Public Health Challenges in the Context of the Global Spread of Mpox Infections

ABSTRACT.

The declaration of the ongoing mpox (formerly monkeypox) outbreak by the WHO as a public health emergency of international concern has put global attention on mpox disease. As of December 4, 2022, a total of 80,221 mpox cases had been confirmed from 110 countries, with a major proportion of cases being reported from previously non-endemic countries. The current global emergence and spread of the disease has highlighted the challenges and the need for efficient public health preparedness and response. There are several challenges posed in the current mpox outbreak, ranging from epidemiological factors to diagnostic and socio-ethnic issues. These challenges may be circumvented with proper intervention measures such as strengthening surveillance, robust diagnostics, clinical management plans, intersectoral collaboration, firm prevention plans, capacity building, addressing stigma and discrimination against vulnerable groups, and ensuring equitable access to treatments and vaccines. To address the above challenges in the wake of the current outbreak, it is essential to understand the gaps and plug them with effective countermeasures.

INTRODUCTION

The world successfully eradicated smallpox in 1980.¹ However, a plethora of animal and human viruses remain a threat to public health. Mpox (formerly monkeypox) in animals was first found in 1958 in captive Asian monkeys in Denmark that were transported from Singapore for research purposes. However, mpox virus in humans was first detected in 1970 in an infant in the Democratic Republic of Congo (DRC) who was initially suspected of having smallpox after it had been eliminated from the country in 1968.² As of today, mpox continues to be a neglected zoonotic orthopoxviral disease. Mpox virus is a DNA virus from the Poxviridae family in the Orthopoxvirus genus.

Monkeypox virus has two characterized genetic clades, named Congo basin (clade I) and west African (clade II).² The former is understood to have severe clinical manifestations with mortality rates as high as 10%, and the latter is considered the milder type (∼1% case fatality ratio).^2,3 Some of the natural hosts of mpox are African rodents such as dormice, Gambian pouched rats, and squirrels. However, some nonhuman primates can also be hosts. There is, at present, an incomplete understanding of the natural history of the disease, including animal reservoirs, affected animal species, transmission dynamics, and human behavior enhancing vulnerability.² Since 1970, 11 African countries have reported human cases periodically.² The DRC is the only country that has reported mpox cases continually during the past five decades.⁴ The disease remained contained in Africa, causing isolated incidents of outbreaks until 2003, when the first outbreak outside the African region was reported in the United States, where the first case was traced to native prairie dogs (Cynomys spp.) housed with rodents.^5,6 Countries such as the United Kingdom, Israel, Singapore, and United States have reported cases in 2018, 2019, 2021, and 2022. Until July 23, 2022, there were more than 16,000 reported mpox cases and 5 fatalities were reported from 75 countries, most of which were previously non-endemic countries with no clear epidemiological links and nonspecific clinical presentations. This prompted the WHO Director-General to announce mpox as a public health emergency of international concern (PHEIC).^7,8 As of December 4, 2022, there were 81,766 confirmed cases, mostly reported from the WHO European region and the Americas; the United States alone has reported > 29,000 cases.⁹ Although there has been a decline in overall mpox cases over the past few months, the current outbreak in 2022 highlights several public health challenges. This perspective examines the changes in the clinical features and epidemiological trends of the ongoing outbreak compared with previous outbreaks, and discusses the public health challenges and approaches needed for countries to mount an effective response to the outbreak.

EPIDEMIOLOGICAL SCENARIOS OF MPOX IN ENDEMIC AND PREVIOUSLY NON-ENDEMIC COUNTRIES

A 10-fold increase in mpox cases over the past five decades has been deduced by a systematic review taking into account the global incidence.⁴ The rising trend, especially in the DRC and Nigeria, has been found to be an actual uptick in cases and not merely a result of improved surveillance and reporting.⁴ Nigeria saw a reemergence of the disease in 2018 after a 40-year hiatus.^4,10 It is hypothesized that some of the risk factors that are associated with mpox are contact of children and young adults with animal host reservoirs, rodents as food, deforestation, climate change, civil unrest and insurgency, migratory population, and weak immunity.¹¹ Studies from the DRC and Nigeria have highlighted interactions with infected animals or humans as the cause, supported by associated risk factors.⁴ However, occurrence of cases in countries outside of Africa has also been reported in the past with history of travel to endemic countries or exposure to animals.¹² The pathway of transmission is speculated to be animal to animal, animal to human, and ultimately human to human.⁴ One possible scenario could be ongoing circulation of virus over a period of weeks or months. Importation of virus from endemic areas and then undetected interhuman transmission chains could be another cause, rather than zoonotic spillover in non-endemic areas.¹³ In the current outbreak, evidence suggests that of > 1,000 cases, the initial route of transmission was intimate sexual contact, but this was not ascertained.^2,14 Exposure to respiratory secretions, droplet nuclei, skin lesions, or fomites increases the odds of infection in healthcare staff and family members. Proximity during sexual contact and exchange of fluids are possibly key factors for transmission, but currently there is no evidence that it is sexually transmitted.¹⁵ Key differences in the clinical features and epidemiological trends of the ongoing outbreak are summarized in Table 1.

