INTRODUCTION
Tuberculosis (TB) is still a major global public health concern. The highest burden of the disease is concentrated in 30 countries, with Brazil ranking 20th in number of new cases.1 It is estimated that 23–50% of the world population is infected with Mycobacterium tuberculosis1–5 and of these, 5–10% will progress at some point to active disease.1,3,6
Children are particularly vulnerable when exposed to acid-fast bacilli smear microscopy–positive pulmonary TB (PTB) cases, known as smear-positive PTB; if they become ill, they progress to death at a higher frequency than those afflicted by meningitis, AIDS, measles, and pertussis.7,8 It was estimated that children aged < 15 years represented 10% of TB cases in 2017.1
Meta-analyses have shown that in low- and middle-income countries, such as Brazil, the prevalence of latent tuberculosis infection (LTBI) and frequency of active TB are approximately 50% and 7%, respectively, among children who had contact with adults with infectious TB.4,9 In addition, systematic reviews conducted by the WHO to develop guidelines for LTBI have shown that the risk of progression from LTBI to active TB in the first 2 years after exposure is 22.9 (95% CI = 7.7–68.6) in children aged < 5 years, and 8.2 (95% CI = 2.3–29.4) in those aged 5–14 years, when compared with the overall population.10 Children aged > 5 years, although they have a lower risk of primary disease than younger children and adults, still benefit from preventive treatment to reduce the risk of developing the disease in the future.10,11
In the TB transmission chain, smear-positive cases increase the probability of infection 15 times among exposed individuals.12 The probability of developing active TB is also increased,7 whereas smear-negative PTB cases are responsible for 13% of new cases.13 Therefore, in view of the importance of contact tracing in TB control, the present study aimed to evaluate the prevalence rate and risk factors for LTBI and active TB in children younger than 15 years exposed to smear-positive index cases (ICs). To the best of our knowledge, there has been no existing study investigating the prevalence of LTBI in children younger than 15 years known to be exposed to smear-positive PTB cases and followed for several years after exposure.
MATERIALS AND METHODS
Study design and population.
We conducted a follow-up cross-sectional study of children aged < 15 years from 2007 to 2016 in Divinópolis, a stable Brazilian municipality with an estimated population of 236,000 inhabitants,14 where the average incidence of TB during the study period was 11.4/100,000 inhabitants with an estimated annual risk of infection ranging 0.2–0.3%.15
Participants were identified from the ICs of TB to which they were exposed. The literature considers an IC to be an individual diagnosed with TB regardless of smear status in an environment where others have been exposed, and a contact is considered any person who has been exposed to the IC.10,16 For the purposes of the present study, we defined an IC as a smear-positive PTB individual sharing the same environment with children aged < 15 years, living in the same or in a different house, whereas contacts were children of this age group who were exposed to them in the symptomatic period before diagnosis.
All ICs diagnosed and reported with positive sputum microscopy from 2007 to 2016 were identified by the National Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação - SINAN), and all their contacts were identified during home visits. In the event of death or if any ICs moved out from Divinopolis, contacts were also identified through information from a close relative.
All contacts aged < 15 years at the time of IC microbiological confirmation by sputum microscopy were recruited for clinical, radiological, and laboratory assessment. The SINAN records were checked to verify if any contacts had developed previous TB. Exclusion criteria were as follows: contacts living with HIV/AIDS and those not living in the municipality of Divinópolis.
Study protocol.
The contacts of ICs diagnosed from 2007 to 2011 were evaluated between January 2012 and August 2013 and reassessed between October 2016 and March 2017, when we also evaluated the contacts of ICs diagnosed from 2012 to 2016.
Demographic, socioeconomic, and epidemiological variables were obtained from the contacts’ legal guardians through an interview conducted by trained researchers using a standardized questionnaire to obtain information on date of birth, gender, number of rooms and cohabitants in the household, average monthly family income, kinship to the IC, any exposure to another case of TB in addition to the IC, duration (in days) in which the IC was symptomatic without treatment, and duration (in hours per week) in which the contact was exposed to the IC.
