ARTICLE

Latent Tuberculosis Infection in Children: A Call for

Revised Treatment Guidelines
S. Maria E. Finnell, MDa,b,c, John C. Christenson, MDb,c, Stephen M. Downs, MD, MSa,d

aChildren’s Health Services Research and bPediatric Infectious Diseases, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana; cCenter for

International Adoption and Geographic Medicine, Riley Hospital for Children, Indianapolis, Indiana; dRegenstrief Institute for Healthcare, Indianapolis, Indiana

The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject What This Study Adds

Isoniazid for 9 months is currently the recommended treatment for latent TB in immi- In this study, we asked whether there is a rate of isoniazid resistance at which a different
grant children. However, worldwide, WHO surveillance data have shown an increased regimen should be considered. This rate was calculated to 11%. This result has the
rate of isoniazid resistance. potential to affect treatment of immigrant children from many countries.

ABSTRACT
BACKGROUND. Guidelines for latent tuberculosis infection do not consider drug-resis-
tance patterns when recommending treatment for immigrant children.
www.pediatrics.org/cgi/doi/10.1542/
OBJECTIVES. The purpose of this research was to decide at what rate of isoniazid resis- peds.2008-0433
tance a different regimen other than isoniazid for 9 months should be considered. doi:10.1542/peds.2008-0433

METHODS. We constructed a decision tree by using published data. We studied 3 Key Words
tuberculosis, antibiotic resistance,
regimens considered to be effective for susceptible organisms: (1) isoniazid for 9 guideline, child, cost-effectiveness analysis
months, (2) rifampin for 6 months, and (3) isoniazid for 9 months plus rifampin for Abbreviations
6 months. In addition, we evaluated a regimen of isoniazid and rifampin for 3 LTBI—latent tuberculosis infection
months. Our base case was a 2-year-old child from Russia with a tuberculin skin test BCG—Bacille Calmette-Guérin
reaction of 12 mm. We assumed a societal perspective and expressed results as cost TB—tuberculosis
TST—tuberculin skin test
and cost per case of tuberculosis prevented. We conducted sensitivity analyses to test WHO—World Health Organization
the stability of our model. MDR—multidrug resistance
Accepted for publication Jun 17, 2008
RESULTS. In our baseline analysis, rifampin was the least costly treatment regimen for
Address correspondence to S. Maria E. Finnell,
any child arriving from an area with an isoniazid-resistance rate of ⱖ11%. Treatment MD, Indiana University School of Medicine,
with isoniazid plus rifampin was the most effective but would cost more than $1 Children’s Health Services Research,
Department of Pediatrics, HITS Building, Room
million per reactivation case prevented. Isoniazid would become the least costly 1020B, 410 W 10th St, Indianapolis, IN 46202.
regimen if any of the following thresholds were met: rifampin resistance given E-mail: sfinnell@iupui.edu.
isoniazid resistance of more than 82%; rifampin resistance given no isoniazid resis- PEDIATRICS (ISSN Numbers: Print, 0031-4005;
tance of ⬎9%; cost of rifampin more than $47/month; effectiveness of rifampin Online, 1098-4275). Copyright © 2009 by the
American Academy of Pediatrics
lower than 63%; effectiveness of isoniazid higher than 74%; and cost of pulmonary
tuberculosis less than $7661. Isoniazid and rifampin for 3 months was the least costly
for all cases from areas with isoniazid resistance of ⬍80% as long as the regimen’s effectiveness was ⬎50% for
susceptible bacteria. However, this assumption remains to be proven.

CONCLUSION. Because of the high prevalence of isoniazid resistance, rifampin should be considered for children with
latent tuberculosis infection originating from countries with ⬎11% isoniazid resistance. Pediatrics 2009;123:816–822

