Sputum scarcity and respiratory sample availability among children with presumptive tuberculosis in high burden countries: a systematic review and meta-analysis

BackgroundTuberculosis (TB) diagnosis typically relies on testing sputum samples, but children often cannot produce sputum. Our review investigated the collection of self-expectorated and induced sputum, and alternative methods of sampling including gastric and nasopharyngeal aspirates, among children evaluated for presumed TB in healthcare facilities. MethodsWe searched PubMed, Embase, Cochrane Library, Web of Science, and clinical trials databases from January 2010 to June 2024. Studies not reporting sufficient information on respiratory sampling or not conducted in high TB burden countries were excluded. Summary data was extracted, and the risk of bias was assessed. Sputum scarcity was defined as the proportion of children who could not provide a sample among those attempting. The pooled estimate of sputum scarcity was calculated by random effects meta-analysis. The review protocol was registered with PROSPERO (CRD42023473882). FindingsThe search identified 6,751 records and 36 studies were included which enrolled 14,018 children from 14 high burden countries. Respiratory sampling methods varied by age. In children under 5, a pooled estimate of 4% (95% CI: 2-6%, n=5) provided self-expectorated sputum, but collection was not attempted routinely. In studies collecting one or two self-expectorated spot sputum samples in children 5 to 15 years, the pooled estimate of sputum scarcity was 38% (95%CI: 20-55%, n=6). Studies performing sputum induction assisted by nasopharyngeal suctioning in children under 15 had pooled scarcity of 3% (95% CI:0-6%, n=8). For studies performing gastric aspirates, the median proportion without a sample was 0.0% (95% CI: 0{middle dot}0-0{middle dot}8%, IQR: 0{middle dot}0-2{middle dot}0%, n=23). InterpretationCollecting respiratory samples in children with presumed TB is complex and age-dependent. Children, especially under 5, are often unable to produce self-expectorated sputum and depend on alternative methods, such as induction or gastric aspirates. TB diagnostics using samples that are easier to collect from children in resource-limited settings are needed. FundingGates Foundation (INV-069540) Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSCurrent diagnostics for tuberculosis (TB) rely on testing sputum samples, and patients unable to produce sputum at the time of evaluation may have a delayed or missed diagnosis. Children, especially those under 5 years of age, have difficulty producing sputum. There are no currently reliable estimates about how many children being evaluated for presumed TB are unable to produce a sputum sample (sputum scarce). Added value of this studyThis systematic review and meta-analysis included data from 36 studies and found that approximately 38% of children between 5 to 15 years of age with presumed TB could not produce one or two sputum samples at the time of evaluation. Alternative methods of respiratory sample collection, such as sputum induction and gastric aspirates, were effective in obtaining samples but are often not available in resource-limited settings. Implications of all the available evidenceSputum scarcity is common in children being evaluated for TB and alternative methods are necessary to collect respiratory samples. These results support the need to develop non-sputum TB diagnostics for children.