Published online June 2, 2008
PEDIATRICS Vol. 121 No. 6 June 2008, pp. e1646-e1652 (doi:10.1542/peds.2007-3138)
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ARTICLE

Symptom-Based Screening of Child Tuberculosis Contacts: Improved Feasibility in Resource-Limited Settings

Alexey Kruk, MD, MSca,b, Robert P. Gie, MD, FCPc, H. Simon Schaaf, MD, MMed, PhDc and Ben J. Marais, MD, FCP, MMed, PhDb,c

a Department of Public Health, Oxford University, Oxford, United Kingdom
b Ukwanda Centre for Rural Health
c Desmond Tutu TB Centre and Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. National tuberculosis programs in tuberculosis-endemic countries rarely implement active tracing and screening of child tuberculosis contacts, mainly because of resource constraints. We aimed to evaluate the safety and feasibility of applying a simple symptom-based approach to screen child tuberculosis contacts for active disease.

METHODS. We conducted a prospective observational study from January through December 2004 at 3 clinics in Cape Town, South Africa. All of the children <5 years old in household contact with an adult tuberculosis source case were assessed by documenting current symptoms and tuberculin skin test and chest radiograph results.

RESULTS. During the study period, 357 adult tuberculosis cases were identified; 195 cases (54.6%) had sputum smear and/or culture positive results and were in household contact with children aged <5 years. Complete information was available for 252 of 278 children; 176 (69.8%) were asymptomatic at the time of screening. Tuberculosis treatment was administered to 33 (13.1%) of 252; 27 were categorized as radiologically "certain tuberculosis," the majority (n = 22) of which had uncomplicated hilar adenopathy. The negative predictive value of symptom-based screening varied according to the case definition used, with 95.5% including all of the children treated for tuberculosis and 97.1% including only those with radiologically "certain tuberculosis."

CONCLUSIONS. Our findings support current World Health Organization recommendations, demonstrating that symptom-based screening of child tuberculosis contacts should improve feasibility in resource-limited settings and seems to be safe.

Key Words: child • tuberculosis • symptom based • screening

Abbreviations: WHO—World Health Organization • NTP—national tuberculosis program • TST—tuberculin skin test • CXR—chest radiograph

Preventing and treating tuberculosis in children is often a low priority in tuberculosis-endemic countries.1 However, although childhood tuberculosis cases are rarely recorded with accuracy, children contribute substantially to the global tuberculosis disease burden.2 It is estimated that, of the 8.3 million new tuberculosis cases diagnosed in 2000, 884019 (11%) were children.3 In high-income countries, childhood tuberculosis constitutes 2% to 7% of all tuberculosis cases and is mainly found among immigrant populations; in low-income countries, childhood tuberculosis exists in close association with conditions of poverty and constitutes 15% to 20% of all tuberculosis cases.3–6 An autopsy study from Zambia found tuberculosis to be a leading respiratory cause of death among HIV-infected and uninfected children.7 In South Africa, tuberculosis has been reported as the third most common cause of death in HIV-infected children admitted to the hospital with a clinical diagnosis of acute severe pneumonia8; a community-based survey recorded a childhood tuberculosis incidence of 407 in 100000 children per year (in children <13 years of age).9

The World Health Organization (WHO) and most national tuberculosis programs (NTPs) advise that all children <5 years of age who are in close contact with a sputum smear-positive source case should be screened for tuberculosis disease.10 These recommendations are motivated by the increased risk of developing tuberculosis and the potential severity of disease observed in young children.11 Once tuberculosis disease has been excluded in these vulnerable children, preventive chemotherapy should be provided to eliminate the chance of developing latent infection and to prevent progression to tuberculosis disease. The best-studied preventive chemotherapy regimen, isoniazid monotherapy for 6 to 9 months, reduces the risk of developing tuberculosis disease in exposed children by at least two thirds and probably by >90% with good adherence.12–14

