Discussion
MIS-C was described at the end of April 2020 as a hyperinflammatory syndrome like-KD, since then thousands of cases have been described in various centers around the world (2, 3).
In adults, COVID-19 acute infection can present as a severe form known as cytokine storm syndrome (CS), with alveolar macrophage activation with release of TNF-α, IL-1β, IL-6, with systemic inflammatory response and multiorgan dysfunction (4). ). In a postmortem study of severe COVID-19 in adults, three of the four cases had histologic evidence of hemophagocytosis in pulmonary lymph nodes, one case had hemophagocytosis in the spleen, but none had hemophagocytosis in the liver or bone marrow (5).
In an autopsy retrospective single-center study, patients who tested positive for COVID-19; hemophagocytosis, ranging from rare to many scattered cells, was identified histologically on H&E and/or CD68 immunohistochemical stains in all of 19 study patients (6). In contrast, Wood et al. and Lorenz et al. reported that secondary HLH is rare in severe adult COVID-19 patients (7, 8). Splenomegaly, a frequent feature of HLH, is rare in CS COVID-19 patients; in fact, autopsies show a reduction of spleen volume and white pulp, lymphocyte apoptosis and splenic thrombosis without evidence of hemophagocytosis (4).
MAS, a term used interchangeably with sHLH, is a potentially fatal complication of infectious and rheumatological diseases including Kawasaki disease (KD). MAS occurs in 1.9-4.7% of KD patients (10).
A validated risk calculator known as the HScore is used to identify those patients with a high probability of a diagnosis of MAS and guide immunosuppressive therapy (11). The HScore carries a diagnostic sensitivity of 90%, and specificity of 79% for HLH. This score have proved to be valuable for the diagnosis of MAS in systemic juvenile idiopathic arthritis patients (12). Mirroring KD, we believe that our two patients with high HScore and the transient nature of the disease presented MAS as a complication of MIS-C. HScore has been explored in severe COVID-19 in adults and has been limited value in guiding immunomodulatory therapy (13).
Our two patients presented a HScore compatible with MAS, with eatures not usually described in MIS-C including hypofibrinogenemia, splenomegaly and bone marrow hemophagocytosis .
Lee et al. performed a retrospective study of patients with MIS-C and compared them with historic cohorts of MAS associated with systemic juvenile idiopathic arthritis or infection and found that soluble IL-12, ferritin, IL-18 and CXCL9 elevations were higher in MAS compared to MIS-C, concluding that MIS-C immunological features do not appear to resemble MAS (14).
The optimal treatment for MAS has not been defined. In our first case, a combined treatment with IVIG, cyclosporin-A, corticosteroids and tocilizumab led to resolution of the disease. Cyclosporin-A has been used in refractory KD and is an integral part of HLH treatment (9, 10, 15). The second case proved to be more aggressive and the decision to give etoposide was made. Interestingly, etoposide was recently used successfully in a 66-year-old patient with CS in COVID-19 resistant to multiple anti-cytokine therapy (16).
MIS-C has been considered part of the KD spectrum, paralleling features of KD such as the presence of coronary aneurysms, the development of shock, and as in our cases the development of MAS as a life-threatening complication (17). MIS-C can be complicated with MAS, disease awareness is essential; with splenomegaly, hypofibrinogenemia, hypertriglyceridemia and bone marrow hemophagocytosis as key features to suspect this complication. CSS and MAS in MIS-C may represent a spectrum of the disease. HScore could be of value in order to provide timely and aggressive treatment.
Acknowledgments
The authors thank Dr. Alberto Unzueta for editing and helpful discussions regarding this manuscript.