++
Two elements determine a child’s risk for developing
tuberculosis disease.1 The first is the likelihood
of exposure to an individual with infectious tuberculosis, which
is primarily determined by the individual’s environment.
The second is the ability of the person’s immune system
to control the initial infection and keep it clinically dormant.
Without treatment, disease develops in 5% to 10% of
immunologically normal adults with tuberculosis infection. In young
children, the risk is greater; as many as 40% of those
younger than 1 year with untreated tuberculosis infection develop
radiographic or clinical evidence of tuberculosis disease. Methods
of preventing disease in infected individuals benefit children and
adolescents even more than adults.
++
About 60% of cases of childhood tuberculosis occur in
infants and children younger than 5 years.2 The
ages of 5 to 14 years are often called the “favored age” because
children in this range may become infected, but usually have the
lowest rate of tuberculosis disease. The gender ratio for tuberculosis
in children is about 1:1 in contrast to adults, in whom males predominate.
++
Children acquire M tuberculosis from adults in
their environment. Environmental risk factors include those characteristics
that make it more likely that the child shares the air with an adult
with infectious tuberculosis. Factors that increase the risk of
a child being infected with M tuberculosis include
(1) birth or travel/residence in a country in which tuberculosis
is endemic; (2) early childhood environments with exposures to multiple
high-risk caregivers, for example, some orphanages; or (3) contact
with high-risk adults who have had previous residence in a jail,
prison, or high-risk nursing home, and homelessness in some communities. Also
included are use of illegal drugs, experience as a health care worker
who cares for high-risk patients, or locally defined risk factors. Factors that
increase the risk of developing disease once infected include age
younger than 2 years, coinfection with HIV, other immunocompromising diseases
or treatments (corticosteroids, tumor necrosis factor-alpha inhibitors),
and malnutrition.3
++
Most children in the United States are infected with M
tuberculosis in the home, but outbreaks of childhood tuberculosis
centered in elementary and high schools, nursery schools, family
daycare homes, churches, school buses, and stores have occurred.4 Childhood
tuberculosis case rates in the United States and in other developed
countries are strikingly higher among ethnic and racial minority
groups and among the poor. In the United States, approximately 85% of
tuberculosis cases in children occur among African American, Hispanic,
Asian, and Native American children.
++
The more recent epidemic of HIV infection has two major effects
on the epidemiology of childhood tuberculosis. First, HIV-infected adults
with tuberculosis may transmit the infection to children, some of
whom will develop tuberculosis disease. Second, children with HIV
infection are at increased risk of progressing to tuberculosis disease
once infected.5 Tuberculosis may be underdiagnosed
in HIV-infected children because of the similarity of its clinical
presentation to other opportunistic infections and because of the
difficulty in confirming the diagnosis with positive cultures. Children
with tuberculosis should have HIV serotesting because the two infections
are linked epidemiologically.6
++
Transmission of M tuberculosis is virtually always
by person-to-person spread via the respiratory route. Mucous droplets
become airborne when the index case coughs, sneezes, laughs, or
sings. Infected droplets dry and become droplet nuclei, which remain
suspended in the air for hours. Environmental factors, such as poor
air circulation, enhance transmission. Rarely, transmission occurs
by direct contact with infected body fluids such as urine or purulent
sinus tract drainage.
++
Of the several patient-related factors associated with transmission
of M tuberculosis, a positive acid-fast smear of
the sputum correlates most closely with infectivity.7 However, adults
with a negative acid-fast sputum smear may still be contagious.
Extensive epidemiologic studies show that most children with typical
tuberculosis disease rarely, if ever, infect other children or adults.
In the absence of cavitary lesions, which are extremely rare in childhood,
the bacilli are relatively sparse in the endobronchial secretions
of children with pulmonary tuberculosis. When children with tuberculosis
cough, they rarely produce sputum and lack the tussive force necessary
to suspend infectious particles in the air. However, adolescents
with reactivation forms of pulmonary tuberculosis, particularly
if they have pulmonary cavities or extensive infiltrates, may be
infectious to others. Many experts initially place hospitalized
children with pulmonary tuberculosis in respiratory isolation, especially
if their parents or adult visitors have not yet been fully evaluated
for tuberculosis. However, the risk of transmission from the young
child with primary tuberculosis is remote.
+++
Mycobacteriology and
Pathophysiology
++
Mycobacteria are nonmotile, nonspore-forming, pleomorphic, weakly
gram-positive rods that are typically slender and slightly bent. The
cell walls contain lipid and wax that make these organisms more
resistant than most others to light, alkali, acid, and the bactericidal action
of antibodies. Growth is slow with a generation time of 14 to 24
hours. Acid fastness, the capacity to perform stable mycolate complexes
with certain aryl methane dyes, is the hallmark of mycobacteria.
Cells appear red when stained with fuchsin (Ziehl-Neelsen or Kinyoun
stain), appear purple with crystal violet, or exhibit yellow-green
fluorescence under ultraviolet light (auramine and rhodamine, as
in Truant stain). Truant stain is the most sensitive method for
visualizing mycobacteria in a clinical specimen.
++
Identification of mycobacteria species depends on their staining
properties and their biochemical and metabolic characteristics. Isolation
on solid media often takes 3 to 6 weeks, followed by another 2 to
4 weeks for drug susceptibility testing. The automated methods using
liquid broth allow isolation from clinical specimens and identification
of mycobacteria within 7 to 10 days.
++
In more than 95% of cases, the portal of entry for M
tuberculosis is the lung. Small particles are inhaled beyond
the normal clearance mechanisms of the lungs and multiply initially within
the alveoli and alveolar ducts. The initial inflammation with polymorphonuclear leukocytes
is replaced by epithelioid cell proliferation and the appearance
of giant cells with lymphocytic infiltration. Macrophages ingest
the bacilli but are not able to kill them. Replication of the organisms
occurs within the macrophages, which carry some of the organisms
through lymphatics to the regional lymph nodes.
++
As the initial cycle of macrophage ingestion and replication
of bacilli continues, development of cutaneous hypersensitivity
and cell-mediated immunity occurs most often between 4 and 8 weeks
after onset of infection. During this time, the initial focus grows larger
and has not yet become encapsulated. Occasionally, this focus is
visible on the chest radiograph, but the radiograph usually remains
normal and the child is asymptomatic. If adequate immunity is established,
the parenchymal portion of the primary complex heals completely
by fibrosis and/or calcification after undergoing caseous
necrosis and encapsulation.
++
During the creation of the parenchymal lesion and the accelerated
caseation brought on by the development of hypersensitivity, the bacilli
from the primary complex spread via the bloodstream and lymphatics
to the apices of the lungs, liver, spleen, meninges, peritoneum,
lymph nodes, bones, and joints. This dissemination can involve large
numbers of bacilli, which leads to disseminated tuberculosis disease.
More commonly, small numbers of bacilli circulate and leave microscopic
foci scattered in various tissues. These metastatic foci are usually
clinically inapparent, but they may be the origin of either extrapulmonary
tuberculosis or reactivation pulmonary tuberculosis later in life.
