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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 2  |  Issue : 1  |  Page : 16-24

Prevelence of latent tuberculosis and associated risk factors in children under 5 years of age in Karachi, Pakistan


Department of Community Medicine, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan

Date of Web Publication5-Feb-2014

Correspondence Address:
Mubashir Zafar
Dow University of Health Sciences, Karachi
Pakistan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2320-8775.126504

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  Abstract 

Background: As infected children represent a large proportion of the pool from which tuberculosis (TB) cases will arise and its associated risk factors that influence TB infection are basic cause for burden of TB. Aim: This study was to determine the prevalence of latent TB and associated risk factors in children less than 5 year of age in Karachi, Pakistan. Setting and Design: Cross-sectional study and it was conducted in tertiary care hospital in Karachi. Materials and Methods: In this study, children who were living in contact with individuals who had proven smear-positive pulmonary TB cases were investigated. A tuberculin skin test (TST) was performed on each child. TST sizes ≥5 and 10 mm, respectively, were considered positive. Statistical Analysis: A random effects logistic regression model, which takes into account the clustering of contacts within households, was used to assess the relationship between the tuberculin response of the contact and risk factors. Results are reported as unadjusted and adjusted odds ratios and their 95% confidence intervals. The likelihood ratio test was used to assess the overall significance of risk factors, tests for trend, and tests for interaction. Results: The distribution of TST responses followed a bimodal pattern, with 135 (35%) children presenting a palpable induration. The risk of positive TST response in the child increased with the geographic proximity of the child to the individual with TB within the household and with the degree of activities shared with the individual with TB. Nutritional status and presence of a bacille Calmette-Guérin (BCG) scar were not independent risk factors for TST positivity in this population. On multivariate analysis, the effect of geographic proximity to the individual with TB, household size, and duration of cough in the index case persisted for TST responses ≥5 mm. Conclusions: Positive TST in a child reflects most probably TB infection rather than previous BCG vaccination. Contact tracing can play a major role in the control of TB in Pakistan.

Keywords: Children, contact, household, tuberculosis, tuberculin skin test


How to cite this article:
Zafar M. Prevelence of latent tuberculosis and associated risk factors in children under 5 years of age in Karachi, Pakistan. J Assoc Chest Physicians 2014;2:16-24

How to cite this URL:
Zafar M. Prevelence of latent tuberculosis and associated risk factors in children under 5 years of age in Karachi, Pakistan. J Assoc Chest Physicians [serial online] 2014 [cited 2019 Jul 17];2:16-24. Available from: http://www.jacpjournal.org/text.asp?2014/2/1/16/126504


  Introduction Top


Tuberculosis (TB) is a leading cause of morbidity and mortality in all age groups especially in developing countries. [1] World Health Organization (WHO) has estimated that 13.7 million of the world's population has active TB and about 1 million (11%) of them are children <15 years of age. [2] This figure varies from 3% to 25% in different countries. [3] However these results are based on smear positive cases and hence are likely to underestimate the magnitude of TB in children.

Pakistan ranks 6 th in Eastern Mediterranean region of WHO and 44% overall prevalence of TB in the country. [4] There are 4% registered cases of TB in children, 2.5% are at risk of getting infection, out of which only 5%-10% of infected children will progress to primary progressive disease while 80-90% will get latent tuberculosis infection (LTBI) in Pakistan. It accounts for 8%-20% of all deaths in children the infection being acquired primarily from the adults from their surroundings. [5]

LTBI represents a substantial public health burden and it is the leading cause of infectious disease worldwide in people of all ages. It is estimated that one third of the world's population carry this latent infection. [6],[7] The overall life time risk of LTBI reactivation is approximately 5%-10% among older children but risk of progression to active disease higher in younger children. [8],[9] It has been shown that up to 50% of infants will develop the disease within 3-9 months of infection and 25% of children 1-5 years of age; 15% of adolescents will develop the disease within 1-2 years of infection. [10] Infection in the childhood establishes the reservoir for the future outbreaks, making proper diagnosis and treatment of LTBI in the endemic region important for TB control by more than 50% of cases of TB. [11]