The clinical evaluation aimed mainly to identify respiratory signs and symptoms suggestive of TB and ascertain neonatal Bacillus Calmette-Guerin (BCG) vaccination status (individual card and BCG scar).
Digital chest X-rays were performed in posteroanterior and lateral views, interpreted by two experienced pediatric pulmonologists, and reported using a standardized form. The pulmonologists were blinded to each other and to contact’s descriptive characteristics, and results of the clinical and laboratory evaluation.
Tuberculin skin testing (TST) with the Mantoux method using purified protein derivative RT23 (Statens Serum institute, Copenhagen, Denmark) and interferon gamma release assay (IGRA) testing (QuantiFERON® TB Gold in Tube (QFT-GIT); Qiagen, Hilden, Germany) were performed. To assess HIV infection status, the rapid test HIV-1/2 Bio-Manguinhos® (Oswaldo Cruz Foundation/Bio-Manguinhos, Rio de Janeiro, Brazil) was also used. Children with positive or inconclusive results to HIV in the rapid test were confirmed by virological testing. All procedures were conducted by trained professionals according to protocols established by the manufacturers.
Follow-up of contacts regarding the development of active TB was carried out in August 2018, approximately 18 months after the inclusion of the last participant in the study, and conducted via telephone calls to legal guardians and accessing the National Notifiable Diseases Information System.
Latent tuberculosis infection was considered the dependent variable. Patients were diagnosed to have LTBI when there were no clinical or radiological signs of active TB, and TST measured ≥ 10 mm and/or QFT-GIT was positive (value of the TB antigen minus nil control was ≥ 0.35 international units/mL and > 25% of nil value). According to the American Thoracic Society, Infectious Diseases Society of America, and the CDC, the positivity of both or just one of the tests is sufficient to diagnose LTBI.17
The independent variables analyzed were age range at the time of diagnosis of the IC, time elapsed between diagnosis of the IC and evaluation, degree of exposure, duration of exposure to the IC before the diagnosis, and relationship to the IC.
The variables were binarily categorized for statistical analysis. The age groups were categorized considering that, between the children, those younger than 5 years are more susceptible to TB disease after exposure to smear-positive TB cases.10 To calculate time elapsed between diagnosis of the IC and evaluation, and age at the time of evaluation, we used the first evaluation, which marked the inclusion of the participant in the study (i.e., the 2012–2013 evaluation was used for the contacts exposed before 2011, and the 2016–2017 evaluation was used for the other contacts). The degree of exposure of the contact to the IC was categorized as ≤ 24 or > 24 hours per week.
Data analysis.
Two researchers double-entered the data using SPSS software, version 20 (IBM Corp, Armonk, NY), to confirm consistency and accuracy. When conflicting entries were identified, a third researcher verified the entry by referring to the original questionnaire.
Continuous variables were summarized as medians with interquartile ranges (IQRs) and total ranges. Categorical variables were presented as absolute and relative frequencies. The bivariate analysis was performed using simple logistic regression models, with the presence or absence of LTBI as the dependent variable, and crude odds ratios and 95% CIs were reported. Multivariate logistic regression analysis by backward method was used to evaluate risk factors for LTBI, using all variables with P-value < 0.20 in the univariate analyses. A P-value < 0.05 was considered statistically significant. Adjusted odds ratios and 95% CIs were computed.
Ethical considerations.
The study protocol was approved by the Research Ethics Committee of the Federal University of São João del-Rei (CAAE 34233614.7.0000.5545). Written informed consent was obtained from legal guardians.
RESULTS
Between January 2007 and December 2016, 99 contacts aged < 15 years exposed to 46 ICs with smear-positive PTB (i.e., 2.15 contacts per IC) were identified (Figure 1).
Recruitment flowchart.
Citation: The American Journal of Tropical Medicine and Hygiene 101, 5; 10.4269/ajtmh.19-0100
Recruitment flowchart.
