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ARTICLE |
a Desmond Tutu Tuberculosis Centre and Department of Paediatrics and Child Health, Tygerberg Children's Hospital, Stellenbosch University, Cape Town, South Africa
b Medical Research Council of South Africa, Cape Town, South Africa
c International Union Against Tuberculosis and Lung Disease, Paris, France
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. A prospective, community-based study was conducted in Cape Town, South Africa. Specific well-defined symptoms were documented in all children <13 years of age reporting a persistent, nonremitting cough of >2 weeks' duration; study participants were thoroughly evaluated for tuberculosis. In addition, all of the children who received antituberculosis treatment during the study period were reviewed by the investigator, irrespective of study inclusion. This concurrent disease surveillance provided a comprehensive overview of all of the childhood tuberculosis cases, allowing accurate assessment of the possible disadvantages associated with this symptom-based diagnostic approach. In the absence of an acceptable gold standard test, optimal case definition is an important consideration. Children were categorized as "bacteriologically confirmed tuberculosis," "radiologically certain tuberculosis," "probable tuberculosis," or "not tuberculosis." Bacteriologically confirmed tuberculosis was defined as the presence of acid-fast bacilli on sputum microscopy and/or Mycobacterium tuberculosis cultured from a respiratory specimen. Radiologically certain tuberculosis was defined as agreement between both independent experts that the chest radiograph indicated certain tuberculosis in the absence of bacteriologic confirmation. Probable tuberculosis was defined as the presence of suggestive radiologic signs and good clinical response to antituberculosis treatment in the absence of bacteriologic confirmation or radiologic certainty. Good clinical response was defined as complete symptom resolution and weight gain of 
10% of body weight at diagnosis, within 3 months of starting antituberculosis treatment. Not tuberculosis was defined as spontaneous symptom resolution or no response to antituberculosis therapy in the absence of bacteriologic confirmation or radiologic signs suggestive of tuberculosis. Pulmonary tuberculosis was defined as a symptomatic child with: (1) bacteriologically confirmed tuberculosis, (2) radiologically confirmed tuberculosis, or (3) probable tuberculosis (as defined), excluding isolated pleural effusion.
RESULTS. In total, 1024 children were referred for evaluation. Resolving symptoms were reported in 596 children (58.2%); 428 (41.8%) children with persistent, nonremitting symptoms at evaluation were investigated for tuberculosis. Pulmonary tuberculosis was diagnosed in 197 children; 96 were categorized as bacteriologically confirmed tuberculosis, 75 as radiologically certain tuberculosis, and 26 as probable tuberculosis. Combining a persistent nonremitting cough of >2 weeks' duration, documented failure to thrive (in the preceding 3 months), and fatigue provided reasonable diagnostic accuracy in HIV-uninfected children (sensitivity: 62.6%; specificity: 89.8%; positive predictive value: 83.6%); the performance was better in the low-risk group (3 years; sensitivity: 82.3%; specificity: 90.2%; positive predictive value: 82.3%) than in the high-risk group (<3 years; sensitivity: 51.8%; specificity: 92.5%; positive predictive value: 90.1%). In children with an uncertain diagnosis at presentation, clinical follow-up was a valuable diagnostic tool that further improved diagnostic accuracy, particularly in the low-risk group. Symptom-based approaches offered little diagnostic value in HIV-infected children. Three (15%) of the 20 HIV-infected children diagnosed with pulmonary tuberculosis failed to report symptoms of sufficient duration to warrant study inclusion, whereas 25% reported persistent, nonremitting symptoms in the absence of tuberculosis. In addition, the tuberculin skin test was positive in <20% of HIV-infected children diagnosed with pulmonary tuberculosis.