Screening of child tuberculosis contacts has a huge potential to reduce the burden of pediatric tuberculosis worldwide; however, although it is universally recommended, it is rarely practiced in resource-limited settings.15 This discrepancy mainly results from resource constraints that limit the availability of tuberculin skin testing and chest radiography, often regarded as prerequisite tests for adequate contact screening.16,17 Lacking the capacity to perform "mandatory" screening tests, clinics in resource-limited settings rarely even attempt to provide preventive chemotherapy to tuberculosis-exposed children. WHO recognized this dichotomy, and to improve access to preventive chemotherapy, the 2006 WHO "Guidance for National Tuberculosis Programs on the Management of Tuberculosis in Children" no longer regarded the tuberculin skin test (TST) and/or chest radiograph (CXR) as mandatory screening tests for all children in settings where these tests are not readily available (Fig 1). 10


Figure 1
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  		FIGURE 1 Suggested approach to contact management when CXR and TST are not readily available (adapted from World Health Organization. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. Geneva, Switzerland: World Health Organization; 2006. WHO/HTM/TB/2006.371). a Isoniazid 5 mg/kg daily for 6 months; b unless the child is infected with HIV (in which case isoniazid 5 mg/kg daily for 6 months is indicated).

 
Although access to preventive chemotherapy should be greatly improved by using simple symptom-based screening, the safety and feasibility of this approach have not been evaluated in prospective studies. A single retrospective study from South Africa demonstrated that symptom-based screening may be useful to identify the subset of children who require further investigation to exclude tuberculosis disease. This would allow the majority of vulnerable contacts who are asymptomatic at the time of screening to access preventive chemotherapy without delay.18 However, concerns have been raised regarding the safety of this simplified approach. The current study aimed to evaluate the safety and feasibility of applying a symptom-based approach to exclude tuberculosis disease among children in household contact with an adult tuberculosis index case.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A prospective observational study was conducted from January 2004 through December 2004 in Cape Town, South Africa. Children were recruited at 3 local clinics served by Tygerberg Children's Hospital as the referral center. The study area is a well-established epidemiologic field site within a predominantly "colored" community (people of mixed ethnicity) that experiences a high tuberculosis incidence (adult tuberculosis incidence: 845 in 100000),9 with a relatively low prevalence of HIV infection19 (<10% of adult tuberculosis patients tested during 2004). Local clinics provide general primary health care services and coordinate the diagnosis and treatment of tuberculosis patients, free of charge. Adult tuberculosis cases are identified by passive case finding and are managed according to the directly observed therapy, short-course (DOTS) strategy.

A tuberculosis source case was defined as an adult (≥15 years of age) with pulmonary tuberculosis, diagnosed on sputum smear and/or culture. Child household contacts were defined as children <5 years of age living and sleeping in the same house, or group of clustered houses on the same plot, as a newly diagnosed tuberculosis source case. In accordance with the South African NTP guidelines,20 all of the children <5 years of age in household contact with a tuberculosis source case were assessed by documenting symptoms suspicious of tuberculosis, as well as TST and CXR results. Children diagnosed with tuberculosis disease received standard tuberculosis treatment as directly observed therapy: 2 months of 3 drugs (isoniazid, rifampin, and pyrazinamide) followed by 4 months of 2 drugs (isoniazid and rifampin), unless they were exposed to an index case with known drug-resistant tuberculosis, in which case individualized treatment was provided. The treating clinician acted independently from the research clinician. According to current WHO recommendations,10 children without tuberculosis disease received unsupervised isoniazid monotherapy for 6 months, with monthly collection of tablets from the clinic.

All of the children in household contact with a newly diagnosed tuberculosis source case (routinely entered into the local tuberculosis register) were identified and invited to the clinic for evaluation, during a home visit by the study social worker. At evaluation, study nurses enquired about the presence of current symptoms (fever, cough, or wheeze, reduced playfulness or unusual fatigue, visible mass in the neck, or weight loss), performed a TST, and arranged for a CXR to be taken. Nurses recorded current symptoms by using a standard data capture document, irrespective of the symptom duration or character. This approach must be differentiated from the strict emphasis on well-defined symptoms that has been promoted for symptom-based diagnosis.21,22 In tuberculosis-endemic areas, the presence of a persistent nonremitting cough or wheeze for >2 to 4 weeks, together with reduced playfulness or unusual fatigue and documented failure to thrive provides good diagnostic accuracy in immune-competent children.21,22 However, for screening purposes, the specificity of the test is less relevant, but excellent negative predictive value is essential to ensure optimal safety.

