Rinn Song1,2,3, Eleanor S Click4, Kimberly D McCarthy4, Charles M Heilig4, Walter Mchembere5, Jonathan P Smith6,7, Mark Fajans4, Susan K Musau5, Elisha Okeyo5, Albert Okumu5, James Orwa5, Dickson Gethi5, Lazarus Odeny5, Scott H Lee4, Carlos M Perez-Velez8,9, Colleen A Wright10, Kevin P Cain11. 1. Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts. 2. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. 3. Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom. 4. US Centers for Disease Control and Prevention, Atlanta, Georgia. 5. Kenya Medical Research Institute, Center for Global Health Research, Kisumu, Kenya. 6. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia. 7. Northrop Grumman, Atlanta, Georgia. 8. Tuberculosis Clinic, Pima County Health Department, Tucson, Arizona. 9. Infectious Diseases, University of Arizona College of Medicine, Tucson. 10. Division of Anatomical Pathology, University of Stellenbosch, Cape Town, South Africa. 11. US Centers for Disease Control and Prevention, Kisumu, Kenya.
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 Participants: In 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 Measures: Cumulative and incremental diagnostic yield of combinations of specimen types and tests relative to the maximum observed yield. Results: Of 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.
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 Participants: In 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 Measures: Cumulative and incremental diagnostic yield of combinations of specimen types and tests relative to the maximum observed yield. Results: Of 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.
Authors: Eleanor S Click; Rinn Song; Jonathan P Smith; Walter Mchembere; Mark Fajans; Parisa Hariri; Elisha Okeyo; Kimberly D McCarthy; Dickson Gethi; Lazarus Odeny; Susan Musau; Albert Okumu; James Orwa; Carlos M Perez-Velez; Colleen A Wright; Mariaem Andres; Ben J Marais; H Simon Schaaf; Stephen M Graham; Andrea T Cruz; Kevin P Cain Journal: Pediatr Infect Dis J Date: 2022-07-13 Impact factor: 3.806
Authors: Claire von Mollendorf; Daria Berger; Amanda Gwee; Trevor Duke; Stephen M Graham; Fiona M Russell; E Kim Mulholland Journal: J Glob Health Date: 2022-07-23 Impact factor: 7.664