative, the isoniazid can be stopped; if the skin test is positive, a full
course of 9 months of isoniazid treatment should be given.

It is important to note that adherence to treatment is no better for children than it is for adults.
[102-105]
When left to self-supervise therapy, many families are unable or unwilling to give
children adequate treatment; failure rates are high and incomplete treatment with isoniazid for
tuberculosis infection is common. In most parts of the United States, it is standard care to
treat tuberculosis disease in children with directly observed therapy.[106] An increasing number
of children are being put on DOT for high risk tuberculosis infection because many studies
have shown drug completion rates for tuberculosis infection with self-supervision are < 50%.

Prevention

In much of the world, the only method available to prevent tuberculosis in children is
administration of a bacille Calmett-Gurin (BCG) vaccine. The BCG vaccines have never
been used in the United States and, currently, only one type is available that is difficult to
administer and of dubious efficacy. When considering the total body of literature of BCG
vaccination of children, the general conclusion is that the BCG vaccines prevent 60 to 90% of
serious tuberculosis cases in children.[107,108] Clearly, the BCG vaccines are better than no
method of prevention, but they are not capable of completely preventing tuberculosis disease
in a population of children. BCG vaccination has worked better in some situations than others.
In the United States, the presence of HIV infection in the child is an absolute contraindication
to giving BCG vaccine; internationally, the presence of asymptomatic HIV infection is not
considered a contraindication to BCG vaccination.

In the United States, the major method of preventing tuberculosis in children is interrupting
transmission through a community-based contact investigation with appropriate
chemotherapy, and the treatment of tuberculosis infection to prevent the development of
disease.[109-111] The contact investigation is the most important activity in the United States for
preventing tuberculosis in children because the yield is high for finding infection and it finds
the most recent infections, which are most likely to develop soon into cases of tuberculosis
disease in children. Several investigations have shown that when contact investigations are
not conducted well or completely, preventable cases of tuberculosis in children inevitably
occur.[112-114]

A current controversy in the United States involves how to find children with tuberculosis
infection so they can be treated to prevent future disease. When tuberculosis infection was
more common, mass skin testing of children made sense. However, tuberculosis has
retreated into relatively discrete pockets in the United States, and mass testing no longer
makes sense.[115] The new approach being developed by pediatricians is to screen children
with a questionnaire to determine if risk factors for tuberculosis infection are present, then
subsequently skin test only those children who have risk factors. In several published studies,
four major questions have emerged that probably account for over 95% of the attributable risk
of tuberculosis infection for children in the United States: [116-118] (1) Was the child born in a
country with a high prevalence of tuberculosis? (2) Has the child traveled (nontourist, > 2
weeks) to a country with a high prevalence of tuberculosis? (3) Has the child been exposed to
an adult with pulmonary tuberculosis? (4) Do other family members have positive tuberculin
skin tests? Applying skin tests only to children with one of these risk factors will significantly
decrease the number of tests performed and decrease the number of false-positive tuberculin
skin tests but insure that children with real risk factors are tested and given appropriate
treatment when necessary.