++
In most cases of tuberculosis infection in children, the infection
is held in check locally and distantly. However, in some individuals, hilar
or paratracheal lymph nodes become enlarged by the host inflammatory
reaction to the tubercle bacilli.8 The nodes may
encroach on the regional bronchus or bronchiole. Partial obstruction
caused by external compression leads to hyperinflation in the distal
lung segment. Inflamed, caseous nodes may attach to the bronchial
wall and erode through it, leading to endobronchial tuberculosis.
Air is reabsorbed beyond this obstruction, and collapse of the segment
of the lung occurs. The resulting lesion is a combination of pneumonia
and atelectasis, commonly referred to as a collapse-consolidation
or segmental lesion.
++
A fairly predictable timetable is apparent for events that may
complicate the initial tuberculosis infection and complications.
Massive lymphohematogenous dissemination leading to tuberculous
meningitis, and miliary or disseminated disease occurs no later
than 2 to 6 months after infection. Clinically significant lymph
node or endobronchial tuberculosis usually appears within 3 to 9
months. Lesions of the bones and joints usually take at least a
year to develop, whereas disease of the genitourinary tract may
be evident 5 to 25 years after infection.
+++
Clinical Manifestations
++
The terminology used to describe various phases of tuberculosis
follows the pathophysiology of the disease. A child is in the exposure stage
when the child “shares the air” with an adult
with contagious tuberculosis. In this stage, there are no clinical
manifestations and the tuberculin skin test remains negative. Some
children in this stage ultimately develop a positive tuberculin
skin test if infection takes hold. Whereas adults in this stage
usually do not get treated, young children are treated because progression
to disease may occur rapidly.
++
Latent infection with tuberculosis means that
replication of M tuberculosis has occurred within
the lungs and, perhaps, in other tissues. The tuberculin skin test
is positive, but the chest radiograph is normal or shows only evidence
of the initial infection. In addition, there are no signs or symptoms
of disease.
++
Tuberculosis disease occurs when clinical manifestations
of pulmonary or extrapulmonary tuberculosis become apparent by clinical
signs and symptoms, chest radiograph, or other diagnostic techniques.
+++
Latent (Asymptomatic)
Infection
++
The vast majority of children with tuberculosis infection develop
no signs or symptoms at any time. Occasionally, the initiation of
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. These children have a reactive tuberculin skin test, and
the purpose of treating them is to prevent them from developing
reactivation tuberculosis in the future.
++
The symptoms and physical signs of pulmonary tuberculosis in
children are surprisingly meager, considering the degree of radiographic
changes often seen.9 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 usually have clinically silent radiographic
disease. More than 50% of infants and children with pulmonary
tuberculosis have no physical findings and are discovered only via
contact tracing of an adult with tuberculosis. Infants are more likely
to experience signs and symptoms because of their small airway diameters
relative to the parenchymal and lymph node changes that occur. Nonproductive
cough and mild dyspnea or wheezing, especially at night, are the
most common symptoms. Systemic complaints such as fever, night sweats,
anorexia, and decreased activity occur less often. Some infants
have difficulty gaining weight or develop a true failure-to-thrive
presentation that does not improve significantly until after several
months of treatment.
++
Pulmonary signs are even less common. Some young children with
bronchial obstruction have signs of air trapping, such as localized
wheezing or decreased breath sounds, that may be accompanied by
tachypnea or frank respiratory distress. These nonspecific symptoms
and signs are sometimes alleviated by antibiotics, suggesting that
bacterial superinfection distal to the focus of bronchial obstruction
caused by tuberculosis has contributed to the clinical presentation
of disease.
++
In chest radiography, the hallmark of pulmonary tuberculosis
in infants and children is the relatively large size of the hilar
or paratracheal lymphadenitis as compared with the less significant
size of the initial parenchymal focus (Fig. 269-1A).10 Hilar
lymphadenopathy is almost invariably present with childhood tuberculosis,
but it may not be distinct on a plain radiograph when calcification
is not present. Significant atelectasis and/or pulmonary
infiltrate make it impossible to discern the lymph node enlargement. A
CT scan of the chest may show the adenopathy, but this is rarely
required to establish the correct diagnosis.11 As the
hilar or mediastinal lymph nodes continue to enlarge, partial bronchial
obstruction caused by external compression from the enlarged nodes
causes air trapping, hyperinflation, and even lobar emphysema. As
the lymph nodes attach to and infiltrate the bronchial wall, reabsorption
of air and atelectasis occurs. The radiographic findings are similar to
those caused by aspiration of a foreign body; in effect, the lymph
node is acting as the foreign body. Multiple segmental lesions in different
lobes may be apparent simultaneously, and segmental atelectasis
and hyperinflation lesions can occur together. Children with tuberculosis
may have the radiographic picture of lobar pneumonia without impressive or
specific adenopathy. Rarely, bullous lesions occur in the lungs
that can lead to pneumothorax. Enlargement of the subcarinal lymph
nodes causes compression of the esophagus and, rarely, a bronchoesophageal fistula.
A sign of subcarinal tuberculosis is horizontal splaying of the
main stem bronchi.
++
++
Adolescents with pulmonary tuberculosis may develop segmental
lesions with adenopathy or apical infiltrates with or without cavitation
that are typical of adult reactivation tuberculosis (Fig.
269-1B). Regional lymphadenitis is absent in the latter type
of disease.
++
The course of thoracic lymphadenopathy and bronchial obstruction
can follow several paths if antituberculosis chemotherapy is not given.
In many cases, the segment or lobe reexpands and the radiographic
abnormalities resolve completely. However, these children are still
at risk for developing reactivation tuberculosis later in life.
In some cases, this segmental lesion resolves, but residual calcification
of the parenchymal focus and regional lymph node occurs. Finally,
bronchial obstruction may cause scarring and progressive contraction
of the lobe or segment, which may be associated with cylindrical
bronchiectasis and chronic pyogenic infection.
++
A rare but serious complication of tuberculosis in children occurs
when the parenchymal focus enlarges and develops a large, caseous center.
This progressive primary tuberculosis presents like bronchopneumonia,
and may be accompanied by high fever, severe cough, dullness to
percussion, rales, and decreased breath sounds. Liquefaction in
the center may result in formation of a thin-walled cavity. Before
the advent of antituberculosis chemotherapy, the mortality rate
of this form of tuberculosis was 30% to 50%. With
effective treatment, the prognosis is excellent for full recovery.
++
Tuberculous pleural effusions, which can be local or general,
originate from the discharge of bacilli into the pleural space from
a subpleural pulmonary focus or caseated subpleural lymph node.
Asymptomatic local pleural effusion is so frequent in childhood
pulmonary tuberculosis that it is basically a component of the primary
complex. Most large and clinically significant effusions occur months to
years after the initial infection. Tuberculous pleural effusion
is infrequent in children younger than 6 years and rare in those
younger than 2 years. Effusions are usually unilateral, but they
can be bilateral. They are virtually never associated with a segmental
pulmonary lesion and are rare in miliary tuberculosis.
