Timely Resolution of SARS-CoV-2-Related Multi-System Inflammatory Syndrome in Children.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe, postinfectious manifestation of coronavirus disease 2019 (COVID-19) in the pediatric population. The disease is manifested by hyperinflammation and can result in cardiac dysfunction, coronary changes, and end-organ damage. Adequate timely treatment can prevent poor outcomes in the short term, but long-term data is lacking. Methods: A large single center MIS-C cohort was followed longitudinally after treatment with intravenous immunoglobulin (IVIG) ± glucocorticoids to determine the natural history of the disease and to describe improvement in laboratory markers and cardiac outcomes. Patient were stratified by disease severity and compared. Results: 137 patients were identified with demographics similar to previously described cohorts. Regardless of disease severity, when adequately treated, initial lab abnormalities rapidly improved by the 6-8 month follow-up period, with some resolved in as little as 1-2 weeks. Similarly, cardiac abnormalities improved quickly after treatment; all abnormalities resolved in this cohort by 1-2 months post-hospitalization. Conclusions: Although MIS-C is a serious sequela of COVID-19, when identified quickly and treated aggressively, laboratory abnormalities, coronary dilatation, and systolic dysfunction rapidly improve with minimal long-term morbidity or mortality.

Cytokine Storm Syndrome.

Cytokine storm syndrome (CSS), which is frequently fatal, has garnered increased attention with the ongoing coronavirus pandemic. A variety of hyperinflammatory conditions associated with multiorgan system failure can be lumped under the CSS umbrella, including familial hemophagocytic lymphohistiocytosis (HLH) and secondary HLH associated with infections, hematologic malignancies, and autoimmune and autoinflammatory disorders, in which case CSS is termed macrophage activation syndrome (MAS). Various classification and diagnostic CSS criteria exist and include clinical, laboratory, pathologic, and genetic features. Familial HLH results from cytolytic homozygous genetic defects in the perforin pathway employed by cytotoxic CD8 T lymphocytes and natural killer (NK) cells. Similarly, NK cell dysfunction is often present in secondary HLH and MAS, and heterozygous mutations in familial HLH genes are frequently present. Targeting overly active lymphocytes and macrophages with etoposide and glucocorticoids is the standard for treating HLH; however, more targeted and safer anticytokine (e.g., anti-interleukin-1, -6) approaches are gaining traction as effective alternatives. Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Biologic disease-modifying antirheumatic drugs to treat multisystem inflammatory syndrome in children.

PURPOSE OF REVIEW: Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primarily affecting children. MIS-C shares features with Kawasaki disease (KD) and cytokine storm syndrome (CSS) frequently requiring intensive care support. Although intravenous immunoglobulin (IVIg) and glucocorticoids (GCs) are effective therapeutics for most, refractory MIS-C is treated with various biologic disease-modifying antirheumatic drugs (bDMARDs). Understanding the clinical features, inflammatory cytokines, and genetic associations provides rationale for bDMARD in treating severe MIS-C. RECENT FINDINGS: Children with MIS-C have clinical KD features and often present in hypovolemic and cardiogenic shock requiring volume repletion (gastrointestinaI losses) and cardiac pressor support (epinephrine). Investigation of MIS-C serum reveals elevated pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18, interferon gamma (IFNγ), tumor necrosis factor (TNF)], but to a lesser extent than other established CSS. Gene sequencing of MIS-C children identifies heterozygous mutations in CSS associated genes. Treatment of refractory (IVIg and GC) MIS-C with bDMARDs to IL-1, IL-6, and TNF is efficacious for survival as well as resolving cardiac and coronary artery inflammation. SUMMARY: MIS-C is a postinfectious complication of SARS-CoV-2 resembling KD and CSS, both genetically and by pro-inflammatory cytokines. MIS-C that is refractory to IVIg and GC is routinely responsive to bDMARDs targeting IL-1, IL-6, and TNF.

Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) affects few children previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In 2020, 45 children admitted to our hospital for MIS-C underwent genetic screening with a commercial 109-immune-gene panel. Thirty-nine children were diagnosed with MIS-C, and 25.4% of the 39 MIS-C patients harbored rare heterozygous missense mutations either in primary hemophagocytic lymphohistiocytosis (pHLH) genes (LYST, STXBP2, PRF1, UNC13D, AP3B1) or the HLH-associated gene DOCK8 (four variants). We demonstrate that foamy virus introduction of cDNA for the four DOCK8 variants into human NK-92 natural killer (NK) cells led to decreased CD107a expression (degranulation) and decreased NK cell lytic function in vitro for each variant. Heterozygous carriers of missense mutations in pHLH genes and DOCK8 may serve as risk factors for development of MIS-C among children previously infected with SARS-CoV-2.

Who Would Have Predicted Multisystem Inflammatory Syndrome in Children?

