Kone-Paut I, Tellier S, Belot A, et al. Phase II open label study of Anakinra in Intravenous Immunoglobulin-Resistant Kawasaki Disease. Arthritis Rheumatol Jan. 2021;73(1):151–61. https://doi.org/10.1002/art.41481.

In addition, viral proteins and inflammatory cytokines induce neutrophil activation, leading to ROS secretion and the formation of neutrophil extracellular traps (NETs) ( 24, 25). HMGB1, which is triggered by ROS, may also play a role in NET activation ( 26). Increased concentration of NETs has been observed in plasma, tracheal aspirate, and lung specimens of autopsies from COVID-19 patients ( 27). NETs further promote and sustain the local inflammation. A high concentration of NETs positively correlates with sepsis severity and organ dysfunction, and they have been shown to contribute to immunothrombosis in the course of inflammatory response ( 27– 30). These early events that involve interaction between SARS-CoV-2 with host cells including, innate immune cells play an important role in inducing endothelial damage, acute lung injury, disruption of lung structure associated with pulmonary edema and pneumonia, multi-organ damage and death in COVID-19 disease. Adaptive Immunity NT-proBNP, N-terminal pro-brain natriuretic peptide; PT, prothrombin; PTT, partial thromboplastin time; KD, Kawasaki disease; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL, interleukin; LDH, lactate dehydrogenase; RT-PCR, reverse transcription-polymerase chain reaction.

Long-Term Sequelae of Mild-Moderate vs. Severe COVID-19

The hallmarks of neuropathic pain are chronic allodynia and hyperalgesia. Allodynia is defined as pain resulting from a stimulus that ordinarily does not elicit a painful response (e.g. light touch). Hyperalgesia is defined as an increased sensitivity to normally painful stimuli. and peroxide (H 2O 2) that, in turn, cause changes in membrane lipids, nucleic acids and other cellular structures ( 48). For this reason, this pathway NF-κB could be a key element to understand the role of OS in severe cases of COVID-19 through increasing the inflammatory process ( 49). Likewise, it is known that during SARS-Cov-2 infection, local and systemic inflammation is generated mediated by pro-inflammatory cytokines, mainly by IL-1, a cytokine with a wide spectrum of biological activities: activation of adhesion molecules, endothelial dysfunction, stimulation in the secretion of TNF and IL-6, as well as an increase in nitric oxide and the release of prostaglandins and thromboxane A2 ( 50), the latter highly related to the development of OS and endothelial damage. On the other hand, it has been proposed that the suppression of the IL-1 and IL-6 response could have therapeutic effects in the management of patients with COVID-19, through an approach directed at IL-37 and IL-38 ( 51). Cole LD, Osborne CM, Silveira LJ, et al. IVIG compared to IVIG Plus Infliximab in Multisystem Inflammatory Syndrome in Children. Pediatr Sep. 2021;21. https://doi.org/10.1542/peds.2021-052702. Laboratory evidence of inflammation: an elevated CRP, ESR, fibrinogen, procalcitonin, D-dimer, ferritin, LDH, or IL-6, elevated neutrophils, reduced lymphocytes and low albumin. The management of MIS-C was based on the severity of illness. Therapy typically incorporated IVIG and varying doses of methylprednisolone depending on disease severity. Those with mild disease received 2 mg/kg/day methylprednisolone for 3–5 days, those with moderate disease received 10 mg/kg/day for 1–3 days, while those with severe disease received 20–30 mg/kg/day for 1–3 days (Table 1). In the moderate and severe groups, this was followed by an oral steroid tapering regimen.

Soon after the trigger of the innate immune response, antibody-producing B cells, CD4+ T cells and CD8+ T cells of the adaptive immunity are primed to control pathogenic infection. While innate immunity is intrinsically involved in COVID-19 immunopathogenesis, there is limited evidence supporting the pathogenic phenomenon of adaptive immunity. In contrast to massive innate cytokines or chemokines associated with immunopathology, elevated T cells are therapeutic and do not worsen the disease. Seroconversion is shown to occur in more than 90% of COVID-19 patients a few weeks post-infection ( 31). Compared to CD8+ T cells, CD4+ T cells present a greater antiviral effect towards SARS-CoV-2 infection and better control of disease severity ( 32, 33). The primary targets of CD4+ T cells include the highly expressed spike, M and nucleocapsid antigen, with significant specificity for nsp3, nsp4 and ORF8 ( 32). Meanwhile, CD8+ T cells showed a slightly different immunoreactivity, with spike protein, nucleocapsid, M, nsp6, ORF8 and ORF3a being the target antigens ( 32). Regarding echocardiogram findings at hospital admission (Table 3), 29% of both cohorts had left ventricular dysfunction. The median LVSF was the same in both groups, at 32%. Five patients (16%) in the anakinra group had coronary artery dilation, which was not different when compared to zero of those without anakinra.Anakinra was used either as a primary or additional therapy during hospitalization. Initial therapy was defined as administration of IVIG or first dose of steroids. Additional therapy was defined as administration of an immunomodulatory agent more than 24 h after treatment initiation of either IVIG and/or steroids (first dose). Additional therapies were prescribed for any of the following indications: fever (38.0 °C or greater) occurring more than 24 h after finishing initial therapy, a new onset fever after 24 h period of initial improvement following the administration of intravenous immunoglobulin (IVIG) or steroids, continued need for vasoactive medications, worsening echocardiogram findings, and/or laboratory evidence of persistently high or worsening markers of inflammation including CRP, D-dimer, and ferritin levels.

