The Pediatric Infectious Disease Journal  •  Volume 33, Number 12, December 2014

HFMD and Coxasackievirus A6

of CVA6 patients were considerably higher (P < 0.001), which was

TABLE 1.  Total Number of Enterovirus With Different
not consistent with the illness severity. Hence, the severity of CVA6
Clinical Diagnosis, Beijing, 2013 HFMD could not be predicted by the elevated C-reactive protein
level, which was consistent with a report from Taiwan.13
Virus No. Percentage No. Cases With Different
Serotype Cases (%) Clinical Diagnosis In all, this study is the first to report a significant change in
the HFMD etiologic agents in Beijing in 2013, which is worthy of
CVA6 56 43.08 50 mild and 6 severe HFMD attention and further research.
EV71 19 14.62 9 mild and 10 severe HFMD
CVA10 6 4.62 Mild HFMD
CVA16 5 3.85 Mild HFMD ACKNOWLEDGMENTS
CVA2 4 3.08 3 mild and 1 severe HFMD
CVA5 3 2.31 Mild HFMD
The authors thank Qu Pei, Liu Yanan, Zhang Ling, Zhan
CVA12 2 1.54 Mild HFMD Yongjing, Zhang Baomin and Ji Tianjiao for excellent technical
E9 2 1.54 Mild HFMD assistance. The authors also thank the team in the Department of
CVA4 1 0.77 Mild HFMD Infectious Diseases and the Department of Pediatrics of Beijing
CVB4 1 0.77 Severe HFMD Ditan Hospital.
E7 1 0.77 Mild HFMD
Negative 30 23.08 22 mild and 8 severe HFMD
Total 130 100 104 mild and 26 severe HFMD
REFERENCES
1. Zhang Y, Tan XJ, Wang HY, et al. An outbreak of hand, foot, and mouth dis-
ease associated with subgenotype C4 of human enterovirus 71 in Shandong,
less than those in EV71 patients (P = 0.027), due to the normal China. J Clin Virol. 2009;44:262–267.
glucose levels observed in most CVA6 patients (76.36%) and the 2. Gopalkrishna V, Patil PR, Patil GP, et al. Circulation of multiple enterovirus
increased levels identified in 61.11% of EV71 patients. Significant serotypes causing hand, foot and mouth disease in India. J Med Microbiol.
2012;61(pt 3):420–425.
differences were not observed in other demographic characteristics
3. Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot,
and laboratory findings from the CVA6 and EV71 patients. and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485–1488.
Meanwhile, 100 HFMD patients (Table 1) were interviewed 4. Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand,
for the presence of onychomadesis. By definition, 13 patients dis- foot, and mouth disease associated with onychomadesis in Taiwan, 2010.
played onychomadesis, including 12 with CVA6 infection (22.64%, BMC Infect Dis. 2011;11:346.
12/53) and 1 with CVA10 infection (16.67%, 1/6). Onychomadesis 5. Bracho MA, González-Candelas F, Valero A, et al. Enterovirus co-infections
was significantly associated with CVA6 infection (P = 0.002). and onychomadesis after hand, foot, and mouth disease, Spain, 2008. Emerg
Infect Dis. 2011;17:2223–2231.
6. Fujimoto T, Iizuka S, Enomoto M, et al. Hand, foot, and mouth disease
DISCUSSION caused by coxsackievirus A6, Japan, 2011 [letter]. Emerg Infect Dis.
In this study, the 243 HFMD cases were mainly concentrated 2012;18:337–339.
in suburban areas and at the edges of urban areas, and cases were 7. Feder HM Jr, Bennett N, Modlin JF. Atypical hand, foot, and mouth disease:
rare in the central cities and outer suburban areas. Dense popula- a vesiculobullous eruption caused by Coxsackie virus A6. Lancet Infect Dis.
2014;14:83–86.