Table 1.

Changes in the clinical and epidemiological features in the ongoing outbreaks

Clinical features/epidemiological features	Previous outbreaks	Current outbreak (2022)
Affected population	The majority of the cases reported from the outbreaks in central Africa (1970–1990) and the DRC (2017) were among children.6,12,16	The majority of the cases (86.1% of the cases reported globally) reported from countries in Europe, North America, and South America (namely Brazil, Canada, Colombia, France, Germany, Mexico, Peru, Spain, United Kingdom, and United States) were largely affecting adults, especially men who have sex with men and in those individuals with multiple sex partners.9,17
Transmission	Animal-to-human transmission through several animal species as the major route of infection, followed by human-to-human transmission through intimate contact with infected individuals.6 International travelers with a travel history to endemic countries, or through animals imported from endemic countries.2,11	Marked human-to-human transmission, with a sexual component contributing to it in a major way.4,6 Persistent chains of transmission reported concurrently in widely disparate geographical areas, including both previously non-endemic countries and endemic countries.2,6 Most cases were reported in individuals with a travel history mainly to countries in North America and Europe or regions without direct or immediate epidemiological links.6,14
Case fatality percentage	0–11%	3–6%
Genetic clades	Both clades I and II; clade I is more commonly reported, given its endemicity and transmissibility, especially in the DRC.2,9	Clade II is mostly reported.3,9
Clinical features	Symptoms such as fever, headache, and the number of skin lesions varying from a few to several hundred.2,18 Incubation period 2–4 weeks.2,18 Lesions on the neck, face, palm and soles, and mucous membranes (70%). Lesions were predominantly reported to affect the face (95%), palms and soles (75%), and mucous membranes (70%), and less commonly the genitals. Lethargy, asthenia, and fatigue (African [Nigeria] and American outbreaks > 80%).23,24 Fever or febrile chills (Sudan, Nigeria, and United States [85–100%]).23,24	Many cases are not presenting the usual clinical symptoms seen in prior outbreaks.19 Lesions are most commonly on the genitals, anus, or perianal skin/genital area.20 Incubation period 5–21 days.21 Fewer cases are reporting fever, with chills (57%; 95% confidence interval 44–71), lethargy, asthenia, and fatigue.21–24 Solitary lesions and swollen tonsils have previously not been recognized as typical symptoms.25 High frequency of penile, perianal, and rectal symptoms requiring hospital admission.25

DRC = Republic of Congo.

PUBLIC HEALTH CHALLENGES

The current outbreak has alerted public health organizations, leading to its declaration as a PHEIC, and still faces several challenges, as follows.

Nonspecific clinical features and a diagnostic dilemma.

The clinical features of mpox are fever, headache, chills, lymphadenopathy, and maculopapular rash, which develops into vesicles and later pustules. The rash may be the only symptom and can be diffused and appear anywhere on the body, including the palms, soles, and anorectal area.^2,25 Age, nutritional status, HIV status, and prior vaccination with smallpox have a bearing on the clinical manifestations, especially in the case of dermatological symptoms.^10,22 These features are not pathognomonic of mpox, and can be confused with other rash-causing infections such as hand-foot-and-mouth disease, chicken pox (Varicella), herpes simplex, measles, chancroid, and molluscum contagiosum.²⁶ Because mpox cases are being reported from previously non-endemic areas, the treating physicians especially in these regions may have a low suspicion index and may misdiagnose, especially in children, who are susceptible to fevers with rash such as chicken pox and hand-foot-and-mouth disease. Correct identification would also be crucial for commencing contact tracing, which is critical to the containment of any outbreak of this nature. Sample collection from lesions can also be challenging and would need training of healthcare staff.

Diagnostic challenges.

