2025 Update on Mpox: Epidemiology, Transmission, Diagnosis, Treatment, and Prevention

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Introduction

This document provides an overview of mpox, formerly known as monkeypox, covering its virology, history, current epidemiology, transmission, clinical presentation, diagnosis, treatment, and prevention. The information is based on a presentation drawing heavily from recent review articles, including one published in JAMA in October 2024 and another from 2022. The nomenclature changed from monkeypox to mpox in November 2022, recommended by the WHO and adopted by the CDC, primarily to reduce stigma associated with the name.

Virology and Clads

Mpox is a large double-stranded DNA virus belonging to the Orthopoxvirus genus within the Poxviridae family. This family can infect a wide range of animals, including mammals, birds, reptiles, and insects. The Orthopoxvirus genus includes other viruses like smallpox (variola virus), vaccinia virus (used in vaccines), and molluscum contagiosum virus. A key feature of orthopox viruses is their immunological cross-reactivity and cross-protection, meaning prior infection or vaccination with one orthopox virus can confer some protection against others in the same genus, such as prior smallpox vaccination potentially offering some protection against mpox.

There are two distinct genetic strains or clads of mpox virus: Clad 1 (historically called Central African clad) and Clad 2 (West African clad). Each clad has subgroups (e.g., 1A, 1B, 2A, 2B). These clads have different geographical distributions and historical disease severities. Clad 1 has historically been endemic in Africa, particularly the Democratic Republic of the Congo (DRC), with a substantial mortality rate of 5-10% in outbreaks prior to 2022. Clad 2B is the strain that caused the widespread global outbreak starting in 2022, and it has a much lower mortality rate, estimated at less than 0.01% globally during this outbreak. Clad 1 outbreaks (1A and 1B) are currently ongoing in Africa, predominantly in the DRC.

Epidemiology and Current Status

The mpox virus was first identified in 1958 in nonhuman primates and the first human case was reported in the DRC in 1970. Prior to 2022, the vast majority of mpox cases occurred in African countries, with localized outbreaks and occasional cases outside Africa primarily linked to international travel or imported animals harboring the virus. The largest outbreak outside of Africa before 2022 occurred in the United States in 2003, involving 47 cases linked to infected pet prairie dogs that had contact with imported animals, with no human-to-human transmission observed in that specific outbreak. A single travel-related case was reported in the US in 2021 with no onward transmission.

The current global outbreak began in the United Kingdom in May 2022. This outbreak, predominantly caused by Clad 2B, has since spread widely. As of December 31, 2024, approximately 125,000 cases and 272 deaths had been reported to the WHO from 128 countries since January 2022. The United States has reported the highest number of cases globally since 2022, with about 34,000 cases. The global epidemic curve showed a large peak in 2022, particularly in the Americas and Europe, followed by a decrease, with low-level transmission ongoing globally. More recently, there has been a significant rise in cases in the African region in 2024, predominantly due to Clad 1 outbreaks.

In the United States, cases peaked dramatically in the summer of 2022 and have since decreased substantially. As of late 2024, the number of daily cases is roughly 0 to 10 nationally. Cumulative deaths in the US reached 58 by January 2024. Harris County mirrored the national trend with a large peak in 2022 and significantly fewer cases currently.

A recent critical development is the WHO Director-General declaring the increase in Clad 1 cases in the DRC and neighboring countries a new public health emergency of international concern in August 2024. These Clad 1 outbreaks are distinct from the ongoing Clad 2B global outbreak. Worryingly, travel-related cases of Clad 1 mpox have recently been diagnosed outside Africa, including the first US case in California in November 2024 and a second in Georgia in January 2025, both in travelers returning from affected areas. Several other countries have also reported travel-associated Clad 1 cases.

Transmission

Transmission of mpox primarily occurs through close contact, including intimate or sexual contact, with a person who has active mpox. This was the most common mode of transmission during the 2022 Clad 2B outbreak, particularly recognized among gay, bisexual, and other men who have sex with men (MSM).

Other possible modes of transmission include contact with contaminated objects (fomites) like bedding or clothing, direct contact with infected animals (animal-to-human spillover), contact with saliva, respiratory secretions, body fluids, and lesions around mucous membranes, as well as hugging, massage, kissing, and theoretically, vertical transmission (mother to child). Transmission via fomites and within households tends to be more common in Clad 1 outbreaks.