tion and poor sanitation might contribute to the increased morbidity
8. Oberste MS, Maher K, Williams AJ, et al. Species-specific RT-PCR ampli-
in these locations. Moreover, the duration of HFMD was 1 month fication of human enteroviruses: a tool for rapid species identification of
longer (May to August) than that reported by Qian et al9 (May to uncharacterized enteroviruses. J Gen Virol. 2006;87(pt 1):119–128.
July). However, this finding was not unexpected given that the tem- 9. Qian HQ, Tian H, Li XT, et al. Epidemiologic investigation of hand foot and
perature in August 2013 was approximately 1–2°C higher than in mouth disease in Beijing from 2007 to 2012 [in Chinese]. Int J Virol, 2013;
previous years. Since 1981, EV71 and CVA16 have been the major 20:6–10.
causes of HFMD in China.10 However, in this study, we found that 10. Wu J. [Epidemiology of hand, foot and mouth disease and severe enterovirus
the presence of EV71 and CVA16 decreased dramatically and that infection]. Clin Pediatr Emerg Med. 2008;15:100–102.
CVA6 was the main causative agent of HFMD in Beijing in 2013. 11. YamashitaT, Ito M, Taniguchi A, et al. Prevalence of coxsackievirus A5, A6,
and A10 in patients with herpangina in Aichi Prefecture, 2005. Jpn J Infect
To our knowledge, this is the first study to report HFMD caused by Dis. 2005;58:390–391.
CVA6 in mainland China.
12. Clementz GC, Mancini AJ. Nail matrix arrest following hand-foot-mouth
CVA6 is one of the major causes of herpangina.4,11 How- disease: a report of five children. Pediatr Dermatol. 2000;17:7–11.
ever, the detection rate of CVA6 in HFMD patients is gradually 13. Lo SH, Huang YC, Huang CG, et al. Clinical and epidemiologic features of
increasing, and it has now become the main etiologic agent of Coxsackievirus A6 infection in children in northern Taiwan between 2004
HFMD in Beijing. Moreover, we found that CVA6 could also cause and 2009. J Microbiol Immunol Infect. 2011;44:252–257.
severe cases of HFMD, and the manifestations of these cases are
very difficult to distinguish from EV71 infection. It is likely that
CVA6 possesses a pathogenic mechanism similar to EV71. Hence,
INCREASED RISK OF MYCOBACTERIUM
changes in both the HFMD etiologic agent and clinical manifesta-
TUBERCULOSIS INFECTION IN HOUSEHOLD
tions caused by CVA6 are worthy of attention. CHILD CONTACTS EXPOSED TO PASSIVE
Onychomadesis is an acute, painless and noninflammatory TOBACCO SMOKE
disease.12 Several onychomadesis outbreaks linked to HFMD have
been reported.3–6 In our study, we reported that CVA6 infection was Saranya Sridhar, MBBS, MS, DPhil, DFPH,*
significantly associated with onychomadesis (P = 0.002), which sug- Nisha Karnani, BA,* David W. Connell, MRCP,*
gested that CVA6 might serve as the main causative agent of onycho- Kerry A. Millington, DPhil,* Davinder Dosanjh, MD,*
madesis after HFMD; however, this hypothesis requires further study.
Mustafa Bakir, MD,† Ahmet Soysal, MD,†
In addition, both the fever duration and glucose levels of
CVA6 patients were significantly reduced compared with EV71
Jonathan Deeks, DPhil,‡ and Ajit Lalvani, DM*
patients, suggesting that the symptoms caused by CVA6 were rela- Abstract: Risk factors associated with Mycobacterium tuberculosis infec-
tively milder. However, the mean serum C-reactive protein levels tion were investigated in a prospective cohort of household child tuberculo-

