The clade Ib mpox outbreak in Uvira primarily affected children under 15 years (63.7%), with limited reported sexual transmission. Occupational healthcare and workplace exposures were rare (1.4% and 1.6%, respectively). The overall case fatality ratio was 0.7%, but immunocompromised patients and infants under one year faced notably high mortality ratio.

Several factors likely contributed to the high incidence of mpox clade Ib among children: (i) cryptic transmission, (ii) prior smallpox immunity in older individuals, and (iii) age-related differences in MPXV susceptibility, exacerbated by child malnutrition. Remarkably, the age distribution of clade Ib cases in Uvira mirrors patterns from historical clade Ia outbreaks.[2,31] However, despite higher mortality among young children, the CFR for clade Ib in infants younger than one year is less than half the 10% CFR reported in pediatric populations during clade Ia outbreaks.[5,32] This lower CFR may reflect the reduced virulence of clade Ib, possibly due to OPG032 gene deletion, which encodes the complement control protein, a key virulence factor.[33,34] Additionally, in remote and hard-to-reach areas where most historical clade Ia outbreaks occurred, surveillance bias may have led to an overestimation of CFR, as only the most severe cases would seek care, with milder cases likely remaining at home, thus biasing the denominator downward. Finally, improved and facilitated healthcare access in Uvira also likely reduced mortality. Unlike previous remote outbreaks in remote and hard-to-reach areas, this one received international support, with non-governmental organizations and the Ministry of Health providing free treatment, food, and hygiene kits.

This outbreak reflects a shift from sexual to non-sexual transmission, with overcrowded housing likely accelerating the spread. Thus, in Uvira where the median household size is eight and a median of four people sleep in each room, the WHO’s home isolation guidance is impractical, a situation common to many similar settings. While isolation at the MTC can reduce household spread, it imposes indirect costs on families and strains on the health system. These challenges suggest the potential for household-level interventions, such as “ring” vaccination,[35] or case-area targeted interventions (CATIs) used in cholera outbreaks, to curb intra-household transmission.[36]

The PCR positivity rate in this study was higher among individuals aged ≥15 years. This trend was also observed in Kamituga, where positivity was significantly higher in those ≥15 compared to <15 years (84.5% vs. 66.2%, p < 0.001).[13] Possible explanations include a likely higher burden of non-mpox rash illnesses (e.g., measles) in children attending MTCs, or differences in lesion type and location. Genital lesions, shown to be more common in older age groups, may carry higher viral loads;[37] if they are also more likely to be sampled (though we lack data on this), this could contribute to the higher PCR positivity rates observed in adults. Finally, samples were collected at random, mainly based on availability of materials. While we have no evidence of bias in sample collection, we cannot exclude the possibility that certain populations were preferentially sampled. Further investigations are needed to better understand the driver of differential mpox PCR positivity by age.

Our findings underscore the urgent need for integrated mpox programs targeting key vulnerable populations. HIV prevalence among suspected mpox cases was nearly three times higher than the estimated national average of 0.7%,[38] and nine times higher than the 0.2% prevalence observed among voluntary blood donors at Uvira Hospital in 2024. Alarmingly, all adult mpox-related deaths (n=2) occurred in HIV-positive individuals with severe necrotizing disease. Limited access to CD4 monitoring and opportunistic infection management complicates treatment, highlighting the importance of integrated mpox-HIV care models and vaccine safety studies for immunocompromised individuals. However, HIV prevalence estimates from the MTC should be interpreted with caution, as not all patients were tested, and selection bias cannot be excluded. Among children, undernutrition is the leading cause of acquired immune deficiency, and is especially concerning in the DRC where nearly half of children under five are stunted.[39] Our study found acute malnutrition rates (12.1%) among suspected mpox cases nearly double the 2023–2024 South Kivu province average of 6.7%.[39] This figure is likely an underestimate, as we relied solely on mid-upper arm circumference (MUAC) measurements without weight-for-height z-scores-scores.[40] Lastly, pregnant and breastfeeding women, who represented 14.5% and 22.5% of women of reproductive age at the Uvira MTC, respectively, also require specific attention given the height CFR of mpox clade Ib in neonates and emerging evidence suggesting potential mother-to-child transmission, including through breast milk.[41] Thus, our findings support WHO recommendations advocating for the vaccination of pregnant and lactating women,[42,43] and emphasize the need for greater investment in understanding the interplay between mpox clade Ib, age, malnutrition, HIV, and pregnancy. Addressing these gaps requires urgent attention, in-depth investigations, and targeted interventions that extend beyond current emergency responses.

