Effectiveness of WHO's pragmatic screening algorithm for child contacts of tuberculosis cases in resource-constrained settings: a prospective cohort study in Uganda

Abstract

Background: Tuberculosis is a leading cause of global childhood mortality; however, interventions to detect undiagnosed tuberculosis in children are underused. Child contact tracing has been widely recommended but poorly implemented in resource-constrained settings. WHO has proposed a pragmatic screening approach for managing child contacts. We assessed the effectiveness of this screening approach and alternative symptom-based algorithms in identifying secondary tuberculosis in a prospectively followed cohort of Ugandan child contacts.

Methods: We identified index patients aged at least 18 years with microbiologically confirmed pulmonary tuberculosis at Old Mulago Hospital (Kampala, Uganda) between Oct 1, 1995, and Dec 31, 2008. Households of index patients were visited by fieldworkers within 2 weeks of diagnosis. Coprevalent and incident tuberculosis were assessed in household contacts through clinical, radiographical, and microbiological examinations for 2 years. Disease rates were compared among children younger than 16 years with and without symptoms included in the WHO pragmatic guideline (presence of haemoptysis, fever, chronic cough, weight loss, night sweats, and poor appetite). Symptoms could be of any duration, except cough (>21 days) and fever (>14 days). A modified WHO decision-tree designed to detect high-risk asymptomatic child contacts was also assessed, in which all asymptomatic contacts were classified as high risk (children younger than 3 years or immunocompromised [HIV-infected]) or low risk (aged 3 years or older and immunocompetent [HIV-negative]). We also assessed a more restrictive algorithm (ie, assessing only children with presence of chronic cough and one other tuberculosis-related symptom).

Findings: Of 1718 household child contacts, 126 (7%) had coprevalent tuberculosis and 24 (1%) developed incident tuberculosis, diagnosed over the 2-year study period. Of these 150 cases of tuberculosis, 95 (63%) were microbiologically confirmed with a positive sputum culture. Using the WHO approach, 364 (21%) of 1718 child contacts had at least one tuberculosis-related symptom and 85 (23%) were identified as having coprevalent tuberculosis, 67% of all coprevalent cases detected (diagnostic odds ratio 9·8, 95% CI 6·8-14·5; p<0·0001). 1354 (79%) of 1718 child contacts had no symptoms, of whom 41 (3%) had coprevalent tuberculosis. The WHO approach was effective in contacts younger than 5 years: 70 (33%) of 211 symptomatic contacts had coprevalent disease compared with 23 (6%) of 367 asymptomatic contacts (p<0·0001). This approach was also effective in contacts aged 5 years and older: 15 (10%) of 153 symptomatic contacts had coprevalent disease compared with 18 (2%) of 987 asymptomatic contacts (p<0·0001). More coprevalent disease was detected in child contacts recommended for screening when the study population was restricted by HIV-serostatus (11 [48%] of 23 symptomatic HIV-seropositive child contacts vs two [7%] of 31 asymptomatic HIV-seropositive child contacts) or to only culture-confirmed cases (47 [13%] culture confirmed cases of 364 symptomatic child contacts vs 29 [2%] culture confirmed cases of 1354 asymptomatic child contacts). In the modified algorithm, high-risk asymptomatic child contacts were at increased risk for coprevalent disease versus low-risk asymptomatic contacts (14 [6%] of 224 vs 27 [2%] of 1130; p=0·0021). The presence of tuberculosis infection did not predict incident disease in either symptomatic or asymptomatic child contacts: in symptomatic contacts, eight (5%) of 169 infected contacts and six (5%) of 111 uninfected contacts developed incident tuberculosis (p=0·80). Among asymptomatic contacts, incident tuberculosis occurred in six (<1%) of 795 contacts infected at baseline versus four (<1%) of 518 contacts uninfected at baseline, respectively (p=1·00).

Interpretation: WHO's pragmatic, symptom-based algorithm was an effective case-finding tool, especially in children younger than 5 years. A modified decision-tree identified 6% of asymptomatic child contacts at high risk for subclinical disease. Increasing the feasibility of child-contact tracing using these approaches should be encouraged to decrease tuberculosis-related paediatric mortality in high-burden settings, but this should be partnered with increasing access to microbiological point-of-care testing.

Funding: National Institutes of Health, Tuberculosis Research Unit, AIDS International Training and Research Program of the Fogarty International Center, and the Center for AIDS Research.

Figure 1. Study profile of symptom-based approaches assessed for child contact investigation, Kampala, Uganda*

*Symptomatic contacts included contacts with any tuberculosis-related symptoms, including chronic cough, fever, night sweats, haemoptysis, weight loss, and loss of appetite. Chronic cough was defined as a continuous, non-remitting cough present for >3 weeks. Fever was defined as body temperature of >38°C for 14 days, after exclusion of common causes such as malaria or pneumonia. Weight loss was defined as reporting of weight loss or failure to thrive with confirmatory evidence from the child’s growth chart. Haemoptysis was defined as the expectoration of blood from the lung airways or parenchyma. Night sweats and loss of appetite were self-reported by children and parents. Asymptomatic contacts included children with cough of <3 weeks’ duration or fever of <2 weeks’ duration, or both.

