Overlooked monkeypox cases among men having sex with men during the 2022 outbreak – a retrospective study

Abstract

Objectives

The aim of this study was to characterize overlooked cases of patients with monkeypox infection in the 2022 outbreak.

Methods

Clinical characteristics of 26 patients who were misdiagnosed with other diseases were described.

Results

Of the 26 patients who were misdiagnosed, six (23%) were given a diagnosis of bacterial tonsillitis, six (23%) were diagnosed with primary syphilis, five (19.2%) with oral or genital herpes, and four (15.3%) with bacterial proctitis or anal abscess. The average time interval between missed and right diagnosis was 4.4 days. There was no difference in the missed cases between the early and the later month of the outbreak.

Conclusion

Monkeypox might still be commonly overlooked, especially in patients presenting with fever and sore throat or solitary ulcer as sole manifestations.

Introduction

Monkeypox (MPX) is an emerging disease outside of Africa, especially in men who have sex with men (MSM) who engage in unprotected sex [1]. Since its first appearance in the current outbreak in early May 2022 [2] more than 60,000 cases have been reported outside of endemic areas [3].

Contrary to travel-associated MPX [4,5] the current outbreak is mainly among MSM and probably transmitted during sexual contact [6].

Many of the patients present with proctocolitis and genital ulcers which may be associated with fever and inguinal lymphadenopathy, while others might present with much milder disease [1,7]. Symptoms and signs may be similar to other sexually transmitted diseases and around 30% of the patients are indeed coinfected with another sexually transmitted infection (STI) [1,8]. MPX is a "new disease" in nonendemic countries, and may present with a wide range of clinical findings including those resembling an STI. As many physicians are not familiar with the disease, it can be easily misdiagnosed or overlooked, leading to delayed diagnosis, delayed isolation, and/or administration of inappropriate treatment.

The main aim of this study was to describe the characteristics of cases of MSM diagnosed with MPX who were initially misdiagnosed as having another disease during the current outbreak.

Methods

This was a retrospective study. Patients who were diagnosed with MPX from May 16, 2022-June 10, 2022 were retrospectively included in the study. Misdiagnosis was defined when MPX was not documented in the differential diagnosis of the examining physician on the first examination but was subsequently diagnosed based on a laboratory confirmatory test. Only patients with a positive polymerase chain reaction assay that was done in a recognized laboratory in at least one sample from any anatomical site were included. We defined May-June as the early phase of the outbreak and July-August as the later part of the outbreak.

Results

A total of 26 patients were included in the study (Table 1). All patients were self-defined as MSM with a definite sexual exposure history. In the primary contact with a physician, they were not asked about contact with an MPX patient. Of the 26 patients, 17 (65.3%) were on HIV pre-exposure prophylaxis, and five (19.2%) tested positive for HIV.

Clinical presentation: Overall, skin (30.7%) and/or anogenital lesions (46%) were the most common presentations, the most common skin lesion were described as vesiculopustular or crusted lesions. The number of lesions varied widely but most patients had <10 lesions. Proctitis alone was observed in 26.9% of the patients at initial presentation, and 23% presented initially only with fever and sore throat.

Diagnosis at presentation (Table 1 ): Of the 26 patients who were misdiagnosed, six (23%) were given a diagnosis of bacterial tonsillitis, six (23%) were diagnosed with primary syphilis, five (19.2%) with oral or genital herpes and four (15.3%) with bacterial proctitis or anal abscess. During the study's early period, 11 patients were misdiagnosed, compared with 15 during the later period, which was not significantly different.

Table 1.

Characteristics of misdiagnosed, men who have sex with men with monkeypox.