++
The clinical onset of tuberculous pleurisy is usually fairly
sudden. It is characterized by low to high fever, shortness of breath, chest
pain on deep inspiration, dullness to percussion, and diminished
breath sounds on the affected side. The presentation is similar to
that of pyogenic pleurisy. The fever and other symptoms may last
for several weeks after the start of ultimately effective antituberculosis
chemotherapy. Although corticosteroids may reduce the clinical symptoms,
they have little effect on the ultimate outcome. The tuberculin
skin test is positive in only 70% to 80% of cases.
The prognosis is excellent, but radiographic resolution may take
months. Scoliosis rarely complicates recovery of a long-standing
effusion.
++
Tuberculous pericarditis occurs in only 0.4% of infected
children. It arises from hematogenous dissemination or direct invasion
from caseous lymph nodes in the subcarinal area. Pericardial fluid
may be serofibrinous or hemorrhagic. However, tubercle bacilli rarely
are found on direct smear of the fluid. Extensive fibrosis of the
pericardial sac may lead to obliteration with development, usually
years later, of constrictive pericarditis. The presenting systems are
usually nonspecific: low-grade fever, poor appetite, failure to
gain weight, and chest pain. A pericardial friction rub may be heard,
or, if a large effusion already is present, distant heart sounds,
tachycardia, and narrow pulse pressure may suggest the diagnosis. In
the prechemotherapy era, half the patients died; now, with appropriate
drugs and use of corticosteroid therapy to diminish the size of
the effusion, the prognosis is excellent.
+++
Disseminated
(Miliary)
++
The lymphohematogenous spread of bacilli that accompanies the
initial infection is usually asymptomatic. Patients rarely experience protracted
hematogenous tuberculosis caused by the intermittent release of
tubercle bacilli as a caseous focus erodes through the wall of the
blood vessel in the lung. Although the clinical picture may be acute,
more often it is indolent and prolonged, with high fevers accompanying
the release of organisms into the bloodstream. Early pulmonary involvement
is surprisingly mild, but diffuse lung involvement becomes apparent
if treatment is not given promptly. Culture confirmation can be
difficult. Bone marrow or liver biopsy with appropriate stains and
cultures may be necessary and should be performed if the diagnosis is
considered and other tests are unrevealing.
++
The most common clinically significant form of disseminated tuberculosis
is miliary disease, which occurs when massive numbers of bacilli
are released into the bloodstream, causing disease in at least two organs.12 This
form of disease usually occurs within 2 to 6 months of the primary
infection. The clinical manifestations are protean, depending on
the number of organisms that disseminate and the focus of infection.
Lesions are usually larger and more numerous in the lungs, spleen,
liver, and bone marrow than in 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,
with the patient becoming gravely ill in several days. More often,
the onset is insidious, the patient not being able to pinpoint the
true time of initial symptoms. The most common signs include malaise,
anorexia, weight loss, and low-grade fever. Within several weeks hepatosplenomegaly
and generalized lymphadenopathy develop in about 50% of
cases. About this time, the fever may become higher and more sustained,
but the chest radiograph is usually normal and respiratory symptoms
are few. Within several more days to weeks, the lungs become filled
with tubercles, causing dyspnea, cough, rales, and wheezing. As
pulmonary disease progresses, alveolar air block syndrome may result
in frank 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. Severe headache
in a patient with miliary tuberculosis usually indicates the presence
of meningitis. Abdominal pain or tenderness is usually a sign of
tuberculous peritonitis. Choroid tubercles occur in 13% to 87% of
patients and are highly specific for miliary tuberculosis. Unfortunately,
the tuberculin skin test is nonreactive in as many as 50% of
patients with advanced disease.
+++
Central Nervous
System
++
Central nervous system tuberculosis is the most serious complication
in children and is fatal without effective treatment. This condition
can arise from massive hematologic dissemination of organisms, but
usually arises from the formation of a caseous lesion in the cerebral
cortex or meninges that develops during the occult lymphohematogenous
dissemination of the initial infection. This lesion, called a Rich
focus, increases in size and discharges small numbers of
tubercle bacilli into the subarachnoid space. The resulting exudate may
infiltrate the cortical or meningeal blood vessels, producing inflammation,
obstruction, and subsequent infarction of the cerebral cortex. This
exudate also interferes with the normal flow of 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 severe damage
that occurs gradually or rapidly. Abnormalities in electrolyte metabolism,
especially hyponatremia caused by SIADH or salt wasting, also contribute
to the pathophysiology.
++
Tuberculous meningitis complicates about 0.3% of untreated
tuberculosis infections in children. This condition is extremely
rare in infants younger than 3 months because pathologic events
usually need this much time to develop. It is most common in children
between 6 months and 4 years of age.
++
The clinical progression of tuberculous meningitis may be rapid
or gradual. Rapid progression occurs more frequently in infants and
young children who may experience symptoms for only several days
before the onset of acute hydrocephalus, seizures, and cerebral
edema. More often, the signs and symptoms progress slowly over
several weeks and can be divided into three 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 neurologic signs are absent, but infants may experience
a stagnation or loss of developmental milestones. The second stage
usually begins more abruptly. Lethargy, nuchal rigidity, Kernig
and Brudzinski signs, seizures, hypertonia, vomiting, cranial nerve
palsies relevant to basilar meningitis, and other focal neurologic
signs are apparent. This clinical picture usually correlates with the
development of hydrocephalus, increased intracranial pressure, and
vasculitis.13 The third stage is marked by coma,
hemiplegia or paraplegia, hypertension, decerebrate posturing, deterioration
in vital signs, and, eventually, death. The prognosis of tuberculous meningitis
correlates closely with the clinical stage of illness at the time
treatment with antituberculosis chemotherapy and corticosteroids
begins.14 The majority of patients in the first
stage have an excellent outcome, whereas most patients diagnosed
in the third stage who survive have permanent disabilities, including blindness,
deafness, paraplegia, and mental retardation. It is imperative that
antituberculosis chemotherapy be considered for any child who develops
basilar meningitis and hydrocephalus or cerebral infarction with
no other apparent etiology. The key to diagnosis is often identifying
the adult from whom the child acquired M tuberculosis.
++
Another manifestation of central nervous system tuberculosis
is the tuberculoma, which presents clinically as a brain tumor. Tuberculomas
account for as many as 40% of brain tumors in children
in some areas of the world, but they are rare in North America. These
lesions, which occur most often in children younger than 10 years,
are usually singular, but they may be multiple. In adults, lesions
are usually supratentorial, but in children, they are often infratentorial,
located at the base of the brain near the cerebellum. The most common
symptoms are headache, fever, and seizures. The paradoxical development
of tuberculomas in patients with tuberculous meningitis while receiving
effective chemotherapy has been recognized since the advent of CT.
The cause and nature of these tuberculomas are poorly understood, but
their development does not require a change in the therapeutic regimen.
