Mpox, HIV, and a Compounding Sepsis Crisis in Africa

ABSTRACT.

Mpox, a zoonotic disease caused by the monkeypox virus (MPXV), has reemerged as a significant global public health threat, particularly in sub-Saharan Africa, where more than 50,000 cases have been reported since 2022. Although HIV-related immunosuppression is a known risk factor for severe MPXV infection, the intersection of mpox, HIV, and critical illness has been largely overlooked in ongoing outbreaks in East and Central Africa. We describe a case of a 45-year-old woman in Uganda, living with WHO stage 3 HIV and active pulmonary tuberculosis (TB), who developed mpox-associated sepsis and acute hypoxemic respiratory failure. One month after initial mpox diagnosis and receipt of supportive care, she developed high fever, hypotension, and hypoxemia and was hospitalized. Painful oropharyngeal and mucocutaneous lesions limited her adherence to oral antiretroviral and anti-TB therapy. Despite oxygen therapy, judicious fluid resuscitation, and empiric antibiotics, the patient deteriorated rapidly and died on hospital day two. This case illustrates the emerging burden of mpox-related critical illness in persons living with HIV in sub-Saharan Africa. In this context, we propose key actions to improve the international mpox response, focusing on the clinical management of mpox-associated sepsis and critical illness.

INTRODUCTION

Mpox, a zoonotic disease caused by the monkeypox virus (MPXV), has re-emerged as a significant global public health threat, particularly in sub-Saharan Africa, where more than 45,000 cases have been reported since 2022.¹ The clinical spectrum of mpox varies widely, ranging from mild febrile illness with lymphadenopathy and vesiculopustular rash to severe, life-threatening disease with multiorgan involvement.² Infection with MPXV clade I, which is currently predominant in East and Central Africa, is associated with more severe disease and case fatality rates of up to 10%.² In contrast, clade II infection typically results in milder disease with case fatality rates of 1–3%.²

Although HIV-related immunosuppression is a well-established risk factor for severe mpox, the intersection of mpox, HIV, and critical illness has been largely overlooked in ongoing outbreaks in East and Central Africa.² Here, we present a case of mpox-associated sepsis and acute hypoxemic respiratory failure in Uganda, highlighting the emerging burden of mpox-related critical illness in persons living with HIV (PLWH) during the escalating outbreak.

CASE REPORT

A 45-year-old woman living with WHO stage 3 HIV infection and active pulmonary tuberculosis (TB) was admitted to a public hospital in central Uganda after presenting with fever, cough, and skin rash. She reported poor adherence to her antiretroviral treatment (dolutegravir/lamivudine/tenofovir) and anti-TB treatment regimens. One month before admission, she developed diffuse skin and mucosal lesions, was diagnosed with polymerase chain reaction-confirmed mpox, and was admitted to a dedicated mpox treatment unit, also in central Uganda. In accordance with WHO guidelines, she received supportive care interventions primarily targeting symptomatic relief, along with a combination of antibacterial agents, including fluoroquinolones, penicillins, and nitroimidazoles. However, she had difficulty tolerating oral medications, including anti-TB and antiretroviral agents because of painful oropharyngeal lesions. The patient subsequently developed a high fever, hypotension, tachypnea, and hypoxemia, and was transferred to a higher-level public hospital for further management, including oxygen therapy. At this point, the patient was screened for eligibility, written informed consent was obtained, and she was enrolled in an institutional review board-approved prospective observational study of sepsis. Upon repeat examination, the patient appeared underweight (mid-upper arm circumference 21 cm), was hypotensive, and showed signs of acute hypoxemic respiratory failure (respiratory rate 48 breaths per minute, peripheral oxygen saturation 85% on 6 L of oxygen therapy via nasal cannula). Several skin lesions exhibited signs of ulceration and secondary infection. Point-of-care blood testing revealed elevated concentrations of lactate (2.9 mmol/L) and creatinine (2.0 mg/dL); bicarbonate was 25 mmol/L. Concentrations of glucose and other electrolytes were within normal limits. Urine testing results for TB lipoarabinomannan were negative, as were serum cryptococcal antigen and whole-blood testing results for malaria. Chest imaging was unavailable. Blood culture results for aerobic bacteria and fungi were negative. Despite locally maximal supportive care, including broadened intravenous antibacterial agents, judicious intravenous fluid replacement, and nasal oxygen therapy, the patient died on hospital day two.