A Mantoux TST, using intradermal injection of 2 tuberculin units of purified protein derivative (PPD RT 23 [Statens Serum Institut, Copenhagen, Denmark]), was performed on the volar aspect of the left forearm. The transverse diameter of induration was measured in millimeter after 48 to 72 hours; an induration of ≥10 mm (≥5 mm in HIV-infected children) provided a proxy for Mycobacterium tuberculosis infection. The diagnosis of tuberculosis disease was primarily made on radiologic grounds. CXRs were read by the same expert who was blinded to all of the clinical information; both anteroposterior and lateral CXRs were performed. Findings were documented on a standard report form and categorized as "certain tuberculosis," "uncertain tuberculosis," or "certain not tuberculosis." All of the CXRs judged to be certain tuberculosis by the first reader were read by a second independent expert. Radiologically certain tuberculosis was defined as agreement between both independent experts. Tuberculosis disease manifestations were classified according to a recently proposed radiologic classification of childhood intrathoracic tuberculosis.23

Written informed consent was obtained from the parent or guardian in the home language of the patient. HIV testing was not routinely performed, as the HIV prevalence among children in this community is low. Nevertheless, all of the children with symptoms suspicious of HIV infection, known HIV exposure, or a diagnosis of tuberculosis disease were offered an HIV test, together with routine pretest and posttest counseling. A rapid test was used to screen for HIV infection (Determine HIV 1/2 rapid test [Abbott, Tokyo, Japan]); no confirmatory tests were required, because none of the children had a positive rapid test. The Western Cape Provincial Tuberculosis Program, the NTP, and the City of Cape Town Health Department were consulted and their consent obtained. The University of Stellenbosch Ethics Committee approved the study.

Data were entered into an Excel (Microsoft, Redmond, WA) spreadsheet. Descriptive analyses were performed by using SPSS 14 (SSPS Inc, Chicago, IL). The sensitivity, specificity, and negative predictive value of using any current symptom to screen for active tuberculosis were calculated. Symptom frequencies recorded in those treated for tuberculosis compared with those not treated for tuberculosis were compared by using the {chi}2 test.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
During the study period, 357 adult tuberculosis cases (245 sputum smear-positive [68.6%]; 201 male [56.3%], 218 15–40 years of age [61.1%]) were identified; 195 subjects (54.4%) were sputum smear and/or culture positive and in household contact with children aged <5 years, representing 187 households with 271 children (on average: 1.45 children <5 years per household). Complete information (symptoms, TST, and CXR) was available in 252 (93.0%) of 271 children; included in the analysis. The mean age of the children was 30 months (range: 1–60 months). Of the child tuberculosis contacts included in the analysis, 240 (95.2%) of 252 were in contact with a sputum smear-positive and 12 (4.8%) with a sputum smear-negative culture-positive source case. In total, 136 (54.0%) of 252 children had a positive TST result, with a mean positive induration of 18 mm (Table 1).


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  		TABLE 1 Demographics of Children in Household Contact With an Adult Tuberculosis Source Case

 
Tuberculosis treatment was administered to 33 children (13.1%); 25 (75.8%) were <3 years of age, 32 (97.0%) had a positive TST result, and 24 (72.7%) had a rapid HIV screening test; all tested negative. Table 2 reflects the tuberculosis disease manifestations recorded in the 27 children categorized as certain tuberculosis; the majority (22 of 27 [81.5%]) had uncomplicated hilar adenopathy. The treating clinician initiated tuberculosis treatment in 6 children with uncertain tuberculosis; all had a positive TST result (mean: 19 mm), and 4 had suggestive symptoms; their average age was <3 years (mean: 35 months). None of the other children with uncertain tuberculosis developed symptoms suspicious of tuberculosis while on preventive therapy.