Whenever a child with tuberculous meningitis deteriorates or develops
focal neurologic findings while on treatment, this phenomenon should be considered.
Corticosteroids may help alleviate the occasionally severe clinical
signs and symptoms. These lesions may be very slow to resolve clinically,
persisting radiographically for months or years.
++
Tuberculosis of the superficial lymph nodes is the most common
form of extrapulmonary tuberculosis in children. Most cases occur
within 6 to 9 months of the initial infection, although some cases
appear years later. The tonsillar, anterior cervical, and submandibular nodes
become involved secondary to extension of a primary lesion of the
upper lung fields or abdomen. Infected nodes in the inguinal, epitrochlear,
or axillary regions, which are rare in children, result from regional
lymphadenitis associated with tuberculosis of the skin or skeletal
system.
++
In the early stages of infection, the lymph nodes usually enlarge
gradually.15 The nodes are firm but not hard, discrete,
and nontender. The nodes usually feel fixed to underlying or overlying
tissue. Disease is most often unilateral, but bilateral involvement
may occur. As infection progresses, multiple nodes are affected,
resulting in a mass of matted nodes. Systemic signs and symptoms
other than low-grade fever are usually absent. The chest X-ray is
usually normal, although adenopathy in the chest may be apparent.
Occasionally, the illness is more acute with rapid enlargement of cervical
nodes, high fever, tenderness, and fluctuance. The infection may
resolve if left untreated, but more often progresses to caseation
and necrosis of the lymph node. The capsule of the node breaks down,
resulting in the spread of infection to adjacent nodes. The skin
overlying the massive nodes becomes thin, shiny, and erythematous.
Rupture results in a draining sinus tract that may require surgical
removal; if the correct diagnosis is made prior to rupture, however,
the process can be cured with antituberculous therapy alone.
++
Skeletal tuberculosis results from lymphohematogenous seeding
of tubercle bacilli during the initial infection. Bone infection
also may originate as a result of direct extension from a regional
lymph node or a neighboring infected bone. The time interval between
infection and clinical disease can be as short as 1 month in cases
of tuberculous dactylitis, or as long as 30 months or more for tuberculosis of
the hip. The infection usually begins in the metaphysis. Granulation
tissue and caseation destroy bone by direct infection and by pressure
necrosis. Soft tissue abscess and extension of the infection through
the epiphysis into the nearby joint often complicate the bony lesion.
++
Weight-bearing bones and joints are most commonly affected.16 The
majority of cases of bone tuberculosis occur in the lower thoracic
and upper lumbar vertebrae, causing tuberculosis of the spine or
Pott disease. Involvement of two or more vertebrae is common; these
vertebrae are usually contiguous, but there may be skip areas between
lesions. Infection in the body of the vertebra leads to bony destruction
and collapse. The infection may extend out from the bone, causing
a paraspinal, psoas, or retropharyngeal abscess. The most frequent
clinical signs and symptoms of tuberculous spondylitis in children are
low-grade fever, irritability, and restlessness, especially at night;
back pain; and abnormal positioning in gait or refusal to walk. Spinal
rigidity may be caused by profound muscle spasm. Other sites of
skeletal tuberculosis, in approximate order of frequency, are the
knee, hip, elbow, and ankle (eFig. 269.1). The
degree of involvement can range from mild joint effusion without
bone destruction to frank destruction of bone and restriction of
the joint caused by chronic fibrosis. The tuberculin skin test is
reactive in 80% to 90% of cases, and culture of
joint fluid or bone biopsy usually yields the organism.
++
++
Tuberculous dactylitis is a form of bone tuberculosis that is
peculiar to infants. Affected children develop distal endarteritis
followed by painless swelling and cystic bone lesions in the hands.
+++
Abdominal and
Gastrointestinal
++
Tuberculosis of the oral cavity or pharynx is very unusual. Tuberculosis
of the larynx causes chronic hoarseness and is often accompanied
by upper-lobe apical pulmonary disease and sputum production in
adolescents and adults. Tuberculosis of the esophagus is very rare
in children and may be associated with a tracheoesophageal fistula.
Tuberculous peritonitis is uncommon in adolescents and rare in young
children.17 Whereas generalized peritonitis is
caused by dissemination of organisms, most localized disease is
caused by direct extension from an abdominal lymph node, intestinal
focus, or tuberculous salpingitis. Initial pain and abdominal tenderness
are mild. Rarely, the lymph nodes, omentum, and peritoneum become
matted in children and can be palpated as a “doughy,” irregular,
nontender mass. Ascites and low-grade fever are common. Tuberculous
enteritis is caused by hematogenous dissemination of organisms in most
cases. However, ingestion of unpasteurized cow’s milk laden
with Mycobacterium bovis still causes this disease
in many areas of the world. The jejunum and ileum near Peyer patches
and the appendix are the most common sites of involvement. Mesenteric
adenitis usually complicates this disease. Lymph nodes may cause
intestinal obstruction or erode through the omentum to cause generalized
peritonitis. This entity should be considered in any child with
chronic gastrointestinal complaints and a reactive tuberculin skin
test.
++
Renal tuberculosis is rare in children, and the incubation period
is several years or longer. Tubercle bacilli can be isolated from
the urine in cases of miliary tuberculosis, even in the absence
of renal disease. In true renal tuberculosis, small caseous tubercles
develop in the renal parenchyma and release M tuberculosis into
the tubules. A mass may develop near the renal cortex that discharges
large numbers of bacteria through a fistula into the renal pelvis. Infection
can spread locally to the ureters, prostate, or epididymis. Renal
tuberculosis is often clinically silent in the early stages. The only
signs may be sterile pyuria and microscopic hematuria. As the disease
progresses, dysuria, flank, or abdominal pain and gross hematuria
develop. Superinfection by other bacteria is frequent and may delay
recognition of the underlying tuberculosis. Hydronephrosis or ureteral
stricture may complicate the disease.
++
Tuberculosis of the genital tract is uncommon in both males and
females before puberty. This condition usually originates from lymphohematogenous
spread, but can complicate direct spread from the intestinal tract
or bone. In adolescent girls, the fallopian tubes are most often
involved, followed by the endometrium, the ovaries, and the cervix.
The usual symptoms are low abdominal pain and dysmenorrhea or amenorrhea.
Chronic infection usually leads to infertility. Genital tuberculosis
in adolescent males is rare. Tuberculous orchitis presents as a
nodular, painless swelling of the scrotum that is usually unilateral.
++
Cutaneous tuberculosis, which was more common decades ago, arises
as an extension of disease from the primary infection, from hematogenous
dissemination, or from hypersensitivity to the bacilli. Skin lesions
associated with the initial infection can be caused by direct inoculation
of the skin through an abrasion, cut, or insect bite. Regional lymphadenitis
is striking, but systemic symptoms are usually absent. The most common
form of hypersensitivity lesion is erythema nodosum, which is characterized
by large, painful, purple-brown, indurated nodules on the shins
and forearms. Scrofuloderma occurs when a caseous lymph node ruptures
to the outside and leaves an ulcer or sinus tract. Papulonecrotic
tuberculids are miliary lesions of the skin that appear most frequently
on the face, trunk, and upper thighs. Their characteristic “apple
jelly” center is best demonstrated by placing a glass slide
over the lesions. Tuberculosis verrucosa cutis is a wartlike lesion,
most common on the arms or legs, that represents autoinoculation
of bacilli in a person already sensitized to the organism.