Citation: The American Journal of Tropical Medicine and Hygiene 101, 5; 10.4269/ajtmh.19-0100
Recruitment flowchart.
Citation: The American Journal of Tropical Medicine and Hygiene 101, 5; 10.4269/ajtmh.19-0100
The demographic, socioeconomic, and epidemiological characteristics of the contacts are presented in Table 1. The median time elapsed between diagnosis of the IC and inclusion in the study was 2.5 years (IQR = 1.5–4.4) and 7.4 years (IQR = 3.8–9.7) when we reassessed the development (or not) of active TB by telephone call and consultation with SINAN records in August 2018.
Demographic, socioeconomic, and epidemiological characteristics of contacts exposed to smear-positive cases of pulmonary tuberculosis
| Characteristic | N = 99 |
|---|---|
| Sex Female (n [%]) | 51 (51.5) |
| Age (in years) at time of exposure (median; IQR; range) | 6.6; 3.3–9.4; 0–13.8 |
| Age (in years) at time of evaluation (median; IQR; range) | 9.3; 6.5–12.1; 0–16.8 |
| Age (in years) at the last follow-up assessment (median; IQR; range) | 14.1; 8.9–17.7; 2.0–22.0 |
| Household | |
| Owned by family (n [%]) | 59 (59.6) |
| More than four rooms (n [%]) | 90 (90.9) |
| More than four cohabitants (n [%]) | 50 (50.5) |
| Daily household income per capita ≤ 7 US$ (n [%]) | 71 (71.7) |
| Neonatal vaccination with BCG (n [%]) | 99 (100) |
| Presence of BCG vaccine scar (n [%]) | 97 (98) |
| Exposure to more than one index case (n [%]) | 9 (9.1) |
IQR = interquartile range.
The contacts never had TB before. None of them had signs or symptoms suggestive of active TB at the time of clinical evaluation, nor did any have radiological findings suggestive of active or prior disease (e.g., calcifications). Just one child (30 month old) had inconclusive result to HIV by rapid test, but virological testing was negative. All other children had rapid test negative for HIV/AIDS.
Of the 99 children and adolescents, 21.2% (95% CI, 14.0–29.9) were diagnosed with LTBI by TST and/or positive QFT-GIT, and none developed active TB. The prevalence of LTBI in children < 5 years and aged 5–14 years was 15.8% (95% CI, 6.6–29.4) and 24.6% (95% CI, 15.0–36.3), respectively. There were 23 of 99 (23.2%) children aged < 3 years at time of exposure to ICs with infectious PTB; three developed LTBI and none progressed to TB disease.
There was no statistically significant difference between the groups and the independent variables in the univariate analyses (Table 2). The variables included in multivariate analyses were degree of exposure to IC, duration of symptomatic period of the IC before treatment, and kinship; none reached statistical significance, demonstrating similarity between both groups.
Characteristics of contacts exposed to smear-positive pulmonary TB according to LTBI or non-LTBI
| Characteristics | LTBI (n = 21), n (%) | Non-LTBI (n = 78), n (%) | Crude odds ratio (95% CI) | P-value |
|---|---|---|---|---|
| Age group at time of diagnosis of the IC | ||||
| < 5 years | 6 (28.6) | 32 (41.30) | 0.58 (0.20–1.64) | 0.30 |
| 5–14 years | 15 (71.4) | 46 (59.0) | 1 | |
| Time elapsed between diagnosis of de IC and evaluation | ||||
| ≥ 2 years | 15 (71.4) | 50 (64.51) | 1.40 (0.49–4.01) | 0.53 |
| < 2 years | 6 (28.6) | 28 (35.9) | 1 | |
| Time elapsed between diagnosis of the IC and TB development follow-up | ||||
| ≥ 5 years | 15 (71.4) | 54 (69.2) | 1.11 (0.38–3.21) | 0.85 |
| < 5 years | 6 (28.6) | 24 (30.8) | 1 | |
| Proximity and intensity of exposure to the IC | ||||
| Degree of exposure to IC | 0.15 | |||
| > 24 hours/week | 17 (81.0) | 50 (64.1) | 2.38 (0.73–7.77) | |
| ≤ 24 hours/week | 4 (19.0) | 28 (35.9) | 1 | |
| Duration of symptomatic period of the IC without treatment* | ||||
| > 30 days | 15 (83.3) | 37 (62.7) | 2.97 (0.77–11.44) | 0.11 |
| ≤ 30 days | 3 (16.7) | 22 (37.3) | 1 | |
| Kinship | ||||
| Parents | 6 (28.6) | 12 (15.4) | 2.20 (0.71–6.80) | 0.17 |
| Others | 15 (71.4) | 66 (84.6) | 1 | |
IC = index case; LTBI = latent tuberculosis infection; TB = tuberculosis.