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  		TABLE 2 Radiographic Disease Manifestations Recorded in Child Tuberculosis Contacts

 
Symptoms recorded at the time of screening are reflected in Table 3; 176 children (69.8%) were completely asymptomatic. Subjective weight loss was reported in 43 children (16.7%), but failure to thrive was documented on the road-to-health card in only 19 subjects (7.4%); 10 of whom were treated for tuberculosis. Among those not treated for tuberculosis, worm infestation with iron deficiency anemia and/or food insecurity was regarded as the most common cause of failure to thrive, because children responded well to deworming and food supplementation. A cough was the most common symptom recorded in those treated for tuberculosis, being present in 18 (54.5%) of 33, but it was present in 44 (19.6%) of 224 children not treated for tuberculosis as well; 21 had perihilar streakiness indicative of possible viral infection, and 2 had symptoms and signs suggestive of bacterial pneumonia.


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  		TABLE 3 Comparing Symptoms Reported in Child Tuberculosis Contacts Treated for Tuberculosis Versus Those Not Treated for Tuberculosis

 
Of the children treated for tuberculosis, 25 (75.7%) of 33 reported symptoms at the time of screening. All 5 of the children with radiographic signs other than uncomplicated hilar adenopathy were symptomatic: 3 with parenchymal consolidation and/or airway compression reported cough and fever (2 had documented weight loss as well), 1 with pleural effusion reported fever and fatigue, and 1 with parenchymal cavitation reported cough, fatigue, and weight loss. On CXR, the 8 asymptomatic children all had uncomplicated hilar adenopathy: 6 with certain tuberculosis and 2 with uncertain tuberculosis; 5 were <3 years of age. Table 4 indicates the diagnostic value of symptom-based screening to exclude tuberculosis disease in child tuberculosis contacts. The negative predictive value of symptom-based screening varied according to the case definition used; 95.6% when using all of the children treated for tuberculosis, 97.2% when only children with radiologic "certain tuberculosis" were included, and 100% if the case definition excluded those with asymptomatic uncomplicated hilar adenopathy.


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  		TABLE 4 Value of Symptom-Based Screening to Exclude Tuberculosis Disease in Child Tuberculosis Contacts: Calculations Performed by Using Different Case Definitions for Tuberculosis Disease

 
Nurses reported that symptom-based screening was quick and easy to perform. TSTs require refrigeration of the purified protein derivative, a diabetic needled syringe, and appropriate expertise on the part of the study nurse to place and interpret the results correctly. Performing a TST is time consuming, especially when taking into consideration the need to record the result at a second visit 2 to 3 days later. CXR was done at the local day and/or referral hospital. It placed a considerable additional workload on radiography services, particularly at the local day hospital, as evidenced by the fact that their annual stock of child radiograph negatives was depleted within 3 months. Although it was not accurately quantified, parents or caregivers spent a considerable amount of time to get the required tests done, especially when they were dependent on public transport.


   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This prospective community-based study demonstrates that screening for tuberculosis disease is feasible using a symptom-based approach. Using a simplified approach has particular relevance in tuberculosis-endemic settings with limited resources, where TST and CXR are not readily available. In our study, more than two thirds of child tuberculosis contacts were completely asymptomatic at the time of screening and would have required no further tests to exclude tuberculosis disease. Although 8 (24.2%) of 33 children treated for tuberculosis during the study were completely asymptomatic, all of these children had uncomplicated hilar adenopathy detected on CXR only. The natural history of tuberculosis in children demonstrates that transient hilar adenopathy is a common finding after recent primary infection. According to the prechemotherapy literature, only a small percentage of these children are likely to develop progressive disease, which would be accompanied by clinical symptoms.11 This suggests that asymptomatic hilar adenopathy is a natural component of the primary (Ghon) complex, reflecting recent M tuberculosis infection rather than active tuberculosis disease.11,12,23