++
Ocular tuberculosis is very rare in children. This condition
usually involves the conjunctiva or cornea and results from direct inoculation. Unilateral
redness and lacrimation are often associated with enlargement of the
preauricular, submandibular, or cervical lymph nodes.
++
Tuberculosis of the middle ear results from a primary focus in
neonates who aspirate infected amniotic fluid or from hematogenous
dissemination in older children. The most common signs and symptoms
are painless otorrhea, tinnitus, decreased hearing, facial paralysis,
and perforated tympanic membrane. Enlargement of local lymph nodes
may accompany infection. Diagnosis can be difficult because stain and
cultures of material from the ear are frequently negative, and the
histology of affected tissue usually shows acute and chronic inflammation
without granuloma formation.
++
True congenital tuberculosis is exceedingly rare, with less than
400 cases reported. M tuberculosis can pass from
the placenta to the fetus through the umbilical vein. The mothers
of these infected infants frequently suffer from tuberculous pleural
effusion, meningitis, or disseminated disease during pregnancy or soon
afterward. However, the diagnosis of tuberculosis in the newborn
often leads to the discovery of the mother’s tuberculosis. Initial infection
in the mother just before or during pregnancy is more likely to
lead to congenital infection than previous infection. However, even
massive involvement of the placenta with tuberculosis does not usually
give rise to congenital infection. The tubercle bacilli first reach
the fetal liver, where an initial focus develops with associated
involvement of regional lymph nodes. Organisms then pass through the
liver into the main fetal circulation, leading to foci in the lung
and other tissues. The bacilli in the lung usually remain dormant
until after birth, when oxygenation and pulmonary circulation increase
significantly. Congenital tuberculosis may also occur by aspiration
or ingestion of infected amniotic fluid if a caseous placental lesion
ruptures directly into the amniotic cavity.
++
Symptoms of true congenital tuberculosis may be present at birth,
but more commonly begin in the second or third week of life. The
most common signs and symptoms, in order of frequency, are respiratory
distress, fever, hepatic or splenic enlargement, poor feeding, lethargy
or irritability, lymphadenopathy, abdominal distention, failure
to thrive, ear drainage, and skin lesions. Many infants have an
abnormal chest radiograph, most often a miliary pattern. Only one
third of affected infants have meningitis. This clinical presentation
in newborns is similar to that caused by bacterial sepsis and other congenital
infections. The diagnosis of neonatal tuberculosis should be suspected
in an infant with signs and symptoms of bacterial or congenital
infection whose response to antibiotic and supportive therapy is
poor, and whose mother has risk factors for developing tuberculosis.
+++
Tuberculosis
and HIV Infection
++
In general, the clinical presentation of tuberculosis in children
with HIV infection is similar to that in children without HIV infection.18 However,
children with HIV infection more commonly have extrapulmonary tuberculosis (especially
meningitis, tuberculoma, and abdominal disease), and pulmonary tuberculosis has
a more aggressive picture, more often leading to substantial infiltrates
or cavitation within the lung. Establishing the diagnosis of tuberculosis
in an HIV-infected child can be difficult because the skin test
is often negative, microbiologic confirmation of disease is difficult
to achieve in many cases, and other opportunistic conditions can
mimic tuberculosis. An aggressive evaluation for tuberculosis should be
undertaken for any child with known HIV infection, or risk factors
for HIV infection, who develops pulmonary disease or any unusual
constellation of signs and symptoms.
++
There are two primary ways in which a child with tuberculosis
can be discovered. The first is when tuberculosis is considered
part of the differential diagnosis of a symptomatic child. This passive
discovery is usually the only means of diagnosis in resource-poor
countries, and children often have advanced disease. The second
is when children with tuberculosis in developed countries are discovered
through contact investigations of adults who are believed to have
infectious tuberculosis. In these cases, children usually have relatively
asymptomatic disease that would have either progressed or escaped
detection if the contact tracing had not occurred. The importance
of the epidemiologic setting of the child in establishing the diagnosis
of tuberculosis cannot be overemphasized. Often, the most important
maneuver in determining whether the child has tuberculosis is testing
the adults in close contact with the child to determine whether
any adult has or recently has had infectious pulmonary tuberculosis.
++
General laboratory and other tests are usually unrevealing for
children with tuberculosis. Screening tests such as a complete blood
count and differential, erythrocyte sedimentation rate, and blood
chemistries are usually normal. When considering a diagnosis of
extrapulmonary tuberculosis, analysis of appropriate tissue or fluids
often leads to establishing the correct diagnosis. In cases of tuberculous
meningitis, the CSF leukocyte count usually ranges from 10 to 500
cells/mm3, but is occasionally higher.
Polymorphonuclear leukocytes may be common initially, but in a majority
of cases, lymphocytes are predominant. The CSF glucose level is
typically less than 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. Although the lumbar CSF is grossly abnormal, ventricular CSF
may have normal chemistries and cell counts because samples are
obtained proximal to the site of obstruction.
++
In cases of pleural tuberculosis, the pleural fluid usually yields
results indicative of a mild exudate: specific gravity is 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). There are typically several hundred
to several thousand white blood cells/mm3,
with an early predominance of polymorphonuclear cells followed by
a high concentration of lymphocytes. Biopsy of the pleura may show
evidence of granuloma formation and the organisms.
+++
Tuberculin Skin
Testing
++
A positive tuberculin skin test is the hallmark of infection
with M tuberculosis.19 The
definitive test is the Mantoux skin test technique, which in the
United States involves intradermal injection of 0.1 mL of purified
protein derivative containing five tuberculin units. The results
are interpreted as the transverse diameter of induration present
48 to 72 hours after injection. A variety of host-related factors—including
very young age, malnutrition, immunosuppression by disease or drugs,
viral infection, measles vaccination, and overwhelming tuberculosis—can
depress tuberculin reactivity in a child infected with M
tuberculosis. Approximately 10% of immunocompetent children
with tuberculosis disease do not react initially to a tuberculin skin
test; however, most become reactive after several months of treatment,
suggesting that the disease contributed to this anergy. Anergy with
tuberculosis may be global or specific to tuberculin, so a positive
control skin test with a negative tuberculin test never rules out
tuberculosis disease. False-positive reactions to tuberculin skin
tests can be caused by cross-sensitization to antigens of nontuberculous mycobacteria
or, in some cases, previous immunization with bacille Calmette-Guérin (BCG)
vaccine. No reliable method distinguishes tuberculin reactions caused
by a BCG vaccination from those resulting from infection with M
tuberculosis. However, many infants who receive a BCG vaccine
never develop a positive tuberculin reaction. When a reaction does
occur, the induration is usually less than 10 mm and the reaction
often wanes after several years. One study of BCG cross-reaction
in Native American children vaccinated at birth showed that all
positive Mantoux reactions occurred within the first 6 months after
vaccination. In general, a reactive area of 10 mm or more in a
BCG-vaccinated child indicates infection with M tuberculosis and
necessitates further diagnostic evaluation and treatment. A history
of prior BCG vaccination is never a contraindication to tuberculin
testing.
