Sensitive and Feasible Specimen Collection and Testing Strategies for Diagnosing Tuberculosis in Young Children

Abstract

IMPORTANCE Criterion-standard specimens for tuberculosis diagnosis in young children, gastric aspirate (GA) and induced sputum, are invasive and rarely collected in resource-limited settings. A far less invasive approach to tuberculosis diagnostic testing in children younger than 5 years as sensitive as current reference standards is important to identify.OBJECTIVE To characterize the sensitivity of preferably minimally invasive specimen and assay combinations relative to maximum observed yield from all specimens and assays combined. DESIGN, SETTING, AND PARTICIPANTSIn this prospective cross-sectional diagnostic study, the reference standard was a panel of up to 2 samples of each of 6 specimen types tested for Mycobacterium tuberculosis complex by Xpert MTB/RIF assay and mycobacteria growth indicator tube culture. Multiple different combinations of specimens and tests were evaluated as index tests. A consecutive series of children was recruited from inpatient and outpatient settings in Kisumu County, Kenya, between October 2013 and August 2015. Participants were children younger than 5 years who had symptoms of tuberculosis (unexplained cough, fever, malnutrition) and parenchymal abnormality on chest radiography or who had cervical lymphadenopathy. Children with 1 or more evaluable specimen for 4 or more primary study specimen types were included in the analysis. Data were analyzed from February 2015 to October 2020. MAIN OUTCOMES AND MEASURESCumulative and incremental diagnostic yield of combinations of specimen types and tests relative to the maximum observed yield. RESULTSOf the 300 enrolled children, the median (interquartile range) age was 2.0 (1.0-3.6) years, and 151 (50.3%) were female. A total of 294 met criteria for analysis. Of 31 participants with confirmed tuberculosis (maximum observed yield), 24 (sensitivity, 77%; interdecile range, 68%-87%) had positive results on up to 2 GA samples and 20 (sensitivity, 64%; interdecile range, 53%-76%) had positive test results on up to 2 induced sputum samples. The yields of 2 nasopharyngeal aspirate (NPA) samples (23 of 31 [sensitivity, 74%; interdecile range, 64%-84%]), of 1 NPA sample and 1 stool sample (22 of 31 [sensitivity, 71%; interdecile range, 60%-81%]), or of 1 NPA sample and 1 urine sample (21.5 of 31 [sensitivity, 69%; interdecile range, 58%-80%]) were similar to reference-standard specimens. Combining up to 2 each of GA and NPA samples had an average yield of 90% (28 of 31).CONCLUSIONS AND RELEVANCE NPA, in duplicate or in combination with stool or urine specimens, was readily obtainable and had diagnostic yield comparable with reference-standard specimens. This combination could improve tuberculosis diagnosis among children in resource-limited settings. Combining GA and NPA had greater yield than that of the current reference standards and may be useful in certain clinical and research settings.

Diagnostic Advances in Childhood Tuberculosis—Improving Specimen Collection and Yield of Microbiological Diagnosis for Intrathoracic Tuberculosis

“…Collecting samples of different types, particularly including samples that are less invasive and easier to implement from a technical point of view, may significantly contribute to increasing the yield of microbiological testing. In the same study of children with presumptive TB in Kenya, combining one NPA and one stool increased the sensitivity to 71% compared to 66% for one NPA specimen, with results similar to what was obtained using two GA or two sputum samples [85]. Similarly, in another international diagnostic accuracy study in HIV-positive children with presumptive TB from four high-incidence countries, Xpert testing of one NPA and one stool increased sensitivity from 69% for NPA only and 62% for stool only, to 75% when using both [62].…”

“…However, this was a conditional recommendation, with a low certainty of evidence in test accuracy for sputum and very low for other specimens [8]. In a study of 300 children with presumptive TB aged <5 years in Kisumu, Kenya, testing a second sample of the same kind (GA, NPA, or IS) led to an average incremental yield of 8% to 10% by Xpert or MGIT, respectively [85]. A systematic review reported that testing a second sample contributes between 6% and 33% of the cumulative microbiological yield using Xpert or culture, regardless of the sample collection method [65].…”

Aetiology of childhood pneumonia in low- and middle-income countries in the era of vaccination: a systematic review

“…However, the detection of S. pneumoniae by PCR ( lytA ) in culture negative blood [ 93 , 94 ] and lung aspirate [ 24 ] specimens is not universally regarded as diagnostic of pneumococcal pneumonia in children, as detection by PCR may reflect carriage rather than disease. Nasopharyngeal aspirate can be used to detect M.tuberculosis, especially given the increasing availability of Xpert MTB/RIF [ 95 ]. In children with respiratory distress, the use of sampling such as nasopharyngeal aspirate or stool has advantages over more invasive sampling such as induced sputum or gastric aspirate [ 96 ].…”

Host-Based Biomarkers in Saliva for the Diagnosis of Pulmonary Tuberculosis in Children: A Mini-Review

“…Unlike in adults, sputum-based reference tests are often not appropriate in young children. Microbiological reference standards based on combinations of alternative samples such as gastric or nasopharyngeal aspirates are therefore recommended ( 68 ). To ensure comparability of results across studies, classification of children should conform to the National Institutes of Health consensus definitions for childhood pulmonary tuberculosis (i.e., confirmed, unconfirmed, and unlikely TB) ( 69 ).…”