Serological methods (based on IgG and IgM antibodies using ELISA and immunohistochemistry for viral antigen detection) are not specific for testing the mpox virus.^2,27,28 Serological cross-reactivity between various orthopoxviruses due to a high degree of antigenic relatedness and also with virus-based vaccines (Vaccinia for smallpox) causes a substantial barrier to laboratory diagnosis of specific mpox viruses.^2,28 Confirmatory diagnostic techniques are molecular tests (real-time/conventional polymerase chain reaction [PCR]) to detect sequences of viral DNA characteristic of the orthopoxvirus. Stand-alone PCR or in conjunction with sequencing can be used for diagnosis as per the availability of resources. However, molecular testing and genome-sequencing facilities are expensive and require enormous computational power that may be sparsely available in resource-poor settings in developing countries, further limiting the capacity to characterize positive samples.²⁹

Fatigue in healthcare systems.

Health systems across the world struggled under the burden of Covid-19. Any mpox outbreak in resource-limited settings such as low-income countries (LICs) may overwhelm the workforce, testing facilities, vaccination programs, and awareness campaigns, further jeopardizing existing public health capacities.

Resources.

Ample resources would be required to effectively combat the outbreak. Resource requirements include 1) material resources: personal protective equipment kits, masks, hand sanitizers, disinfectants, primers and PCR test kits, next-generation vaccines for post- and pre-exposure prophylaxis, antiviral drugs, and other drugs for symptomatic relief; 2) trained human resources: a medical and paramedical workforce; 3) health programs tailored to individual settings’ needs; and 4) nonpharmaceutical social interventions tailored to different sociocultural milieus. All of the above are a strain on the healthcare systems of countries, especially LICs.

Differential availability of vaccines and drugs.

Equitable distribution of vaccines recommended by the WHO (ACAM2000, MVA-BN, and LC16) and therapeutics (tecovirimat is currently approved) has been recognized as a challenge by the WHO director-general while declaring it a PHEIC.^7,14 The high cost of vaccines also makes them unaffordable and inaccessible to LICs (third-generation MVA-BN is ∼$100 per dose).³⁰ Piling up of vaccines and vaccine nationalism by high-income countries can lead to vaccine inequity and delayed control of the outbreak especially in low- and middle-income countries, as seen in the Covid-19 pandemic.³¹

Ethnic considerations and stigmatization.

Past outbreaks are important pointers toward ethnic and social issues surrounding mpox. In the context of current public health concern, it is important to address these issues in control strategies via public outreach programs. In the DRC mpox outbreak of 2017, indigenous hunter-gatherers of Aka ethnicity were affected. Certain behavioral attributes increased their odds of contact with mpox-infected animals/material, such as touching animal excreta, the presence of dead animals in/around the home, animal bites, consumption of dead animals, visits to forests, and sleeping in the open.³² Similarly, local zoonotic spillover from rodents was reported in the 2017 outbreak in Nigeria.³³ Other social issues reported from previous outbreaks include stigma and discrimination, fear and anxiety due to potential disfigurement, suicides due to misinformation and misconception, and even challenges in the burial of the mortal remains of mpox-infected individuals.³⁴

In the recent outbreak, a significant proportion of cases were initially reported among homosexual and bisexual men. However, available evidence does not indicate mpox to be sexually transmitted but only suggests these sexual behaviors enhance the proximity of physical contact with a positive case, thus increasing the chances of transmission.² Concerns have also been raised about the language and pictures portraying people with different gender orientations and race as sources of the outbreak, which have resulted in generated stigma and homophobic behavior directed at certain groups of people/communities.³⁵ Focused risk communication and awareness drives are therefore essential.

Gaps.

The reasons for the current outbreak and its rapid spread to non-endemic areas are still unclear.^2,36 This unprecedented spread in non-endemic areas creates the potential of “reverse zoonoses” and “spillback” into local susceptible animal populations, which can establish mpox as an enzootic infection.¹⁹ Uncertainty remains in understanding the transmission characteristics, coinfection outcomes, long-term outcomes, genomic evolution, variable epidemiology, ecologic niches, and animal reservoir(s) of mpox virus.³⁷

CONTROL EFFORTS RECOMMENDED IN DIFFERENT SCENARIOS

With the declaration of mpox as a PHEIC by the WHO, a set of temporary recommendations have been released that can be adopted by affected countries depending on their epidemiological situation, transmission intensity, infrastructure, and expertise available in their health systems.^38,39

Establishing surveillance mechanisms and diagnostic facilities.