++
The interpretation of the tuberculin reaction should be influenced
by the purpose for which the test was given and the consequences
of false classification.20 Because there is always
some overlap in reactions to the Mantoux test between groups of
individuals with and without infection with M tuberculosis, false-positive
and false-negative results always occur within a population. To
try to minimize false results, reaction size limits for determining
a positive result are made. Patients are then stratified by risk
of infection (Table 269-1). For adults and
children at the highest risk of having infection progress to disease,
a reactive area of at least 5 mm is classified as a positive result.
For other high-risk groups, including children younger than 4 years,
a reactive area of at least 10 mm is considered positive. For all
other low-risk persons, the cutoff point for a positive reaction
is raised to 15 mm. The key to this scheme is obtaining an adequate
history of possible risk factors for acquiring infection with M
tuberculosis. Classifying children by this scheme depends
on the willingness and ability of the clinician and family to create
a thorough history for the child and for the adults who are in the child’s
environment. In general, tuberculin skin testing of low-risk children
yields few positive results, and in low prevalence populations the majority
of these positive results will be false positive.
++
+++
Interferon Release
Assays
++
Advances in molecular biology and genomics have led to alternatives
to the TST.21 Two new in vitro tests have been
developed. Lymphocytes in whole blood are stimulated with M tuberculosis antigens,
and the release of interferon-γ is measured. Both
tests use two proteins—early secreted antigen target-6
and culture filtrate protein—that are found on M tuberculosis and
only a few fairly rare species of nontuberculous mycobacteria, but
not on the bacilli Calmette-Guérin (BCG) or the Mycobacterium
avium complex. The first test is QuantiFERON-TB (QFT; Cellestis,
Carnegie, Australia), which measures whole blood IFN production.
The second format is the enzyme-linked immunospot (ELISPOT) (T-SPOT.TB; Oxford
Immunotec, Oxford), which measures the number of mononuclear cells
that produce INF.
++
Both formats of IFN release assays have been studied primarily
in adults. In many clinical situations, these tests have a higher
specificity than the TST, better correlation with surrogate measures
of recent exposure to M tuberculosis in low incidence
settings and less cross-reactivity than the TST caused by previous
BCG vaccination. Two clear advantages of the IFN release assays
are the need for only one patient encounter (two with the TST) and
the lack of possible boosting of the result because the patient
is not exposed to any biologic material.
++
More recent studies of IFN release assays in children are few
for both ELISPOT and QFT. Studies of child household contacts of
adults with pulmonary tuberculosis have shown that children who
previously received a BCG vaccination were more likely to have a
positive TST, but a negative ELISPOT result. A study from the Gambia
showed an 83% agreement between TST and ELISPOT in child
household contacts, with a nonsignificant trend toward the ELISPOT being
less sensitive than the TST.22 In this study, previous
BCG vaccination did not significantly impact the results of either
test.
++
IFN release assays are becoming more widely used and are recommended
by the Centers for Disease Control and Prevention (CDC). However,
there are few published data for children younger than 5 years and
immunocompromised persons. Although the IFN release assays show
great promise for improving the diagnosis of tuberculosis infection,
too little is known about their characteristics in young children and
immunocompromised hosts to recommend their routine use in these
groups.
++
The most important laboratory tests for the diagnosis of tuberculosis are the acid-fast stain and mycobacterial culture.
The best culture specimen for pulmonary tuberculosis in a child
has been the early morning gastric aspirate obtained before the child
has risen and before peristalsis has emptied the stomach of the
pooled secretions that were swallowed overnight. In general, acquisition
of these samples has required hospitalization. Unfortunately, even
under optimal conditions, three gastric aspirates yield M
tuberculosis in less than 50% of cases. Therefore, negative
cultures never exclude the diagnosis of tuberculosis in a child.
The culture yield from bronchoscopy in children with tuberculosis
is usually less than the yield from properly obtained gastric samples.
More recent studies from South Africa have demonstrated a culture yield
from outpatient induced sputum (using warm nebulized saline and
a suction catheter to capture the mucus) equal to that for inpatient gastric
aspirates in children with extensive pulmonary disease.
++
Fortunately, the need for culture confirmation in children with
tuberculosis is not always necessary. If a 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. Cultures always should be obtained from a child
with suspected tuberculosis when the source case is not known, or
when the source case has a drug-resistant isolate.
++
Unfortunately, acid-fast stain of various fluids and tissues
from children with tuberculosis disease is often unrevealing. Acid-fast
stain of gastric samples is positive in less than 10% of
cases, and staining and culture of other infected material is positive
in less than 25% to 50% of cases.
+++
Nucleic Acid
Amplification
++
The main form of nucleic acid amplification studied in children
with tuberculosis is the polymerase chain reaction (PCR), which
uses specific DNA sequences as markers for microorganisms. Various
PCR techniques have a sensitivity and specificity of more than 90%, as
compared with sputum culture, for detecting pulmonary tuberculosis
in adults. However, in children, the sensitivity of PCR has varied
from 25% to 83%, and specificity has varied from
80% to 100% when compared to clinical diagnosis.
A negative PCR result never eliminates tuberculosis as a diagnostic
possibility. The major use of PCR is in evaluating children with
significant pulmonary disease when the diagnosis is not established
readily by clinical or epidemiologic grounds. PCR may be particularly
helpful in evaluating immunocompromised children with pulmonary disease,
or in children with extrapulmonary disease.
++
Mycobacteria replicate slowly and remain dormant in the body
for prolonged periods. The treatment of tuberculosis is affected
by the presence of naturally occurring drug-resistant organisms
in large bacterial populations, even before chemotherapy is initiated.
This drug resistance is caused by mutation at one of several chromosomal
loci. The loci for resistance to one drug are not linked to the
loci for resistance to other antituberculosis drugs. Although a
population as a whole may be considered drug susceptible, a subpopulation
of drug-resistant organisms occurs at fairly predictable frequencies
within the main population. The frequency for these drug-resistant organisms
varies for the various drugs: streptomycin, 105;
isoniazid, 106; and rifampin, 107. A
cavity containing 109 bacilli will have thousands
of drug-resistant organisms, whereas a caseous lesion with a much
smaller population contains but few resistant organisms.
++
These microbiologic characteristics of M tuberculosis explain
why single antimicrobial drugs cannot cure tuberculosis disease
in adults. The major biologic determinant of the success of antituberculosis
therapy is the size of the bacterial population within the host.