	Missed diagnosed (N = 26)
Age (year, mean, range)	34.5 (21-48)
HIV positive, N (%)	5 (19.2)
On pre-exposure prophylaxis, N (%)	17 (65.3)
Period of diagnosis (early), N (%)	11 (42.3)
Time interval between missed and right diagnosis in days. average (median, range)	4.4 (4, 1-9)
Cause of presentation, N (%)
Skin ulcer	8 (30.7)
Anal and perirectal	7 (26.9)
Penile ulcer	4 (15.3)
Fever and sore throat	6 (23)
Fever, lymphadenopathy	5 (19.2)
Groin pain	3 (11.5)
Intra urethral lesion	1 (3.8)
Primary (mis)diagnosis
Tonsilitis	6 (23)
Syphilis	6 (23)
Herpes	5 (19.2)
Proctitis	4 (15.3)
Skin lesions not defined	2 (7.6)
Warts	2 (7.6)
Medical professions that missed diagnosis
Primary care - general	11 (42.3)
Primary care - LGBT clinics	2 (7.6)
Emergency department physician	7 (26.9)
Dermatologist	8 (30.7)
Proctologist	2 (7.6)
Urologist	1 (3.8.2)

LGBT = lesbian, gay, bisexual, and transgender.

Two patients were missed diagnosed by two different physicians. The 28 physicians who misdiagnosed the patients on initial presentation included 11 (39%) primary care physicians, eight (28.5%) dermatologists, seven (25%) emergency care physicians, and two (7.5%) proctologists. Of the 21 physicians that rightly diagnosed MPX on a later examination nine (43%) were emergency care physicians, seven (33%) were primary care physicians and five (24%) were infectious disease specialists. In seven cases the patient himself suggested the diagnosis to the physician.

On average there was a gap of 4.4 days (median 4, range 1-9) between the missed and the right diagnosis.

Overall, three patients were coinfected with gonorrhea (two rectal and one pharyngeal) and one with syphilis (by serology, asymptomatic).

Discussion

In this study, we show that MPX infection may be easily overlooked and be confused with other diseases, mainly other STIs. Owing to the nature of its transmission, and its nonclassical presentation of lesions concentrated in the anogenital areas in about 75% of the patients [1], it is most commonly confused with other STIs such as syphilis and genital herpes simplex infection. Furthermore, 23% of the patients in this study were initially diagnosed as having tonsilitis/pharyngitis, with the oropharyngeal lesions probably resulting from an oral sexual mechanism of transmission.

Our findings are in accordance with more traditional STIs, which are more likely to be correctly diagnosed when presenting in the classical genital areas, and more likely to be misdiagnosed when presenting in extragenital sites [9].

Among the patients, five (19.2%) were coinfected with HIV, and four with bacterial STIs (three with gonorrhea and one with syphilis). HIV and other STIs have been reported in the current global MPX outbreak. Persons with HIV infection or STIs are disproportionately represented among persons with MPX [10]. Given the fact that many of the patients are on pre-exposure prophylaxis and probably are involved in condomless sex, it is important to test for coinfections with other STIs.

Although since the beginning of the MPX outbreak in May 2022, several webcasts and newsletters were delivered to all physicians, misdiagnoses continued to occur in the later phase of the outbreak.

Our study has several limitations. Mainly, a small sample size limited our ability to identify factors significantly associated with misdiagnosis. Another limitation is a lack of a control group of patients with a timely diagnosis. Although at the same time about 257 patients were diagnosed with MPX in Israel we do not know the rate of overlooked diagnosis in all populations and our patients may not reflect the entire population of patients with MPX in the country.

In conclusion, MPX might still be commonly misdiagnosed, especially among patients presenting with fever and sore throat as sole manifestations, most probably because of a lack of expertise regarding MPX. Continuously raising awareness for this disease and its varied range of symptoms and signs is essential for making early diagnoses and limiting transmission. Since other STIs may commonly co-exist they should also be tested.

CRediT authorship contribution statement

Anat Wieder-Feinsod: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. Tal Zilberman: Data curation. Oran Erster: Data curation, Methodology. Gal Wagner Kolasko: Data curation. Asaf Biber: Data curation. Ruth Gophen: Data curation. Tomer Hoffman: Conceptualization, Data curation, Writing – review & editing. Vladislav Litchevsky: Data curation. Liraz Olmer: Methodology. Dafna Yahav: Formal analysis, Methodology, Writing – original draft, Writing – review & editing. Itzchak Levy: Project administration, Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing.