HPeV-3 is thought to circulate among infants in nursery schools, as well as in households. However, most related cases of myalgia occur in adults and are thought to have been transmitted from young children [12]. In previous reports, most adult patients with epidemic myalgia due to HPeV-3 infection are aged between 20 to 40 years [3,4,5,6]. While the overall seropositivity rate (cut-off value of greater than 8×) for HPeV-3 was 79.4% in residents of Yamagata prefecture (next to Fukushima prefecture, where the case patient lived), the necessary antibody titer for preventing HPeV-3 infection (neutralizing [NT] antibody titer equal to or higher than 32×) decreases in adults as they age [13]. This might suggest that adults who do not have sufficient titers of NT antibodies may develop HPeV-3 infection after occasional contact with infected children, and a few individuals may have further complication, such as with epidemic myalgia.
Previously, Mizuta et al. reported 22 cases involving epidemic myalgia in adults (average age: 37 years [range: 23–66 years]) [3]. All but one patient had muscular weakness, and 18 of 22 (82%) presented with high fever. In those cases, severe myalgia mainly occurred in the proximal upper and/or lower limbs, and laterality was generally not recognized. Furthermore, Mizuta et al. reported elevated CRP levels in 86% of patients, although the values were relatively low (average: 1.95 [0.1–6.8] mg/dL). Elevated CK and myoglobin levels occurred in 55% (average: 443 [43–1598] mg/dL) and 73% (average: 101 [18–253] mg/dL) of patients, respectively, indicating that CK and myoglobin are not always elevated in patients with epidemic myalgia, regardless of severity. Other symptoms reported by Mizuta and colleagues included pharyngeal pain and orchiodynia, a specific symptom of epidemic myalgia with an unknown mechanism that was reported by 27% of male patients, as well as by our patient. In another report, Tanaka et al. used computed tomography to detect swollen testis and peritesticular effusion in a patient [4]. Yamakawa and Mizuta et al. also reported 17 confirmed epidemic myalgia adult cases (average patient age: 36.8 years [range: 21–50 years], 14 males and 3 females) in 2017 [7]. All patients had myalgia and muscular weakness; 14 patients (82%) presented with high fever, 8 patients (47%) exhibited upper respiratory symptoms, and 4 (24%) had gastroenteritis. Scrotal pain occurred in 4 of 14 male patients (29%). In these cases, all but one showed an elevated level of CK (average value: 1017 [61–6155] IU/L, normal value; 55–175 IU/L). Mild leukocytopenia occurred in 7 of 17 patients (average value: 4391 [2730–5610] cells/mm3, normal value; 3900–9000 cells/mm3). Increases in CRP value were mild (average value: 0.771 [0.21–5.138] mg/dL, normal value; 0.000–0.300 mg/dL) [6]. Interestingly, the levels of CK and CRP did not increase proportionally in these patients. The CRP level of the patient who had the highest CK level (6155 IU/L, patient number 5) was 0.342 mg/dL. On the other hand, the CK level of the patient who had the highest CRP value (5.138 mg/dL, patient number 14) was only slightly elevated (248 IU/L) [7]. In our case, despite the severe myalgia of the patient, which prevented him from laying down on the bed throughout the night, his CK level was normal and his CRP elevation was relatively low. There is the possibility that we did not detect CK elevation of the case patient due to the time points of our blood tests (initial visit, 2 days later, and 2 weeks later). However, systemic myositis including all extremities and trunk muscles is usually accompanied by a remarkable elevation of CK; additional mechanisms inducing systemic myalgia after HPeV-3 infection other than myositis are suggested in this patient.
In addition, many issues regarding epidemic myalgia due to HPeV-3 remain unclear. First, we have not yet determined why adult epidemic myalgia due to HPeV-3 has only been reported in Japan, despite the passage of several years since the first report. We might attribute this phenomenon to a racial variation, difference in the clinical testing system, or recognizability of this disease amongst general physicians (i.e., not pediatricians). Second, it remains unknown why only HPeV-3 causes severe epidemic myalgia in adults, as similar cases attributed to HPeV-1 or HPeV-2 have not yet been reported.
Compared to HPeV-3, influenza virus and enterovirus more commonly cause myalgia and myositis. Epidemic pleurodynia (also known as Bornholm disease) is generally caused by coxsackievirus type B, and less frequently by echovirus and coxsackievirus type A. This disease is characterized by fever and paroxysmal spasms of the chest and abdominal muscles. Most cases occur during localized summer outbreaks amongst adolescents and adults [14, 15]. In addition, severe rhabdomyolysis and renal failure can be induced by various viruses, including influenza viruses A and B [16]. In this case, however, the time frame in which our patient visited our institution was not in the local endemic influenza season (typically from late November to next March), and the antigen-based rapid influenza test result was negative. Serological assays for the tested coxsackievirus type A and B, or echovirus between the acute and convalescent phases did not indicate the acute infection.
Because the epidemiological evidence indicates that not all adults infected with HPeV-3 develop epidemic myalgia, we hypothesized that severe myalgia may be associated with an increase in cytokine production. As such, we measured the cytokine levels in serum samples from our patient at the initial visit and 2 weeks later. Among the cytokines measured, IL-6 level was exclusively elevated. IL-6 is a known inflammatory cytokine that causes pain by inducing prostaglandin E2 production. When administered to humans, IL-6 can cause side effects including fever, headache, and myalgia [17]. IL-6 has been correlated with the development of symptoms including myalgia caused by influenza virus infection [18]. In recent research, coxsackievirus type B4 was found to induce production of IL-6 together with interferon-α and TNF-α from human mononuclear cells [19]. Considering these reports and the current case, elevated levels of acute inflammatory cytokines may play a role in myalgia or myositis caused by viral infections. Although further studies are required to elucidate the pathogenesis of severe epidemic myalgia after HPeV-3 infection, the elevated level of IL-6 in the case patient’s serum may correlate with the development of this disease.
This is the first report to demonstrate increased IL-6 levels in an adult patient with epidemic myalgia due to HPeV-3 infection. Further virologic, genetic, epidemiologic, and pathologic studies are needed to verify our hypothesis regarding the relationship between elevated IL-6 levels and myalgia severity in adult patients with HPeV-3 infection.
