Figure 1

Figure 1. Sites of monkeypox lesions in observational cohort study of evolving epidemiologic, clinical, and virological features of monkeypox in southern France, 2022. A) Primary inoculation site showing an irregular pustule with...

We enrolled a total of 136 patients who had a laboratory-confirmed monkeypox diagnosis; 133 were men, and 3 were women. We collected demographic (Table 1), clinical (Table 2), and microbiological (Table 3) information for the patients. We determined 125 (92%) patients were MSM and 5 (4%) patients were heterosexual. Information on sexual orientation was not available for the remaining 6 patients. The median age was 36.0 (IQR 30.0–42.0) years. Of the 136 enrolled patients, 15 (11%) reported previous smallpox vaccination, and 21 (16%) were HIV-positive, of whom 5 (24%) had a CD4 cell count of <500 cells/mm³. Among 3 heterosexual women, only 1 declared that her regular sexual partner had a monkeypox diagnosis, and the other 2 reported a new sexual partner within the previous 3 weeks. Travel to MPXV-endemic regions was not reported by any patient, whereas 17 (12.5%) reported recent travel to a country that is part of the current outbreak, which includes Spain (n = 11 patients), United States (n = 2 patients), Germany (n = 1 patient), Belgium (n = 1 patient), Canada (n = 1 patient), and Italy (n = 1 patient). Seven (5.2%) patients had attended a Pride event in the previous 21 days in Spain (n = 2) and France (n = 5). The most frequent lesions were located in the genital (68 [53%] patients), perianal (65 [49%] patients), and oral/perioral (22 [17%] patients) areas (Figure 1). The number of skin lesions was <10 in 98 (73%) patients. An asynchronous rash was observed in 41 (30%) of 129 symptomatic patients. Localized lymphadenopathy in lesion areas was observed in 47 (36.4%) patients. Systemic manifestations before or when the patient was first seen included fever (72 [56%] patients), influenza-like illness (44 [35%] patients), and sore throat (11 [8.5%] patients), which preceded the rash in 90 (70%) patients.

A concomitant diagnosis of another STI occurred for 19 (15%) patients, including 2 patients who had a new diagnosis of HIV-1 infection. Of 63 patients with perianal lesions, 55 (87.3%) reported practicing receptive anal sex, and 12 (19%) had concomitant N. gonorrhoeae (n = 9), C. trachomatis (n = 2), or M. genitalium (n = 1) infections diagnosed from a rectal swab sample. Of 23 patients with oral ulcers or peri-oral lesions, 6 (26%) had concomitant N. gonorrhoeae (n = 4), C. trachomatis (n = 1), or T. vaginalis (n = 1) infections, and 20 (87%) reported practicing oral-receptive sex. Concomitant syphilis was diagnosed in 1 patient from a genital swab sample, and 3 patients had serologic results indicating active syphilis infections.

We observed complications in 37 (27%) patients, which included proctitis (n = 30), tonsillitis (n = 5), penile edema (n = 5), skin abscesses (n = 5), and exanthem (n = 3). Hospital admission was required for 6 (4.5%) patients, some of whom had multiple issues; 5 required perianal pain relief, 3 required management of bacterial abscesses, 1 had dysphagia because of oral lesions, and 1 was admitted for social reasons. All 6 patients had favorable outcomes. None of the patients received antiviral treatment. Opioid prescription for perianal pain relief was required for 3 hospitalized patients and 2 outpatients.

Figure 2

Figure 2. Comparison of monkeypox virus loads between different clinical sampling sites in an observational cohort study of evolving epidemiologic, clinical, and virological features of monkeypox in southern France, 2022. Each colored...

We determined the PCR Ct values were lower for skin, genital, and rectal swabs (combined mean) than for pharyngeal specimens (mean Ct ± SD 27.4 ±4.9 vs. 32.2 ±3.4; p<0.0001) (Figure 2). Of 129 symptomatic patients, 15 (12%) had samples taken from 4 sites (pharynx, rectum, skin lesion, genital lesion), 73 (57%) had samples taken from 3 sites, 43 (33%) had samples taken from 2 sites, and 5 (4%) had samples taken from only 1 site (4 skin swabs, 1 genital swab). We observed 92 (68%) patients with isolated anal, genital, skin, or oral lesions when they were first seen, including 56 (61%) patients who had >1 other PCR-positive site without visible lesions. Some PCR-positive samples did not come from visible lesions at the time of testing (40/50 oropharyngeal, 4/67 genital, and 5/68 rectal samples). PCR Ct values from the lesions were not significantly different from those for sites that had no visible lesions (data not shown). The combination of genital and rectal swab testing led to the diagnosis of 111 (86%) MPX cases.

We determined that 7 (5%) patients were asymptomatic; 1 had an MPXV-positive pharyngeal sample and 6 had MPXV-positive rectal samples. We showed that the PCR Ct values obtained from rectal swabs were not significantly different between asymptomatic patients (n = 6) and symptomatic patients (n = 62) (Appendix Figure 3). None of the asymptomatic patients had been previously vaccinated against smallpox virus. We did not find differences in clinical features and MPXV loads between clinical samples from patients who reported receiving smallpox vaccination and those who did not receive vaccination (data not shown) or between patients who reported being HIV-positive and those who did not (Appendix Figure 4).

