Challenges in clinical diagnosis of Clade I Mpox: Highlighting the need for enhanced diagnostic approaches

Background: Due to limited diagnostic capacity and availability of point-of-care tests, diagnosis of Clade I mpox in the geographical regions most affected is usually on clinical grounds. This may be complicated due to the similarity between mpox and varicella (chickenpox) lesions. Visual assessment of lesions is also used for determining clinical progress and to assess patient outcomes in clinical trials. However, there has been no investigation into whether clinicians can (i) identify Clade I mpox compared to other viral lesions (ii) differentiate between Clade I mpox lesion stages. Methodology/Principle findings: The objective of this study was to evaluate inter-rater reliability and agreement between clinicians assessing lesions in patients with Clade I mpox. We presented experienced clinicians with 17 images of Clade I mpox or varicella and asked them to independently indicate the most likely diagnosis–mpox or varicella–and to categorise the lesions according to their stage. When selecting the most likely diagnosis, accuracy varied across all images, the inter-rater reliability was poor (κ = 0.223; z = 10.1) and agreement was moderate (Po = 68%). When categorising lesions according to their type, if a single lesion type was present in the image, inter-rater reliability was moderate (κ = 0.671, z = 40.6) and agreement was good (Po = 78%), but when multiple lesion types were shown in an image, both inter-rater reliability (κ = 0.153, z = 10.5) and agreement (Po = 29%) decreased substantially. Conclusions: This study demonstrates that there are presently limitations in using visual assessment to diagnose Clade I mpox and evaluate lesion stage and treatment outcomes, which have an impact on clinical practice, public health and clinical trials. More robust indicators and tools are required to inform clinical, public-health, and research priorities, but these must be implementable in countries affected by mpox. Author summary: Mpox is a zoonotic illness caused by the monkeypox virus (MPXV), for which there are two distinct sub-clades. Clade I is typically found in central Africa and is associated with worse patient outcomes than Clade II. Diagnosis of mpox is most commonly performed using PCR, but in settings with limited laboratory capacity diagnosis is usually performed on clinical grounds taking lesion presentation in to account. Lesion presentation is also used to assess patient outcomes in both clinical and research settings. However, there has been no investigation into whether clinicians can (i) identify Clade I mpox compared to other viral lesions (ii) differentiate between Clade I mpox lesion stages, which has important implications for clinical practice, research and public health. Our study, which presented 16 clinicians with 17 sets of images of Clade I mpox or varicella and asked them to i) provide the most likely diagnosis and ii) categorise the lesions in to their stages, demonstrates that there are presently limitations in using visual assessment to diagnose Clade I mpox and evaluate lesion stage and treatment outcomes. Alternative methods and tools are therefore required that can be easily implemented in affected countries.