By convention, asymptomatic hilar adenopathy is currently treated as tuberculosis disease in most countries. The current study was unable to evaluate the risk of providing isoniazid monotherapy to children with asymptomatic hilar adenopathy, because all of these children received full tuberculosis treatment. However, early experience with isoniazid monotherapy (the US Public Health trials of the 1950s and 1960s) demonstrated that preventive chemotherapy should be sufficient in these cases.12 From a public health perspective, it is important to balance the minimum potential risk experienced by children with asymptomatic hilar adenopathy receiving isoniazid monotherapy, with the high disease risk of not providing any preventive therapy to tuberculosis-exposed children, because of an inability to screen for tuberculosis disease. Insistence that TST and CXR are mandatory screening tests severely limits the access of child tuberculosis contacts to preventive chemotherapy, especially in resource-limited settings, where children are most likely to be exposed to tuberculosis at a young and vulnerable age.17 The most important benefit demonstrated is the fact that less than one third of child tuberculosis contacts reported symptoms that required additional investigation to exclude tuberculosis disease. This implies that the majority of young and vulnerable children can receive preventive chemotherapy without delay; the excellent negative predictive value achieved (≤100% with the exclusion of asymptomatic hilar adenopathy) also indicates that symptom-based screening seems to be safe.

In addition, any child who develops symptoms suggestive of tuberculosis, even after the provision of preventive chemotherapy, should be evaluated to exclude tuberculosis disease. This provides a safety net for those children in whom isoniazid monotherapy may be ineffective. Another concern that is frequently mentioned is the risk of encouraging the development and spread of isoniazid resistance. Although this may be a valid concern in adults who receive isoniazid monotherapy without adequately ruling out tuberculosis disease, it is less of a concern in children. Children tend to develop paucibacillary disease, which reduces the likelihood of transmission and the risk of acquiring drug resistance.16 Asymptomatic children would have even lower bacillary loads, posing a negligible risk of acquiring isoniazid resistance.

A positive TST result provides proof of M tuberculosis infection, but it is less reliable in very young, malnourished, and/or immunocompromised children and may take up to 3 months to convert.24 Its main clinical applications would be to identify latent tuberculosis infection in vulnerable groups (eg, in oncology patients before the initiation of chemotherapy) and to provide supportive evidence for a tuberculosis case definition in symptomatic children. Because of delayed TST conversion, tuberculosis infection can only be reliably excluded in immune-competent children 3 months after tuberculosis exposure ended, which explains why the American Thoracic Society guidelines use the 3-month TST result to guide early termination of preventive chemotherapy.25 In resource-limited settings where TST is not routinely available, the benefit versus cost (including nursing time, patient time, transport costs, and inappropriate management because of misinterpretation) should be carefully considered. It seems important to prioritize CXR access as the diagnostic test of preference to exclude tuberculosis disease in symptomatic children15,26; the yield in this group of children was high (22 of 76 [28.9%]). In the absence of objective diagnostic tests to confirm tuberculosis disease, symptom-based diagnosis may be considered, but this requires a strong emphasis on careful symptom definition for improved diagnostic accuracy.21,22

The reality in most tuberculosis-endemic areas is that curative tuberculosis services are already overburdened, and clinics cannot spare the resources required to screen and treat child tuberculosis contacts. Implementing a simple symptom-based approach makes screening far more feasible. Feasibility may be further improved by restricting the focus to those children who stand to benefit most from the provision of preventive chemotherapy. The natural history of disease demonstrated that very young (<3 years of age) and/or immunocompromised children are at highest risk of developing tuberculosis disease after exposure.11 In our study, 16 (72.7%) of 22 children who met the case definition of tuberculosis disease were <3 years of age, including all of the children with complicated disease. Although tuberculosis disease should be excluded in any child with symptoms suspicious of tuberculosis, restricting the provision of preventive chemotherapy to those at highest risk after tuberculosis exposure (<3 years and/or immunocompromised) will drastically reduce the additional load placed on already overburdened health care services; 36.5% of child tuberculosis contacts in this study were >3 years of age.

