Pediatric Tuberculosis
Pediatric Tuberculosis: Excerpt from Pediatric Infectious Disease
Epidemiology
After years of decline in the national rates of tuberculosis, there were
discussions in the early 1980s regarding the elimination of the disease in the
United States. However, from the mid-1980s to the early 1990s, there was a 15%
increase in reported cases. Children were even more greatly affected by this
trend, with an increase in reported cases in children 5 to 14 years of age of
almost 40%. The increase in cases of tuberculosis was thought to be the result
of an increase in medically underserved populations, an increased number of
patients from endemic areas, and an increase in patients infected with human
immunodeficiency virus (HIV) resulting in large numbers of contagious patients.
Although infection control efforts have been somewhat successful in controlling
tuberculosis, it remains a major cause of morbidity and mortality in selected
areas of the United States. This chapter discusses both the pathophysiology of
pediatric tuberculous infection and the diagnosis and therapy of latent and
active disease.
Etiology
Infection with Mycobacterium tuberculosis (MTB) begins with the inhalation of airborne bacilli. After inhalation, the
bacilli reach the pulmonary alveoli and are transported through pulmonary
lymphatic channels to hilar lymph nodes. They can then enter the bloodstream by
way of the thoracic duct. Although the entrance of MTB into the host is
respiratory, the organism can thus be spread to virtually every organ in the
body. Spread of small numbers of bacilli result in clinically inapparent foci
of infection. Regions most commonly seeded include the meninges, the pleura,
and the bone. A reaction involving macrophages, lymphocytes, and ingested
organisms then occurs, and tubercles are formed. When this reaction occurs, a
tuberculin skin test will become positive, indicating that exposure to MTB has
occurred.
The initial immune containment of clinically inapparent infection may not be
permanent, and reactivation is possible at any time. Infants younger than 1
year of age have about a 50% chance of developing active disease. In children
younger than 5 years of age, the risk for reactivation to active disease is
about 25%.
Presentation of Latent Tuberculosis
A child who is infected with MTB without clinical or radiographic signs is
defined as having latent infection. There is a great advantage in diagnosing
and treating latent infection because it can avoid subsequent reactivation and
the development of active disease.
Diagnosis
Tuberculin skin testing (TST) is the method used for diagnosing latent
infection. The TST used is the Mantoux test, containing five tuberculin units
administered intradermally. This test is read as millimeters of induration at
48 to 72 hours.
The definition of a positive TST is based on a variety of epidemiologic and
clinical factors. Induration of greater than 15 mm is considered positive in
children older than 4 years of age without specific risk factors. A TST of
greater than or equal to 10 mm is positive in children younger than 4 years of
age and in children with other medical conditions, including renal failure,
diabetes, or malignancy. This is also considered positive in children with
increased risk for exposure, including those residing in areas with a high
prevalence of tuberculosis. An induration of greater than 5 mm is considered
positive in children receiving immunosuppressive therapy or with underlying
immunodeficiency conditions. This induration is also considered positive if one
has close contact with a case of active tuberculosis or has clinical or
radiographic evidence of the disease (Table 12.1).
Use of Anergy Testing
Up to 20% of patients with active tuberculosis have a negative TST at initial
presentation. In the 1970s, the idea of evaluating negative tuberculin tests
results by assessing reactions to a panel of unrelated antigens (such as
candida or tetanus) was proposed. This concept of
anergy testingbecame a routine adjunct to tuberculin skin testing. Despite its widespread use,
the validity of this approach has never been proved. The ability to respond to
other antigens has been shown not to improve the reliability of a negative TST
test. Studies have also shown that the results of anergy testing do not predict
the risk for progression to active disease in either HIV-negative or
HIV-positive patients. For this reason, routine anergy testing, used as a
validation to tuberculin skin testing, is not recommended by most infectious
disease specialists.
Although Bacille Calmette-Guérin (BCG) vaccine is not routinely given in the United States, the pediatrician
will need to interpret TST in children who have received this vaccine. After
BCG vaccination, distinguishing a positive reaction secondary to latent
infection from reactivity to BCG is difficult. One study found that only 8% of
persons who had received BCG vaccine at birth had a positive TST 15 years
later. It is for this reason that the American Academy of Pediatrics recommends
the same criteria for TST interpretation in patients who have received BCG.
