Widespread
implementation of the strategy of directly observed treatment short
course (DOTS) during the 1990s resulted in improved global control of
tuberculosis.
1
However, its effectiveness has been limited in areas where poverty and
infection with the human immunodeficiency virus (HIV) or drug-resistant
tuberculosis are prevalent, and the emphasis on a positive sputum smear
as the diagnostic criterion actually excludes most children from care.
2
Tuberculosis remains a major but often unrecognized cause of disease
and death among children in areas where the disease is endemic
3;
service delivery in such areas is hampered by the absence of pragmatic
strategies to guide diagnosis and management. This article provides a
brief overview of basic principles, current controversies, and recent
advances related to the care of children with tuberculosis, with an
emphasis on intrathoracic disease.
Disease Burden and Recent Epidemiologic Shifts
Poor
ascertainment and reporting of cases of tuberculosis prevent accurate
estimation of the global burden of disease from tuberculosis in
children.
4
Among the 4,452,860 new cases reported in 2010 by the 22 countries with
the highest burden of disease from tuberculosis, only 157,135, or 3.5%
(range, 0.1 to 15.0), were in children. Best estimates suggest that
children (defined as persons younger than 15 years of age) account for
approximately 11% of the burden of disease from tuberculosis,
5
suggesting that just over 332,000 cases of tuberculosis in children
went undiagnosed or unreported in these countries. Although
overdiagnosis does occur, underdiagnosis is the rule in most areas where
there is a high burden of disease and children with tuberculosis can
access services only through referral hospitals. The problem of
underdiagnosis in children is illustrated by the low pediatric caseload
reported in four countries with a high disease burden, where rates
exceeding 10% of all reported cases would be expected: Russia, 0.8%;
India, 1.1%; Nigeria, 1.4%; and Brazil, 3.5%.
1
In areas such as North America and Western Europe, where there is
minimal internal transmission and routine provision of postexposure
prophylaxis, a smaller proportion of children is affected, and most
cases of childhood tuberculosis occur in immigrant populations.
6,7
Coinfection
with HIV has had a major epidemiologic effect, especially in
sub-Saharan Africa. Apart from leading to an increase in the absolute
number of patients with tuberculosis, it has induced a pronounced shift
in the age and sex of patients toward young women of childbearing age.
8
The effect of this demographic shift can be seen in the high rates of
exposure to tuberculosis among infants born to mothers infected with HIV
9 and in the high rates of tuberculosis among infants infected with HIV.
10
Early initiation of antiretroviral therapy is the single most important
intervention for reducing overall mortality and the risk of
tuberculosis among HIV-infected infants,
11 with isoniazid preventive therapy providing additional benefit.
12
The emergence of drug-resistant tuberculosis poses a major threat to global tuberculosis control.
13
The initial complacency in addressing the problem was influenced by
studies indicating that the acquisition of isoniazid resistance reduced
the pathogenicity of the strain.
14
However, the development of multidrug-resistant tuberculosis
(characterized by resistance to isoniazid and rifampin) in children
exposed to persons with infectious drug-resistant tuberculosis,
15 as well as its clonal spread in New York City
16 and the Russian prison system,
17
has provided clinical evidence of the transmissibility of
multidrug-resistant strains. Additional proof was provided by an
explosive outbreak of extensively drug-resistant tuberculosis
(multidrug-resistant bacteria with additional resistance to a
fluoroquinolone and a second-line injectable agent) among patients with
HIV infection in South Africa.
18
Although the incidence of drug-resistant tuberculosis among children is
unknown, pediatric cases provide a valuable epidemiologic perspective,
since they reflect ongoing transmission within communities. In places
where the rates of drug-resistant tuberculosis in children have been
monitored, the rates among children were similar to those among adults
from the same community.
15
The World Health Organization (WHO) estimated that in 2008, 3.6% of
incident tuberculosis cases globally were of the multidrug-resistant or
extensively drug-resistant type, which suggests that there was a similar
burden of this type of disease among children.