There are many factors which predispose to latent TB like living in the same house with close family members or friends who had active TB is significantly [8.69 confidence interval (CI): 3.00-25.18] associated with LTBI. [12] Large family size and small house predisposes 9 times a risk to develop LTBI (CI: 3.00-25.28). [13] LTBI is also more prone to develop where ventilation and sunlight are inadequate because Mycobacterium would not easily move away or killed. [14],[15] Smoking is also contributing factor for latent infections [odds ratio (OR) 3.20 (1.30-8.20)]. [16]

The diagnosis remains challenging because latent TB never shows signs and symptoms. The identification of M. TB in clinical specimens (the gold standard for diagnosis of TB in adults) is seldom possible in children. [17] Periodic skin testing by the Mantoux method is recommended in children living in regions of high TB prevalence [18],[19] and should be done at intervals based on the epidemiology of TB in the region.

The rationale for screening children younger than 5 year of age is due to more prevalent cases of LTBI at this age group and also high progression to active disease which lead to high mortality. Children have more years to potentially develop TB, so it is important that they are identified and treated. Early detection of the LTBI cases will decline mortality and also the overall burden of the disease. In low-income countries where TB is prevalent and resources are limited, tuberculin skin test (TST) is used for early diagnosis and treatment of LTBI. Medication used to treat LTBI is well-tolerated by children and there is a low risk of toxicity.

Aim

To determine the prevalence of latent TB infection and associate risk factors among children less than 5 year of age in Karachi, Pakistan.


  Materials and Methods Top


Study design and setting

This was cross-sectional study and patients were recruited from National Institute of Child Health (NICH) in Karachi, Pakistan.

Participants and data collection

All patients who had newly detected smear-positive pulmonary TB and were under 5 years and had been living at the same address for >2 months were eligible for the study. Sample size was calculated by using the prevalence of 3.5% LTBI in 1-5-year-old children in a study by Masoumi-Asl et al. [20] Total 325 patients were included in the study. Nonprobability consecutive sampling was done to recruit children. All children of age less than 5 year and visited in outpatient department of NICH were included in this study. Children who recently received live attenuated vaccine like measles, mumps, rubella, and oral polio were excluded from study. Children who were treated or on treatment for TB, recent Mantoux test or BCG vaccination (less than 1 year), recent viral infection (measles, mumps, chickenpox, HIV, etc), severe malnutrition, malignancy and children on treatment with cytotoxic drugs, immunosuppressive drugs and steroids were also excluded from study. Selection of participants shows in [Figure 1].
Figure 1: Flow diagram

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Operational definitions

Latent TB

Those children who have positive TST (Mantoux test), TB disease suspected if the interviewees reported chronic cough (longer than 3 weeks), weight loss, night sweats, and fever.

Monteux test

The reading of Monteux test is stratified into the following:

  • Negative: Induration less than 10 mm
  • Positive: Induration greater than 10 mm
  • Strongly positive: Induration greater than 15mm.


Family history or close friends

Those children live in the house where any family member affected by TB or children have close friend have TB.

Smoking

Those children who live in the house where any family member were smoker.

Household structure

House where few rooms and number of person live many and there were no ventilation and lighting mechanism were present.

Degree of contact was defined as close if patients and children usually share the same meal or the same bed, or live in the same room.

Duration of contact was the reported time period from the onset of the disease to the beginning of the directly observed therapy.