A stark difference was however observed between our findings, which indicated no mpox-related adverse pregnancy outcomes, and those from Kamituga, a major mining hub where 57.8% (8/14) of pregnant women with mpox Clade Ib reported abortion, and mpox DNA was detected in one placenta. [41] Conflicting evidence on mother-to-child transmission of clade II mpox further highlights existing knowledge gaps.[5,44] Differences in environmental exposures, mpox severity, mode of acquisition, and co-infections, such as HIV or congenital co-infections may contribute to the observed disparities. In South Kivu, birth defect rates were nearly four times higher in mining areas like Mwenga, near Kamituga, even before the mpox outbreak.[45] Research from Lubumbashi, over 1,000 km south, linked paternal mining exposure, prenatal metal levels, and poor maternal nutrition to malformations in mining sites.[46] Additionally, Kamituga’s high commercial sex activity raises concerns about co-infections that may exacerbate pregnancy complications. Only one syphilis case was detected among 276 patients in Uvira, with no comparable data from Kamituga. Larger studies are needed to clarify the potential causal relationship between mpox clade Ib infection and pregnancy outcomes.

This study has several limitations. It relied on facility-based surveillance from MTC due to the lack of data on cases in private facilities or the community. The clinical case definition used in the MTC was broad, and the low proportion of cases tested may have led to misclassification. However, the high positivity rate among those tested provides some assurance that case definition was generally adequate. Some mpox cases could have not been managed in MTC, limiting their recording in our dataset.

Additionally, many patients were admitted to the MTC primarily for isolation, sometimes at their own request, rather than for inpatient care, limiting the interpretability of the significance of hospitalization status in our data set, particularly in the outbreak’s early months. The dataset also lacked precision regarding lesion distribution. For example, due to the structure of the questionnaire used in routine surveillance, we were unable to distinguish patients with isolated genital lesions from those with genital lesions in addition to lesions elsewhere on the body, limiting our ability to assess the role of sexual transmission in Uvira compared to other settings like Kamituga.

Our reliance on the GeneXpert®L Xpert Mpox assay posed several challenges. While the high positivity rate supports the clinical case definition used, this test detects MPXV Clade II and non-variola orthopoxviruses but cannot directly confirm Clade I. In our context, Clade I was inferred when results were positive for orthopoxvirus and negative for Clade II. Although this approach aligns with WHO guidance and is common in DRC, its performance, especially for Clade Ib, remains poorly characterized. However, a clade-typed subsample from Uvira confirmed all tested cases as Clade Ib, providing some reassurance.

Operational constraints further limited diagnostic accuracy. These included the absence of on-site testing, delays in sample transport and processing which may have affected specimen quality, GeneXpert stockouts, competing demands from tuberculosis testing, and communication gaps with laboratories.

Testing for other common causes of skin lesions (e.g., varicella-zoster, measles, herpes simplex virus) was not routinely performed, making it difficult to determine the etiology of mpox-negative cases.

Misclassification, whether from clinical diagnosis or imperfect testing, not only affects burden estimation but also raises infection control concerns. Patients admitted to MTCs based on clinical suspicion alone may have been exposed to, or may have exposed others to, infectious diseases. For this reason, we included both confirmed and unconfirmed cases to reflect the real-world complexity of mpox management and to highlight the urgent need for decentralized diagnostics, dedicated platforms, and stronger laboratory networks in outbreak-prone settings.

In conclusion, the Uvira outbreak signals a major shift in mpox transmission, with household-driven spread disproportionately affecting children. This pattern, distinct from the clade II outbreaks in men who have sex with men and early clade Ib cases in Kamituga linked to heterosexual transmission, presents a global risk. Response efforts in DRC, however, have been shaped by the epidemiology in Kamituga with vaccination targeting key adult populations. However, this strategy may be less effective in areas like Uvira, where transmission has already entrenched, particularly among young children. Surveillance suggests similar patterns of non-sexual household transmission may be occurring throughout much of South Kivu, emphasizing the need for broader interventions. Sustained child-centered transmission could fuel widespread epidemics, particularly in high-birth rate, resource-limited settings where residual protection from smallpox vaccination efforts is largely gone. Urgent global action including accelerating pediatric vaccine development, expanding therapeutic access, and implementing household-level interventions, is essential to contain clade Ib and mitigate its long-term health impacts on individuals and populations.