13
Natural History of Disease
An
understanding of the natural history of tuberculosis is required to
appreciate both the variations in susceptibility to disease and the
diverse spectrum of clinical manifestations observed in children.
Meticulous descriptions of tuberculosis in the literature published
before the introduction of chemotherapy provide valuable insight into
the sequence of events that follows primary infection with
Mycobacterium tuberculosis (
Table 1Table 1
Clinical Syndromes Associated with Tuberculosis in Children. and
Figure 1Figure 1
Clinical Syndromes of Intrathoracic Tuberculosis in Children.).
19,20
An important observation documented in these earlier studies was the
presence of transient hilar adenopathy, and even excretion of
M. tuberculosis, in children who had never had progression to disease.
21
This finding poses a major problem in case definition for studies, such
as vaccine efficacy trials, that use active case-finding strategies in
populations of asymptomatic children who have been exposed to persons
with infectious disease.
22
The recent formulation of an international consensus on reference
standards and uniform research methodology should facilitate progress.
23-25
The
sequence of events that follows reinfection (which is common in areas
where tuberculosis is endemic) remains poorly defined. In cases of
recurrent tuberculosis, strain typing makes it possible to differentiate
relapse from reinfection but cannot be used to quantify the risk of
reinfection. Composite data analysis suggests that there is a 79%
reduction in the risk of disease progression among previously infected
immunocompetent adults as compared with previously uninfected adults
after documented exposure
26; however, the epidemic contribution made by reinfection depends on the frequency of its occurrence in a particular environment.
It
is important to differentiate infection from disease, since infection
is a common event and the approaches to managing the two conditions are
very different. Disease progression is usually indicated by persistent,
nonremitting symptoms, although the rate of progression is variable.
21
In the vast majority of cases (>90%), disease occurs within 1 year
after the primary infection, with the youngest children at greatest risk
for progression. The risk profile is bimodal, with adolescents being at
increased risk.
21
Exploring the mechanisms underlying the increased risk and the sudden
switch in phenotype toward adult-type cavitary disease that occurs with
the onset of puberty should provide new insights into the
immunopathogenesis of tuberculosis.
27
Approaches to Diagnosis
Children
are usually evaluated for tuberculosis after presenting with symptoms
or signs suggestive of disease (passive case finding) or as a result of
contact investigation or routine immigration screening (active case
finding). The clinical presentation of children whose infection is
detected through active case finding differs from that of children whose
infection is detected through passive case finding, with the former
group often having infection but not disease or having disease in a very
early phase. Among children in whom
M. tuberculosis infection
is detected, young children and those with recent exposure are at
increased risk for progression to disease. Knowledge of the child's
status regarding the likelihood of exposure changes the pretest
probability of disease and the positive predictive value of subsequent
investigations.
Clinical Evaluation
Taking
a careful patient history is essential for exploring the nature of the
exposure and accurately characterizing the symptoms.
28
The diversity of the clinical presentation and the nonspecific nature
of most symptoms complicate diagnosis. Constitutional symptoms often
include failure to thrive (deviation from the expected growth-curve
trajectory) and reduced playfulness; low-grade or intermittent fever is
seen less frequently.
28
With airway involvement, the usual presenting symptom is a persistent,
nonremitting cough or wheeze that is unresponsive to the treatment for
likely alternative causes. Clinical signs are often subtle, and no
diagnostic scoring system has been adequately validated
29;
the sensitivity and specificity of the clinical diagnostic approaches
for tuberculosis are particularly poor in children with HIV infection.
30
Imaging Studies
In
clinical practice, chest radiography is one of the most useful
diagnostic studies. Both frontal and lateral views should be obtained,
since a lateral view assists in the assessment of the mediastinal and
hilar areas. The radiographic findings vary, but pronounced hilar
adenopathy, with or without airway compression, is highly suggestive of
tuberculosis. The International Union against Tuberculosis and Lung
Disease compiled an atlas of illustrative cases.