© 2014 Lippincott Williams & Wilkins www.pidj.com | 1303

Sridhar et al The Pediatric Infectious Disease Journal  •  Volume 33, Number 12, December 2014
sis contacts. A significantly increased risk of acquiring infection was asso-
ciated with exposure to passive cigarette smoke, higher number of index
cases, younger age and reduced household monthly income.
Key Words: childhood tuberculosis, infection, interferon-gamma release
assay, smoking
Accepted for publication July 29, 2014.
From the *Tuberculosis Research Centre, Department of Respiratory Medicine,
National Heart and Lung Institute, Imperial College London, Norfolk Place,
London; †Department of Paediatrics, Marmara University School of Medi-
cine, Istanbul, Turkey; and ‡Department of Public Health, Epidemiology and
Biostatistics, Public Health School of Health and Population Sciences, Uni-
versity of Birmingham, Edgbaston, United Kingdom
The authors have no conflicts of interest to disclose.
This study was funded by the UNICEF/UNDP/World Bank/WHO Special Pro-
gramme for Research and Training in Tropical Diseases (TDR) and the Well-
come Trust. A.L. is a Wellcome Senior Research Fellow in Clinical Science.
The funders had no role in study design, data collection and analysis, deci-
sion to publish, or preparation of the manuscript.
Ethical approval was granted by the IRB of Marmara University School of Medi-
cine, Istanbul; The Turkish Ministry of Health, Ankara and the WHO Steer-
ing Committee on research involving human subjects, Geneva.
Address for correspondence: Ajit Lalvani, MA, DM, FRCP, Tuberculosis
Research Centre, Department of Respiratory Medicine, National Heart and
Lung Institute, Imperial College London, 2 Norfolk Place, London W2 1PG,
United Kingdom. E-mail: a.lalvani@imperial.ac.uk.
Copyright © 2014 by Lippincott Williams & Wilkins
DOI: 10.1097/INF.0000000000000506
A n estimated, one third of the global population is infected with
Mycobacterium tuberculosis (Mtb)1 with 8.6 million incident
cases in 2012 alone.2 Individuals with latent tuberculosis infection,
at risk of progression to active tuberculosis (TB), act as a signifi-
cant reservoir of incident cases and are therefore a major target for
TB control programs.3
Control of latent tuberculosis infection necessitates knowl-
edge of biological and environmental risk factors that determine
acquisition of infection to allow design and implementation of
cost-effective interventions. While host characteristics such as age,
exposure to an infectious case, bacillus Calmette–Guérin (BCG)
vaccination and ethnicity have been well studied,4 data on environ-
mental and socioeconomic determinants more amenable to inter-
vention are more limited. Investigating these risk factors in chil-
dren, who are most susceptible to developing severe disseminated
TB is therefore of public health importance.
Accurate diagnosis of Mtb infection is a barrier to investi-
gating risk factors for Mtb infection. The challenges in identifying
risk factors lie in distinguishing infection from progression to dis-
ease, use of the less specific tuberculin skin test (TST) rather than
the interferon-gamma release assay (IGRA) and testing for Mtb
infection at a single time point when using IGRAs with potential of
misclassifying individuals who subsequently revert or convert their
IGRA results at a later time point.5
We report a new analysis of a previously described child
cohort of household TB contacts6,7 incorporating hitherto unavail-
able follow-up data. Use of a 2-time point IGRA screen offering a
more robust diagnosis of Mtb infection, by excluding IGRA revert-
ers and correctly classifying IGRA converters, is used to identify
risk factors associated with acquisition of infection in children
exposed to TB in the household.
METHODS
Study Population
We used data from a Turkish cohort described previously7 in
which childhood contacts of sputum smear-positive TB cases were
recruited. All participants were tested with TST and an ex-vivo
1304  |  www.pidj.com
IFN-g ELISpot assay at the time of recruitment and a second ELIS-
pot assay was repeated 6 months later. At enrollment, BCG vaccina-
tion status was assessed by the presence of a scar and demographic
and socioeconomic information recorded. Details of the follow-up
and incident cases have been previously published.6
Ex vivo IFN-g ELISPOT Assay
ELISpot was performed as described previously using
ESAT-6 and CFP-10 peptides7 which is comparable to the commer-
cially available T-Spot.TB IGRA. Responses were scored as positive
if the test wells contained a mean of at least 5 spot-forming cells
more than the mean of the negative control wells, and, additionally,
this number was at least twice the mean of the negative control wells.
Statistical Analysis
The primary outcome for this analysis is TB infection
assessed by IGRA results at baseline and 6-month follow-up time
point. Individuals with TB infection were defined as those with
either persistent positive IGRA result (at baseline and 6-months)
or IGRA converters (IGRA negative at baseline and IGRA positive
at 6 months). Those without TB infection were defined by persis-
tent negative IGRA (at baseline and 6-months). Individuals with an
IGRA reversion (IGRA positive at baseline and IGRA negative at 6
months) were excluded as the clinical and biological significance of
an IGRA reversion is uncertain. Descriptive statistics were used to
describe characteristics of the 2 groups in each analysis, TB infec-
tion versus no TB infection, including frequencies (percentages) and
means with standard deviations. Where relevant, the Fisher exact test
or the χ2 test were used to compare proportions and the independent
groups’ t test was used to compare means between the 2 groups. A
multivariable logistic regression model was built to investigate the
effect of different risk factors on TB infection and progression to
active disease. Before fitting the main model, univariable logistic
regression models were used to investigate the association between
variables and IGRA reversion. A model was then fitted contain-
ing variables associated with TB infection on univariate regression
(P < 0.2) along with age and sex (irrespective of their P value) and
stepwise backward selection was conducted to remove variables 1
at a time based on Wald statistics. An overall P value of 0.05 was
considered to be statistically significant. Statistical analyses were
undertaken using Stata version 11 (StataCorp, College Station, TX).
RESULTS
There were 714 children with available IGRA results at
baseline and the 6-month follow-up time point. As defined above,
341 (47.76%) children were classified as infected with Mtb, which
comprised 273 children with a persistent positive IGRA and 68
IGRA converters. Three hundred and seventy-three (52.24%) indi-
viduals had a persistent negative IGRA and were defined as not
being infected with Mtb. The median age of the cohort was 7.5
years (range 1 month to 16 years).
Univariate analysis of host, environmental and socioeco-
nomic risk factors for Mtb infection (Table 1) showed a significant
association (P < 0.05) with age, number of index patients in the
household, having a smoker in the household, monthly household
income and mother’s education.
Independent risk factors for TB infection, after fitting a mul-
tivariate model, were age, BCG status, number of index patients
in the household, having a smoker in the household and monthly
household income (Table 1). A smoker in the household [odds ratio
(OR): 1.52, 95% confidence interval (CI): 1.09–2.12) increased
risk of acquiring TB infection in child contacts while a household
monthly income ≥US$75 decreased risk of infection (OR: 0.55,
95% CI: 0.38–0.79). Children were more likely to be infected with
© 2014 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal  •  Volume 33, Number 12, December 2014 HFMD and Coxasackievirus A6