DISCUSSION. The combined presence of 3 well-defined symptoms at presentation (persistent, nonremitting cough of >2 weeks' duration; objective weight loss [documented failure to thrive] during the preceding 3 months; and reported fatigue) provided good diagnostic accuracy in HIV-uninfected children 3 years of age, with clinical follow-up providing additional value. The approach performed less well in children <3 years. However, the presence of a persistent, nonremitting cough together with documented failure to thrive still provided a fairly accurate diagnosis (sensitivity: 68.3%; specificity: 80.1%; positive predictive value: 82.1%), illustrating the importance of regular weight monitoring in young children. Clinical follow-up also offered additional diagnostic value, but caution is required, because very young children have an increased risk of rapid disease progression. The approach performed poorly in HIV-infected children. Recent household contact with an adult index case seemed to provide more diagnostic value than a positive tuberculin skin test, but novel T-cell-based assays may offer the only real improvement in sensitivity to diagnose M tuberculosis infection in HIV-infected children. The variable diagnostic value offered by this symptom-based diagnostic approach illustrates the importance of risk stratification, as demonstrated by the fact that 11 (91.7%) of 12 children with severe disease manifestations who failed to meet the entry criteria were <3 years of age or HIV infected. Particular emphasis should be placed on the provision of preventive chemotherapy after documented exposure and/or infection in these high-risk children. Study limitations include the small number of HIV-infected children, but on the positive side, the large number of HIV-uninfected children permitted adequate evaluation in this important group. It is often forgotten that HIV-uninfected children constitute the majority of child tuberculosis cases, even in settings where HIV is endemic. This study demonstrates the importance of ascertaining a child's HIV status before symptom-based diagnosis is attempted. Because children were recruited at both the clinic and hospital level, some selection bias may have been introduced; however, the only significant difference between the 2 groups was the proportion of HIV-infected children. Pulmonary tuberculosis was diagnosed with different levels of certainty, but no significant differences were recorded between these groups.
CONCLUSIONS. Pulmonary tuberculosis can be diagnosed with a reasonable degree of accuracy in HIV-uninfected children using a simple symptom-based approach. This offers the exciting prospect of improving treatment access for children, particularly in resource-limited settings where current access to antituberculosis treatment is poor.
Key Words: symptom-based • diagnosis • tuberculosis • children
Abbreviations: TST—tuberculin skin test • CXR—chest radiograph • PPV—positive predictive value • OR—odds ratio • CI—confidence interval
Tuberculosis control programs place an almost exclusive emphasis on adults with sputum smear-positive disease, because they are most infectious. However, children contribute a significant proportion of the global tuberculosis caseload1,2 and experience considerable tuberculosis-related morbidity and mortality.3 Few children in endemic areas have access to antituberculosis treatment,4 and diagnostic difficulty is a major contributing factor.5,6
The diagnosis of tuberculosis in children is complicated by the absence of a practical reference test, because respiratory specimens are difficult to collect, and the reported bacteriologic yield is low5,6; sputum smears are positive in <10%–15% of children diagnosed with tuberculosis, and confirmation by culture is achieved in only 30%–40%.4,7 The value of the classic diagnostic triad: (1) exposure to an adult index case, (2) a positive tuberculin skin test (TST), and (3) the presence of suggestive signs on the chest radiograph (CXR), is greatly reduced in endemic areas where exposure to and/or infection with Mycobacterium tuberculosis are common. Consequently, in endemic areas, the diagnosis of childhood tuberculosis rests predominantly on the subjective interpretation of the CXR,8,9 which is subject to pronounced interobserver and intraobserver variability10 and is rarely available in resource-limited settings.
In general, there is a sense of scepticism regarding the potential diagnostic value of symptom-based approaches. A recent comprehensive review of symptom-based diagnostic approaches emphasized the absence of standard symptom definitions and the inadequate validation of current approaches.11 Previous descriptive studies were mostly hospital based,12,13 complicating the extrapolation of results to the community level. A recent community-based survey reported that poorly defined symptoms traditionally associated with tuberculosis occur commonly in randomly selected healthy children; they occur too commonly to offer any real diagnostic value.14
However, the natural history of childhood tuberculosis demonstrates that symptoms may have diagnostic value if appropriate risk stratification is applied.15 In low-risk children (immune competent, 3 years of age), disease progression after primary M tuberculosis infection is rare and is associated with the presence of persistent, nonremitting symptoms.15 In high-risk children (<3 years of age and/or immune compromised), disease progression occurs more frequently and may be associated with acute symptom onset,15 which reduces the opportunity for and safety of symptom-based diagnosis.
In a small pilot study, the use of well-defined symptoms with a persistent, nonremitting character provided good diagnostic value in low-risk children.16 However, the true value of these well-defined symptoms required further evaluation in a large prospective study, with community-based recruitment to limit selection bias and concurrent disease surveillance to document potential disadvantages. The current study aimed to determine the value of well-defined symptoms to diagnose childhood pulmonary tuberculosis in a tuberculosis-endemic area.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Population
Study entry criteria were children <13 years of age who reported a persistent, nonremitting cough of >2 weeks' duration, without response to a course of oral antibiotics. Nurses within the selected clinics were requested to refer all of the eligible children to the investigator. The investigator visited each clinic twice weekly to evaluate referred children. The following measures were put in place to ensure that all of the children who met the entry criteria were included in the study: (1) training of all of the pediatric nurses within the study clinics, (2) posting of prominent reminders, and (3) giving weekly feedback and motivation to the nurses. In addition, a study nurse was employed to screen all of the children admitted to the local referral hospital (Tygerberg Children's Hospital). Hospitalized children who met the entry criteria were referred to the investigator by the study nurse and were evaluated in the same fashion as those referred by the clinic nurses.