Because of its cross-sectional design, we are unable to comment with certainty on the safety of symptom-based screening; however, ongoing disease surveillance continued in 2 of the 3 study clinics. Only 2 children who received preventive chemotherapy presented with tuberculosis disease during the following year; both were <3 years of age and reported poor adherence to preventive chemotherapy, only collecting tablets once. Additional study limitations include potential recall bias and reporter subjectivity; these influences were limited by the focus on current symptoms and the use of standardized data capture forms that were completed before TST and CXR evaluation. Investigator bias was further limited by the fact that radiographs were reviewed by independent experts blinded to all of the clinical information.

None of the children in this study were known to be HIV infected, which limits our ability to reflect on this group. It seems reasonable to expect that the complete absence of symptoms would still exclude tuberculosis disease, although a smaller percentage of HIV-infected children is expected to be completely asymptomatic at any point in time. In addition, we cannot comment on the safety of using isoniazid monotherapy in HIV-infected children with asymptomatic hilar adenopathy. WHO advises routine HIV testing of all children with symptoms suspicious of tuberculosis in countries with a high HIV prevalence; this recommendation should be included in national tuberculosis guidelines as well.10

We collected limited source case information, but previous studies from Africa described an increased transmission risk depending on sputum smear grading and if the source case is the mother or primary caregiver of the child.15,27 Data were collected by well-trained research nurses, and it is uncertain whether the findings would be similar in routine clinical care; however, symptom enquiry relied on 5 simple questions, and responses were captured on a standardized data capture sheet that would be easy to implement. A remaining challenge is poor adherence to unsupervised preventive chemotherapy.28,29 The development of short-course regimens and the implementation of other measures to improve adherence to preventive chemotherapy requires further evaluation.12,27–30


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our findings support current WHO recommendations that encourage symptom-based screening of child tuberculosis contacts in tuberculosis-endemic areas with limited resources; most importantly, strategies with improved feasibility should improve access to preventive chemotherapy for those children at greatest risk of developing tuberculosis disease.


   ACKNOWLEDGMENTS
 
We thank the study nurses Susan van Zyl, Danite Bester, and Annie Barker and the study social worker Cherise Pedro. We also thank the primary health care clinics involved, the patients and their parents, Dr Ivan Toms (City of Cape Town Health Department), and Nathan Wilson, who assisted Dr Kruk during his stay in South Africa. We are grateful to Steve Graham for critical appraisal of the article.


   FOOTNOTES
 
Accepted Dec 3, 2007.

Address correspondence to Ben J. Marais, MD, FCP, MMed, PhD, Stellenbosch University, Department of Paediatrics and Child Health, Faculty of Health Sciences, PO Box 19063, Tygerberg 7505, South Africa. E-mail: bjmarais{at}sun.ac.za

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

Dr Kruk entered and analyzed the data, wrote the first draft of the article, assisted with drafting the final article, and gave approval of the version to be published; Dr Gie acted as an expert chest radiograph reader, assisted with data interpretation and drafting the article, and gave approval of the version to be published; Dr Schaaf acted as an expert chest radiograph reader, assisted with data interpretation and drafting of the article, and gave approval of the version to be published; and Dr Marais conceived and designed the study, and acted as the study supervisor.


What's Known on This Subject

Providing preventive chemotherapy to tuberculosis contacts at high risk of developing tuberculosis disease is important for reducing tuberculosis-related morbidity and mortality among children. Preventive chemotherapy is rarely made available to children in tuberculosis-endemic countries because of a perceived inability to adequately screen child tuberculosis contacts for tuberculosis disease.

 

What This Study Adds

This study demonstrates that symptom-based screening provides a feasible alternative in resource-limited settings with poor access to tuberculin skin testing and chest radiography. It also seems safe, because only children with asymptomatic hilar adenopathy, which is more indicative of recent primary infection than tuberculosis disease, were missed by this approach.

 


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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