Booster Phenomenon
Reactivity from TST resulting from MTB exposure may actually decrease over time
in some patients, resulting in a nonreactive test despite a history of past
exposure and latent infection. In these cases, the stimulus of a tuberculin
test may actually
“boost” or increase the size of any subsequent TST. This positive TST may be misleading
because it may suggest recent tuberculin conversion when in fact latent
infection has been present for years. Adults who undergo annual TST,
particularly health care workers, often undergo two-step testing on initial
evaluation with a second TST administered 1 week after the initial test. In
this way, the boosting phenomenon can be appropriately evaluated and not
mistaken for a recent skin test conversion.
Management of Latent Infection
Children who have a positive TST require a chest x-ray. In children younger than
18 years of age with a positive TST and negative chest x-ray, the diagnosis of
latent tuberculous infection is made. Monotherapy is acceptable only in the
case of latent tuberculosis infection. Patients younger than 18 years of age
who have latent infection with an isoniazid-sensitive organism are treated with
isoniazid for 9 months.
Latent infection with an isoniazid-resistant organism is treated with a 6-month
course
of oral rifampin. Children younger than 5 years of age have a very high risk for
severe tuberculosis when exposed to a contagious index case. Even if such a
child
’s first TST is negative, it is recommended that antituberculosis medication be
given. Medication can then be discontinued if a second TST 3 months later
remains negative and the child has no clinical signs of tuberculosis.
Previously, the Centers for Disease Control (CDC) recommended prophylaxis with
pyrazinamide and ethambutol for patients exposed to isoniazid- and
rifampin-resistant mycobacteria. Surveillance done by the CDC has reported
numerous cases of severe liver injury in patients receiving this prophylaxis.
The updated recommendation is for clinicians to practice extreme caution in
treating latent infection with the combination of pyrazinamide and ethambutol,
especially if there are risk factors for liver injury, including concurrent
hepatotoxic medications or alcohol consumption. Patients who elect to take this
regimen should be followed closely, both clinically and with frequent
measurement of serum aminotransferase levels.
Active Tuberculous Infection
In a percentage of cases after exposure to MTB, the latent tuberculous infection
can reactivate. At this point, the child is considered to have active
tuberculous infection. It is important to note that there are a variety of
clinical syndromes associated with active disease.
Tuberculous Pneumonia
Epidemiology
The most common clinical manifestation of active pediatric tuberculous disease
is pulmonary tuberculosis. Unlike adults who present with cavitary disease,
pediatric pulmonary tuberculosis usually presents as hilar adenopathy.
Presentation
The hilar enlargement of pulmonary tuberculosis typically produces little or no
symptoms in older children; up to 80% of children older than 5 years of age are
asymptomatic. Unlike older children, infants with hilar adenopathy may become
symptomatic. The smaller caliber of bronchi in infants is more easily
compressed by the enlarging lymph nodes, and the progressive lymphadenopathy
can cause obstruction with resultant air trapping and wheezing (Figs. 12.1 and
12.2).
Diagnosis
The diagnosis of pulmonary tuberculosis in the child often rests on a positive
TST and a chest radiograph that shows pulmonary disease. Therefore, accurate
radiographic diagnosis is crucial for correct diagnosis of pediatric pulmonary
tuberculosis. When there is uncertainty about whether hilar adenopathy is
present, computed tomography (CT) has been shown to be helpful in confirming
the diagnosis.
Isolation of MTB from clinical specimens remains the gold standard for
diagnosis. Isolation of MTB in children is more difficult than in adults, who
frequently have cavitary disease and can produce large amounts of sputum for
culture. An aggressive workup aimed at isolation of infective mycobacteria
should always be attempted because this will guide subsequent therapy.
Even in tertiary medical centers, the diagnosis in children of MTB is confirmed
by culture no more than 40% of the time. Bronchoalveolar lavage (BAL) yields a
pathogen in about 20% of cases. The low yield for BAL is likely due to the
specimen collected over a brief time period and only in selected pulmonary
segments. The fact that children often swallow respiratory secretions can be
used in the isolation of MTB. Gastric lavage of early-morning stomach contents
contains material collected over an entire evening and can yield the positive
culture in up to 50% of cases. A recent study also suggested that this
procedure could be successfully done during serial outpatient visits, provided
appropriate support systems were in place. The use of proper technique in the
collection of gastric aspirate is crucial in maximizing the yield of this
procedure. Gastric aspiration should be performed in the early morning when the
patient has been without food for at least 8 hours. Stomach contents are
aspirated first through an 8 French feeding tube. Following this, 30 mL of
sterile water (not saline) is placed into the stomach and then removed and
added to the first collection. Gastric pH should be neutralized within 30
minutes because MTB does not tolerate acid environments. Gastric pH is
typically neutralized with a 10% sodium bicarbonate solution. Specimens need to
be refrigerated and transported within 4 hours of collection.