PURPOSE OF REVIEW: Multisystem inflammatory disease in children (MIS-C) is a novel post-infectious phenomenon following coronavirus disease-19 (COVID-19). Herein, we present an in-depth review of the latest MIS-C literature related to clinical findings, pathophysiology, imaging and laboratory studies, treatment algorithms, and disease outcomes. RECENT FINDINGS: With its non-specific presentation of fever, gastrointestinal symptoms, cardiovascular injury and shock, systemic inflammation, and Kawasaki disease (KD)-like features, MIS-C can be a diagnostic challenge, overlapping with KD and active COVID-19 infection. However, common laboratory features, imaging findings, and historical clues can lead to accurate diagnosis and allow for appropriate treatment with a variety of immunomodulatory therapies, including intravenous immunoglobulin (IVIG). Aggressive treatment of MIS-C leads to good outcomes. Longitudinal studies continue to illuminate long-term cardiac sequelae and recovery. MIS-C presents with fever, KD features, gastrointestinal symptoms, cardiac inflammation, and shock. Early recognition and prompt institution of IVIG and glucocorticoids provide for rapid improvement.

A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome.

BACKGROUND: Primary (familial) hemophagocytic lymphohistiocytosis (pHLH) is a potentially lethal syndrome of infancy, caused by genetic defects in natural killer (NK) cell and CD8 T cell cytotoxicity, leading to hyperinflammation, elevated cytokine levels, and a disorganized immune response resulting in multi-organ system failure and frequently death. Secondary HLH (sHLH) can be triggered in the setting of malignances, diseases of chronic immune system activation, or by infectious etiologies. While pHLH is usually a result of homozygous gene mutations, monoallelic hypomorphic and dominant-negative mutations in pHLH genes have been implicated in sHLH. Coronavirus disease 2019 (COVID-19) has been an omnipresent viral infection since its arrival, and severe cases can present with cytokine storm and have clinical features and laboratory findings consistent with sHLH. Herein, we report an adolescent with severe COVID-19, decreased NK cell function, and features of sHLH. Her genetic evaluation identified a monoallelic missense mutation in the pHLH gene STXBP2, and NK cell assays of her blood showed decreased cytolysis and degranulation ex vivo. METHODS: Patient data was extracted through an electronic medical record review. Using a lentiviral approach, the patient's STXBP2 mutation and wild-type (WT) STXBP2 were separately transduced into the NK-92 human NK cell line. The WT and mutant STXBP2 transduced NK-92 cells were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro, and NK cell degranulation and cytolysis were measured via CD107a expression and Live/Dead near-IR dye, respectively. RESULTS: Compared to WT STXBP2, the patient's STXBP2 mutation caused significantly decreased NK cell cytolysis and associated degranulation in vitro. CONCLUSION: These findings add weight to the hypothesis that some severe cases of COVID-19 may be accompanied by sHLH and hyperinflammation, especially in the setting of heterozygous pHLH genetic mutations. This has implications both diagnostically and therapeutically for severe COVID-19.

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children.

PURPOSE OF REVIEW: This review is meant to describe the genetic associations with pediatric severe COVID-19 pneumonia and the postinfectious complication of the multisystem inflammatory syndrome in children (MIS-C). Multiple genetic approaches have been carried out, primarily in adults with extrapolation to children, including genome-wide association studies (GWAS), whole exome and whole genome sequencing (WES/WGS), and target gene analyses. RECENT FINDINGS: Data from adults with severe COVID-19 have identified genomic regions (human leukocyte antigen locus and 3p21.31) as potential risk factors. Genes related to viral entry into cells (ABO blood group locus, ACE2, TMPRS22) have been linked to severe COVID-19 patients by GWAS and target gene approaches. Type I interferon (e.g. IFNAR2) and antiviral gene (e.g. TLR7) associations have been identified by several genetic approaches in severe COVID-19. WES has noted associations with several immune regulatory genes (e.g. SOCS1). Target gene approaches have identified mutations in perforin-mediated cytolytic pathway genes in children and adults with severe COVID-19 and children with MIS-C. SUMMARY: Several genetic associations have been identified in individuals with severe COVID-19 and MIS-C via various genetic approaches. Broadly speaking, COVID-19 genetic associations include genes involved with antiviral functions, viral cell entry, immune regulation, chemotaxis of white blood cells, and lymphocyte cytolytic function.

Performance of Cytokine Storm Syndrome Scoring Systems in Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children.