Data Collection
A screening questionnaire documented the presence and uninterrupted duration of symptoms. Children who were referred but whose symptoms resolved or showed marked improvement before evaluation were not investigated for tuberculosis. However, all of the referred children completed the screening questionnaire and were followed until symptom resolution. Children were instructed to return if symptoms recurred. Referral was not restricted to a single episode; children were evaluated in a similar fashion in the event of a second referral.
Initial Assessment and Management
Investigation for tuberculosis included completion of a comprehensive questionnaire, weight measurement and assessment of weight gain on the Road-to-Health growth chart during the preceding 3 months, performance of a TST and CXR, and attempts to collect 1 gastric aspirate and/or sputum specimen. HIV testing was offered together with standard pretest and posttest counseling to all of the children.
Children diagnosed with tuberculosis were started on standard antituberculosis 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 resistance in which case treatment was individualized. Children <2 years of age with known exposure and/or a positive TST result received isoniazid preventive chemotherapy once active tuberculosis was excluded. All of the other children were treated according to the most likely alternative diagnosis and reviewed after 2 to 4 weeks. If symptoms persisted beyond an additional 4 weeks, full assessment, including TST (if previously negative), CXR, and mycobacterial cultures, were repeated. At this time, every effort was made to establish a final diagnosis and all children <5 years of age with documented tuberculosis exposure or infection, but not diagnosed with active tuberculosis, were put on isoniazid preventive chemotherapy as prescribed by the National Tuberculosis Programme. The duration of uninterrupted symptoms until spontaneous symptom resolution or the onset of antituberculosis chemotherapy was recorded. Children who received antituberculosis treatment were reviewed after 3 months to document response to therapy.
Concurrent Disease Surveillance
All of the children who received antituberculosis treatment during the period of study enrollment and for an additional surveillance period of 3 months were documented and reviewed by the investigator. This concurrent disease surveillance provided a comprehensive overview of all the children treated for tuberculosis, irrespective of study inclusion, allowing an accurate assessment of the possible disadvantages associated with this symptom-based diagnostic approach.
TST
A 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 millimeters after 48 to 72 hours. A positive TST was regarded as a measurement of 10 mm in HIV-uninfected children, and 5 mm in HIV-infected children.
CXR
Standard anteroposterior and lateral views were done and read by 2 independent experts, blinded to all of the clinical information and to each other's interpretation. Findings were documented on a standard report form and categorized as "certain tuberculosis," "uncertain tuberculosis," or "certain not tuberculosis." Disease manifestations were classified according to a recently proposed radiologic classification of childhood intrathoracic tuberculosis.18
HIV Testing
A rapid test was used to screen for HIV infection (Determine HIV 1/2 rapid test; Abbott, Tokyo, Japan). All of the children with a positive rapid test result were referred to the HIV family clinic at Tygerberg Children's Hospital for confirmatory tests (by polymerase chain reaction in children <18 months and ELISA in older children) and clinical management.
Specimen Collection and Mycobacterial Culture
We attempted to collect 1 culture specimen from each child; multiple specimens were collected from children sent to the referral hospital. Samples were inoculated into liquid media using either BACTEC or MGIT systems (Becton Dickinson, Sparks, MD). Positive cultures were confirmed to be M tuberculosis by routine polymerase chain reaction speciation.19
Definitions
Children were categorized as "bacteriologically confirmed tuberculosis," "radiologically certain tuberculosis," "probable tuberculosis," or "not tuberculosis." Bacteriologically confirmed tuberculosis was defined as the presence of acid-fast bacilli on sputum microscopy and/or M tuberculosis cultured from a respiratory specimen. Radiologically certain tuberculosis was defined as agreement between both independent experts that the CXR indicated certain tuberculosis in the absence of bacteriologic confirmation. Probable tuberculosis was defined as the presence of suggestive radiologic signs and good clinical response to antituberculosis treatment in the absence of bacteriologic confirmation or radiologic certainty. Good clinical response was defined as complete symptom resolution and weight gain of 10% of body weight at diagnosis, within 3 months of starting antituberculosis treatment. Not tuberculosis was defined as spontaneous symptom resolution or no response to antituberculosis therapy in the absence of bacteriologic confirmation or radiologic signs suggestive of tuberculosis. Pulmonary tuberculosis was defined as a symptomatic child with: (1) bacteriologically confirmed tuberculosis, (2) radiologically confirmed tuberculosis, or (3) probable tuberculosis (as defined), excluding isolated pleural effusion.
