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.