de intensivist

Abstract

Beginning in May 2022, there was a sudden increase in mpox infections worldwide. For a short time, there was concern that this infection, like COVID-19, would spread rampantly. Fortunately, the outbreak of mpox (formerly known as monkeypox) has been brought under control and is now largely gone. Still, it is good to review what infections the mpox virus causes and how it could have briefly become so widespread. In this review, we describe what the mpox virus is, what infections it causes, how it was able to flourish, and what we should do to prevent new outbreaks.

Introduction   

Mpox was first discovered in 1958 when monkeys shipped from Singapore to a Danish research facility developed skin lesions.[1] The first confirmed human infection occurred in a nine-month-old infant in the Democratic Republic of the Congo in 1970 during the global smallpox outbreak.[2] Since then, the virus has remained endemic on the African continent. The first notable outbreak outside the endemic areas of Africa occurred in the United States (US) in 2003. This outbreak was reportedly caused by a Gambian hamster rat shipped from Ghana, which in turn infected prairie dogs that were then sold as pets in Illinois and transmitted the disease to humans. A total of 53 people were infected during this outbreak,[3] and sporadic cases have since been reported outside of endemic areas. However, as of May 2022, multiple cases have been reported in Europe, North and South America, Australia, and Asia. Since the start of the outbreak in 2022, approximately 26,000 cases have been confirmed in Europe (Figure 1), and a total of 88,000 cases have been confirmed worldwide. Many of the cases cannot be directly linked to endemic areas in Africa, indicating a new and worrying direct human-to-human spread in non-endemic countries.[4]

Figure 1 Geographic distribution of cumulative confirmed cases of mpox per million population in the EU, Balkans and Turkey, as of July 6, 2023.
Source: European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Mpox surveillance bulletin, July 6, 2023

Virology

Mpox is caused by the mpox virus, a double-stranded DNA zoonotic orthopoxvirus. It is similar to variola virus, which causes smallpox, and to vaccinia virus, the virus used in smallpox vaccines. This explains why the clinical features of mpox are similar to those of smallpox, and why vaccines and antivirals that are effective against smallpox appear to have some effect against mpox. Although the virus was first discovered in and named after monkeys, the natural reservoir is thought to be African rodents, not monkeys. There are currently two genetically distinct strains, the Central African strain and the West African strain. Mortality for the Central African strain is as high as 11% in unvaccinated children,[5] the West African strain has a more favorable prognosis with a mortality of < 1%. The Central African strain is more commonly reported, while the West African strain is considered less virulent and has fewer reported cases of human-to-human transmission.[6, 7] However, the May 2022 outbreak is caused by this West African strain.[8]

Clinical features

In most patients, symptoms are similar to smallpox but milder. Severe cases are more common in children, pregnant women, and immunocompromised patients.[9] Signs and symptoms that have been described include rash, fever, chills, lymphadenopathy, headache, and myalgia.[10] After infection, there is an incubation period of one to two weeks during which the virus multiplies at the site of inoculation and invades the local lymph nodes. There is then a primary viremia that allows the virus to spread to other organs. This viremia coincides with symptoms of fever and lymphadenopathy. Oropharyngeal and cutaneous lesions appear one to three days after the onset of symptoms. Skin lesions usually begin on the face and trunk and spread in a centrifugal pattern to the extremities, including the soles and palms (Figures 2 and 3). Over the next two to four weeks, the lesions progress synchronously in several stages from macules, papules and vesicles to pustules and finally to crusts. After all crusts have fallen off, the patient is no longer considered infectious. The lesions may leave scars.[11]

Figure 2 Lesions on the palms of a monkeypox case-patient in the Democratic Republic Congo (DRC), 1997. Source: CDC/ Brian W.J. Mahy, BSc, MA, PhD, ScD, DSc (public domain). Available from: https://phil.cdc.gov/Details.aspx?pid=12761

Figure 3 Monkeypox lesions on hand and leg of a 4-year-old in Liberia, 1971. Source: CDC (public domain) Available from: https://phil.cdc.gov/Details.aspx?pid=2329
Human infection with monkeypox-like virus in 4 year-old female, Bondua, Grand Gedeh County, Liberia. Infection was caused by a pox virus of the vaccinea, variola, monkeypox type.
1971
tray #26, B71-990