31
Unfortunately, the technical quality of the radiographs obtained in
areas where tuberculosis is endemic is often poor or radiographic
facilities are not available.
Ultrasonography is useful in
confirming the presence of pericardial or pleural effusions and
abdominal lymphadenopathy. High-resolution computed tomography (CT)
offers excellent anatomical visualization,
32
but because of the high cost of CT and the high level of radiation to
which the patient is exposed, as compared with other forms of imaging,
it should be reserved for complicated cases. Both CT and magnetic
resonance imaging (MRI) are particularly helpful in visualizing the
intracranial effects of disease, although MRI is more sensitive to the
detection of brain-stem lesions and early perfusion defects in patients
with tuberculous meningitis, and it also allows superior evaluation of
the spine and soft tissues.
33
Laboratory Studies
Table 2Table 2
Diagnostic Studies for Tuberculosis in Children. provides an overview of the laboratory examinations used in the diagnosis of tuberculosis. (See the
Supplementary Appendix,
available with the full text of this article at NEJM.org, for a list of
references that includes recent comprehensive studies that focus on
children.) Microscopical examination of sputum smears is the cornerstone
of diagnosis in most countries, but its usefulness is limited in young
children with paucibacillary disease who are unable to expectorate. Both
the tuberculin skin test and the interferon-γ release assay fail to
differentiate
M. tuberculosis infection from active disease. The WHO recommends that the assay not be used in place of the tuberculin skin test,
34
although the two tests may be complementary, improving the sensitivity
or specificity of the assessment in specific clinical circumstances.
35
Collecting
specimens of spontaneously produced sputum in young children is
problematic; gastric aspiration and sputum induction (with or without
laryngopharyngeal suction) are feasible alternative methods of
collection.
36
The “string test” (which involves the use of an esophagogastroduodenal
nylon yarn that can absorb swallowed sputum) works well in adults with
HIV infection who have little sputum,
37 and preliminary test results in children seem promising.
38 Fine-needle aspiration biopsy is very useful in children with a peripheral lymph-node mass.
39 Although the Xpert-MTB/RIF assay (Cepheid) is less sensitive than liquid cultures for the detection of
M. tuberculosis
in both children and adults, it provides results quickly, is highly
specific, and detects resistance to rifampin. When two sputum samples
are used, the assay detects three times as many cases as when microscopy
is used
40 but only about 70% of the cases when liquid culture is used.
41,42
Currently, access to the Xpert-MTB/RIF assay is limited, but the
efforts of the Global Laboratory Initiative, a working group of the Stop
TB Partnership, should increase its availability.
Each of the
diagnostic approaches described has limitations. However, when a
combination of clinical, radiologic, laboratory, and histopathologic
findings are consistent with a diagnosis of tuberculosis and there is
epidemiologic evidence of exposure to tuberculosis or immunologic
evidence of
M. tuberculosis infection, an accurate diagnosis is possible in most cases.
42
Principles of Disease Management
Although
every effort should be made to attain bacteriologic confirmation of
disease, confirmation rates remain low, and treatment initiation should
not be delayed in immunologically vulnerable children. Unfortunately,
some tuberculosis-control programs will not initiate treatment without
bacteriologic confirmation, citing the risk of adverse events from
treatment and concerns about amplifying drug resistance. However,
adverse events are rare in young children who are treated with
first-line tuberculosis drugs, and they are at low risk for acquiring or
transmitting drug-resistant tuberculosis. Despite differences between
adult and pediatric tuberculosis (see Table S1 in the
Supplementary Appendix),
the principles of disease management are similar. The purpose of
tuberculosis treatment is to cure the individual patient, whereas the
intent of public health efforts is to terminate transmission and prevent
the emergence of drug resistance. Rapidly metabolizing bacilli are
quickly killed by bactericidal agents with high activity, thereby
terminating transmission, ameliorating symptoms, and decreasing the risk
of drug resistance (by reducing the population from which
drug-resistant mutants emerge). The use of drugs with sterilizing
activity is required to eradicate persistent subpopulations of
intermittently metabolizing bacilli, thereby preventing relapse and
effecting a long-term cure. Pragmatic disease classification should
guide case management (
Figure 2Figure 2
Algorithm for the Diagnosis and Classification of Tuberculosis in Children.).