Study protocol

Pulmonary TB was confirmed by two consecutive sputum smears positive for acid-fast bacilli and/or positive culture. Informed consent was obtained before enrollment. Households of individuals who had TB were visited at the time of recruitment, and consent was sought from the head of the household to undertake the study. Information was collected using standardized questionnaires on various variables, including household size, house structure, hygiene, and socioeconomic status. Detailed demographic information was collected from each member of the household, including duration of residence in the compound, relatedness to the index case, exposure to the index case, medical history, and presence of symptoms of TB. Field workers checked the presence of a BCG scar on the left or right deltoid region and measured the weight, the height, and the middle-upper arm circumference (MUAC) in children younger than 5 years. A TST was performed on the volar surface of the left forearm of each household member aged >3 months, using 2 TU of RT 23 (Statens Serum Institut, Copenhagen, Denmark). Induration diameters were measured along and across the arm within 48-72 hours by trained field workers. For ensuring validity of the TST reading and to reduce intraobserver and interobserver variability, TST reading by each field worker was tested regularly during the course of the study against the same reference reader. Those who departed from standard reference reading were retrained. For analysis purposes, the average of width and length diameters was considered. Various criteria for skin test positivity were explored and cutoff points of 5 and 10 mm were chosen. [21],[22] Control households were selected at random in the neighborhood of the TB cases. The study was explained to the members of the household, and after taken consent, the household was recruited in the study. Members of the household were then investigated in a similar way as for the household of the case, including tuberculin skin testing. The nutritional status of children was assessed through the use of the weight-for-age and weight-for-height indices. These are expressed as z scores, which represent the distribution in a reference population standardized to a mean of 0 and a standard deviation (SD) of 1. The World Health Organization recommends that 2 SD below the reference median (z = −2) is the cutoff point for defining abnormally low values.

The study was approved by the Ethical review committee of Dow university of Health Sciences, Karachi before conducting the study. Confidentiality was maintained and parents/guardian of participants were accordingly informed about their test results. Participants who are diagnosed with latent TB infection study were provided free treatment. No financial compensation was provided by the research study.

Statistical analysis

Epi Data Entry software version 3.1 was used for data entry to optimize documentation and error detection. All records were cross-checked with the original data sheets. Data were double-entered and checked for data-entry errors. A random effects logistic regression model, which takes into account the clustering of contacts within households, was used to assess the relationship between the tuberculin response of the contact and risk factors. Results are reported as unadjusted and adjusted ORs and their 95% CIs. The likelihood ratio test was used to assess the overall significance of risk factors, tests for trend, and tests for interaction. All statistical analyses were conducted using software of SPSS version 16.


  Results Top


Study population

Data were collected in the households of 106 individuals with infectious TB. The number of contacts in the households was 1870 (median household size: 8; minimum: 2; maximum: 43), 325 (13.4%) being under the age of 5. Among them, 45 (11.7%) were aged <1 year. To assess the background situation, we first compared the distribution of TST responses in households of individuals with TB with control households (n = 325). For both chosen cutoff points, the risk of being TST-positive was found to be higher in children who were in contact with individuals with infectious TB than in those who were in contact with community controls (OR: 7.43; 95% CI: 3.96-17.8; P < 0.001; and OR: 20.21; 95% CI: 10.03-31.39; P <0.001, for TST positivity defined as ≥5 and ≥10 mm, respectively). Among the latter, the mean induration size was 11.9 mm (SD: 4.3 mm) and the median size was 11.5 mm. Using the set criteria for TST positivity, 33.6% children had a TST response ≥5 mm and 25.8% had a TST response ≥10 mm.

[Table 1] shows sociodemographic characteristic of study participants. Median age of data was 2.4 years. More than half (54%) were males and more than one-quarter (30.4%) belonging to Punjab. More than two-third (91%) were literate. More than half (69%) had less than two rooms in the house. More than two-third (90.5%) of houses had more than five persons livings in single room. More than one-third (38.5%) child room had no ventilation. Nearly half (45%) of child were malnourished. More than half (60%) had BCG vaccination history or BCG scar. Nearly one-third (23.7%) had family member TB history. Nearly two-third (70.1%) had smoker in the family.
Table 1: Sociodemographics characteristic of study participants and clinical summaries of study participants


