Etiological and pathophysiological enigmas of severe coronavirus disease 2019, multisystem inflammatory syndrome in children, and Kawasaki disease.

During the coronavirus disease 2019 (COVID-19) pandemic, a novel multisystem inflammatory syndrome in children (MIS-C) has been reported worldwide since the first cases were reported in Europe in April 2020. MIS-C is temporally associated with severe acute respiratory syndrome coronavirus 2 infection and shows Kawasaki disease (KD)-like features. The epidemiological and clinical characteristics in COVID-19, KD, and MIS-C differ, but severe cases of each disease share similar clinical and laboratory findings such as a protracted clinical course, multiorgan involvement, and similar activated biomarkers. These findings suggest that a common control system of the host may act against severe disease insult. To solve the enigmas, we proposed the protein-homeostasis-system hypothesis in that every disease involves etiological substances and the host's immune system controls them by their size and biochemical properties. Also, it is proposed that the etiological agents of KD and MIS-C might be certain strains in the microbiota of human species and etiological substances in severe COVID-19, KD, and MIS-C originate from pathogen-infected cells. Since disease severity depends on the amounts of inflammation-inducing substances and corresponding immune activation in the early stage of the disease, an early proper dose of corticosteroids and/or intravenous immunoglobulin (IVIG) may help reduce morbidity and possibly mortality among patients with these diseases. Corticosteroids are low cost and an analogue of host-origin cortisol among immune modulators. This study's findings will help clinicians treating severe COVID-19, KD, and MIS-C, especially in developing countries, where IVIG and biologics supplies are insufficient.

Immunopathogenesis of COVID-19 and early immunomodulators.

The novel coronavirus disease 2019 (COVID-19) is spreading globally. Although its etiologic agent is discovered as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), there are many unsolved issues in COVID-19 and other infectious diseases. The causes of different clinical phenotypes and incubation periods among individuals, species specificity, and cytokine storm with lymphopenia as well as the mechanism of damage to organ cells are unknown. It has been suggested that in viral pneumonia, virus itself is not a direct cause of acute lung injury; rather, aberrant immune reactions of the host to the insults from viral infection are responsible. According to its epidemiological and clinical characteristics, SARS-CoV-2 may be a virus with low virulence in nature that has adapted to the human species. Current immunological concepts have limited ability to explain such unsolved issues, and a presumed immunopathogenesis of COVID-19 is presented under the proteinhomeostasis-system hypothesis. Every disease, including COVID-19, has etiological substances controlled by the host immune system according to size and biochemical properties. Patients with severe pneumonia caused by SARS-CoV-2 show more severe hypercytokinemia with corresponding lymphocytopenia than patients with mild pneumonia; thus, early immunomodulator treatment, including corticosteroids, has been considered. However, current guidelines recommend their use only for patients with advanced pneumonia or acute respiratory distress syndrome. Since the immunopathogenesis of pneumonia may be the same for all patients regardless of age or severity and the critical immune-mediated lung injury may begin in the early stage of the disease, early immunomodulator treatment, including corticosteroids and intravenous immunoglobulin, can help reduce morbidity and possibly mortality rates of older patients with underlying conditions.

The solution on enigmas in COVID-19: the protein-homeostasis-system hypothesis

Infectious diseases, including coronavirus disease 2019 (COVID-19), are representative, of which etiology is known in all human diseases. However, many enigmas persist in relation to COVID-19, including different clinical phenotypes and incubation periods across individuals, species-specificity, appearance of cytokine storm and lymphopenia, and the mechanism of damage to organ cells. Current immunological concepts have limitations to explain these unsolved issues. Meanwhile, results of clinical, pathological, and animal studies have suggested that the virus itself is not a direct cause of acute injury to the lung or other organ cells. For better understanding of COVID-19, a presumed immunopathogenesis of COVID-19 is presented under the protein-homeostasis-system hypothesis;every disease, including COVID-19, has associated etiological substances, and the host immune system controls these diverse substances according to the size and biochemical property. These etiological substances, inducing inflammation and subsequent tissue injury, are smaller substances derived from virus-infected cells. Initially acting nonspecific adaptive immune reaction with cytokine imbalance may be responsible for target cell injury. Furthermore, substances from initial target cell injury and secondary bacterial invasion can induce further inflammation if released from local or systemic circulation. COVID-19 patients with pneumonia show hypercytokinemia with lymphocytopenia corresponding to the severity of pneumonia at early stages. Thus, early immune-modulator treatment, including corticosteroids and intravenous immunoglobulin, has an immunological rationale. It could help reduce the morbidity and possibly mortality of older patients with underlying conditions.