For patients with a large population of bacilli, such as adults
with cavities or extensive infiltrates, many drug-resistant organisms
are present initially, and at least two antituberculosis drugs must
be given. Conversely, for patients with infection but no disease,
the bacterial population is small, drug-resistant organisms are
rare or nonexistent, and a single drug, such as isoniazid, can be
given. Children with pulmonary tuberculosis and patients with extrapulmonary tuberculosis
have medium-size populations in which significant numbers of drug-resistant
organisms may or may not be present. In general, these patients
are treated with at least two, and usually three or four, drugs.
+++
Drugs for Tuberculosis
++
Table 269-2 details the first-line antituberculosis
drugs used to treat tuberculosis in children.
++
++
Isoniazid (INH), a synthetically produced drug, is the most potent
and valuable single drug in the treatment of tuberculosis. An oral
dose attains a plasma concentration 20 to 80 times the usual level
required to inhibit the growth of tubercle bacilli (0.02–0.05 μg/mL) within
several hours, with high concentrations persisting for 6 to 8 hours
in plasma and sputum. INH penetrates readily into the CSF, even
in the absence of inflammation, and into caseous tissue. It is partially
conjugated in the liver to an acetylated, inactive, nontoxic form. The
rate and degree of acetylation are genetically determined.
++
The principal side effects of INH are peripheral neuritis and
hepatitis. Peripheral neuritis results from competitive inhibition
of pyridoxine metabolism. This is more likely to occur at higher
dosages of INH (> 10 mg/kg/d) in alcoholics and
people who are poorly nourished. This is rarely a problem in children,
although precautions must be taken during adolescence, for breast-feeding
babies, during pregnancy, or when the total daily dose of INH exceeds
300 mg. Pyridoxine (10 mg for each 100 mg of INH) should be given
daily when indicated.
++
Hepatotoxicity is a problem in patients older than 35 years.
In children, hepatitis is rare and usually mild. Slight elevation
of serum liver enzymes occurs in 1% to 5% of children taking
INH, but symptomatic hepatitis is very rare. Concomitant use of
rifampin or phenytoin increases the likelihood of hepatitis, as
do INH dosage regimens in excess of 15 mg/kg/d.
++
Children who are taking INH need not have serum liver enzyme
testing unless they have a previous history of liver disease, predisposition
to the development of liver disease, or are taking other liver toxic
drugs. A careful symptom review should be performed monthly, with
warnings to report such symptoms as nausea, loss of appetite, or
right upper-quadrant pain promptly. Other infrequent side effects
are convulsions, psychoses, loss of memory, allergic manifestations,
and a lupuslike syndrome with arthritis and antinuclear antibodies.
++
Rifampin is a semisynthetic drug that has wide antimicrobial
activity against bacteria and mycobacteria. It is absorbed readily
from the gastrointestinal tract after oral administration, with
peak concentrations of 6 to 32 μg/mL (MIC
for M tuberculosis 0.5 μg/mL)
occurring in 3 hours. Rifampin readily diffuses to most tissues
and body fluids; CSF levels are low but adequate for treatment.
It is excreted primarily through the biliary tract and kidneys.
++
Rifampin is relatively nontoxic; the principal side effect is
hepatitis, which occurs with a frequency of < 1%. Hepatitis
seems to be more common in patients who are treated with the combination
of rifampin and INH. Gastrointestinal disturbances, rashes, reversible
leukopenia, thrombocytopenia, and elevation of blood urea nitrogen
have been reported. Rifampin interacts with many drugs, including dicumarol,
corticosteroids, antifungal agents, and many anti-HIV agents. Rifampin
may chemically interfere with birth control pills, making them ineffective.
Administration of the drug may also impart an orange-red color to
feces, urine, sputum, saliva, tears, and sweat. The suggested dosage
is 10 to 20 mg/kg/d (maximum, 600 mg). A liquid
preparation is not commercially available, but can be prepared in
community pharmacies.
++
Pyrazinamide (PZA) is a bactericidal drug that attains a therapeutic
concentration in the CSF and in macrophages. It is recommended as
the third drug of a three- or four-drug regimen, particularly for
the first 2 months of therapy. In doses of 20 to 40 mg/kg/d
(adult dose 2 g/d), it is well tolerated by children. Adverse
reactions are rare in children, but may include hepatitis, joint
pain, and itching with or without a rash.
++
Ethambutol is an odorless water-soluble compound rapidly absorbed
from the gastrointestinal tract and excreted in the urine, mainly
with its form unchanged. It is bacteriostatic at the usual dose
of 20 mg/kg/d. The only important toxic effect
is a retrobulbar neuritis that infrequently results in loss of visual
acuity, defects in visual fields, and inability to distinguish between
red and green; the visual changes are usually reversible. This side
effect should be monitored by monthly studies of visual acuity and
visual fields and tests for green color vision when possible. The inability
to monitor for this complication has limited the use of this agent
in young children. However, at doses of 20 mg/kg/d,
it can be safely administered to children of all ages.23 Ethambutol
is used as the fourth drug in a multidrug regimen, and its major
purpose is to prevent emergence of resistance to other drugs.
++
Streptomycin was the first effective antituberculosis drug. It
is given intramuscularly and is rapidly absorbed into the bloodstream,
reaching peak levels that are 50 to 100 times more than the MIC
of 0.2 μg/mL. It diffuses readily into
the pleural fluid, but does not diffuse into the CSF unless the meninges
are inflamed. Streptomycin is excreted mainly in the urine, with
80% recovery within 24 hours. The principal toxic effect
is eighth nerve damage, mainly of the vestibular branch, resulting
in vertigo and ataxia that is usually permanent. Hearing loss is
less common and usually affects the high-frequency range before
affecting the lower frequencies. Children readily adjust to vestibular
defect with minimal difficulty. At current dosage schedules, hearing
defects are rare in children. Streptomycin is a second-line drug
in most developed countries, used mostly in cases of drug-resistant
tuberculosis.
++
These drugs are controversial in the management of tuberculosis.
They can be used only if effective antituberculosis therapy is in
place. They are useful when the host inflammatory response to M
tuberculosis contributes to tissue damage. Generally accepted indications
are for the management of tuberculous meningitis, tuberculous pleural
effusion, pericarditis, and endobronchial disease. Prednisone at
2 mg/kg/d is used commonly for 4 to 6 weeks, then
weaned slowly.
++
The emergence of multidrug-resistant M tuberculosis strains
occasionally requires the use of secondary drugs. Ethionamide, cycloserine,
capreomycin, amikacin, rifabutin, and fluoroquinolones have been
used, but an expert in tuberculosis always should be consulted when
their use is contemplated in a child.
+++
Treatment of
Exposure and Infection
++
In the United States, children exposed to potentially infectious
adults with pulmonary tuberculosis should be started on treatment
with isoniazed if the child is younger than 5 years or has other
risk factors for the rapid development of tuberculosis disease.
