Mpox and Varicella Zoster Virus Cocirculation Complicates Rash Diagnosis in Uganda
Uganda’s mpox response now has a second diagnostic problem layered on top of an active outbreak: varicella zoster virus is circulating at the same time as monkeypox virus clade 1b. In a genomic study of clinically suspected cases from July through December 2024, investigators found that many patients who looked clinically like mpox were instead infected with VZV, while confirmed mpox cases continued to cluster within clade 1b and remain closely related to earlier Uganda and Democratic Republic of Congo sequences.
The diagnostic overlap matters at the bedside. Early mpox lesions can resemble chickenpox or other vesicular eruptions before the rash fully evolves, and fever, malaise, and skin lesions do not reliably separate one infection from another. Lymphadenopathy still leans toward mpox, while a lower-grade fever more often accompanies chickenpox, but those clues are imperfect when patients present early or with mixed infections.
A single rash syndrome is no longer a single pathogen problem.
Sequencing Confirmed Clade 1b Mpox While Negative Samples Carried Other Viruses
Researchers tested 1,072 samples from patients with clinically suspected MPXV infection by real-time PCR. Of those, 193 tested positive for MPXV. Confirmed mpox cases were nearly evenly split by sex, with 48.7% male and 51.3% female, and the largest age group fell between 16 and 30 years, accounting for 47.8% of cases. Most samples, 65%, came from central Uganda, reflecting where the surveillance network drew much of its material.
The more revealing finding came from the 879 samples that were negative for MPXV by PCR. Investigators randomly selected 127 of those negative specimens for sequencing to search for alternative pathogens. That approach exposed the practical weakness of relying on clinical appearance alone during an outbreak: a patient can fit the mpox case definition and still have another viral or bacterial diagnosis.
Among the MPXV-positive specimens, 115 were genotyped using target enrichment next-generation sequencing. The resulting phylogenetic analysis placed the new Uganda sequences within clade 1b and showed close genetic relatedness to earlier Uganda and DRC isolates. In plain terms, the virus was not drifting into a wholly different lineage; it was continuing to circulate in a regional genetic cluster already documented in East-Central Africa.
APOBEC Signatures Marked Ongoing Viral Adaptation
Mutational analysis of 137 Uganda strains, including 115 new sequences and 22 previously reported sequences, identified 284 mutation events across synonymous, nonsynonymous, and intergenic sites. Of these, 118 mutations, or 41.4%, were consistent with APOBEC3-mediated cytosine deamination, reflected by TC-to-TT or GA-to-AA dinucleotide substitutions. In orthopoxvirus biology, that mutational pressure is important because APOBEC editing can leave a recognizable molecular fingerprint on viral evolution.
The gene-level pattern suggested that the circulating strains are not evolving randomly. Amino acid changes mapped to proteins involved in host-response inhibition, immune evasion, transcription, RNA metabolism, virion morphogenesis, and viral entry or egress. In effect, the sequence data point toward selective pressure on pathways that shape how efficiently the virus replicates, counters host immunity, and spreads from cell to cell. The functional annotations in these newer strains differed from earlier Uganda sequences, with relatively fewer prior annotations tied to apoptosis inhibition, viral maturation, and mRNA decapping.
Genomic change does not prove improved transmissibility by itself, but the biology fits an organism that continues to adapt under immune pressure while circulating in human populations.
Varicella Zoster Virus Dominated the MPXV-Negative Specimens
The most striking alternate diagnosis was VZV. Among the 127 sequenced MPXV-negative specimens, 106, or 83%, carried varicella zoster virus with genome coverage above 80%. Those VZV sequences were genetically similar to viruses previously identified in Nigeria, Ghana, and Guinea-Bissau, reinforcing that chickenpox-like illness is not only clinically plausible in this setting but molecularly documented across the region.
Other pathogens appeared at lower frequency: coxsackievirus A6 in 9 specimens, measles virus genotype B3 in 7, and polyomaviruses in 5. Bacterial organisms also appeared in some samples, including Cutibacterium acnes, Staphylococcus aureus, Streptococcus pyogenes, and Corynebacterium diphtheriae. Those findings broaden the differential diagnosis even further. A febrile rash in the middle of an mpox outbreak cannot be assumed to be mpox, and a negative PCR should prompt a search for other causes rather than a default assumption of test failure.
Co-infection Was Found in the Sole Fatal Case
Metagenomic sequencing identified MPXV-VZV co-infection in the study’s only fatal mpox case. The fatal outcome is clinically sobering, but the available data do not establish whether dual infection contributed to death. Co-infection is biologically plausible as a driver of more severe disease, yet this report stops short of proving causality. The safest interpretation is narrower: simultaneous circulation of both viruses creates real diagnostic ambiguity, and in at least one severe case, both pathogens were present in the same patient.
That finding should change how field teams think about case definitions and specimen collection. If clinicians rely only on syndromic criteria, they may overcount mpox in some patients and miss VZV or another infection in others. Molecular testing becomes the gatekeeper for reliable outbreak classification, especially when fever, vesicles, papules, and crusting lesions overlap across diseases.
Surveillance Needs to Move Beyond the Syndromic Case Definition
The study carries a direct public health message for Uganda and neighboring countries. Ongoing MPXV and VZV cocirculation likely explains the rising number of MPXV PCR-negative samples among patients who still meet a clinical suspicion threshold. In that setting, surveillance systems built around rash-based case definitions can inflate suspected mpox counts unless they are paired with molecular confirmation.
Cross-border surveillance also becomes essential because the viruses do not respect administrative boundaries. Uganda’s data fit a regional pattern already seen in Kenya, Ethiopia, the Democratic Republic of Congo, and Burundi, where varicella or mpox-VZV co-infection has repeatedly complicated outbreak investigation. Genomics adds a practical advantage here: it distinguishes true mpox clusters from look-alike illnesses and shows whether circulating viruses are staying within known lineages or acquiring new mutational features.
The study has clear limits. Investigators noted presumed underreporting of mpox cases and suboptimal genotyping because sequencing resources were limited. Even so, the dataset is large enough to support a firm operational conclusion: in Uganda, mpox and varicella are circulating side by side, and both can present as a febrile rash illness that looks similar at first glance. For outbreak control, that means molecular confirmation is not optional; it is the only reliable way to separate a clade 1b mpox case from a case of chickenpox, co-infection, or another rash-causing infection.