TABLE 1.  Risk Factors for Mtb Infection in Child Contacts

Unadjusted Adjusted†
Uninfected* Infected*
OR (95% CI) P value OR (95% CI) P value

Host risk factors

 Sex‡
   Female 175 (50.87%) 169 (49.13%) 1
   Male 198 (53.66%) 171 (46.34%) 0.89 (0.67–1.20) 0.457
 Median age in months (inter- 84(38–126) 98 (56.5–140) 1.06 (1.03–1.10) 0.001 1.06 (1.03–1.10) 0.001
quartile range)
 BCG vaccination‡
   0 63 (45.32%) 76 (54.68%) 1 1
   ≥1 310 (54.01%) 264 (45.99%) 0.71 (0.49–1.02) 0.067 0.67 (0.46–0.99) 0.046
Environmental risk factors
 Number of index patients in household‡
   1 369 (53.48%) 321 (46.52%) 1 1
   >1 4 (17.39%) 19 (82.61%) 5.46 (1.84–16.22) 0.002 6.42 (2.09–19.74) 0.001
 Smoker in the household
   No 138 (58.97%) 96 (41.03%) 1 1
  Yes 235 (48.96%) 245 (51.04%) 1.5 (1.09–2.06) 0.012 1.52 (1.09–2.12) 0.014
Socioeconomic risk factors
 Monthly income‡
   <75 US$ 66 (38.60%) 105 (61.40%) 1 1
   ≥75 US$ 306 (56.46%) 236 (43.54%) 0.49 (0.34–0.69) <0.001 0.55 (0.38–0.79) 0.001
 Mother’s profession
   Routine/manual 11 (47.83%) 12 (52.17%) 1.01 (0.77–1.32) 0.930
   Intermediate occupations 2 (100.00%) 0 (0.00%)
   Managerial/professional 7 (70.00%) 3 (30.00%)
   Other 353 (51.99%) 326 (40.01%)
 Father’s profession
   Unemployed 49 (46.67%) 56 (53.33%) 0.89 (0.73–1.07) 0.206
   Routine/manual 279 (52.74%) 250 (47.26%)
   Intermediate occupations 14 (50.00%) 14 (50.00%)
   Managerial/professional 19 (63.33%) 11 (36.67%)
   Other 12 (54.55%) 10 (45.45%)
 Mother’s education
  No education or primary school 316 (51.13%) 302 (48.87%) 1
   Intermediate/high school/university 57 (59.38%) 39 (40.63%) 0.62 (0.43–0.89) 0.010
  Father’s education§
  No education or primary school 260 (50.29%) 257 (49.71%) 1
   Intermediate/high school/university111 (57.81%) 81 (42.19%) 0.74 (0.53–1.03) 0.075
 Attends school
   No 170 (55.37%) 137 (44.63%) 1
  Yes 203 (49.88%) 204 (50.12%) 1.25 (0.93–1.68) 0.146
 Mobile phone ownership
   No 129 (48.31%) 138 (51.69%) 1
  Yes 244 (54.59%) 203 (45.41%) 0.78 (0.57–1.05) 0.105
*Mtb infection was defined by a combination of IGRA results at baseline and the 6-month follow-up time point. Individuals with TB infection were defined as either a positive
IGRA result at baseline and 6 months or those with IGRA negative at baseline and IGRA positive at 6 months (IGRA converters). Mtb Uninfected was defined as negative IGRA at
baseline and 6 months.
†Estimated by stepwise logistic regression with Mtb infection as dependent variable with sex, age, BCG, number of index cases in household, smoker in the household, monthly
income, mother’s education, father’s education, school attendance and mobile phone ownership as independent variables.
‡Data available for 713 of 714 individuals with IGRA results.
§Data available for 709 of 714 individuals with IGRA results.