The duration of infectiousness is generally considered to be from the onset of symptoms until the rash has fully healed. There is currently no evidence of transmission from asymptomatic individuals.

It is important to note that transmission modes vary somewhat by clad. Clad 1A (ongoing in DRC) is more associated with contact with infected animals, household transmission, and sometimes patient care, and often affects children. Clad 1B, a newer strain, has been observed to spread more through sexual contact among different demographics, including heterosexual spread via sex trade workers. Clad 2B, responsible for the global outbreak, remains mostly spread through sexual contact, with the highest proportion of cases among MSM.

Clinical Presentation

The mean incubation period for mpox is typically 2 to 21 days, though it was thought to be shorter (7-10 days) during the 2022 Clad 2B outbreak.

Classically, the illness begins with a prodromal phase in about two-thirds of patients, characterized by non-specific constitutional symptoms such as fever, malaise, myalgia, headache, and notably, lymphadenopathy (swollen lymph nodes), which is a distinguishing feature from smallpox.

This prodrome is followed by the development of a characteristic rash. Classically, the rash was described as appearing on the face, trunk, and extremities, often with a large number of lesions. The rash progresses through distinct stages: macules, papules, vesicles, and pustules, before scabbing over and healing. This progression is often described as vesiculopustular. The entire process typically takes 2-3 weeks, but the rash can last up to four weeks.

However, during the 2022 global outbreak, atypical presentations were frequently observed. These included fewer lesions, lesions only in certain areas of the body (e.g., genital or perianal), and absent or minimal constitutional symptoms. Other clinical findings seen in the 2022 outbreak included proctitis, pharyngitis, urethritis, and ocular disease.

While the vast majority of cases during the Clad 2B outbreak are mild and self-limited, mpox can range in severity and potentially be life-threatening. Serious complications, though uncommon, can occur and include necrotizing skin lesions, bacterial superinfection, pneumonia, encephalitis, and myocarditis.

Risk Factors for Severe Disease

Certain patient populations are at increased risk for progressive or severe disease. These include individuals with severe immune compromise, particularly those with advanced HIV who are not on antiretroviral therapy. Other immunocompromising conditions such as solid organ transplant or stem cell transplant also increase risk.

Patients with certain active skin conditions like extensive eczema or psoriasis may also be at increased risk for dissemination. Severe disease manifestations necessitating consideration for advanced treatment include extensive lesions over a large body surface area (especially if confluent, necrotic, or hemorrhagic), sepsis, cardiopulmonary disease, encephalitis, or orbital infections. In prior Clad 1 outbreaks, young children and pregnant individuals were also noted to be at higher risk for more aggressive disease.

Diagnosis

Suspecting the diagnosis of mpox requires considering a compatible rash (including atypical presentations) along with key epidemiological history. Essential history includes potential contact with a known mpox case, sexual history (given the predominant mode of spread in the Clad 2B outbreak), and travel history to regions with ongoing mpox outbreaks, particularly areas affected by the Clad 1 outbreaks.

The differential diagnosis for mpox rash includes various conditions, such as disseminated herpes simplex or varicella-zoster infections (due to the vesicular component), syphilis (which can have atypical presentations), impetigo or folliculitis, molluscum contagiosum (another pox virus), other orthopox viruses, viral exanthems, and drug reactions. Differentiating from molluscum contagiosum can be aided by mpox typically being more painful, having a more rapid progression, and often including a prodrome, unlike molluscum.

Diagnostic testing is primarily performed via PCR of lesion material. A non-variola orthopox virus PCR test is commonly used, which detects the viral DNA. Clad-specific testing to determine if it is Clad 1 or Clad 2B is available through the CDC. In 2023, the FDA authorized point-of-care testing for rapid results, and in April 2024, granted Emergency Use Authorization (EUA) for a home self-collection sampling kit to improve access and potentially reduce stigma.

Treatment

The cornerstone of mpox management is supportive care. This includes pain control, managing specific symptoms like proctitis or pharyngitis, and addressing complications. In patients with underlying conditions, restoring immune function where possible, such as starting antiretroviral therapy for advanced HIV, is crucial. Most patients who are not severely immunocompromised and have mild disease can recover with supportive care alone.

Antiviral treatments are available, but not all patients require them. The most frequently used antiviral in the United States is tecovirimat (TPOXX). Tecovirimat inhibits a protein (P37) present in all orthopox viruses and was originally developed as a countermeasure for smallpox. It was approved by the FDA in 2018 and used widely under an expanded access protocol during the 2022-2023 outbreak. While generally considered to have a good safety profile, recent randomized controlled trials (RCTs) provided surprising results.