T UBERCULOSIS (TB) INFECTION continues to be a global public health issue,1,2 and treatment of latent tuberculosis
infection (LTBI) is an important part of the TB elimination plan for the United States.3
Resistance to anti-TB medication is an increasing problem. Reports from the World Health Organization (WHO)
reveal isoniazid-resistance rates among new cases as high as 42% in some regions.1,4 Most clinical trials for latent TB
regimens were conducted in the 1950s and 1960s when drug resistance was a minimal or nonexisting problem. TB
reactivation despite recommended treatment has been reported, and an analysis of adult data suggests that alter-
native regimens may be more cost-effective for certain patients.5
Young children are at high risk of reactivating LTBI.6,7 Research suggests a reactivation risk of 10% to 20% for
children ⬍5 years of age. The Pediatric Tuberculosis Collaborative Group,8 therefore, recommends treatment of latent
TB in children in the United States. Based on results from clinical trials,9–12 the currently recommended treatment
regimen is 9 months of isoniazid.
Current targeted TB screening recommendations ask clinicians to screen for TB in foreign-born children from
certain parts of the world.8 Therefore, it is common for providers to make treatment decisions for TB infections

816 FINNELL et al
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FIGURE 1
A decision model. The decision tree branches from left to right. Branches from the square (decision) node represent alternative regimens. Branches from round (chance) nodes represent
chance events. For simplicity, only branches from the “rifampin” node are shown.
acquired abroad. The current guidelines only recom-
mend an alternative therapy to isoniazid if a patient has
been exposed to a known case of isoniazid-resistant TB.13
They do not provide guidance for treatment of children
arriving from countries with high rates of drug resistance
without a known exposure.
Decision models addressing isoniazid resistance have
been published previously.5,14 However, these articles
focus on adults who have a different reactivation risk
and liver toxicity rate than children. In our model, we
sought to determine the background drug-resistance
rate at which a different regimen other than the recom-
mended isoniazid for 9 months should be considered for
children.
METHODS
Study Design
We constructed a decision model by using decision anal-
ysis software (Tree Age Pro Suite [TreeAge Software,
Williamstown, MA]) to compare the cost-effectiveness
of 4 different latent TB treatment regimens (Fig 1). Our
base case was a 2-year-old adopted child from Russia
with a TB skin test (TST) of 12 mm induration not
previously treated for TB and in whom active TB had
been excluded. We assumed a societal perspective and
expressed results as cost and cost per case of TB pre-
vented.
Assumptions
We assumed that (1) the likelihood of resistant TB in-
fection in immigrant children reflects the prevalence of
resistance in the child’s country of origin, (2) treatment
of latent TB infection provides lifelong benefit by reduc-
ing the subsequent risk of reactivation, (3) treatment
with a drug to which the organism is resistant provides
no benefit in reducing the risk of reactivation, (4) there
is no synergism of the combined treatment beyond that
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of the more effective drug, and (5) reactivation leads to
pulmonary TB.
The Decision Model
The decision tree (Fig 1) included a decision node
(square) followed by branches representing the treat-
ment options: (1) isoniazid for 9 months; (2) rifampin
for 6 months; (3) combination treatment with isoniazid
for 9 months and rifampin for 6 months; and (4) no
treatment. Isoniazid alone is the most commonly recom-
mended treatment. Rifampin is recommended for pa-
tients exposed to isoniazid-resistant TB.8 Combined
treatment with isoniazid and rifampin is an approach
taken by some clinicians assuming an increased likeli-
hood that the pathogen will be susceptible to at least 1 of
the 2 medications. We included a no treatment branch
for comparison.
Each treatment branch was followed by a chance
node (circle), which represents the risk that a child de-
velops liver failure as a treatment adverse effect. Al-
though many children who receive isoniazid or rifampin
for latent TB will experience increases in serum liver
enzymes, it is generally clinically silent.15–17 We included
liver failure as a rare but important outcome.
If no liver failure occurs, the patient may or may not
be infected with resistant TB. For children infected with
bacteria susceptible to the treatment given, the risk of TB
reactivation was adjusted by the effectiveness of the
chosen regimen. With combined isoniazid and rifampin,
the reactivation risk was adjusted by the effectiveness of
the more effective drug. In case of multidrug resistance
(MDR), the effectiveness would be zero.
Finally, the child may or may not experience TB
reactivation. In our model, if TB reactivation occurred,
the child was assumed to get the most common form of
the disease, pulmonary TB.11 Ignoring other more severe
PEDIATRICS Volume 123, Number 3, March 2009 817
 TABLE 1 Variables for Decision Model
Variable Baseline Reported Range Threshold Value
Probability (References) (Branch Favored if
Threshold Value Is Met)
Lifelong risk of TB reactivation, % 13 5–40 (6, 48) ⬍9 (no intervention)
Isoniazid resistance, % 26.40 0–42.6 (1) ⬍11 (isoniazid 9 mo)
⬎71 (no intervention)
Rifampin resistance given isoniazid resistance, % 57 0–74 (1) ⬎82 (isoniazid 9 mo)
Rifampin resistance given no isoniazid resistance, % 0.27 0–0.08 (1) ⬎9 (isoniazid 9 mo)
Effectiveness isoniazid, % 68 64–100 (10, 11, 49) ⬎74 (isoniazid 9 mo)
Effectiveness rifampin, % 68 68–100 (20, 45) ⬍63 (isoniazid 9 mo)
Liver failure from isoniazid/persons treated, % 0.0032 0–0.0032 (29, 50) ⬎0.01 (no intervention)
Liver failure from rifampin/persons treated, % 0.0032 ⬎0.02 (isoniazid 9 mo)
Cost of isoniazid (150 mg/d) for 1 mo, $ 1 1–2 (21) Not sensitive for 0–500
Cost of rifampin (150 mg/d) for 1 mo, $ 37 37–47 (21) ⬎47 (isoniazid 9 mo)
Cost of TB reactivation, $ 10 871 9653–10 871 (26–28) ⬍7661 (no intervention)
Cost of liver failure, $ 500 000 (32) 137 000–219 000 (32–34) ⬎8.0M (no intervention)
Cost of monthly nurse visit, $ 28 (22) ⬍7 (isoniazid 9 mo)
⬎68 (no intervention)
Cost of lost parental work time, $ 23 (23, 24) ⬍2 (isoniazid 9 mo)
⬎63 (no intervention)
Cost of drive to follow up visit, $ 5 (25) ⬎45 (no intervention)