Failure to do so may result in the development of severe tuberculosis
even before the tuberculin skin test becomes reactive; the “incubation” of
disease may be shorter than that for the skin test. The child is
treated for a minimum of 3 months after contact with the infectious
case is broken. After 3 months, the tuberculin skin test is repeated.
If the second test is positive, infection is documented and isoniazid
should be continued for a total of 9 months; if the second skin test
is negative, the treatment can be stopped.
++
Two circumstances of exposure deserve special attention. A difficult
situation arises when exposed children are anergic because of HIV
infection or other immunocompromise. These children are particularly
vulnerable to rapid progression of tuberculosis, and it may not
be possible to tell whether infection has occurred. In general,
these children should be treated as if they have tuberculosis infection. The
second situation is potential exposure of a newborn to a mother
or other adult with possible pulmonary tuberculosis. In general,
this exposure should be treated the same as for an older infant.
The neonate should be started on isoniazid and continued on it until
tuberculosis disease in the adult can be ruled out, or for 3 months
after the person with tuberculosis is no longer contagious.
++
The treatment of children infected with M tuberculosis before
they have developed disease is a mainstay of modern tuberculosis
control.20 Many large, well-documented studies have
shown that isoniazid is extremely effective in preventing the development
of tuberculosis disease in infected children. Because isoniazid
is so safe in this age group, any child or adolescent with a “positive” tuberculin
skin test or interferon-gamma release assay result and no evidence
of tuberculosis disease should receive treatment. In most cases,
treatment is 9 months of isoniazid. Isoniazid is usually given every
day by self-supervision, but can be administered twice weekly under
the direct observation of a health care worker in cases of high-risk
infection, particularly if an adult with active tuberculosis who
is also being treated twice a week is present in the home. The optimal
length of isoniazid therapy has been debated for 40 years. The summary
opinion of experts is that 9 months of therapy is the optimal length
of treatment for children with tuberculosis infection.
++
If a child is exposed to or infected with an isoniazid-resistant
but rifampin-susceptible strain of M tuberculosis, rifampin
should be given for 6 months. If the infecting strain is resistant
to both isoniazid and rifampin, usually two other drugs are used,
but an expert in tuberculosis should be consulted for this situation.
++
Over the past three decades, a large number of trials of antituberculosis
therapy for children with drug-susceptible pulmonary tuberculosis have
demonstrated that the optimal regimen is 6 months’ duration,
starting with at least three antituberculosis medications, usually
isoniazid, rifampin, and pyrazinamide.24 Isoniazid and
rifampin are continued for the entire 6 months, whereas pyrazinamide
is used only for the first 2 months of therapy. Medications are
usually given every day for the first 2 weeks to 2 months of therapy.
After this time, medications can be given safely and effectively
twice or thrice weekly under the observation of a health care worker.
In all the reported trials for these regimens, the overall success rate
for therapy was greater than 98%, and the incidence of
clinically significant adverse reactions was less than 2%.
If the child is at risk for being infected with isoniazid-resistant
tuberculosis because of previous treatment of the adult source case,
or because the child has lived in an area of the world where resistance rates
are high, most experts would add a fourth drug, usually ethambutol,
to the initial regimen, until the exact drug susceptibility of either
the child’s isolate or the adult source case’s
isolate can be established.
++
Controlled clinical trials for treating various forms of extrapulmonary
tuberculosis are almost nonexistent.25 Extrapulmonary
tuberculosis is usually caused by fairly small numbers of mycobacteria.
Most non–life-threatening forms of extrapulmonary tuberculosis
respond well to a 6-month treatment regimen using three or four
drugs in the initial phase, similar to that used for pulmonary tuberculosis.
One exception may be bone and joint tuberculosis, which is associated
with a higher failure rate when only 6 months of chemotherapy is
used, especially if surgical intervention has not been performed.
Some experts recommend at least 9 to 12 months of therapy for bone
and joint tuberculosis. Tuberculous meningitis has not usually been
included in trials of extrapulmonary tuberculosis because of its
serious nature and low incidence. Several more recent trials suggest
that 6 to 9 months of therapy is effective if isoniazid, rifampin, and
pyrazinamide are administered during the initial phase of treatment.
The official recommendation of the American Academy of Pediatrics
for tuberculous meningitis is 9 to 12 months of therapy that includes
at least isoniazid and rifampin and usually one or two other drugs
in the initial phase of treatment. Most experts add a fourth drug
at the beginning of therapy to protect against initial drug resistance.
++
In general, the treatment of tuberculosis in HIV-infected children
is the same as it is in children without HIV infection.26 Although some
experts previously recommended lengthening the duration of therapy
to 9 to 12 months in HIV-infected children, many trials have shown
that adults with HIV infection and tuberculosis can be treated for
the same length of time as adults without HIV infection who have
tuberculosis.
++
The incidence of drug-resistant tuberculosis is increasing in
many areas of the world. In the United States, approximately 10% of
isolates of M tuberculosis are resistant to at
least one drug. Many countries in Latin America and Asia routinely
report drug resistance rates of 20% to 30%. Rates
of drug resistance are unknown in many African countries. Patterns
of drug resistance among children tend to mirror those found in
adults in the same population. For children in the United States,
certain epidemiologic factors, such as being immigrants from Asia
or Latin America, or a history of previous antituberculosis treatment
in the adult source, correlate with drug resistance. Therapy for
drug-resistant tuberculosis is successful only when two bactericidal
drugs to which the infecting strain of M tuberculosis is susceptible
are given. When a child has a possible drug-resistant tuberculosis
disease, at least three, and usually four or five, drugs should
be administered initially, until the susceptibility pattern is determined
and a more specific regimen can be designed. The specific treatment
plan must be individualized for each patient, but durations of therapy
of 12 to 18 months are not uncommon.
++
Activity does not need to be restricted in children with tuberculosis
unless the child develops respiratory embarrassment or immobilization
is needed for treatment, as in some cases of vertebral tuberculosis.
Adequate nutrition is important, although reestablishment of weight
gain may take several months. The major problem with treating tuberculosis
in children and adults is nonadherence with therapy. Suspected cases
of tuberculosis must be reported to the local health department
so that it can compile accurate statistics, perform necessary contact
investigations, and assist both patients and health care providers
in overcoming barriers to adherence with therapy. In general, patients
with tuberculosis disease should be treated with directly observed
therapy, employing the help of a third party, such as a health department
worker who observes the child and family during the administration
of medication.
++
In general, children undergoing treatment for tuberculosis infection
or disease should be seen every 4 to 6 weeks to monitor adherence, to
observe for adverse reactions to medications, and to follow improvement
in clinical course. Routine biochemical monitoring for adverse reactions
is not necessary in asymptomatic children. Radiographic changes
with intrathoracic tuberculosis occur slowly, and frequent chest
radiographic monitoring is not necessary. A common practice for
treating pulmonary tuberculosis is to obtain a chest radiograph
at diagnosis and several months after the initiation of therapy
to ensure that no unusual changes have occurred. Children with tuberculosis
infection do not need a repeat chest radiograph.