Miliary Tuberculosis
Epidemiology
Miliary tuberculosis represents one of the most severe manifestations of
tuberculosis. It represents unchecked dissemination of bacilli to secondary
sites, including the liver, brain, and bones.
Presentation
Fever, poor weight gain, and increased respiratory rate are common presenting
signs of miliary tuberculosis. Patients with miliary disease may also have
diffuse lymphadenopathy and organomegaly.
Diagnosis
Appearance of too-numerous-to-count nodules in the chest x-ray suggests miliary
tuberculosis. The nodules may be visualized on CT of the brain even in the
absence of cerebrospinal pleocytosis. It is important to realize that, in the
setting of an ineffective immune response to tuberculosis, skin testing is
frequently negative in miliary disease (Figs. 12.3 and 12.4).
In the setting of miliary disease, cultures bronchoscopy and gastric aspirate
are often positive. Biopsy samples of affected organ sites, such as liver,
lung, or bone marrow, can also yield the organism.
Tuberculous Meningitis
Etiology
Tuberculosis meningitis arises from hematogenous dissemination that forms
tubercles in the brainstem. After reactivation, these foci may rupture,
discharging bacilli into the spinal fluid. A thick exudate subsequently
develops, which then impedes the flow of cerebrospinal fluid (CSF).
Presentation
A typical history for tuberculous meningitis is one of progressive lethargy and
vomiting over several weeks as hydrocephalus develops and intracranial pressure
increases. The chronicity of tuberculosis meningitis helps distinguish it from
the more common self-limited pediatric illnesses, such as viral meningitis or
gastroenteritis.
Diagnosis
In tuberculosis meningitis, CSF examination reveals several hundred cells, most
of which are lymphocytes. Cerebrospinal glucose is low, and protein is often
elevated. CT of the brain often shows basilar enhancement with hydrocephalus
(Fig. 12.5). CT can also be helpful in suggesting the diagnosis because
hydrocephalus is a rare occurrence in viral or uncomplicated bacterial
meningitis. Acid-fast staining and culture of 1 mL of CSF rarely shows
organisms; obtaining a larger volume of up to 15 mL and then cytocentrifuging
this larger volume can result in positive acid-fast stain and culture in up to
90% of cases. Although there has been considerable experience in the use of
nucleic acid amplification tests for the detection of MTB in respiratory
specimens, the use of this technology in CSF is still investigational.
Tuberculous Pleural Effusion
Etiology
Tuberculous pleural effusion is secondary to rupture of subpleural foci into the
pleural space. The rupture of subpleural foci into the pleural space 6 to 12
weeks after primary infection then promotes a delayed hypersensitivity response
to the mycobacterial proteins, resulting in a pleural effusion.
Presentation
Patients can present with fever, cough, and pleuritic pain. Night sweats and
hemoptysis are occasionally seen. The chest radiograph often reveals a
unilateral pleural effusion (Fig. 12.6). The natural history of tuberculous
pleural effusion is complete or significant clearance of the effusion, even
without treatment. However, untreated patients have a high rate of developing
active pulmonary or extrapulmonary disease within a year. Progression to active
disease is greater in young children and immunocompromised patients.
Diagnosis
The diagnosis is suggested in a patient with a unilateral pleural effusion who
has a history of exposure to tuberculosis. A one-time thoracentesis is usually
indicated because it allows examination of the pleural fluid for diagnostic
purposes and can help exclude other etiologies. The pleural fluid usually
reveals several hundred cells, most of which are lymphocytes. Less than one
third of patients have a positive acid-fast stain or acid-fast culture from
pleural fluid. Yield of pleural biopsy is significantly higher and approaches
75%. Adenosine deaminase (ADA) is an enzyme involved in purine catabolism; high
levels of ADA have been reported in pleural fluid of patients infected with
tuberculosis. Elevated levels of ADA can also be found in patients with an
increased number of lymphocytes in the pleural fluid; thus, patients with
leukemias and lymphomas can have misleading results. Polymerase chain reaction
for the detection of mycobacterial DNA in pleural effusions is increasingly
performed and has a sensitivity of 70% with a specificity of 100%. Most
patients with tuberculous pleural effusion have strongly reactive skin tests,
and empiric treatment is often given to a patient with a unilateral pleural
effusion, a strongly reactive TST, and no other obvious etiology for the
effusion.
