An international collaboration of clinicians has identified the clinical symptoms in people infected with monkeypox in the largest case study series to date. Their findings will improve future diagnosis, help to slow the spread of infection, and help the international community prioritize the limited global supply of monkeypox vaccines and treatments to communities most at risk.

The number of monkeypox cases in the United States has surpassed 2,500 (the number of cases was 2,891 on July 22). The states with the highest case counts are New York, California, and Florida (900, 356, and 247, respectively.) The latest numbers (as of July 20) from the World Health Organization (WHO) are 14,000 cases, from more than 70 countries and territories, including 5 deaths—all in Africa.

Just a few months ago, before April, monkeypox virus infection in humans was not typically reported outside African regions—where it is endemic. Basic information that will aid the public health response, like transmission, risk factors, clinical presentation, and outcomes of infection, are not well understood.

Now, a study—which is the result of an international collaboration across 16 countries—is adding some useful information to the current understanding. The study identifies new clinical symptoms of monkeypox infection, which will aid the ability to diagnose the infection in the future and help to slow the spread of infection. It is the largest case series to date, reporting on 528 confirmed infections (from 43 sites in 16 countries) between April 27 and June 24, 2022.

The report is published in The New England Journal of Medicine (NEJM) in the paper, “Monkeypox Virus Infection in Humans across 16 Countries—April–June 2022.”

Many of the infected individuals reviewed in the study presented with symptoms not recognized in current medical definitions of monkeypox. These symptoms include single genital lesions and sores on the mouth or anus. The clinical symptoms are similar to those of sexually transmitted infections (STIs) and can easily lead to misdiagnosis. In some people, anal and oral symptoms have led to people being admitted to the hospital for management of pain and difficulties swallowing. This points to the importance that these new clinical symptoms be recognized and healthcare professionals be educated on how to identify and manage the disease. Misdiagnosis can slow detection and thus hinder efforts to control the spread of the virus. The study will therefore lead to increased rates of diagnosis when persons from at-risk groups present with traditional STI symptoms.

The authors noted that transmission was suspected to have occurred through sexual activity in 95% of the persons with infection. In this case series, 95% of the persons presented with a rash (with 64% having less than 10 lesions), 73% had anogenital lesions, and 41% had mucosal lesions (with 54 having a single genital lesion).

The study includes data on common systemic features preceding the rash: they included fever (62%), lethargy (41%), myalgia (31%), and headache (27%); the swelling of lymph nodes was also common (reported in 56%).

Among the 23 persons with a clear exposure history, the median incubation period was 7 days (with a range of 3 to 20). Monkeypox virus DNA was detected in a large proportion (29 of the 32 persons) in whom seminal fluid was analyzed. However, “this may be incidental,” said John Thornhill, PhD, consultant physician in sexual health and HIV and clinical senior lecturer at Barts NHS Health Trust and Queen Mary University of London. “We do not know that it is present at a high enough level to facilitate sexual transmission. More work is needed to understand this better.”

“This truly global case series has enabled doctors from 16 countries to share their extensive clinical experience and many clinical photographs to help other doctors in places with fewer cases,” noted Chloe Orkin, MBChB, FRCP, MD, professor of HIV medicine at Queen Mary University of London and director of the SHARE collaborative. “We have shown that the current international case definitions need to be expanded to add symptoms that are not currently included, such as sores in the mouth, on the anal mucosa, and single ulcers. These particular symptoms can be severe and have led to hospital admissions so it is important to make a diagnosis. Expanding the case definition will help doctors more easily recognize the infection and so prevent people from passing it on. Given the global constraints on vaccine and anti-viral supply for this chronically underfunded, neglected tropical infection, prevention remains a key tool in limiting the global spread of human monkeypox infection.”

In addition, noted Thornhill, “we identified new clinical presentations in people with monkeypox. While we expected various skin problems and rashes, we also found that one in ten people had only a single skin lesion in the genital area, and 15% had anal and/or rectal pain. These different presentations highlight that monkeypox infections could be missed or easily confused with common sexually transmitted infections such as syphilis or herpes. We, therefore, suggest broadening the current case definitions.”

The findings of this study, including the identification of those most at risk of infection, will help to aid the global response to the virus. There is a global shortage of both vaccines and treatments for human monkeypox infection. Public health interventions aimed at the high-risk group could help to detect and slow the spread of the virus. Although sexual closeness is the most likely route of transmission in most cases, researchers stress that the virus can be transmitted by any close physical contact, through large respiratory droplets and potentially through clothing and other surfaces. The findings from this study will help public health measures—such as enhanced testing and education—to be developed and implemented, working with at-risk groups to ensure that they are appropriate and non-stigmatizing.