Figure 2. Tuberculosis-related outcomes* stratified by WHO’s symptom-based approach for the management of child contacts†

TST=tuberculin skin test. *Individuals with coprevalent disease were excluded from analyses of incident disease. In this analysis, tuberculosis infection was defined as a tuberculin skin-test induration response of ≥10 mm. Percentages might not total 100% because within-characteristic percentages were rounded to the nearest integer. †Participants were included in the pragmatic guideline if they had one tuberculosis-related symptom including chronic cough, fever, night sweats, haemoptysis, weight loss, and loss of appetite. Chronic cough was defined as a continuous, non-remitting cough present for >3 weeks. Fever was defined as body temperature of >38°C for 14 days, after exclusion of common causes such as malaria or pneumonia. Weight loss was defined as reporting of weight loss or failure to thrive with confirmatory evidence from the child’s growth chart. Haemoptysis was defined as the expectoration of blood from the lung airways or parenchyma. Night sweats and loss of appetite were self-reported by children and parents. Asymptomatic contacts included children with cough of <3 weeks’ duration or fever of <2 weeks’ duration, or both. The difference between coprevalent tuberculosis among symptomatic and asymptomatic contacts was statistically different (23% vs 3%, p<0.0001). Contacts with tuberculosis infection (tuberculin skin-test induration ≥10 mm) did not result in increased risk for incident tuberculosis (among symptomatic contacts, 5% vs 5% incident tuberculosis rates among contacts infected and uninfected at baseline, p=0.80; among asymptomatic contacts, <1% vs <1% incident tuberculosis rates among contacts infected and uninfected at baseline, p=1.0)

Figure 3. Tuberculosis-related outcomes* in children screened following the WHO symptom-based approach for the management of child contacts, stratified by the age of the child†

*Individuals with coprevalent disease were excluded from analyses of incident disease. In this figure, tuberculosis-free indicates contacts free from tuberculosis, but these contacts might have had tuberculosis infection. Percentages might not total 100% because within-characteristic percentages were rounded to the nearest integer. †Participants were included in the pragmatic guideline if they had one tuberculosis-related symptom including chronic cough, fever, night sweats, haemoptysis, weight loss, and loss of appetite. Chronic cough was defined as a continuous, non-remitting cough present for >3 weeks. Fever was defined as body temperature of >38°C for 14 days, after exclusion of common causes such as malaria or pneumonia. Weight loss was defined as reporting of weight loss or failure to thrive with confirmatory evidence from the child’s growth chart. Haemoptysis was defined as the expectoration of blood from the lung airways or parenchyma. Night sweats and loss of appetite were self-reported by children and parents. Asymptomatic contacts included children with cough of <3 weeks’ duration or fever of <2 weeks’ duration, or both. The difference between coprevalent tuberculosis among symptomatic and asymptomatic contacts was statistically different for children younger than 5 years (33% vs 6%, p<0.0001) and aged 5 years or older (10% vs 2%, p<0.0001).

Figure 4. Tuberculosis-related outcomes* in children screened following the WHO symptom-based approach for the management of child contacts, stratified by the HIV-serostatus of the child†

*Individuals with coprevalent disease were excluded from analyses of incident disease. In this figure, tuberculosis-free indicates contacts free of tuberculosis, but these contacts might have had tuberculosis infection. Percentages might not total 100% because within-characteristic percentages were rounded to the nearest integer. †In this flowchart, infants with tuberculosis-related symptoms (including chronic cough, fever, night sweats, haemoptysis, weight loss, and loss of appetite,) were included to be screened in the algorithm. Chronic cough was defined as a continuous, non-remitting cough present for >3 weeks. Fever was defined as body temperature of >38°C for 14 days, after exclusion of common causes such as malaria or pneumonia. Weight loss was defined as reporting of weight loss or failure to thrive with confirmatory evidence from the child’s growth chart. Haemoptysis was defined as the expectoration of blood from the lung airways or parenchyma. Night sweats and loss of appetite were self-reported by children and parents. Asymptomatic contacts included children with cough of <3 weeks’ duration and/or fever of <2 weeks’ duration. This analysis included only 1414 child contacts who took an HIV test. The difference between coprevalent tuberculosis among symptomatic and asymptomatic contacts was statistically different for HIV-seropositive children (48% vs 7%, p<0.0001) and HIV-seronegative children (23% vs 4%, p<0.0001).

Figure 5. Tuberculosis-related outcomes* in children screened following a modified WHO decision-tree† classifying asymptomatic child contacts into high-risk and low-risk groups‡

*Individuals with coprevalent disease were excluded from analyses of incident disease. In this figure, tuberculosis-free indicates contacts free of tuberculosis, but these contacts might have had tuberculosis infection. Percentages might not total 100% because within-characteristic percentages were rounded to the nearest integer. †This algorithm was first proposed by Marais and colleagues. ‡Children with tuberculosis-related symptoms are shown in figure 2 and included children with either chronic cough, fever, night sweats, haemoptysis, weight loss, or loss of appetite. Chronic cough was defined as a continuous, non-remitting cough present for >3 weeks. Fever was defined as body temperature of >38°C for 14 days, after exclusion of common causes such as malaria or pneumonia. Weight loss was defined as reporting of weight loss or failure to thrive with confirmatory evidence from the child’s growth chart. Haemoptysis was defined as the expectoration of blood from the lung airways or parenchyma. Night sweats and loss of appetite were self-reported by children and parents. Asymptomatic contacts included children with cough of <3 weeks’ duration or fever of <2 weeks’ duration, or both. The modified decision-tree, which proposes to group asymptomatic contacts into high-risk and low-risk groups, symptomatic contacts were at highest-risk for disease (23% and 5% coprevalent and incident disease; p<0.05 vs both other groupings). High-risk asymptomatic contacts had higher rates of coprevalent disease compared with low-risk asymptomatic contacts (6% versus 2%, p<0.01) and similar rates of incident disease (1% vs <1%, p=0.23). If both symptomatic and high-risk asymptomatic contacts were screened and followed up, 79% and 71% of all coprevalent and incident cases, respectively, would be assessed.