We report epidemiologic, clinical, and virologic data from 136 patients who had confirmed monkeypox at the outpatient unit of the University Hospital Institute Méditerranée Infection in Marseille, France, during June 4–August 31, 2022. We observed systemic manifestations in approximately two thirds of these patients. Lymphadenopathy often occurred in lesion areas, which differs from that reported for endemic monkeypox in countries of Africa. We observed that the evolution of rashes in our study was also atypical because rashes did not always occur with monomorphic and synchronous vesicular umbilicated lesions (3). Similar to recent studies, the cases in our study occurred almost exclusively within the MSM community (2,7–10). However, the percentage of MSM in this study (92%) was lower compared with a previous multicountry report (98%) (2). Of note, both male patients in our study who identified as heterosexual had perianal lesions, which raises the question of reporting bias. We also found that most patients had a low number of lesions (<10) located in the genital, anal, and oral regions. Most patients had previous sexual exposure to a person known to have monkeypox or had high risk for sexually transmitted diseases, such as having single or multiple new sexual partners within 21 days before their monkeypox diagnosis or attendance at a Pride event. Similar to results from 3 other large cohorts of patients with monkeypox (2,8,9), we found a high rate (15%) of concurrent STI diagnoses, including 2 patients with a new diagnosis of HIV-1 infection. These findings suggest that the sexual route was the main transmission method for amplification of the monkeypox outbreak. For example, 3 large MSM gatherings have been implicated as monkeypox amplifying and superspreading events in Antwerp, Belgium, and in Madrid and the Canary Islands, Spain (14). Although we did not collect this specific information, some patients in our study likely participated in these events. Furthermore, we found that MPXV PCR Ct values in skin, genital, and rectal swab samples were substantially lower than in pharyngeal swab samples. In contrast to a previous report (15), we found that MPXV PCR Ct values in genital and rectal swab samples were not significantly lower than those in skin swab samples. These differences might be explained in part by sampling bias; a single site swab might be insufficient for microbiological confirmation of monkeypox. Among clinical samples and independently of the lesion site, we found that genital swab specimens had the highest MPXV positivity rate (97%), followed by skin swab specimens (82%). Rectal swab specimens had a positivity rate of 65% and also contributed to a monkeypox diagnosis. In contrast, the MPXV positivity rate of pharyngeal swab samples was relatively low (43%). Genital and rectal swab specimens together had a remarkably high sensitivity (86%) in this patient cohort, which is noteworthy because these specimens are routinely collected in STI clinics. We also found that some positive samples did not come from areas with visible lesions at the time of testing. Testing specimens from multiple sites on persons with exposure history could, therefore, be relevant depending on the symptoms and potential risks the person had during close contact.

We observed that 15 patients had acquired monkeypox despite having been vaccinated against smallpox during childhood or having received a preexposure or postexposure vaccine. The median period between postexposure vaccination (first dose), and the onset of symptoms was 15 (IQR 8.6–22.4) days. Symptoms occurred at 33 and 35 days in 2 patients after first dose preexposure vaccination. These results warrant further investigation to determine the extent of protection provided by vaccination and highlight the insufficient protection provided by the first dose of vaccine. In addition, 15% of patients were HIV-positive, including 5 patients with CD4 cell counts of <500 cells/mm³. Clinical features and MPXV loads did not differ between persons who were HIV-positive and HIV-negative. None of the patients in our study had a CD4 cell count of <200 cells/mm³; therefore, we cannot extrapolate our results to immunocompromised patients. Although >25% of patients had complications that required supportive care and antimicrobial drugs for bacterial skin abscesses, we observed a benign course of disease that did not require antiviral therapy. Of note, hospitalized patients did not have conditions that were considered risk factors for a severe form of monkeypox, such as being immunocompromised, a child, or a pregnant or breastfeeding woman. However, to our knowledge, an evaluation of risk factors for severe outcomes during the current outbreak has not been performed. In a recent report on a cohort of 264 monkeypox cases (7), 6% of patients were hospitalized exclusively for the management of severe local complications at the site of the rash and for pain relief. All patients were men who were not immunosuppressed. Compassionate use of tecovirimat for the treatment of monkeypox infection has been proposed in some centers (16) but requires further evaluation and rational use considering the generally benign course of disease in the current outbreak.

In our study, 7 patients with laboratory-confirmed monkeypox were asymptomatic. In contrast, most large cohort studies during the outbreak have included only symptomatic patients who were positive for MPXV (2,7–9). We tested asymptomatic MSM attending our institute only when they reported recent high-risk exposure, and we likely underestimated the incidence of asymptomatic patients who had laboratory-confirmed monkeypox because this was not part of a systematic screening process. Positive MPXV quantitative PCR results have been identified from anal samples in 13/323 (4%) asymptomatic MSM by assessing the presence of MPXV in anorectal samples from asymptomatic MSM who were routinely tested for STIs (17). Moreover, MPXV was identified by PCR in anorectal samples from 3 asymptomatic men in another study; MPXV was cultured from 2 of these samples, indicating viral shedding that could lead to transmission (18). These findings suggest that testing and quarantine for only symptomatic persons might be insufficient to contain the current outbreak.

In conclusion, the ongoing human monkeypox outbreak features unusual characteristics, such as the predominant involvement of MSM who have isolated anal, genital, or oral lesions. The high proportion of concomitant STIs showed transmissibility of monkeypox occurred through local inoculations during sexual activity. Testing specimens from multiple sites in persons with relevant exposure history could be relevant, regardless of the presence of visible lesions. Furthermore, asymptomatic carriage of MPXV suggests that some monkeypox cases might remain undiagnosed, and testing and quarantine of only symptomatic patients might be insufficient to contain transmission. Undiagnosed infections might play a role in overall disease transmission during the outbreak among MSM who have a dense sexual network that includes anonymous contacts, which hampers efficient contact tracing. Physicians should be aware that monkeypox symptoms might overlap with those of other STIs, more specifically in MSM with at-risk sexual activity. Prevention, including vaccination campaigns targeting at-risk groups, are ongoing in multiple countries and should be expanded. Intensified testing for all STIs at different sites (pharynx, rectum, genital, and skin) and in urine and increased contact tracing might also be helpful to control the outbreak.