The hyper- inflammatory syndrome because of severe cytokine release occur about 3–6 weeks after SARS-COV2 infection or closed contact with COVID-19. The antibodies against SARS-COV2 were more important than PCR in this study like the other articles. These antibodies probably display the function of acquired immune system against auto-antigens and lead to activation of the other immune cells; such as T-cell, macrophages, neutrophils and ultimately result in cytokine storm with multiple organs involvement.14
In this study, the mean age (5.94 ± 3) was lower than the other studies and the male to female ratio was nearly similar to other studies. The differences were due to selection of patients with one to two positive laboratory data and at least two organs involvement and echocardiography- and sonography-positive data.15, 16
Multisystem inflammatory syndrome in children (MISC) and Kawasaki-like syndrome both illustrate the hyper- inflammatory syndrome. Some articles emphasize that MISC is a novel disease after COVID − 19 pandemic in children with older age and more gastrointestinal manifestations and myocarditis.17 On the other hand, there are some reports about more Kawasaki-like syndrome, with features of atypical Kawasaki disease and coronary abnormalities, after SARS-COV2.18,19
Furthermore, there are some similarities between MISC and Kawasaki disease. Cytokine storm lead to hyperinflammatory condition with myocarditis in both of them.20 In addition, high level of ferritin can be seen in both MISC and MAS in Kawasaki disease.20, 21 Moreover, autoantibodies in MISC patients have some special target auto-antigens on endothelial cells and myocardial cells leading to small and medium-sized vasculitis similar to KD.22 These auto-antigens were also reported in KD. 23However, the exact pathogenesis of MISC still remains unclear.
The mucocutaneous involvement, conjunctivitis, lymphadenopathy are seen in both MISC and atypical KD. The cardiac manifestations such as coronary and myocardial involvement have the same presentation in MISC and atypical-KD, especially myocarditis in Kawasaki disease shock syndrome (KDSS). The KDSS in acute phase of Kawasaki disease is IVIG-resistant with higher level of inflammatory cytokines such as IL6, TNFα, and IL1 and good response to methylprednisolone pulses.7, 24 Nowsadays, the researchers work on methyl prednisolone pulses instead of IVIG treatment in acute phase of Kawasaki disease. In acute phase of Kawasaki disease, the innate immune system are involved with cytokines released as a hyper-inflammatory process. 25, 26
In this study, the mucocutaneous involvement and cardiac manifestations were the most clinical presentations. The patients were divided in two groups of less or more than 7 years old. The majority of Kawasaki disease are in the age of 2–5 years old with mucocutaneous- lymph node syndrome. The MISC patients are older with more prominent organ involvement; gastrointestinal, myocarditis and shock. The purpose was to separate these two phenomena according to special presentations. However, there were no significantly difference in gastrointestinal and cardiac involvement between two age groups. So, MISC and KD- like disease may be the similar hyper-inflammatory syndromes with wide spectrum of organ involvements.4, 27, 28 These findings may be against assumption of difference between MISC and Kawasaki-like disease based on age ranges and organ involvements.1, 3
In this study, cervical lymphadenopathy was more frequently seen in ≥ 7 years old group. First-Node Kawasaki Disease (FNKD) in an unusual presentation of atypical Kawasaki disease in older ages, similar to this study. 29, 30The FNKD patients have more hyper-inflammatory process with more coronary involvements and IVIG- resistance. In NFKD, the IL6, AST, CRP, ESR are in higher levels in comparison with other atypical Kawasaki disease.29 This study, with evaluation of hyper-inflammatory syndrome after SARS-COV-2, found significant correlation between AST and cervical lymphadenopathy (p-value = 0.02). So, the reticuloendothelial system involvement may be more prominent in these age group.
In this study, the initial treatment was methyl-prednisolone pulse, in contrast with the other articles using IVIG in FNKD. There was no significant correlation between coronary involvements and cervical lymphadenopathy (P-Value = 0.6). Therefore, the cervical lymphadenopathy may predict the IVIG-resistant hyper-inflammatory syndrome with good responses to methylprednisolone pulses. In addition, the earlier use of pulse in our study might decrease the coronary involvement.29, 30
Macrophage activation syndrome (MAS) is a cytokine storm with increased level of ferritin produced by activated macrophages. 5, 31 Secondary HLH like MAS, primary HLH and probably MISC, may initially have different mechanisms in stimulation of inflammatory pathway, nevertheless all of them lead to activated macrophages, neutrophils, histiocytes and the other cells and subsequently elevated ferritin level and ultimately cytokine storm with some organ damages.32In addition, the acute phase of Kawasaki disease is presented with activation of innate immune system as a cytokine storm, especially in KDSS with myocarditis and elevated ferritin level.7, 33
In this study, the correlation between ferritin level and carditis were near-significant. With more sample size, the correlation can be significant. So, Ferritin level may be a valuable predictor of carditis, with effect on decision for aggressive treatment.
In this study, one to three doses of Methylprednisolone pulses were the initial treatment. In some studies, Biologic treatments were used in resistant patients more than this study.10, 17, 34 IVIG and low dose glucocorticoid were the principle treatment in these studies.35, 36, 37 However, one study demonstrated no significant differences between IVIG and glucocorticoid and high dose glucocorticoid alone as first-line treatment.39 In our study, the biologic treatment were prescribed in only two patients and the mortality were zero. However, one patient presented persistent aneurysm in 1–2 weeks following echocardiography.
There were significant differences between inflammatory laboratory data before and after methylprednisolone pulses treatment with rapid decrease within two to three days after methyl prednisolone pulses. On the other hand, the delayed initiation methyl prednisolone pulses were associated by more ICU admission. So, decreasing inflammatory parameter might have an effect on low rate of complications and lower use of Biologic treatments.36, 37, 38
The main limitations of this study were low sample size and retrospective design. Higher sample size and prospective study would be more valuable. Furthermore, the presence of control group will yield more accurate result. Further clinical trials for evaluation of selected treatments should be considered.
In conclusion, although one cause of selection of methylprednisolone pulse as an initial step of treatment were availability, methyl prednisolone pulse may be as effective as IVIG plus low dose methyl prednisolone with good responses and low complications and mortality as a first step of treatment of hyper-inflammatory syndrome after SARS-COV-2 infection in children.
Furthermore, the ferritin level may be one of the predictor of severe hyper-inflammatory syndrome leading to aggressive and urgent treatment with methylprednisolone pulse.