Robust surveillance is to be supported by the development of protocols and operational definitions of cases (imported, exposed, suspected, probable, and confirmed). Sensitization and training of healthcare staff for screening, triage, and clinical assessment are vital. For the confirmation of a suspected case, PCR for the Orthopoxvirus genus followed by specific mpox virus DNA PCR is recommended. If facilities are available, virus isolation and next-generation sequencing may be used to identify the strain/clade. Genomics can also be used for surveillance and detection of emerging variants.

Clinical management.

Healthcare staff will need to differentiate clinical manifestations, including skin lesions from other similar rash illnesses. Standardized treatment protocols including symptomatic supportive management needs to be implemented. An antiviral agent (tecovirimat, approved by the European Medicines Agency) is to be used in clinical research contexts.⁴⁰ The Centers for Disease Control and Prevention in the United States has validated the use of tecovirimat in infected people with severe disease (hemorrhagic disease, sepsis, and encephalitis) and in immunocompromised people (HIV/AIDS, leukemia, malignancy, organ transplantation, etc.).⁴¹

Prevention and control measures.

Public health measures including surveillance, early detection, isolation, and subsequent contact tracing are the recommended mainstay for the control of human mpox. As per the WHO’s recent interim guidance (August 24, 2022), vaccination at the population level is currently not recommended. Postexposure preventive vaccination is recommended for close contacts of cases at high or medium risk of exposure with any of the three vaccines—ACAM2000, LC16, or MVA-BN—depending on availability.⁴¹ The degree of risk based on exposure has also been described by the WHO.¹⁷ Primary preventive or pre-exposure vaccination is advised for individuals with a high risk of exposure, especially for gay and bisexual men, men having sex with men, and healthcare workers and laboratory personnel. For young children, pregnant women, and immunocompromised individuals, ACAM2000 is not recommended.⁴² Besides vaccination, raising awareness and engagement of communities about transmission, preventive measures, targeted risk communication, and protecting vulnerable population groups/communities is important.^2,43

Active one health response.

To mount an effective response, there is a need to plug the gaps in our understanding of mpox transmission and its maintenance in nature. The primary animal reservoir has not been conclusively determined, and the environmental conditions conducive to its emergence are also not fully recognized. Risk factors for zoonotic and human-to-human transmission and its outbreak potential are inadequately comprehended. Epidemiological studies and theoretical models indicate that interhuman transmission cannot be an ongoing phenomenon without repeated introduction from zoonotic sources of infection.⁴⁴ Therefore, it is important that multidisciplinary investigations into potential animal sources of infection may help us understand the transmission course and drivers of the infection so that relevant preventive steps can be initiated. There has been a report of human-to-animal transmission (reverse zoonoses) in a pet dog from a symptomatic human, which needs deeper inquiry.⁴⁵ Laboratory-based studies to assess host susceptibility and field studies to understand the occurrence of the disease are needed in conjunction. Ethnocultural and anthropological factors are also playing a role in the transmission of mpox. Consumption of wild animals (especially rodents) as a source of protein is common in some parts of Africa where human mpox occurs. Consumption of bushmeat has also been found to be linked to certain cases occurring in both rural and urban areas of Africa.⁴⁶ In these cases, awareness campaigns to reduce contact with wild animals and reliance on them as a food source, including carcasses, are recommended. Moreover, in the LICs of Africa, food security still remains an issue, which requires an active role of the agriculture sector to enhance food availability. Even human mpox cases outside Africa have been linked to captive animals and pets.⁵ It is well recognized that human and animal health are linked to each other and to the environment. Mpox may not be a significant animal health concern but it requires intersectoral, multidisciplinary approaches for its effective control as a public health problem.⁴⁴

CONCLUSION

The world continues to grapple with the Covid-19 pandemic since the first reported case in 2019. Amid this, cases of another viral infection of animal origin, mpox, began to appear in early 2022 and soon spread to previously non-endemic regions, raising public health concerns of impending outbreaks. The low transmission intensity, severity of the disease, and lessons learned from the Covid-19 pandemic have enabled the WHO and scientific community to formulate effective responses to the outbreak. However, as applicable to any emerging and reemerging infection, there remain many challenges to public health responses. These range from the need for robust surveillance systems and affordable, accessible, and equitable point of care/collection diagnostic tests, to the availability of therapeutics and vaccines and containment of outbreaks in the context of international spread, and to the need for sensitive and tailor-made approaches for vulnerable groups from the perspective of social and ethical considerations.