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LTBI prevalence

Intensity of exposure is also related to the infectivity of the case. All 256 index TB cases were sputum positive, 193 of them being confirmed on culture. Of those, 19 presented atypical mycobacteria on culture, but no difference was noted in the distribution of TST responses in their contact children compared with the others (data not shown). The risk of TST positivity in contacts was not influenced by the density of acid-fast bacilli in the sputum of the individual with TB but increased with the duration of cough and with the number of lung zones affected on the chest radiograph of the individual with TB. It was not associated with the age or gender of the individual with TB and was not modified by the human immunodeficiency virus status of the individual with TB (OR: 1.37; 95% CI: 0.33-4.10 for TST ≥5 mm and OR: 2.01; 95% CI: 0.23-3.48 for TST ≥10 mm).

Factor associated with LTBI

[Table 2] and [Table 3] on univariate analysis, the risk of being TST-positive (defined as ≥5 mm and ≥10 mm, respectively) within the households of the individuals with TB seemed to be higher after 1 year of age and in girls. The risk of TST positivity was associated with the total number of people living in the household of the individual with TB, the risk being higher in smaller than in larger households (test for trend, P <0.001). It was not associated, however, with the average number of people per room in the household (OR for <5 people per room as compared with >5: 1.03; 95% CI: 0.51-2.12 for TST positivity ≥5 mm and OR: 1.31; 95% CI: 0.56-3.07 for TST positivity ≥10 mm).
Table 2: Risk factors associated with tuberculin skin test positivity (positive tuberculin skin test defined as ≥5 mm) in children in contact with individuals with tuberculosis: Univariate analysis (n=325)


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Table 3: Risk factors associated with tuberculin skin test positivity (positive tuberculin skin test defined as ≥10 mm) in children in contact with individuals with tuberculosis: Univariate analysis (n=325)


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To evaluate the degree of exposure to the individual with TB, we recorded the geographic proximity of the children to the individual with TB within the household at nighttime and the extent of activities shared with the individual with TB during the day. As can be seen, the risk of positive TST response increased with the geographic proximity of the child to the individual with TB (test for trend, P < 0.001) and with the importance of activities shared with the individual with TB (test for trend P = 0.007 for cutoff point of 5 mm).

Intensity of exposure is also related to the infectivity of the case. All 256 index TB cases were sputum positive, 193 of them being confirmed on culture. Of those, 19 presented atypical mycobacteria on culture, but no difference was noted in the distribution of TST responses in their contact children compared with the others (data not shown). The risk of TST positivity in contacts was not influenced by the density of acid-fast bacilli in the sputum of the individual with TB but increased with the duration of cough and with the number of lung zones affected on the chest radiograph of the individual with TB. It was not associated with the age or gender of the individual with TB and was not modified by the human immunodeficiency virus status of the individual with TB (OR: 1.37; 95% CI: 0.33-4.10 for TST ≥5 mm and OR: 2.01; 95% CI: 0.23-3.48 for TST ≥10 mm).

We also investigated the effect of potential child-related risk factors. The risk of TST positivity in child contacts was not associated with the presence of a BCG scar, for either chosen cutoff points (OR: 0.81, 95% CI: 0.98-1.55 for TST positivity ≥5 mm and OR: 0.89; 95% CI: 0.66-1.15 for TST positivity ≥10 mm). Positive TST responses were not associated with the nutritional status of the child, although this analysis was performed on a reduced number of children, of whom only 10 (3%) of 295 were undernourished (MUAC <12.5 cm). A no significant trend was observed, the risk of TST positivity being higher in the few undernourished children compared with the others (MUAC ≥13.5 cm; OR: 3.93; 95% CI: 0.56-15.42 for the cutoff point of 5 mm and OR: 4.09; 95% CI: 0.65-21.32 for the cutoff point of 10 mm). The OR for weight-for-age z score <−2 was 3.42 (95% CI: 0.90-3.53) for TST positivity ≥5 mm and 2.42 (95% CI: 0.93-3.78) for TST positivity ≥10 mm.