Although the symptoms are similar to a mild version of smallpox, there are some notable differences. Lymphadenopathy is a feature that occurs in mpox but does not appear to occur in smallpox. Lymphadenopathy in mpox can be either generalized or localized.[7] Although most cases are mild, serious complications have been described, including bacterial superinfection of the skin and ocular complications, including permanent scarring of the cornea. Pneumonia has also been described, as well as severe dehydration due to vomiting, diarrhea, and decreased intake from oropharyngeal lesions, sepsis, and encephalitis.[12] In a retrospective study of 34 patients during the 2003 U.S. outbreak, 5 of 10 children (50%) and 2 of 23 adults (9%) were admitted to the intensive care unit. [10] The two most seriously ill patients were children. [13,14]

Treatment

In most patients, infections are mild; in severe cases, supportive care may be required. Antiviral drugs may be considered in severe cases and in patients who are expected to have a more severe infection, such as immunocompromised patients and young children. Tecovirimat is an antiretroviral drug approved by the European Medicines Agency for use in mpox infections.[15] Tecovirimat has been shown to be effective against smallpox in animal models[16, 17] and is believed to be effective against mpox. A large safety study has shown that the drug is safe and well tolerated in humans, with only minor side effects,[16] but there are no data yet on the efficacy of treating mpox in humans with this drug. Cidofovir has been extensively tested in mpox infections both in vitro[18] and in animal models[19, 20] and has shown promising results. There is limited data on brincidofovir in animal models[21] and no clinical data on mpox infections in humans for either drug. In a retrospective study of seven mpox patients in the United Kingdom between 2018 and 2021[22], three were treated with brincidofovir and all developed mild hepatic dysfunction. One of the seven was treated with tecovirimat and experienced no side effects. The patient treated with tecovirimat had a significantly shorter viral clearance time compared to the other patients, although it is impossible to say whether this relationship was causal based on this study design.

Prevention

The disease usually has an incubation period of 6 to 13 days, but ranges from 5 to 21 days. Fever precedes lesion formation by one to three days, and patients may be infectious during this period.[23] Since there is no asymptomatic infectious period, it is likely that timely isolation of symptomatic individuals will limit the spread of the virus. Patients with suspected or confirmed mpox should be isolated, and isolation should be maintained until all skin crusts have fallen off. In critical care settings, the Center for Disease Control and Prevention (CDC) recommends isolating patients in negative pressure chambers with contact, drip, and air precautions.[24]

People vaccinated against smallpox (until 1974 in the Netherlands) also show some immunity to mpox. This cross-effect has also been observed previously with smallpox and cowpox.[25] The smallpox vaccine originated in the late eighteenth century. The practice was to inoculate people transcutaneously with a small dose of live smallpox. People did get smallpox, but the disease was much milder than in a regular outbreak. It is an oft-repeated myth that Dr. Jenner learned of the benefits of cowpox from milkmaids who boasted of their unblemished skin without scars from smallpox. In fact, it was country doctor Fewster who observed that people who had been exposed to cowpox showed no response to transcutaneous inoculation with a low dose of live smallpox. The importance of this observation was recognized by Jenner, who experimented with inoculation with this much safer cowpox virus (vaccinia virus) and published the results[26], and thus the first vaccine was born. Smallpox was successfully eradicated in 1980 after an intensive worldwide vaccination campaign, still to this day one of the greatest victories of vaccinations over infectious diseases.

In the summer of 2022, due to an infection peak in the Netherlands, vaccination of high-risk individuals with the imvanex vaccine was started. A total of approximately 18,000 people in the Netherlands were vaccinated with this vaccine.

 Pandemic potential

Transmission can occur from animal to human or from human to human. In animal-to-human transmission, the virus is usually acquired through contact with body fluids of infected animals or by bite. Human-to-human transmission occurs through direct contact with infected skin lesions.

The WHO reports that the current outbreak outside endemic areas is occurring primarily, but not exclusively, among men who have sex with men (MSM)[9], and because most cases present with lesions on the genitals or peri-genital area, it is believed that the main mode of transmission is likely to be through intimate contact during sexual activity.[8]

It is hypothesized that the global eradication of smallpox and the subsequent discontinuation of smallpox vaccination and increase in unvaccinated populations in recent years has allowed for a resurgence of mpox.[27] Since mpox is endemic in the interior of Africa, it is likely that the actual number of cases is higher.[6] Furthermore, although human-to-human transmission has been limited, it is believed that with a growing population of unvaccinated people, there is a serious pandemic potential for mpox.[28]

Conclusion

The mpox virus is an orthopox virus closely related to the smallpox virus that has been with us for some time, but now appears to be experiencing a resurgence due to the global eradication of smallpox and the resulting cessation of smallpox vaccination. Most patients experience only mild symptoms, but serious complications and deaths have been reported, particularly in children and the immunocompromised. Intimate contact during sexual activity appears to play an important role in transmission.

Disclosures

All authors declare no conflict of interest. No funding or financial support was received.