The Role of Clinical Symptoms in the Diagnosis of Intrathoracic Tuberculosis in Young Children.

Globally, an estimated half a million children develop tuberculosis (TB) annually, contributing approximately 6%–10% of all TB cases. About 80,000 of these children die every year, making TB one of the major causes of mortality in children younger than 5 years.1,2 Clinical trials of new TB vaccines in infants are planned to coincide with peak childhood TB incidence, and highest risk of severe morbidity and mortality, as these occur during the first 2 years of life.3,4 For this reason, accurate diagnosis of TB in these very young children is critical for diagnostic, preventive and therapeutic studies. Childhood TB lacks definitive diagnostic criteria.5 The diagnosis of childhood TB is particularly difficult because TB disease in young children is pauci-bacillary and usually culture negative.6 A recent expert consensus statement recommends the following clinical case definitions for confirmed, probable and possible intrathoracic TB in clinical research to evaluate diagnostic assays: signs and symptoms suggestive of TB plus microbiologic confirmation for confirmed TB; signs and symptoms suggestive of TB plus a positive CXR, in addition to either (1) a positive response to anti-TB treatment or (2) documented exposure to Mycobacterium tuberculosis (MTB) or (3) immunologic evidence of MTB infection, for probable TB; and signs and symptoms suggestive of TB with either (1) a positive CXR or (2) a positive response to anti-TB treatment or (3) documented exposure to MTB or (4) immunologic evidence of MTB infection, for possible TB.7 However, in TB-endemic countries, symptoms associated with TB frequently occur in association with other common childhood illnesses, and this lack of specificity may limit their diagnostic usefulness.8,9 In addition, in children younger than 3 years of age, rapid progression of disease to severe forms, such as miliary TB or TB meningitis, may shorten the period for detection of classic respiratory symptoms, and thus limit the opportunity for respiratory symptom-based diagnosis.8 We have previously shown that clinical response to treatment may have limited value as a diagnostic criterion for pediatric trials of TB diagnostics and vaccines,10 and chest radiographic features of intrathoracic TB may be difficult to interpret.11 The diagnosis of childhood TB in the setting of clinical trials is further complicated by active TB disease surveillance, isoniazid preventive therapy, and effective short-course chemotherapy.12 Therefore, the phenotype of TB cases in such research settings is likely to represent early, mild disease that is associated with higher diagnostic uncertainty,11,12 and might not reflect the typical phenotype of TB disease occurring in communities where routine health service interventions are less efficient.6,11,13 In particular, the symptom profile of TB cases is likely to be affected, along with altered radiologic disease severity and sputum bacillary burden.6 Our hypothesis was that classic respiratory symptoms, including persistent cough and wheeze, are not useful for diagnosis of the mild TB disease phenotype that would be observed most often in a clinical trial setting. Detailed understanding of the relationship between individual symptoms, including cough and wheeze, and both culture confirmation of MTB (the current diagnostic gold standard) and radiologic evidence of intrathoracic TB, will be key to design of diagnostic endpoints for accurate diagnosis of pediatric childhood TB in future trials. We present an analysis of the relationships between individual symptoms and these microbiologic and radiologic diagnostic criteria; we examine the usefulness of individual symptoms for diagnosis of TB disease and for differentiating between severe and nonsevere intrathoracic TB disease, in the setting of a clinical trial.