In this study, an observed CFR of 11.54% was reported among confirmed cases. This is markedly higher than figures reported in recent global outbreaks, where most studies reported CFR to remain consistently below 1%[36–38]. This high CFR is similar to earlier studies from the Democratic Republic of Congo (DRC), where surveillance between 2001 and 2013 revealed CFRs ranging from 6% to 10.6%, particularly in children and unvaccinated individuals [39,40]. Furthermore, similar mortality rates were documented in the CAR during earlier outbreaks in the 1980s [41]. The high CFR in CAR can be attributed to factors such as the endemic circulation of the more virulent clade I Mpox virus among CAR cases, limited healthcare access, poor health-seeking behavior, and frequent delays in case detection and isolation, especially in rural communities. This highlights the need for collaborative and resilient healthcare systems to reduce this mortality.

Notably, our analysis showed a higher CFRs among confirmed in the Eastern Health Regions (11.11%; 95% CI: 5.08–22.60) compared to the Western Regions (0.0%; 95% CI: 0.00–100.00), with elevated mortality particularly concentrated in localities reporting a higher burden of suspected cases. These areas overlap with regions most affected by the prolonged conflict following the 2013 arm conflict, such as Haute-Kotto, Vakaga, Mbomou, and Ouham [42]. These zones have experienced repeated armed violence, mass displacement, and targeted attacks on health facilities, severely compromising access to healthcare services. Médecins Sans Frontières and other humanitarian agencies have reported recurrent looting, destruction of infrastructure, and withdrawal of essential health services in conflict-affected health districts such as Batangafo, Bambari, and Bangassou [43]. The ongoing insecurity continues to restrict healthcare workers’ mobility and disrupt medical supply chains, further impeding timely diagnosis, isolation, and treatment of Mpox cases.

These conflict-driven vulnerabilities likely contribute significantly to the elevated mortality and underscore the urgent need for collaborative and resilient healthcare systems that can operate effectively amid political instability and violence to reduce Mpox-related deaths in CAR.

The Central African Republic’s extensive border with the Democratic Republic of Congo (DRC) - the regional epicenter of Mpox - represents a critical transmission risk, particularly in Health Region 6 where the highest disease severity rate was documented. This border region’s dense forest ecosystems and local populations’ dependence on hunting, gathering, and agricultural activities create frequent human-animal interactions that facilitate zoonotic spillover [44]. The combination of cross-border movement and traditional livelihoods in these forested zones likely explains the elevated Mpox transmission observed in these communities and subsequent likelihood of high severity in this setting.

About 61% of cases with clinical severity in CAR reported symptoms such as fever (91%), rash (86%), photophobia (89%), and fatigue (55%). These presentations are consistent with earlier descriptions of Clade I infections, which are known to be responsible for systemic illness with complications such as secondary bacterial infections, dehydration, and acute respiratory distress[40,45]. The WHO has previously characterized Clade I as causing more severe and widespread disease, with a higher propensity for complications and mortality compared to Clade IIa or IIb [46].

On the other hand, the 2022–2023 Mpox outbreaks, predominantly caused by Clade IIb, presented with milder disease profiles. An extensive multinational cohort study across 16 countries by Thornhill et al. found that most patients exhibited localized anogenital lesions with minimal systemic symptoms, and hospitalization was required in less than 10% of cases [37]. Similarly, Tarín-Vicente et al [36] observed that although pain was a common symptom, especially with perianal lesions, life-threatening complications were rare, and the CFR was negligible. This phenotypic difference reflects both virological differences and contextual health infrastructure disparities across many countries, especially in Africa, where timely access to quality and affordable healthcare remains limited in most countries.

Another major challenge in CAR is underreporting, which underestimates the actual burden of Mpox reported over the years. Rural communities often lack access to quality healthcare, including diagnostic testing and trained personnel. Studies have highlighted that several cases may go undetected for every confirmed Mpox case in endemic areas due to inadequate surveillance [47]. Moreover, symptoms of Mpox can overlap with other endemic conditions like varicella, measles, or bacterial skin infections, leading to misclassification and diagnostic delays [48]. The low testing and reporting rates hinder effective outbreak response, delay contact tracing, and impair understanding of virus evolution.

On the other hand, during recent outbreaks, a number of African nations have shown successful testing and reporting techniques. For example, Nigeria expanded molecular diagnostics through the Nigeria Centre for Disease Control during the 2022–2023 mpox outbreak, allowing for weekly situation reporting and prompt case confirmation [49]. Similarly, real-time reporting and trend monitoring of monkeypox have been enhanced in the Democratic Republic of the Congo through the implementation of surveillance technologies such as DHIS2 and systematic case notification [50].