Why is improving screening for pulmonary tuberculosis in children important?
Tuberculosis is one of the leading causes of death worldwide. Most children who die from tuberculosis are never diagnosed or treated. Screening may be useful to identify children with possible tuberculosis and refer them for further testing. As well, screening could be used to identify children without tuberculosis, who should be considered for preventive treatment. A false-positive result means that children may undergo unnecessary testing and treatment and may not receive preventive treatment promptly. A false-negative result means that children have tuberculosis, but may miss further testing to confirm the diagnosis.
What is the aim of this review?
To determine the accuracy of screening tests for active pulmonary tuberculosis in children in high-risk groups, such as children with HIV and close contacts of people with tuberculosis.
What was studied in this review?
Screening tests were: one tuberculosis symptom; one or more of a combination of tuberculosis symptoms; the World Health Organization (WHO) four-symptom screen (one or more of cough, fever, poor weight gain, or tuberculosis contact) in children with HIV, recommended at each healthcare visit; chest radiography (CXR); and Xpert MTB/RIF.
What are the main results in this review?
Nineteen studies assessed the following screening tests: one symptom (15 studies, 10,097 participants); more than one symptom (12 studies, 29,889 participants); CXR (10 studies, 7146 participants); and Xpert MTB/RIF (two studies, 787 participants).
Symptom screening
For every 1000 children screened, if 50 had tuberculosis according to the reference standard:
One or more of cough, fever, or poor weight gain in tuberculosis contacts (composite reference standard (CRS) (4 studies)
– 339 would screen positive, of whom 294 (87%) would not have tuberculosis (false positive).
– 661 would screen negative, of whom 5 (1%) would have tuberculosis (false negative).
One or more of cough, fever, or decreased playfulness in children under five, inpatient or outpatient (CRS) (3 studies)
– 251 to 636 would screen positive, of whom 219 to 598 (87% to 94%) would not have tuberculosis (false positive).
– 364 to 749 would screen negative, of whom 12 to 18 (2% to 3%) would have tuberculosis (false negative).
One or more of cough, fever, poor weight gain, or tuberculosis close contact (WHO four-symptom screen) in children with HIV, outpatient (CRS) (2 studies)
– 88 would screen positive, of which 57 (65%) would not have tuberculosis (false positive).
– 912 would screen negative, of which 19 (2%) would have tuberculosis (false negative).
Abnormal CXR in tuberculosis contacts (CRS) (8 studies)
– 63 would screen positive, of whom 19 (30%) would not have tuberculosis (false positive).
– 937 would screen negative, of whom 6 (1%) would have tuberculosis (false negative).
Xpert MTB/RIF in children, inpatient or outpatient microbiologic reference standard (MRS) (2 studies)
– 31 to 69 would be Xpert MTB/RIF-positive, of whom 9 to 19 (28% to 29%) would not have tuberculosis (false positive).
– 931 to 969 would be Xpert MTB/RIF-negative, of whom 0 to 28 (0% to 3%) would have tuberculosis (false negative).
How reliable are the results of the studies in this review?
Diagnosing tuberculosis in children is difficult. This may lead to screening tests appearing more or less accurate than they actually are. For Xpert MTB/RIF, there were few studies and children tested to be confident about results.
Who do the results of this review apply to?
Children at risk for pulmonary tuberculosis. Results likely do not apply to children in the general population. Studies mainly took place in countries with a high burden of tuberculosis.
What are the implications of this review?
In children who are tuberculosis contacts or living with HIV, screening tests using symptoms or CXR may be useful. However, symptoms and CXR formed part of the reference standard, which may falsely elevate the accuracy of the results. We urgently need better screening tests for tuberculosis in children to better identify children who should be considered for tuberculosis preventive treatment and to increase the timeliness of treatment in those with tuberculosis disease.
How up-to-date is this review?
To 14 February 2020.
We found that in children who are tuberculosis contacts or living with HIV, screening tests using symptoms or CXR may be useful, but our review is limited by design issues with the index test and incorporation bias in the reference standard.
For Xpert MTB/RIF, we found insufficient evidence regarding screening accuracy.
Prospective evaluations of screening tests for tuberculosis in children will help clarify their use. In the meantime, screening strategies need to be pragmatic to address the persistent gaps in prevention and case detection that exist in resource-limited settings.
Globally, children under 15 years represent approximately 12% of new tuberculosis cases, but 16% of the estimated 1.4 million deaths. This higher share of mortality highlights the urgent need to develop strategies to improve case detection in this age group and identify children without tuberculosis disease who should be considered for tuberculosis preventive treatment. One such strategy is systematic screening for tuberculosis in high-risk groups.
To estimate the sensitivity and specificity of the presence of one or more tuberculosis symptoms, or symptom combinations; chest radiography (CXR); Xpert MTB/RIF; Xpert Ultra; and combinations of these as screening tests for detecting active pulmonary childhood tuberculosis in the following groups.