Management of Active Pediatric Tuberculosis
Critical to effective therapy of tuberculosis is the understanding of the
presence of naturally occurring mutant organisms within a large population of
tuberculous bacilli. Subpopulations of drug-resistant bacteria are always
present within a population of drug-susceptible bacteria. Effective treatment
of tuberculosis requires the administration of at least two drugs to which the
bacilli is sensitive. If only one effective medication is given, secondary
resistance develops within the entire bacilli population.
There was a time when effective two-drug therapy could be guaranteed with the
administration of isoniazid and rifampin. The incidence of drug-resistant
tuberculous disease continues to increase, largely the result of improper
treatment and poor compliance. When initiating treatment for tuberculosis, one
can no longer assume isoniazid sensitivity.
When initiating treatment, there should always be an aggressive workup to
determine susceptibilities of the infecting mycobacteria. Often, this can be
done by finding the index case and obtaining sensitivities on that isolate.
This is successful in about one half of cases. If this process is unsuccessful,
gastric aspirates and bronchoscopy are often used in an effort to isolate
infecting organisms.
In an effort to ensure the use of at least two drugs to which the infecting
organism is sensitive, the initial regimen often includes four drugs. The
following is a summary of the front-line medications used in pediatric
tuberculosis (Table 12.2):
Isoniazid. This drug is bactericidal and penetrates the CSF. Dosage is 10 to 15 mg/kg per
day. INH is metabolized in the liver by acetylation. In children, there is no
correlation between acetylation efficiency rate and the rate of adverse
reaction. The side effects of hepatitis are extremely rare in children. The
routine monitoring of liver function tests and vitamin supplementation in
patients taking isoniazid alone is not recommended.
Rifampin. This drug is bactericidal and again metabolized by the liver. Dosage is 15 mg/kg
per day. Major side effects include orange discoloration of body fluids and
interference with oral contraceptives.
Pyrazinamide. This is a well-tolerated drug that penetrates the CSF well. The dose is 20 to 40
mg/kg per day. The major side effects, which are extremely rare, include
hepatitis and an increase in uric acid levels.
Ethambutol. Reports of optic neuritis, which manifests clinically as color blindness,
previously precluded use in children because it was thought that children may
not be able to verbalize any early visual changes. It has been shown that, at a
lower dose of 15 mg/kg per day, the optic neuritis does not occur. Ethambutol
is now considered the front-line fourth drug when a fourth drug is indicated.
Duration of Treatment
Using data from thousands of children being treated for tuberculous disease, the
American Academy of Pediatrics has issued guidelines for treatment. A 6-month
regimen consisting of isoniazid, rifampin, and pyrazinamide for the first 2
months, followed by isoniazid and rifampin for the remaining 4 months, is
recommended for the treatment of drug-susceptible pulmonary MTB disease.
Extrapulmonary tuberculosis, including meningitis and miliary disease, is
generally treated for a total of 12 months.
Selected Readings
Abernathy RS. Tuberculosis: an update. Pediatr Rev 1997;18(2):50–8.
Janner D, Rutherford M, Azimi P. Tuberculous meningitis in children. Pediatr Emerg Care 1993;9(5):
281–284.
Jasmer RM, Nahid P, Hopewell, PC. Latent tuberculosis infection. N Engl J Med 2002;347(23):
1860–1866.
Lobato MN, Loeffler AM, Furst K, et al. Detection of Mycobacterium tuberculosis
in gastric aspirates collected from children: hospitalization is not necessary.
Pediatrics 1998;102(4):E40.
Neu N, Saiman L, San Gabriel P, et al. Diagnosis of pediatric tuberculosis in
the modern era.
Pediatr Infect Dis J 1999;18(2):122–126.
Slovis BS, Plitman JD, Haas DW. The case against anergy testing as a routine
adjunct to tuberculin skin testing.
JAMA 2000;283(15):2003–2007.
Pictures
Book Source Details
- Book Title: Pediatric Infectious Disease
- Author(s): Donald Janner MD
- Year of Publication: 2004
- Copyright Details: Pediatric Infectious Disease, Copyright © 2004 Lippincott Williams & Wilkins.
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Title: Pediatric Infectious Disease
Authors: Donald Janner MD
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Copyright: 2004
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