Atypical mucosal lesions may help in the early diagnosis of monkeypox

Abstract

Since May 2022, monkeypox has been gradually spreading across countries. In past reports and treatment consensus, monkeypox is most widely known for its characteristic skin lesions, which are hard, spherical rashes that appear as herpes and pustules and are widely distributed centrifugally over all parts of the body. Prior to the appearance of the rash, carriers of monkeypox are likely to spread the virus to more susceptible people. Attention to the early atypical mucosal manifestations of monkeypox allows for early identification of potential cases of monkeypox, thereby controlling the further spread of the epidemic.

To the editor,

Since May 2022, the monkeypox epidemic was first detected in the United Kingdom and gradually spread from Western countries to countries around the world, and the World Health Organization declared the highest level of public health alert, calling the monkeypox epidemic a public health emergency of international concern. According to WHO, as of 9 September 2022, the cumulative number of confirmed monkeypox cases worldwide has exceeded 62,000. ¹

An observational analysis published recently suggests that it is highly likely that monkeypox virus is further transmitted in men who have sex with men (MSM) by forming local inoculum through close skin or mucosal contact. ² This mode of transmission is closely related to the recent emergence of a series of atypical clinical manifestations of monkeypox. And it can be understood as direct contact transmission closely related to sexual intercourse. Here we focus on the atypical mucosal lesions that may occur in patients with monkeypox under a specific route of transmission and review nine cases in this paper.

We conducted a literature search in PubMed by the keywords “Monkeypox” and “mucosal lesions” and identified seven papers, including nine cases of monkeypox with mucosal lesions.^3–9 All nine monkeypox patients listed in Table 1 were male and ranged in age from 30 to 69 years. Eight out of the nine patients had male-to-male contacts and recent male-to-male sex. Eight of the nine patients with monkeypox developed mucocutaneous lesions during the course of the infection and before the characteristic lesions or symptoms of monkeypox. In one patient, mucosal lesions preceded cutaneous ones by up to 7 days, suggesting that we might consider mucosal lesions as one of the precursors to monkeypox infection. ⁶ Most of the mucosal manifestations were greyish-white ulcers, which could involve the tongue, oropharynx and mucosa near the perineum. Only one patient presented an atypical genital rash without systemic symptoms prior to the diagnosis of monkeypox. ⁹

Table 1.

Case reports of 9 patients with atypical clinical manifestations of monkeypox.

Case number	Author	Age and gender	MSM	Unprotected sex in the previous weeks	HIV infection	First symptoms	Mucosal manifestations	Mucosal manifestations before or after the classic clinical manifestations of monkeypox	Mucosal lesion ’s number; location; manifestations
1 3	Evelyn Lepka de Lima, et al.	41, male	Yes	Yes	Unknown	Genital ulcers	Yes	Before	2; penile glans; ulcers
2 4	Óscar Guillermo Pérez-Martín, et al.	40, male	Yes	Yes	Unknown	Skin eruption on the penis	Yes	Before	1; penis; vesicle, became pustule and crust later
3 5	Luigi Pisano, et al.	45, male	Yes	Yes	Yes	Painful oral ulcerative lesions	Yes	Before	2; oral cavity; ulcers
4 5	Luigi Pisano, et al.	69, male	Yes	Yes	Yes	Painful oral ulcerative lesions	Yes	Before	1; oral cavity; ulcer
5 6	Timothy Mathieson, et al.	34, male	Yes	Yes	Unknown	sore throat	Yes	Before	Several; tongue and oropharynx; ulcerating vesicles
6 7	Scott M. Peters, et al.	38, male	Unknown	Unknown	Unknown	Anterior tongue lesion	Yes	Before	1; tongue; tan-gray ulcer
7 7	Scott M. Peters, et al.	30, male	Yes	Yes	Yes	Painful oral lesion	Yes	Before	1; tongue; tan-gray ulcer
8 8	Lotfi Benslama, et al.	34, male	Yes	Yes	Unknown	Mouth rash	Yes	Before	Several; tongue and oral cavity; ulcerating vesicles
9 9	V. Paparizos, et al.	59, male	Yes	Yes	Yes	Rashes in pubic area and the base of penis	No	/	Several; pubic area; macules, developed into papules

In three monkeypox case analysis papers, a total of 910 patients with confirmed monkeypox were listed in Table 2.^10–12 Of the 910 patients, 99.9% were male, 98.7% were MSM, and approximately 42% were HIV-infected. Aatish Patel et al. (2022) suggested in the literature that all 197 patients included with confirmed monkeypox presented with mucosal lesions and that 32.7% had mucosal lesions earlier than the appearance of the characteristic manifestations of monkeypox. ¹¹ The number of MSM in the other two case groups accounted for 98% and 99% of the total number of cases in each.^10,12 The article by J.P. Thornhill, et al. stated that 41% of the confirmed patients with monkeypox had developed mucocutaneous lesions. ¹⁰ A systematic review raised the possibility of local inoculation through close skin and mucosal contact during sexual activity. ¹³

Table 2.

Summary of 3 retrospective analysis literatures of monkeypox case.

Case group	Author	Number of cases	Median age	Male proportion (%)	MSM proportion (%)	HIV positive proportion (%)	Mucocutaneous lesions (%)	Mucosal manifestations before the classic clinical manifestations of monkeypox (%)	Mucosal manifestations but no systemic symptoms
1 10	J.P. Thornhill, et al.	528	38	>99	98	41	41	Unknown	Unknown
2 11	Aatish Patel, et al.	197	38	100	99.5	35.9	100	32.7	13.7
3 12	Alba Català, et al.	185	38.7	100	99	42	Unknown	Unknown	Unknown

Monkeypox is a zoonotic disease caused by infection with monkeypox virus. In past reports and treatment consensus, the typical clinical manifestations of monkeypox have been highlighted, including an incubation period of 5 to 21 days and non-specific systemic symptoms (chills, fever, headache, lethargy, malaise, myalgia, lymph node enlargement). Monkeypox is most widely known for its typical skin lesions, which are hard, spherical rashes that appear as pseudopustules without liquid content and are widely distributed centrifugally over all parts of the body. ¹⁴ To initiate the screening and diagnosis only after the appearance of the characteristic lesions of monkeypox could be late. Before the rash appears, monkeypox carriers are likely to transmit the virus to a wider susceptible population.

In an article (Kristi L. Koenig 2022), clinicians are urged to raise awareness of the atypical presentation of monkeypox. ¹⁵ Early identification of potential monkeypox cases is the top priority to control the further spread of the epidemic. Based on the characteristics of the nine cases listed above and the relevant literature, it can be assumed that when MSM develops oral or perineal mucosal lesions, especially HIV-infected people, after unprotected sex, the monkeypox infection needs to be ruled out. We should perform PCR testing for monkeypox virus on their lesions as soon as possible, thus enabling early diagnosis, isolation and control of monkeypox. Because there are few descriptions and reports of mucosal symptoms in monkeypox cases, only the above seven articles are included in this article as arguments. When more relevant information is available, we can further study the pattern and characteristics of mucosal lesions caused by monkeypox virus.