Last, information was collected on several variables reflecting the socioeconomic status and the structure of the house. In this population, the risk of TST positivity seemed to be inversely associated with ownership of the house (P < 0.07). It was not related, however, to other markers of socioeconomic status (employment and income of the household head, ownership of items) or with the structure of the house and general hygiene conditions (water supply, sanitation, refuse disposal, etc; data not shown).

In [Table 4], a multivariate model was constructed to control for confounders. The effect of geographic proximity to the case, household size, and duration of cough in the individual with TB remained when TST responses ≥5 mm was considered positive. Other variables, including age and gender, were no longer significant. when the cutoff point of ≥10 mm was chosen, the effect of household size only remained significant. Geographical proximity of the contact to the individual with TB seemed to be confounded by household size, the ORs for proximity being reduced once household size was controlled for geographic proximity are, as expected, strongly related variables (collinearity).
Table 4: Risk factors associated with tuberculin skin test positivity (positive tuberculin skin test defined as ≥5 mm and positive tuberculin skin test defined as ≥10 mm) in children in contact with individuals with tuberculosis: Univariate analysis (n=325)


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  Discussion Top


The general distribution of TST responses was observed in this population which follows the classic bimodal pattern and it was found in households elsewhere in Africa [23] and other places, [24] with a large proportion of children being TST-negative. Those results are similar from an earlier tuberculin survey conducted in 1984 in The Gambia among children aged 0-9, using intradermal injection of 10 TU of purified protein derivative. [25]

The prevalence of positive reaction to TST in the general population is commonly reported to increase with age. [23],[26] In this study, the main effect of age is observed before 1 year, when the majority of children are TST-negative, after which there is little variation (overlap of CIs), especially when a cutoff point of 10 mm is considered. However, this apparent effect was not confirmed in multivariate analysis after adjusting for household size and proximity to the individual with TB. Similarly, we observed in univariate analysis that female children were more likely to be TST-positive than male children, but this was not confirmed in multivariate analysis, as the effect was probably confounded by the geographic proximity to the individual with TB.

Various studies which were conducted in different parts of world showed that household contacts of individual with TB had higher risk of infection than individuals in the general population. [27],[28],[29] This was also confirmed in several recent studies conducted among children in New York City, [30] Botswana, [31] and Brazil, [32] in which contact with an individual with TB came out as the strongest risk factor for TB infection. In this study, the level of infection in children was directly related to the intensity of exposure to the individual with infectious TB (as assessed through both the geographic proximity to the individual with TB at nighttime and the extent of activities shared with the individual with TB during day time) as well as to the infectivity of the individual with TB (duration of cough). As TB is an airborne disease, the risk of an uninfected person's becoming infected is strongly associated with the probability of coming into contact with an individual with infectious TB and the intimacy of that contact. [33],[34] We did not observe a variation in TST positivity with crowding, assessed through the average number of people per room in the household, similar to studies conducted in Botswana [31] and in New York City. [30] In this limited group of children under 5, however, we observed a clear inverse association between household size and TST positivity, as well as a positive association between the risk of TST positivity and the intensity of exposure to the individual with TB within the household. This finding has recently been substantiated in a study in India that showed that among contacts of individual with infectious TB, the immunologic response to specific mycobacterial antigens increased with the spatial proximity of the subject to the individual with TB within the household. [35] Altogether, this suggests that, more than the proportion of people per room, it is the increased occurrence and the intimacy of contact with the individual with TB that determine the transmission of infection.

Poor nutritional status has been reported to decrease TST reactivity in children. [36],[37] In these studies, severe malnutrition was shown to depress immune responsiveness to BCG, although there was some uncertainty about the effect of mild malnutrition. We did not find an association between TST induration and nutritional status, similar to what was reported previously in other study in developing country [25] and in Botswana. [31] In this study, however, the proportion of undernourished children was very small among the contacts of individuals with TB, which gave low power to detect an effect.