Ethics
Parents gave written informed consent for study participation and gave separate written consent for HIV testing. Ethics approval was obtained from the Institutional Review Board of Stellenbosch University, the City of Cape Town Health Department, and from local community health advisory boards.
Statistical Analysis
Data were dually entered into an Access (Microsoft, Redmond, WA) relational database and validated. Descriptive analyses were done using SPSS 13.0 (SSPS Inc, Chicago, IL). The sensitivity, specificity, and positive predictive value (PPV) of individual variables were calculated. Multivariate tree regression analysis was used to identify the individual variables that statistically contributed most diagnostic value. For analysis purposes, 2 high-risk groups were identified: (1) HIV-uninfected children <3 years of age and (2) HIV-infected children. HIV-uninfected children 3 years were regarded as low-risk. The sensitivity, specificity, and PPV were calculated for each of these relevant risk groups when cumulatively combining the 3 variables that statistically contributed the most diagnostic value on multivariate tree regression analysis.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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3 years). The only mortality was a 3-month-old HIV-uninfected child who presented with acute symptom onset and died in hospital with disseminated (miliary) disease.
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Table 3 indicates the value of individual variables to diagnose pulmonary tuberculosis at presentation within the relevant risk groups. The value of a positive TST differed significantly between relevant risk groups. Comparing the value of a positive TST in HIV-uninfected and HIV-infected children demonstrated that the sensitivity of the TST was significantly better in HIV-uninfected children (156 of 179 [87.2%] vs 3 of 17 [17.6%]; OR: 31.6; 95% CI: 7.6–151.5). In HIV-infected children, a history of household contact with an adult tuberculosis index case seemed more sensitive (9 of 17 [52.9%]) than a positive TST (3 of 17 [17.6%]), but this failed to reach statistical significance (OR: 5.2; 95% CI: 0.89–34.7).
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3 years: specificity: 98.9%; PPV: 85.1%; <3 years: specificity: 82.6%; PPV: 88.6%), with further improvement after >4 weeks in children <3 years of age (specificity: 98.6%; PPV: 88.6%). However, persistence of a nonremitting cough added less diagnostic value in HIV-infected children, in whom optimal accuracy was achieved when objective weight loss and reported fatigue at presentation were combined with a persistent cough at follow-up (sensitivity: 56.2%; specificity: 75.0%; PPV: 77.2%). |
DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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3 years of age. It is often assumed that these low-risk children contribute little to the tuberculosis disease burden, but they contributed 
50% of the pulmonary tuberculosis caseload in this study. The vast majority of individuals in highly endemic areas become infected with M tuberculosis during childhood, but after 2 years of age. The large number of infections probably explains the high disease burden in these children, despite their relatively low risk to progress to disease.
The combined presence of 3 well-defined symptoms at presentation: (1) a persistent, nonremitting cough of >2 weeks' duration; (2) objective weight loss (documented failure to thrive) during the preceding 3 months; and (3) reported fatigue, provided good diagnostic accuracy in HIV-uninfected children 3 years of age. However, a sensitivity of 81% implies that 20% of pulmonary tuberculosis cases would have been missed, because they failed to meet these strict diagnostic criteria. Fortunately, clinical follow-up proved to be a valuable additional diagnostic tool that differentiated tuberculosis from other common conditions, particularly in this low-risk group.
The symptom-based diagnostic approach performed less well in HIV-uninfected children <3 years of age. Fatigue added little diagnostic value, because it was difficult for parents/legal guardians to comment on its presence. However, the presence of a persistent, nonremitting cough together with documented failure to thrive provided a fairly accurate diagnosis on its own (sensitivity: 68.3%; specificity: 80.1%; PPV: 82.1%), which illustrates the importance of regular weight monitoring. In our experience, documenting the response to simple measures, such as food and/or iron supplementation and/or deworming, further improves the diagnostic value of documented failure to thrive. The observation that inclusion of a positive TST only provided improved diagnostic performance in children <3 years of age may be expected in highly endemic settings where a large percentage of older children would have been exposed to tuberculosis before.20 As in older children, clinical follow-up offered additional diagnostic value, but more caution is required, especially in very young children who have a greatly increased risk of rapid disease progression.