Preliminary "topline" results from two recent RCTs indicate that tecovirimat, while safe, did not significantly improve the resolution of symptoms or pain compared to placebo in patients with mild to moderate disease caused by either Clad 1 (in the DRC trial) or Clad 2B (in the US STOMP trial). The STOMP trial specifically excluded patients with severe immunocompromise or severe infection from the main randomized part.

Despite these trial results, current CDC eligibility criteria for tecovirimat still include patients with severely immunocompromising conditions (especially advanced HIV), active skin conditions increasing dissemination risk, life-threatening manifestations, pregnancy, and children. The decision to use tecovirimat in these higher-risk scenarios is based on the potential for benefit and the drug's relatively low risk, though clear RCT data demonstrating effectiveness in these specific populations is still lacking and not expected from new trials soon.

Other less commonly used or studied antiviral options include cidofovir and its prodrug brincidofovir (primarily used for CMV but with some activity), Vaccinia Immune Globulin Intravenous (VIGIV) (passive immunity using antibodies against vaccinia virus), and topical trifluridine for ocular involvement. Combination therapy is sometimes used in severe cases, but there is no clear data on its effectiveness.

Prevention

Prevention strategies include behavioral changes and vaccination. During the early part of the 2022 outbreak, there was evidence of individuals reducing their number of sexual partners or frequency of encounters, which may have contributed to the decline in cases. Appropriately directed public health messaging was thought to be effective in promoting these changes.

There are two FDA-approved vaccines for preventing mpox and smallpox. ACAM2000 is a live, replicating vaccinia virus vaccine given as a single dose via skin pricks, causing scarification. However, it sheds live virus and has potential for serious side effects, limiting its use in certain populations.

The preferred vaccine currently used during the 2022 outbreak is JYNNEOS (MVA-BN). This is a live, but weakened and non-replicating, vaccinia virus vaccine. Licensed in 2019, it was initially developed for smallpox bioterrorism preparedness as a safer alternative to ACAM2000, particularly for immunocompromised individuals. JYNNEOS is administered as a two-dose series separated by four weeks. It has a much better safety profile than ACAM2000 and can be used in immunocompromised patients.

Current CDC recommendations for JYNNEOS vaccination include post-exposure prophylaxis for known close contacts of someone with mpox. Pre-exposure prophylaxis is recommended for individuals at higher risk of acquiring infection due to sexual activity, such as those with multiple sex partners, sex at commercial venues, or whose partners meet these criteria. This recommendation applies regardless of sexual orientation or gender. Additionally, due to the recent rise in Clad 1 cases in Africa, vaccination is also recommended for travelers to countries with ongoing Clad 1 outbreaks (like DRC) who anticipate engaging in high-risk activities.

Over a million doses of JYNNEOS were administered in the US, mostly in 2022 and 2023. However, as of mid-2023 data, only about a quarter of at-risk individuals in the US had received the full two-dose series. It remains somewhat of an open question how the outbreak subsided so substantially with relatively low full vaccination rates. Potential factors include behavioral changes, undiagnosed mild cases resulting in natural immunity, or fewer reservoirs.

Reinfection with mpox is considered extremely rare (<0.001% in the US) and typically results in much milder illness. Therefore, there is no current recommendation for vaccination for individuals who have previously had mpox and recovered.

Future Considerations

Mpox cases have increased significantly globally since 2015. Factors contributing to its potential for wider spread include increased human exposure to wildlife reservoirs, increased international travel, its efficient spread via sexual contact (particularly the Clad 2B strain), and diminishing population immunity to orthopox viruses due to the cessation of routine smallpox vaccination. The emergence of efficiently spreading clads with relatively moderate mortality (like Clad 2B) paradoxically gives them higher pandemic potential compared to highly lethal diseases like Clad 1 or Ebola, where rapid death can limit transmission.

Key open questions for the future include whether the low-level transmission of the Clad 2B global outbreak will persist, potentially with future increases. A major focus is on achieving control of the current Clad 1 outbreaks in Africa, particularly the DRC, which will require substantial effort, including vaccination campaigns. While currently focusing on vaccinating at-risk populations in endemic areas, there is theoretical discussion about the potential for broader vaccination campaigns to increase general population immunity.

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