forms of TB biases the model against more aggressive
treatment.
Variables
The probabilities and cost estimates used are presented
in Table 1. We selected variables from published litera-
ture on the basis of quality and the similarity between
the study conditions and the base case for our model.
Studies of children with latent TB were prioritized over
studies of active TB. We ran sensitivity analyses, includ-
ing the highest and lowest reported value for each vari-
able, to test how our conclusions varied if variables
changed.
Probability of TB Reactivation
For our base case, we assumed a 13% lifetime reactiva-
tion risk. This probability was derived from the lifetime
reactivation risk model presented by Horsburgh6 for a
child ⬍5 years of age with recent TST conversion and a
current TST induration of 10 mm to 14 mm. It is lower
than many reported values,7,9,11,18 biasing against treat-
ment.
ported “mono R” (rifampin resistance alone) rate by the
rate of nonisoniazid nonrifampin resistance. We con-
ducted 2-way sensitivity analysis on the variables isoni-
azid resistance and rifampin resistance given isoniazid
resistance as a way to identify the least costly treatment
regimen for immigrant children from a particular area
(Fig 2).
Effectiveness of Treatment Regimen
Reported effectiveness of latent TB treatment var-
ies.7,11,18,19 Published literature primarily includes data
measuring effectiveness with different treatment dura-
tions. The authors of the American Academy of Pediatrics
Red Book,13 stated that the efficacy of isoniazid treatment
in children approaches 100%, although most results
from clinical trials show a lower effectiveness. Most
likely, the lower numbers reflect imperfect adherence.

Resistance Rate of Isoniazid and Rifampin

For the isoniazid-resistance rate (26.4%) and rifampin-
resistance rate (16.7%), we used data from the Tomsk
Oblast region, Russia, published by the WHO.1,4 We
found a significant correlation between isoniazid and
rifampin resistance. The degree of correlation is variable
across different regions. Therefore, we included the vari-
ables “rifampin resistance given isoniazid resistance” and
“rifampin resistance given no isoniazid resistance.” MDR
means resistance to at least isoniazid and rifampin, and
we used the reported MDR rate divided by the overall
isoniazid-resistance rate to calculate rifampin resistance FIGURE 2
given isoniazid resistance. Rifampin resistance given no Drug resistance and least costly treatment. Patterns represent the least costly strategy for
isoniazid resistance was calculated by dividing the re- every combination of isoniazid and rifampin resistance.