* Data for 77 and 90 participants, respectively.
Isoniazid preventive therapy (IPT) was prescribed at the time of diagnosis of the IC for only two of the 99 children (2.0%). However, one of these children began IPT even with negative TST, and did not meet the LTBI criteria. This child received IPT for only 1 month. The second child presented with a positive TST at the time of exposure and received IPT for 5 months. When re-evaluated in the present study, this last patient still met our LTBI criteria.
DISCUSSION
The prevalence of LTBI (21.2%) in our study is lower than that found in a meta-analysis that examined low- and middle-income countries (52.9% prevalence), such as Brazil, and high-income countries (34.8% prevalence).4 Even though Brazil is among the 22 countries with the highest rate of TB,1 the city of Divinópolis is in an area of low TB incidence and high human development index (HDI = 0.764).14,15 According to official Brazilian records, during the time of the study, the incidence rate in this municipality corresponded to almost one-third of the national average.15 Thus, the epidemiological situation of TB in Divinópolis seems to be close to that found in high-income countries with a low TB burden; we found a lower prevalence of LTBI in contacts exposed to smear-positive ICs in Divinópolis (21.2%) than in those countries (34.8%) for contacts exposed to smear-positive ICs.4,18
In the comparison by age group from the aforementioned meta-analysis, the prevalence of LTBI in the present study was also lower than that found in low- and middle-income countries: 15.8% versus 35.5% for children aged < 5 and 24.6% versus 53.1% for children aged 5–14 years. In the age group comparison with high-income countries, the prevalence was similar to that of children aged < 5 years (16.3%) and higher in those aged 5–14 years (18.4%).4 However, Fox and others4 considered the proportion of contacts with LTBI against those exposed to overall TB in a stratified analysis, whereas in the present study, we only considered smear-positive PTB, the most transmissible form of the disease. For this reason, the discrepancy between our findings and those for low- and middle-income countries could have been even greater, and the prevalence rates by age group possibly lower than high-income countries.
Using the same definition criteria for LTBI, a recent study developed by Indian authors19 involving 226 children younger than 14 years found a 54.4% prevalence of TB infection in all TB contacts (either smear-positive or negative PTB). This is an intermediate prevalence rate compared with those observed in other Brazilian regions, where the variation (33.0–69.6%) was also higher than that found in our study.20–22 If a TST cutoff point of 5 mm was considered, the prevalence of LTBI would be only slightly altered (from 21.2% to 22.2%) because only two children presented TST of 5–9 mm. Thus, the Divinópolis municipality remained with rates still below those reported in the literature.
In infected individuals, it is expected that approximately 5–10% will develop TB in the future.1 A study conducted by Brazilian authors with participants aged > 18 years identified progression of 25.0% during the 1-year follow-up period.23 Considering that children represent a risk group for TB progression,7 it is expected that the rate of progression in this group would be even higher among our participants.