Vaccination with BCG has been reported to induce cross-reactivity with tuberculin-purified protein derivative, but the degree of tuberculin sensitivity after BCG immunization has been shown to be highly variable, depending on the vaccine strain used, the dosage, the method of administration, the time since vaccination, the age and nutritional status at time of vaccination, and factors known to influence the reaction to TST. [38],[39],[40] TST reactivity in BCG-vaccinated children fades over time but can be boosted in children with repeated skin testing. [41],[42] There is no reliable method to distinguish tuberculin reactions caused by vaccination with BCG from those caused by natural mycobacterial infections. [21] In a study which was conducted in Malawi, the prevalence of TST positivity was consistently higher over all ages in individuals with a BCG scar than in individuals without a BCG scar. [41] Similar findings were reported among school entrants as well as among household contacts of children with latent TB infection in New York City. [43],[44] In this study, however, we did not find a difference in the prevalence of TST positivity among children with and those without a BCG scar for both cutoff points of 5 and 10 mm. Similar observations were reported among children under 5 years of age in Botswana-when TST positivity was set at 10 mm diameter [31] and in New York City, [30] as well as among children aged 1-15 in Brazil [32] and in Northern Canada. [45]

Some discrepancy between effective BCG vaccination and presence of a scar is to be expected, as scars are not invariably present among all vaccines. [46] Thus, in The Gambia, a scar was found in only 71% of children aged 0-9 years with a health-card record of a vaccination. [25] In the Canadian study, 17% of subjects with a record of past BCG vaccination showed no visible scar. [45] As BCG is given immediately after birth in Pakistan and vaccination coverage is reported to be high (>75%), the absence of association between BCG scar and TST positivity can be attributable to the waning of tuberculin sensitivity induced by BCG with time. [39],[47] It was, thus, reported that, in Malawi, BCG rarely induces very strong tuberculin sensitivity and that the majority of vaccinated individuals lost their BCG-induced tuberculin sensitivity shortly after the vaccination. [48] In many tropical countries, postvaccination sensitivity cannot be entirely attributed to BCG in the presence of naturally acquired low-grade sensitivity caused by environmental mycobacteria. [23],[27] Thus, some evidence for cross-protection from natural exposure to certain environmental mycobacteria has been associated with the geographic distributions of mycobacterial disease in Malawi. [49]

Children who are in contact with individuals with infectious TB are at high risk of developing TB. [50] Despite the former vaccination with BCG, it has been suggested that a positive TST in a child who has close contact with an adult with infectious TB most likely represents infection with M TB, and treatment of this latent infection should be considered, especially if the child is younger than 5 years. [51] This finding is of importance in light of the increasing rates of TB in sub-Saharan Africa, where children who are vaccinated with BCG are exposed to adults with active TB. Tracing of the children who are in contact with individuals with infectious TB has been relatively neglected within TB control programs in developing countries, mainly because of managerial difficulties. In this study, in the absence of more specific markers of infection, TST can continue to be used to assess TB infection in children who live in the household of individuals with infectious TB in areas with high BCG coverage. They also support the importance of contact tracing activities in the control of TB in developing countries, associated with early case detection and treatment.

Data set from this study provides a unique opportunity to assess the distribution of responses to TST among children who have been recently exposed to an individual with smear-positive TB and to examine the influence of various factors on this distribution, given exposure, in a developing country with high BCG vaccination coverage. We found that positive TST responses were found in the households of individual with TB had larger in size than in the households of controls. In this study, after confirming that recent exposure to an individual with infectious TB was a major factor for TST positivity in children by comparing with control households, we focused on the distribution of TST responses in children within the households of the individuals with TB.


  Acknowledgement Top


We are thankful to all participants who have volunteered for this study. We would also like to thank Prof. Dr Nighat Nisar for his input in this study.

 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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