increasing age, for every 1 year increase in age the risk of acquir-
ing infection increased by 6% (OR: 1.06, 95% CI: 1.03–1.10), and
exposure to more than 1 index case in the household (OR: 6.42,
95% CI: 2.09–19.74), whereas children with a BCG scar were 20%
less likely to become infected (OR: 0.67, 95% CI: 0.46–0.99).
DISCUSSION
There is growing public health concern of the impact of
smoking on the TB epidemic. While several meta-analyses have
confirmed the increased risk of TB infection and disease in active
smokers,8,9 data on the association of passive smoking and risk
of Mtb infection is sparse. Our cohort study of child household
contacts of smear positive pulmonary TB revealed second-hand
tobacco smoke to increase the risk of acquiring Mtb infection after
controlling for other risk factors associated with Mtb infection.
Unlike adults in whom disentangling the independent effects
of active and passive smoking is difficult, children who do not
smoke offer an ideal setting in which to assess the effect of passive
smoking on Mtb infection. Children in contact with an infectious
case were at a 52% increased risk of acquiring Mtb infection when
exposed to a smoker in the household [adjusted odds ratio (aOR)
1.52]. This effect independent of age, sex, socioeconomic status
and the amount of exposure to infection is similar to the risk of
Mtb infection associated with active smoking obtained by several
meta-analyses (aOR ~1.5).8,9 The magnitude of effect in our study
is similar to that obtained by Godoy et al10 in over 7000 contacts
across different age groups in Catalonia (aOR: 1.52) but, lower
than an unadjusted estimate by Singh et al.11 in Indian child house-
hold contacts (OR: 2.68) and lower than that reported by den Boon
et al12 from a cross-sectional survey of the general population in

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Sridhar et al The Pediatric Infectious Disease Journal  •  Volume 33, Number 12, December 2014
South Africa (aOR: 4.60). The lower estimate in our study is prob-
ably a result of using the IGRA assay to diagnose infection, which
has greater accuracy in children than the TST used in previous
reports.13,14 However, other reasons such as the manner of recording
exposure to passive smoking and study design and sample size may
also account for the difference in estimates. One other study used
IGRAs to diagnose Mtb infection but did not find any association
between exposure to tobacco smoke and acquiring Mtb infection
in child contacts.15 Our study, unlike previous studies, used a com-
bination of IGRA results at baseline and a follow-up time point
to generate a more robust system to diagnose Mtb infection. This
minimizes the potential for misclassification of individuals who
subsequently converted or reverted their IGRA results, thus ena-
bling identification of hitherto unrecognized risk factors.
Passive tobacco smoking has been implicated in increasing
risk of clinical disease and our finding, for the first time reports
an association between passive tobacco smoking and acquisition
of TB infection diagnosed using IGRA. If future studies were to
show increased risk of progression from infection to active disease,
it would implicate passive tobacco smoking in every stage of the
natural history of TB.
Independent of passive smoking, a higher household
monthly income, BCG scar and younger age were associated with a
reduced risk of infection while exposure to more than 1 TB case in
the household increased risk of Mtb infection among child contacts
in our study. This corroborates our previous analysis from this child
contact cohort which only used baseline IGRA results to diagnose
Mtb infection, highlighting the strength of the association of these
risk factors.7
Our study has certain limitations. Although active smoking
in Turkish children during the time of our study was uncommon,
we did not specifically collect this information and therefore can-
not rule out the effect of active smoking on TB infection. Simi-
larly, the contribution of indoor air pollution was not measured.
Although we recorded exposure to passive smoking, we did not
record which household member smoked or their smoking habits.
Thus, we were unable to distinguish the independent contributions
of passive smoke from the index case from that of other household
members or report a dose–response relationship that has previously
been shown.16 Future studies will need to undertake such analysis
to identify the most appropriate target groups if smoking cessation
interventions were to be incorporated into TB control strategies.
Our finding, adding to the small body of evidence, of an
association between passive tobacco smoke and an increased risk of
Mtb infection in children has vital public health implications. With
an estimated 700 million children worldwide, approximately 40%
of all children exposed to second-hand tobacco smoke at home17
and 80% of global smokers in countries with the highest TB burden
and the least stringent tobacco control, our study has found new
evidence to support the incorporation of smoking cessation strate-
gies into TB control programs.
1306  |  www.pidj.com
Acknowledgements
Authors’ contributions: S.S. and A.L. designed the research
question. S.S., N.K., J.D. and A.L. analyzed the data. M.B., A.S.,
K.M., D.D. and A.L. completed the study and the experiments. S.S.,
N.K. and A.L. wrote the manuscript.
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© 2014 Lippincott Williams & Wilkins