818 FINNELL et al
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 TABLE 2 Cost-effectiveness of Examined TB-Treatment Regimens
Regimen Average Incremental Average
Cost, $ Cost, $ Effectiveness
Rifampin 1173 — 0.94489
Isoniazid 1235 62 0.93503
Isoniazid ⫹ rifampin 1364 191 0.94504
No treatment 1413 49 0.87
Strategies that are dominated cost more and are less effective.
As there are so many ways in which nonadherence can
occur (missed doses, early cessation of therapy, etc), we
found no meaningful way to model adherence separate
from efficacy. For our model, we therefore estimated
68% as the effectiveness of 9 months of the isoniazid
alone as published in a randomized, controlled trial by
Ferebee and Mount.11 We found only 1 published ran-
domized, controlled trial comparing isoniazid and
rifampin.20 That trial was poorly controlled and included
only adults. With no better data available, we estimated
68% effectiveness for rifampin as for isoniazid.
Cost of Medication
The monthly costs of isoniazid ($1) and rifampin ($37)
were based on the Red Book Pharmacy Fundamental
Reference for wholesale prices.21
Cost of Administration
From a societal perspective, the cost of therapy also
includes monthly visits to the health department ($28),
based on the 2007 Medicare reimbursement for a nurse-
only visit (CPT code 99211).22 The cost of 2 hours’ lost
parental work ($23) per monthly visit was estimated by
multiplying twice the average hourly salary in Indiana
(US Department of Labor) by the percentage of house-
holds in which all adults living in the home worked (US
census data).23,24 The cost of driving to visits ($5) was
based on the average drive to and from the health de-
partment in Marion County, Indiana (10 miles) times
the Indiana University Travel Management Services
mileage reimbursement ($0.5 per mile) for use of own
car.25
Cost of Treating Reactivated Pulmonary TB
For the estimated cost of treating reactivated pulmonary
TB ($10 871), we used data published in the study by
Flaherman et al.26 Similar cost estimates for treating
pulmonary TB both for children abroad and for adults in
the US have been previously published.27,28
Probability and Cost of Liver Failure
We derived the probability of liver failure because of
treatment (3.2 in 100 000) from data published by Wu et
al29 In this study, the risk of developing liver failure was
calculated by dividing retrospectively identified cases of
liver failure among children who had received isoniazid
treatment for latent TB, by the number of children
treated after contact investigations nationally. Because
the denominator does not include children treated for
LTBI, this is a high estimate, biasing against treatment.
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Incremental Average Incremental
Effectiveness Cost-effectiveness, $ Cost-effectiveness, $
— 1241 —
⫺0.00986 1321 Dominated
0.000145 1443 1 313 917
⫺0.075037 1624 Dominated
No published data suggested the rate of liver failure
from rifampin alone. We assumed it to be the same for
isoniazid. Because in children on combined therapy, liver
failure can result from either drug, we estimated the risk of
liver failure from the combination of isoniazid and rifampin
with the following formula:30 1⫺([1⫺p(failure兩isoniazid) ⫻
(1⫺p(failure兩rifampin)]).
The cost of liver failure ($500 000) was estimated
from Treem.31 Lower costs based on data from the first
year after transplant have been published.32–34 We used
the higher cost, biasing against treatment.
All costs were adjusted to 2007 monetary values by
using the US Department of Labor, Bureau of Labor
Statistics, medical care index or inflation calculator costs
as appropriate.23
Sensitivity Analysis
We performed sensitivity analyses to determine at which
threshold value of each variable the least-costly treat-
ment strategy would change. We performed 1-way sen-
sitivity analysis (changing 1 parameter at a time) on all
variables. To determine the least expensive treatment
strategy for different combinations of isoniazid resistance
and rifampin resistance given isoniazid resistance, we
conducted a 2-way analysis (both parameters simulta-
neously) on these 2 variables.
Modified Decision Model
In addition to the model presented, we also analyzed a
regimen of 3 months of combined isoniazid and
rifampin. This regimen is currently the recommended
treatment for children with latent TB in some coun-
tries.35 The effectiveness of this regimen, given no resis-
tant organisms, was assumed to be 68%. A meta-analy-
sis including trials in adults showed no difference
between this regimen and longer regimens,36 and pedi-
atric studies presented similar results.37,38 In the case
where resistance to either isoniazid or rifampin oc-
curred, the effectiveness of this regimen was assumed to
be 21% based on early trials of isoniazid prophylaxis for
3 months.39 In cases of MDR, the regimen was assumed
to be ineffective.
RESULTS
Cost-effectiveness
Rifampin for 6 months is the least costly strategy in our
model. Table 2 displays the incremental cost-effective-
ness ratios of the different treatment regimens. The first
column shows the regimens in order of increasing aver-
PEDIATRICS Volume 123, Number 3, March 2009 819