The body makes CRP from interleukin-6 (IL-6), a powerful inflammation-causing immune chemical. IL-6 is a key cell communication molecule, and it tells the body's immune system to go into a full rage, releasing CRP and many other inflammation-causing substances. Histopathological changes of the human brain, including cerebral micro thrombosis and acute cerebral infarcts, mediated by neuroinflammation and immunoreactivity, have been reported in post-mortem autopsies ( 80). Using SARS-CoV-2-infected human brain organoid, SARS-CoV-2 is seen to exploit host cell metabolic machinery for its replication, promoting a hypermetabolic and hypoxic environment, resulting in neuronal death in infected and adjacent cells ( 94). The study further demonstrated significant disturbance of brain vasculature in mice models, which may explain the association between hypoxia and micro-ischemic damage found in human organoid and post-mortem brain autopsies ( 94). Feldstein LR, Tenforde MW, Friedman KG, et al. Characteristics and outcomes of US children and adolescents with Multisystem Inflammatory Syndrome in Children (MIS-C) compared with severe Acute COVID-19. JAMA Mar. 2021;16(11):1074–87. https://doi.org/10.1001/jama.2021.2091.Intravenous immunoglobulin (IVIG), a solution of antibodies, and aspirin are the 2 main medicines used to treat Kawasaki disease. In the propensity score matched groups, the median time from presentation to first IVIG administration was 14.1 h in the anakinra group vs. 17.6 h in the no anakinra group with no difference. The median time to steroids was 12.9 h in the anakinra group vs. 15.8 h in the no anakinra group with no difference. The median duration of steroid use was 5 days in the anakinra group vs. 4 days in the no anakinra group with no difference. The median time from presentation to first anakinra administration in the anakinra group was 26.1 h. The median duration of anakinra use was 5 days. Outcomes of matched cohort We included children admitted from May 2020 to May 2021 diagnosed with MIS-C based on CDC criteria. The exposure of interest was anakinra use at any point during admission. The anakinra exposed group and the anakinra unexposed group were propensity score matched based on demographic and clinical severity indicators at initial presentation. Our primary outcome was length of hospital stay. Secondary outcomes were duration of vasoactive support, vasoactive inotropic score (VIS), level of respiratory support, time to fever resolution, reduction of CRP levels, and length of ICU stay. We used Wilcoxon rank sum, t-test, Chi square and Fisher’s exact tests. Results

Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a Pediatric Inflammatory Multisystem Syndrome temporally Associated with SARS-CoV-2. JAMA Jul. 2020;21(3):259–69. https://doi.org/10.1001/jama.2020.10369. There was no statistically significant difference between the matched groups relative to baseline variables not used in the propensity score. There was also no difference in age, gender, or co-existing conditions between the two matched groups. The median temperature on admission was 39.0 °C in the anakinra group, 38.9 °C in the no anakinra group. Moreover, no differences were observed in the initial laboratory tests including CRP, D-dimer, ALT, ferritin, and creatinine between the two matched groups. Microscopic polyangiitis is usually treated with steroid medicine or other medicines that reduce the activity of the immune system. Temporal arteritis, also known as giant cell arteritis, is a type of vasculitis where the arteries at the side of the head (the temples) become inflamed.

Henoch-Schönlein purpura

In our matched cohort, the anakinra group had a longer median length of hospital stay. Additionally, anakinra was not associated with improvement in vasoactive medication duration, time to fever resolution, organ support and ICU length of stay. The absence of statistically or clinically meaningful improved outcomes in the matched cohort suggests that anakinra, when given in addition to IVIG and steroids, does not improve patient outcomes in MIS-C. Since 93% of all patients received IVIG and 99% received steroids, the possibility of a confounding effect from those immunomodulators is minimized. However, with its relatively low risk profile, anakinra may still be beneficial in managing severe disease states. As demonstrated above, the progressive nature of COVID-19 is characterized by its hyperinflammatory effect. The pediatric population has mostly been left unscathed with only mild to moderate disease trajectory ( 115). Recently, however, a rare but critical complication of COVID-19 known as the multisystem inflammatory disease in children (MIS-C) has been reported in a small subset of children about 2-6 weeks post-SARS-CoV-2 infection ( 115). Presentations include persistent fever for at least 24 hours and multi-organ impairment involving gastrointestinal, dermatological, neurological, renal, respiratory, cardiac and/or hematological systems ( 115). In comparison to non-MIS COVID-19 patients, MIS-C displayed more pronounced T cell activation and proliferation, particularly the CD8+ T cells, as well as prolonged and altered plasmablast responses ( 116). MIS-C also had marked T cell lymphopenia compared to its other COVID-19 pediatric counterpart ( 116). Buerger's disease affects blood vessels in the legs and arms, leading to reduced blood flow to the hands and feet. It's closely linked to smoking.