The risk of mpox false positive results in high transmission settings: evidence from a multi-site observational study in DR Congo

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BACKGROUND: Environmental viral DNA contamination is a recognised challenge for DNA viruses when using highly sensitive assays such as quantitative PCR (qPCR). We aimed to quantify the impact of environmental monkeypox virus (MPXV) DNA on routine mpox diagnosis and case ascertainment during a widespread outbreak in DR Congo. METHODS: For this multi-site observational study, we collected cycle threshold (Ct) values from 2724 people with a valid qPCR test who had mpox-compatible illness (ie, suspected cases) and attended mpox treatment centres across four locations (Goma, Kamituga, Kinshasa, and Uvira) in DR Congo between May, 2024, and April, 2026. In two of these locations (Uvira and Kamituga), we conducted surface sampling of clinic and laboratory environments. We developed a Bayesian latent class model to distinguish qPCR-positive results of true MPXV infections from those consistent with environmentally derived MPXV DNA, taking into account key biological features that can influence Ct values. We estimated the proportion of qPCR-positive results attributable to the environmental MPXV DNA burden by clinical and demographic factors and diagnostic Ct value cutoffs. Model-based classifications were externally evaluated with longitudinal serological data from a subset of participants. FINDINGS: We estimated that 35% (95% credible interval [CrI] 31-39) of qPCR results with Ct values less than 40 were likely to be false positive results and therefore consistent with the environmental burden of MPXV DNA rather than true infection. Among a subset of participants with serological data, 31 (88·6%) of 35 inferred as environmentally derived false positives had no serological evidence of orthopoxvirus infection, whereas 20 (66·7%) of 30 inferred as true infections had serological evidence of infection. Lowering the diagnostic cutoff to Ct values less than 37 reduced the false positive rate to 18% (95% CrI 16-20) and reducing the cutoff to less than 34 reduced the false positive rate to 5% (3-6), with only marginal losses in sensitivity. INTERPRETATION: More than one in three qPCR-positive mpox diagnoses in these settings might have been driven by the environmental MPXV DNA burden, with serological data independently supporting this finding. Strengthened decontamination of clinical areas, Ct value cutoffs optimised to the local context, and additional investigation of high-Ct specimens, including clinical progressions, epidemiological links, and repeat testing, could substantially improve diagnostic specificity while preserving sensitivity. FUNDING: Gates Foundation, Schmidt Science Fellows in partnership with the Rhodes Trust, European & Developing Countries Clinical Trials Partnership (EDCTP2 and EDCTP3), Belgian Directorate-General for Development Cooperation and Humanitarian Aid, and Research Foundation-Flanders. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

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