FIGURE 3
Risk of TB reactivation and treatment cost. Each line represents a different strategy, plot-
ting cost per case as a function of the probability of TB reactivation.
age cost. The second column shows the average cost for
each case of latent TB including costs for medication,
administration, treatment of liver failure, and TB reacti-
vation. The third column shows the difference in aver-
age cost. The fourth and fifth columns show the average
effectiveness and the incremental effectiveness in terms
of TB reactivation prevented. The sixth column lists the
incremental cost-effectiveness ratio for each treatment
strategy. That is the additional cost per case of TB reac-
tivation prevented.
Isoniazid for 9 months is dominated, meaning it is
both more costly and less effective than rifampin for 6
months. The combined regimen isoniazid for 9 months
plus rifampin for 6 months is slightly (0.01%) more
effective than rifampin for 6 months but costs over $200
more per treatment. As a result, the cost for each addi-
tional case of TB reactivation prevented by using this
regimen is $1 313 917.
Sensitivity Analysis Results
The fourth column in Table 1 shows the threshold value
for each variable, at which treatment other than
rifampin alone becomes the least costly strategy. For any
child from an area with an isoniazid-resistance rate of
ⱖ11%, rifampin alone was the least costly regimen. Our
model was sensitive to a TB reactivation rate of ⬍9%
(Fig 3), rifampin resistance given isoniazid resistance of
⬎82%, rifampin resistance given no isoniazid resistance
of ⬎9%, effectiveness of rifampin of ⬍63%, effective-
ness of isoniazid of ⬎74%, cost of rifampin more than
$47/month, and cost of treating pulmonary TB less than
$7661. If any of these thresholds is met, another regi-
men would be the least expensive regimen. Other vari-
ables did not effect the decision.
Figure 2 displays the 2-way sensitivity analysis on
isoniazid and rifampin resistance given isoniazid resis-
tance. Using this figure to interpret the WHO surveil-
lance data,1 rifampin alone would be the least expensive
regimen for children ⬍5 years of age with recent TST
conversion from the following countries: Andorra, Ar-
menia, Azerbaijan, China, Côte d’Ivoire, Ecuador, Esto-
nia, Georgia, India, Kazakstan, Latvia, Lebanon, Lithua-
nia, Republic of Moldova, Mozambique, Perú, Russia,
Ukraine, Uzbekistan, and Vietnam.
In our analysis of 3 months of isoniazid and rifampin,
the shorter regimen is the least costly ($988) for all cases
820 FINNELL et al
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from areas with isoniazid resistance of ⬍80% as long as
the regimen’s effectiveness is ⬎50% for susceptible bac-
teria. This is the result of the lower administration cost of
3 months of follow-up. This regimen is, however, 0.7%
less effective than rifampin for 6 months. The cost for
each extra case of TB reactivation prevented by instead
using the 6 months of rifampin was $26 797.
Bacille Calmette-Guérin
Bacille Calmette-Guérin (BCG) status was not explicitly
incorporated into the model. BCG could affect the prob-
ability of reactivation in 2 ways. First, BCG vaccination
in infancy may create an absolute increase in the likeli-
hood of a TST reaction ⬎10 mm by 7%.40 This means
some positive TST results would be false-positives not
resulting in TB reactivation. The relative impact of false-
positives is less important in high prevalence areas as in
our base case.41 Second, BCG may provide protection
against TB reactivation. However, protection against
pulmonary TB is highly variable.42,43
To explore the impact of BCG, we adjusted the reac-
tivation rate. Under the assumptions that the prevalence
of positive TST results in immigrant children from Russia
is 30%,41 and 7% of these are false-positive results,40 we
calculated that the positive predictive value of a positive
TST result would be 23% lower. Applying this to the
reactivation rate of 13%, the resulting life-time risk of
reactivation is 10%, and above our threshold. Thus,
even accounting for BCG, rifampin is still less costly and
more effective than isoniazid.
DISCUSSION