Symptom-based approaches offered limited diagnostic value in HIV-infected children. Three (15%) of the 20 HIV-infected children diagnosed with pulmonary tuberculosis failed to report symptoms of sufficient duration to warrant study inclusion, whereas 25% reported persistent, nonremitting symptoms in the absence of tuberculosis. In addition, the TST was positive in <20% of HIV-infected children diagnosed with pulmonary tuberculosis. The poor sensitivity of the TST in HIV-infected children is well documented and correlates with the degree of immune suppression.21 This indicates the importance of evaluating more sensitive tests to confirm or exclude M tuberculosis infection in immune-compromised children. New T-cell-based assays, particularly the ELISPOT test, seem to offer improved sensitivity in HIV-infected children with tuberculosis,22 whereas the performance is unaffected by the degree of immune suppression in adults.23 In this study, recent household contact with an adult index case seemed to provide more diagnostic value than a positive TST, but the sensitivity and specificity achieved remained poor.
The variable diagnostic value offered by this symptom-based approach illustrates the importance of risk stratification,24 which provides the motivation behind current World Health Organization guidelines to screen all children <5 years in household contact with an adult index case.25 However, relevant risk stratification has not been widely incorporated into clinical diagnostic approaches. The natural history of disease demonstrates a substantial reduction in the risk to progress to disease if primary infection occurs after 2 years of age. As disease progression usually occurs within the first 12 months, we defined HIV-uninfected children <3 years of age, and all HIV-infected children irrespective of age, as high risk.15,26 The importance of risk stratification is demonstrated by the fact that 11 (91.7%) of 12 children with parenchymal consolidation and/or airway compression and/or disseminated (miliary) disease who did not meet the entry criteria were either <3 years or HIV infected. Particular emphasis should be placed on the provision of preventive chemotherapy after exposure and/or documented infection in these high-risk children.
Study limitations include the small number of HIV-infected children enrolled, which limits our ability to comment on this particular group. However, we were able to demonstrate that a symptom-based approach, which does not include an accurate measure of M tuberculosis infection, has little diagnostic value in HIV-infected children. On the positive side, the large number of HIV-uninfected children provided an excellent opportunity to describe both the diagnostic performance and potential disadvantages of this novel symptom-based approach in this group of children. HIV-uninfected children remain an important group, because they constitute the majority of tuberculosis cases, even in settings where most adults with tuberculosis are HIV infected.3,27 The study emphasizes the importance of ascertaining a child's HIV status before symptom-based diagnosis is attempted.
Because children were recruited at both the clinic and hospital level, hospital-based recruitment may have introduced some selection bias. However, the only significant difference between the 2 groups was the proportion of HIV-infected children. Pulmonary tuberculosis was diagnosed with different levels of certainty, but there were no significant differences between the symptoms recorded in children with bacteriologically confirmed tuberculosis versus those with radiologically certain tuberculosis or probable tuberculosis. Isolated pleural effusion was excluded from the case definition, because it represents a different pathologic mechanism and has a different prognosis. All 17 of the children with isolated pleural effusion presented with a distinct clinical picture: localized unilateral chest pain, intermittent fever, the absence of acute illness or respiratory distress, and the presence of extensive unilateral dullness on percussion.
The diagnostic accuracy achieved in this highly endemic setting, using a combination of symptoms at presentation and/or follow-up, may be much reduced in nonendemic areas where the pretest probability of tuberculosis is lower. In addition, all of the assessment, evaluation, and follow-up were performed by the investigator, and it is presumed that this was done in a more rigorous manner than would be achieved at primary health care clinics in general. It would be helpful if the diagnostic value of this symptom-based approach was confirmed in a different setting.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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We thank the primary health care clinics involved, the City of Cape Town Health Department, and, in particular, the patients and their parents for their participation.
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FOOTNOTES |
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Address correspondence to Ben J. Marais, MRCP, FCP, MMed, PhD, Department of Paediatrics and Child Health, Desmond Tutu Tuberculosis Centre, Faculty of Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg, 7505, South Africa. E-mail: bjmarais E-mail: bjmarais{at}sun.ac.za
The authors have indicated they have no financial relationships relevant to this article to disclose.
Dr Marais had full access to all the data reported in this study and had final responsibility for the decision to submit for publication.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This article has been cited by other articles:
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  B. J Marais and M. Pai Recent advances in the diagnosis of childhood tuberculosis Arch. Dis. Child., May 1, 2007; 92(5): 446 - 452. [Abstract] [Full Text] [PDF]
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