The
most important variables to consider in disease management are
bacillary load and anatomical location. Drug resistance should be
considered in children from areas with a high prevalence of
drug-resistant tuberculosis and in those who have had documented contact
with a person with drug-resistant disease, with someone who died during
treatment for tuberculosis or who is not adhering to therapy, or with
someone who is undergoing retreatment for tuberculosis. Young children
with uncomplicated disease who are from areas with a low prevalence of
isoniazid resistance can be treated with three drugs (isoniazid,
rifampin, and pyrazinamide) during the 2-month intensive phase of
treatment, followed by isoniazid and rifampin only during the 4-month
continuation phase.
43
However, children who have extensive or cavitary lung disease (either
of which suggests a high bacillary load) or who are from areas with a
high prevalence of isoniazid resistance should receive a fourth drug
(ethambutol, which is safe in children of all ages) during the 2-month
intensive phase of treatment.
43 Table S2 in the
Supplementary Appendix
summarizes the mechanism of action, main adverse effects, and
recommended pediatric dosages of drugs prescribed for the first-line
treatment of tuberculosis.
In the absence of drug resistance, the
most frequent cause of a poor response to treatment is nonadherence to
the regimen. Although empirical evidence of the value of DOT is limited,
as a method of medication administration, it is preferable to
unsupervised administration and to administration by a parent.
44
In most instances, a recurrence of tuberculosis more than 12 months
after treatment represents reinfection. Standard first-line treatment is
appropriate in the absence of exposure to a person who is believed to
have drug-resistant tuberculosis. Use of an escalated retreatment
regimen that includes streptomycin is discouraged.
43
When there is a poor clinical response in a patient with a history of
adherence to treatment, a reevaluation of the diagnosis should be
conducted, including consideration of the immune reconstitution
inflammatory syndrome (IRIS) and drug resistance. Principles for the
management of drug-resistant tuberculosis in children have been
summarized elsewhere,
45 and excellent outcomes have been reported.
46
Immune
recovery after the initiation of antiretroviral treatment for
HIV-coinfected individuals or nutritional rehabilitation may unmask
subclinical disease or induce paradoxical deterioration, despite
adequate treatment for tuberculosis. A finding of IRIS does not indicate
treatment failure, and treatment should not be interrupted; patients
with severe IRIS may require a course of glucocorticoids. Despite the
risk of IRIS, data on adults indicate that antiretroviral therapy is
most effective when initiated within 8 weeks after the start of
tuberculosis treatment, or for patients with severely compromised immune
systems, within 2 to 4 weeks after the start of treatment.
47 The only exception would be patients with central nervous system tuberculosis, in whom IRIS can have devastating consequences.
48
With HIV-associated tuberculosis, treatment should be given daily, and a
prolonged course may be required, depending on the degree to which the
patient's immune system has been compromised and the extent of disease.
49,50
Prevention and Control
Transmission
of tuberculosis within health care facilities is a particular concern
in settings where immunologically vulnerable children may be exposed. In
hospitals and clinics, careful consideration should be given to areas
where patients are treated and to air-exchange patterns. It is also
important to recognize that symptomatic parents or caregivers may pose
transmission risks.
51
Vaccination with bacille Calmette–Guérin (BCG) reduces the risk of
disseminated (miliary) disease and tuberculosis meningitis in young
children but offers no consistent protection against adult-type
tuberculosis.
52
No benefit of BCG vaccination has been established in HIV-infected
children, and it is contraindicated in such children because of the risk
of disseminated BCG disease.
53 The development of a safe and effective vaccine remains a top priority among global health researchers.
With
good adherence, a 6-month course of isoniazid preventive therapy
provides excellent protection against tuberculosis disease.