Rifampin alone for 6 months is the least costly strategy
per case of TB prevented in our base case analysis. Ri-
fampin is less costly than isoniazid for 9 months, because
it saves administration costs and is effective against iso-
niazid-resistant bacteria not resistant to rifampin. Com-
bined therapy with 9 months of isoniazid and 6 months
of rifampin is effective for the extremely few cases with
rifampin-resistant but isoniazid-sensitive TB. It is slightly
more effective than rifampin alone, but the cost per
additional case of TB reactivation prevented, $1 313 917,
exceeds any commonly accepted cost-effectiveness bench-
marks.44
Our model was sensitive to rifampin resistance given
isoniazid resistance (⬎82%) and rifampin resistance
given no isoniazid resistance (⬎9%). Currently, only the
Dominican Republic is reporting resistance rates that
meet those criteria.1
Our model was sensitive to the TB reactivation rate. If
we assume a reactivation risk of ⬍9%, any treatment
would be more costly than no treatment. Depending on
age and health status, such low risk may apply to certain
children. In those cases, there will be a net cost per case
of reactivation prevented.
Our model was also sensitive to the effectiveness of
rifampin. If rifampin is ⬍63% effective, it would be more
expensive than isoniazid. Likewise, if the effectiveness of
isoniazid for 9 months were ⬎74%, isoniazid alone
would be the least costly treatment. We found few arti-
cles addressing rifampin effectiveness in latent TB treat-
ment.20,45 None suggested that rifampin would be less
effective than isoniazid.
Adherence affects the effectiveness of different regi-
mens. Long regimens result in worse adherence,46 which
would favor shorter treatment durations. Treatment
complexity also affects adherence.47 Rifampin and isoni-
azid are both once-daily regimens, but if any length of
combined therapy is considered, an isoniazid and
rifampin fixed-dose combination may be beneficial. This
combination exists and is marketed by Sanofi-Aventis as
Rifamate. Unfortunately, the high cost of this medica-
tion would offset savings from possible adherence im-
provements.
The cost of rifampin and treating reactivated TB also
affect our results. A month of rifampin could cost more
than $47 for payers. With our societal perspective, cost
estimates for medications assumed large purchases (eg,
by health departments). However, with the current
trend of increasing health care costs, it is unlikely that
the medical care cost would decrease to less than $7166
per case treated.
If 3 months of isoniazid and rifampin combined is
considered, this would be the least-costly strategy as
long as the isoniazid-resistance rate is ⬍80% and effec-
tiveness is ⬎50% for susceptible bacteria. However, this
is a relatively new regimen, and additional studies may
be warranted before adopting it.
As with all decision analyses, our study is limited by
the accuracy of chosen probabilities. We had to estimate
probabilities when few data were available. If assump-
tions change, the least costly strategy might also change.
CONCLUSIONS
From a societal perspective, the recommended treat-
ment for latent TB, 9 months of isoniazid, is both more
expensive and less effective than rifampin. Rifampin
should be considered for children with latent TB infec-
tion when the risk of isoniazid resistance exceeds 11%.
It will be important that future LTBI guidelines address
the possibility of drug resistance in high-risk individuals
such as children who are internationally adopted, immi-
grants, or refugees.
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 Latent Tuberculosis Infection in Children: A Call for Revised Treatment
Guidelines
S. Maria E. Finnell, John C. Christenson and Stephen M. Downs
Pediatrics 2009;123;816
DOI: 10.1542/peds.2008-0433

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 Latent Tuberculosis Infection in Children: A Call for Revised Treatment
Guidelines
S. Maria E. Finnell, John C. Christenson and Stephen M. Downs
Pediatrics 2009;123;816
DOI: 10.1542/peds.2008-0433

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/123/3/816

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