Because worsening infection (i.e., antecedent fever) with acute organ dysfunction (hypotension, respiratory failure, kidney injury) was the primary trigger of clinical decompensation, sepsis was determined to be the proximal cause of death.³ Notably, however, this case highlights the diagnostic uncertainty frequently encountered in resource-limited settings. Although clinical features were consistent with existing sepsis definitions, the absence of confirmatory microbiological data—possibly due to previous antibiotic exposure—limits our ability to definitively attribute the syndrome to disseminated mpox infection versus secondary bacterial infection. Nonetheless, the clinical and temporal relationship among symptom onset, mucocutaneous barrier disruption, and systemic decompensation with signs of severe acute infection supports the plausibility of mpox-associated sepsis in an immunocompromised host.

DISCUSSION

In Uganda, where mpox incidence is escalating, cases such as these are increasingly common.⁴ In our work as clinicians, researchers, and public health specialists, we have observed sepsis to be a frequent and underrecognized manifestation of severe mpox in Uganda, particularly in PLWH. In fatal mpox cases, nearly all of which have occurred in PLWH, sepsis or septic shock has been determined to be the proximal cause of death in over 80% of cases. Our observations are consistent with those from the Democratic Republic of the Congo and data from Nigeria, where HIV coinfection has been associated with an increased risk of severe secondary bacterial infection and death in adults with mpox.^5,6 With inadequate vaccine availability and the rapid expansion of mpox into other high-HIV-burden settings in sub-Saharan Africa, we are deeply concerned about the emergence of a parallel epidemic of mpox-related sepsis and critical illness.⁷

Before the mpox epidemic, ∼40% of global sepsis cases occurred in sub-Saharan Africa, where high HIV prevalence is a major driver of poor sepsis outcomes.^8,9 Further increases in sepsis and critical illness due to mpox are likely to place additional strain on already overburdened and underresourced acute care systems.

In conjunction with the urgent need to expand vaccination, we propose several key actions to improve the international mpox response, focusing on the clinical management of mpox-associated sepsis and critical illness (Figure 1). Without efforts to elucidate the epidemiology, pathobiology, and optimal treatment approaches for mpox-associated sepsis and critical illness, global disparities in sepsis outcomes are likely to worsen.

Figure 1.

List of key actions to improve the international mpox response, with a focus on the clinical management of mpox-associated sepsis and critical illness.

First, efforts should be made to establish the incidence, clinical presentation, and outcomes of mpox-associated sepsis and critical illness, including the impact of HIV, high-burden and opportunistic coinfections, and other comorbidities. Second, an improved understanding of the microbiological spectrum of secondary bacterial infections in mpox-associated sepsis is necessary to optimize empiric antimicrobial treatment strategies, especially in settings with limited laboratory capacity. This is particularly important given the high prevalence of antimicrobial resistance in many African settings. In parallel, further research should elucidate the mechanisms of organ dysfunction in severe mpox, including the roles of direct viral cytotoxicity and host-related tissue injury, particularly in the context of HIV-related immunosuppression. Expanding access to clinical trials for novel antiviral therapies and ensuring the inclusion of patients with severe illness and HIV coinfection in such studies is also critical. Finally, the early recognition and treatment of complications, including necrotizing skin and soft tissue infections, must be emphasized to optimize supportive care for patients with mpox-associated sepsis. Although the optimal approach to sepsis resuscitation in resource-limited settings is poorly defined, the provision of close monitoring is likely to improve outcomes for patients with severe manifestations of mpox.¹⁰