– Tuberculosis contacts, including household contacts, school contacts, and other close contacts of a person with infectious tuberculosis.
– Children living with HIV.
– Children with pneumonia.
– Other risk groups (e.g. children with a history of previous tuberculosis, malnourished children).
– Children in the general population in high tuberculosis burden settings.
We searched six databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, on 14 February 2020 without language restrictions and contacted researchers in the field.
Cross-sectional and cohort studies where at least 75% of children were aged under 15 years. Studies were eligible if conducted for screening rather than diagnosing tuberculosis. Reference standards were microbiological (MRS) and composite reference standard (CRS), which may incorporate symptoms and CXR.
Two review authors independently extracted data and assessed study quality using QUADAS-2. We consolidated symptom screens across included studies into groups that used similar combinations of symptoms as follows: one or more of cough, fever, or poor weight gain and one or more of cough, fever, or decreased playfulness. For combination of symptoms, a positive screen was the presence of one or more than one symptom.
We used a bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs) and performed analyses separately by reference standard. We assessed certainty of evidence using GRADE.
Nineteen studies assessed the following screens: one symptom (15 studies, 10,097 participants); combinations of symptoms (12 studies, 29,889 participants); CXR (10 studies, 7146 participants); and Xpert MTB/RIF (2 studies, 787 participants). Several studies assessed more than one screening test. No studies assessed Xpert Ultra. For 16 studies (84%), risk of bias for the reference standard domain was unclear owing to concern about incorporation bias. Across other quality domains, risk of bias was generally low.
Symptom screen (verified by CRS)
One or more of cough, fever, or poor weight gain in tuberculosis contacts (4 studies, tuberculosis prevalence 2% to 13%): pooled sensitivity was 89% (95% CI 52% to 98%; 113 participants; low-certainty evidence) and pooled specificity was 69% (95% CI 51% to 83%; 2582 participants; low-certainty evidence). Of 1000 children where 50 have pulmonary tuberculosis, 339 would be screen-positive, of whom 294 (87%) would not have pulmonary tuberculosis (false positives); 661 would be screen-negative, of whom five (1%) would have pulmonary tuberculosis (false negatives).
One or more of cough, fever, or decreased playfulness in children aged under five years, inpatient or outpatient (3 studies, tuberculosis prevalence 3% to 13%): sensitivity ranged from 64% to 76% (106 participants; moderate-certainty evidence) and specificity from 37% to 77% (2339 participants; low-certainty evidence). Of 1000 children where 50 have pulmonary tuberculosis, 251 to 636 would be screen-positive, of whom 219 to 598 (87% to 94%) would not have pulmonary tuberculosis; 364 to 749 would be screen-negative, of whom 12 to 18 (2% to 3%) would have pulmonary tuberculosis.
One or more of cough, fever, poor weight gain, or tuberculosis close contact (World Health Organization four-symptom screen) in children living with HIV, outpatient (2 studies, tuberculosis prevalence 3% and 8%): pooled sensitivity was 61% (95% CI 58% to 64%; 1219 screens; moderate-certainty evidence) and pooled specificity was 94% (95% CI 86% to 98%; 201,916 screens; low-certainty evidence). Of 1000 symptom screens where 50 of the screens are on children with pulmonary tuberculosis, 88 would be screen-positive, of which 57 (65%) would be on children who do not have pulmonary tuberculosis; 912 would be screen-negative, of which 19 (2%) would be on children who have pulmonary tuberculosis.
CXR (verified by CRS)
CXR with any abnormality in tuberculosis contacts (8 studies, tuberculosis prevalence 2% to 25%): pooled sensitivity was 87% (95% CI 75% to 93%; 232 participants; low-certainty evidence) and pooled specificity was 99% (95% CI 68% to 100%; 3281 participants; low-certainty evidence). Of 1000 children, where 50 have pulmonary tuberculosis, 63 would be screen-positive, of whom 19 (30%) would not have pulmonary tuberculosis; 937 would be screen-negative, of whom 6 (1%) would have pulmonary tuberculosis.
Xpert MTB/RIF (verified by MRS)
Xpert MTB/RIF, inpatient or outpatient (2 studies, tuberculosis prevalence 1% and 4%): sensitivity was 43% and 100% (16 participants; very low-certainty evidence) and specificity was 99% and 100% (771 participants; moderate-certainty evidence). Of 1000 children, where 50 have pulmonary tuberculosis, 31 to 69 would be Xpert MTB/RIF-positive, of whom 9 to 19 (28% to 29%) would not have pulmonary tuberculosis; 931 to 969 would be Xpert MTB/RIF-negative, of whom 0 to 28 (0% to 3%) would have tuberculosis.
Studies often assessed more symptoms than those included in the index test and symptom definitions varied. These differences complicated data aggregation and may have influenced accuracy estimates. Both symptoms and CXR formed part of the CRS (incorporation bias), which may have led to overestimation of sensitivity and specificity.