54
Despite universal recommendations regarding the provision of preventive
therapy and strong evidence of the greatly increased risk of
tuberculosis and the increased mortality among children in close contact
with persons who have tuberculosis,
55
the implementation of preventive strategies remains poor. Pragmatic
solutions are required to close the pronounced gap between policy and
practice.
56
Parents are often reluctant to provide preventive treatment for an
otherwise well child, and the long duration of preventive therapy is a
source of further discouragement. One study showed that a 3-month course
of preventive therapy with isoniazid and rifampin was similar in
efficacy to a 9-month course of isoniazid alone.
57 A regimen of 12 doses of weekly rifapentine and isoniazid has been shown to be efficacious in adults,
58
but this regimen is not yet recommended for children younger than 12
years of age because specific data on safety and efficacy in this age
group are required. The efficacy of abbreviated regimens has not been
well studied in children with HIV infection. A disadvantage of the
regimens that include rifampin or rifapentine is the interactivity of
these drugs with the protease inhibitors included in the antiretroviral
therapy provided for infection with HIV
49,50; rifabutin is less reactive, but its use in preventive therapy regimens has not been evaluated.
Although
the value of postexposure prophylaxis is universally acknowledged, the
value of preexposure prophylaxis remains in question. Successive
randomized, controlled trials of preexposure prophylaxis in children
with HIV infection have had contradictory findings. The first of these
trials, involving children with minimal access to antiretroviral
therapy, was discontinued because of increased mortality in the placebo
group.
59
The reduction in mortality among those receiving isoniazid preventive
therapy was confined to the first 2 to 3 months of treatment, raising
the possibility that subclinical tuberculosis was present at trial
entry. The second trial enrolled young infants (3 to 4 months of age)
who had been exposed to HIV but had no known exposure to tuberculosis.
60
The infants were randomly assigned to receive open-label isoniazid or
placebo; those who were infected with HIV also received early
antiretroviral therapy. All infants were closely monitored for
subsequent exposure to tuberculosis. The investigators found no
significant difference in the incidence of tuberculosis or mortality
between the treatment and placebo groups, suggesting that preexposure
prophylaxis against tuberculosis has little value if HIV-infected
infants are enrolled in management programs early, with meticulous
monitoring for tuberculosis exposure and provision of postexposure
prophylaxis. However, the value of preexposure prophylaxis in areas
where monitoring for tuberculosis exposure is likely to be poor remains
unresolved.
49,54
With
the use of isoniazid preventive therapy after the completion of
tuberculosis treatment in HIV-infected adults, it has been estimated
that 83 recurrences can be prevented for every 1000 cases treated.
12
The WHO recommends isoniazid preventive therapy for 6 to 36 months
after the completion of tuberculosis treatment in all patients with HIV
infection, including children who live in areas with a high prevalence
of tuberculosis. However, the added value of preventive therapy as
compared with ongoing screening for tuberculosis exposure and meticulous
postexposure prophylaxis has not been evaluated.
It is possible
to drastically reduce the morbidity and mortality associated with
pediatric tuberculosis if case detection is improved and preventive
therapy and curative treatment are made more accessible globally. Many
challenges and research priorities remain (Table S3 in the
Supplementary Appendix),
but while we await the development of new vaccines, better diagnostics,
and shorter treatment regimens, much can be achieved with pragmatic
approaches and sensible application of existing tools.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No potential conflict of interest relevant to this article was reported.
We thank Mario Perez, M.D., for his valuable assistance with an earlier version of Figure 1.
Source Information
From
Grupo Tuberculosis Valle-Colorado and Clínica León XIII, IPS
Universidad de Antioquia, Medellín, Colombia (C.M.P.-V.); and the Sydney
Emerging Infections and Biosecurity Institute and Children's Hospital
at Westmead, University of Sydney, Sydney (B.J.M.).
Address
reprint requests to Dr. Marais at the Clinical School, Children's
Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW 2145,
Australia, or at
ben.marais@health.nsw.gov.au.
