There have been some case reports of high fever and rhabdomyolysis associated with COVID-19 [3, 4], however, the exact relations of these clinical conditions in patients with COVID-19 are still unknown. In our case, we diagnosed malignant hyperthermia with rhabdomyolysis, and the patient was given dantrolene. After the administration of dantrolene, his fever and serum CK and myoglobin levels were reduced to the normal range.
Malignant hyperthermia is triggered by various stimulations, such as anesthetic agents, heat stroke [5] and viral infections [6]. A possible mechanism of malignant hyperthermia is a hypersensitivity of calcium release from the sarcoplasmic reticulum. These include mutations in [7] or the activation [8] of the skeletal muscle ryanodine receptor calcium release channel. In the presence of mutations in or the activation of the ryanodine receptor, skeletal muscle cells can release proinflammatory cytokines, such as IL-6, and exhibit excessive muscle contraction, which might lead to rhabdomyolysis with heat production, resulting in high fever and serum CK and myoglobin levels in the clinic, as in previous reports [6-8].
Dantrolene is essential to achieve the best possible outcome for patients with malignant hyperthermia and neuroleptic malignant syndrome, and these effects of dantrolene have also been demonstrated to reduce CK levels and high body temperature immediately in previous reports [6, 9]. Indeed, dantrolene is a ryanodine receptor antagonist and is used as an anti-inflammatory agent [10]. The effectiveness of dantrolene acts on a Ca-releasing channel from the sarcoplasmic reticulum in skeletal muscle fibers, inhibits Ca release, and blocks interleukin (IL)-6, which is known as endogenous pyrogen release [8]. The proinflammatory cytokines IL-1β, IL-6 and IL-18 are inflammatory markers that are responsible for high fever and elevated plasma levels of CRP and ferritin in the clinic [11]. In particular, IL-6 can also be used as a marker to predict SARS-CoV-2 disease deterioration [12]. Previous studies demonstrated that dantrolene could prevent the activation of the ryanodine receptor and block IL-6 release [8]. In our patient, a decrease in CK and myoglobin levels was observed after the use of dantrolene, with prompt alleviation of high fever. Interestingly, decreased plasma levels of CRP and ferritin were found at the same time. In a recent report, it was suggested that hyperpyrexia may be caused by a SARS-CoV-2-related exuberant immune response. Therefore, hyperpyrexia with aggravated and excess immune responses becomes a predictor of worse outcomes in COVID-19 patients [13]. Therefore, it is suggested that the anti-inflammatory effects of dantrolene might contribute to resolving rhabdomyolysis and high fever in patients with COVID-19.
Case reports of patients diagnosed with SARS-CoV-2 infection presenting with rhabdomyolysis are rare [3, 4]. There have been several possible hypotheses explaining the pathogenesis of viral-induced rhabdomyolysis: direct viral invasion can lead to rhabdomyolysis, a robust immune response to viruses results in cytokine storms and damages muscle tissues, and circulating viral toxins may directly destroy muscle cell membranes [4, 14]. In a previous case report, two case reports of patients with simple pneumonia [3, 4] showed that an increase in CK following hospitalization was thought to be caused by myositis due to direct viral invasion and/or muscle twitching with shivering. Our patient presented high fever, hyperferritinemia, and elevated plasma levels of CRP, and rhabdomyolysis was observed with higher plasma CK levels. These clinical data improved to their normal ranges after the administration of dantrolene. Taken together, additional hypotheses could be considered as rhabdomyolysis-induced skeletal muscle ryanodine receptor mutations or activation. However, whether COVID-19 itself could be a direct trigger for mutation in or the activation of the skeletal muscle ryanodine receptor and whether our patient has an inherited malignant hyperthermia susceptibility trait or a potential predisposition remain unclear.
In summary, rhabdomyolysis with high fever is a complication that is rarely found in COVID-19. The administration of dantrolene showed potential efficacy for rhabdomyolysis, high body temperature due to inflammation, and increased inflammatory markers. The underlying mechanisms might be a similar pathogenesis in malignant hyperthermia.