Although the evolution of LTBI to active TB occurs most commonly within the first 2 years after infection, the possibility of endogenous reactivation remains throughout life.1,3,6 It should be noted that in the present study, the contacts were followed for a sufficient time period (7.4 years; IQR = 3.8–9.7) to notice the development of active TB; no such progression to this form of the disease was observed. To the best of our knowledge, the present study is the first to follow up a population aged < 15 years with known exposure to smear-positive PTB for a length of time that exceeded the high risk period of progression to active disease.6,10,21,24
There was no statistically significant difference between the groups with or without LTBI for any of the demographic, socioeconomic, or epidemiological variables analyzed. Chandrasekaran and others,19 in evaluating the positivity of TST or IGRA in relation to the intensity of exposure reported as hours per day of exposure, did not find any significant association. Another recent study showed that even sporadic exposure to a case of smear-positive PTB before treatment may lead to infection.25 Kinship with the IC was not verified by Beyanga and others26 as a risk factor. Late diagnosis, although prolonging the transmission time,27,28 was not significantly associated with LTBI.
The low prevalence of LTBI and the lack of progression to active TB among contacts with LTBI in the present study are not associated with the factors investigated here. Thus, they are believed to be related, among other factors, to the coverage and/or protective effect of the BCG vaccine. As shown in Table 1, all 99 contacts studied here received BCG in the neonatal period. However, the low prevalence of LTBI in Divinópolis cannot be attributed to high vaccination coverage because this coverage is also high (≥ 95% average from 2007 to 2016) in all regions of the country.29 A meta-analysis carried out to determine whether BCG vaccination protects children aged < 16 years against LTBI and active TB showed 27% (Risk Ratio = 0.73) and 58% (risk ratio = 0.42) protection, respectively.30
The heterogeneity of both LTBI prevalence and progression to active TB in geographic areas within the same country and/or region raises questions that go beyond the BCG effectiveness and demographic, socioeconomic, and epidemiological characteristics. The influence of feature of M. tuberculosis strains and human genetics would be other factors to consider31–34 and may have contributed to the different scenario verified in the municipality where our study was carried out.
Analysis of genetic factors (humans or bacterial) was not included here, even though it is worth noting the TB-protective effect of some human polymorphisms already studied in the Brazilian population, namely, rs735239 (OR = 0.46) and rs4804803 (OR = 0.61) of the CD209 gene35; the GA genotype of polymorphism rs2275913 of gene IL17A (OR = 0.44)36 and GC genotype of polymorphism rs1800795 of the IL6 gene (OR = 0.55).36 Studies investigating human protective genetic factors and M. tuberculosis strains as features that impact immunogenicity and virulence in the population of Divinópolis might contribute to clarify the low prevalence verified for LTBI and the lack of progression of LTBI to active TB among the participants of the present study.
Our study has some limitations. Recall bias is one of them because data on contact exposure were collected months or even years after the diagnosis of the ICs. However, efforts were made to control this by helping ICs and contacts’ legal guardians to recall moments of the year of IC diagnosis, such as, proximity of the some holidays, whether the child was in school, and where they were working, among other information that referred to the symptomatic period before the definitive diagnosis of TB.
Despite the apparent sample size insufficiency, a post hoc calculation showed that it would require 11 individuals in each of the LTBI and non-LTBI groups to detect a statistically significant difference between the two proportions found in this study (21.2% and 78.8%, respectively; i.e., a ratio of 1:3.7), accepting alpha and beta errors of 0.05 and 0.20, respectively. In other words, our results are probably not random, and suggest that the presence or absence of LTBI is related to factors other than those investigated here.
Another important consideration is the certainty that 20 of the 21 children aged < 15 years with LTBI (95.2%) did not receive IPT and one received it for 5 month, that is, less than the minimum of the recommended 6 months and recognized as necessary to prevent TB10,37; they followed the TB natural evolution and did not get ill over the 7–8-year time period in which we reassessed for the development of active TB.
We can conclude, therefore, that there was a low prevalence of LTBI and absence of active TB among the contacts studied, which could be explained by the HDI of the municipality, the protective effect of BCG vaccination in the neonatal period, and potentially protective genetic factors. Studies concomitantly investigating these and other factors associated with susceptibility or resistance to M. tuberculosis, including biomarkers of protection or susceptibility, are important to understand the differences between regions of the same or even different countries and should be the subject of further study.
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