OBJECTIVE: The objective of this study is to evaluate pediatric patients using existing macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) scoring systems to determine how these systems identify patients with cytokine storm syndrome (CSS) in the setting of a multisystem inflammatory syndrome in children (MIS-C) and active coronavirus disease 2019 (COVID-19) infection. METHODS: Hospitalized pediatric patients with MIS-C and active COVID-19 infection at a single institution were identified. Infectious data, clinical findings, and laboratory values were collected, and patients were stratified by disease severity. Eight historically used scoring systems for MAS, HLH, and CSS were examined in the cohort of patients with MIS-C and pediatric COVID-19. RESULTS: The HLH-2004 criteria and HScore did not identify any patients as having CSS on admission, with only one patient with COVID-19 meeting criteria at peak disease severity. The 2016 systemic juvenile idiopathic arthritis (sJIA)/MAS criteria, ferritin/erythrocyte sedimentation rate (ESR) ratio, and COVID-19 CSS Quick Score most frequently identified CSS in this population and distinguished between COVID-19 and MIS-C hyperinflammation. The 2019 MAS/sJIA (MS) score and the COVID-19-associated hyperinflammatory syndrome (cHIS) criteria were less likely to identify CSS, as the MS score overestimated CSS and the cHIS resulted in similar scores regardless of severity or disease type. The Caricchio COVID-Cytokine Storm (COVID-CS) criteria identified patients with COVID-19 frequently but was less useful in MIS-C because of its COVID-19-specific criteria. CONCLUSION: MIS-C and pediatric COVID-19 result in relatively unique CSSs and patterns of inflammation. Existing scoring systems for CSSs likely do not capture the full breadth of this disease process in MIS-C and pediatric COVID-19.

The role of antirheumatics in patients with COVID-19.

The COVID-19 pandemic has resulted in more than 2 million deaths globally. Two interconnected stages of disease are generally recognised; an initial viral stage and a subsequent immune response phase with the clinical characteristics of hyperinflammation associated with acute respiratory distress syndrome. Therefore, many immune modulators and immunosuppressive drugs, which are widely used in rheumatological practice, have been proposed as treatments for patients with moderate or severe COVID-19. In this Review, we provide an overview of what is currently known about the efficacy and safety of antirheumatic therapies for the treatment of patients with COVID-19. Dexamethasone has been shown to reduce COVID-19 related mortality, interleukin-6 inhibitors to reduce risk of cardiovascular or respiratory organ support, and baricitinib to reduce time to recovery in hospitalised patients requiring oxygen support. Further studies are needed to identify whether there is any role for glucocorticoids in patients with less severe COVID-19. Although evidence on the use of other antirheumatic drugs has suggested some benefits, results from adequately powered clinical trials are urgently needed. The heterogeneity in dosing and the absence of uniform inclusion criteria and defined stage of disease studied in many clinical trials have affected the conclusions and comparability of trial results. However, after the success of dexamethasone in proving the anti-inflammatory hypothesis, the next 12 months will undoubtedly bring further clarity about the clinical utility and optimal dose and timing of other anti-rheumatic drugs in the management of COVID-19.

Distinguishing active pediatric COVID-19 pneumonia from MIS-C.

IMPORTANCE: Active pediatric COVID-19 pneumonia and MIS-C are two disease processes requiring rapid diagnosis and different treatment protocols. OBJECTIVE: To distinguish active pediatric COVID-19 pneumonia and MIS-C using presenting signs and symptoms, patient characteristics, and laboratory values. DESIGN: Patients diagnosed and hospitalized with active COVID-19 pneumonia or MIS-C at Children's of Alabama Hospital in Birmingham, AL from April 1 through September 1, 2020 were identified retrospectively. Active COVID-19 and MIS-C cases were defined using diagnostic codes and verified for accuracy using current US Centers for Disease Control case definitions. All clinical notes were reviewed for documentation of COVID-19 pneumonia or MIS-C, and clinical notes and electronic medical records were reviewed for patient demographics, presenting signs and symptoms, prior exposure to or testing for the SARS-CoV-2 virus, laboratory data, imaging, treatment modalities and response to treatment. FINDINGS: 111 patients were identified, with 74 classified as mild COVID-19, 8 patients as moderate COVID-19, 8 patients as severe COVID-19, 10 as mild MIS-C and 11 as severe MIS-C. All groups had a male predominance, with Black and Hispanic patients overrepresented as compared to the demographics of Alabama. Most MIS-C patients were healthy at baseline, with most COVID-19 patients having at least one underlying illness. Fever, rash, conjunctivitis, and gastrointestinal symptoms were predominant in the MIS-C population whereas COVID-19 patients presented with predominantly respiratory symptoms. The two groups were similar in duration of symptomatic prodrome and exposure history to the SARS-CoV-2 virus, but MIS-C patients had a longer duration between presentation and exposure history. COVID-19 patients were more likely to have a positive SAR-CoV-2 PCR and to require respiratory support on admission. MIS-C patients had lower sodium levels, higher levels of C-reactive protein, erythrocyte sedimentation rate, d-dimer and procalcitonin. COVID-19 patients had higher lactate dehydrogenase levels on admission. MIS-C patients had coronary artery changes on echocardiography more often than COVID-19 patients. CONCLUSIONS AND RELEVANCE: This study is one of the first to directly compare COVID-19 and MIS-C in the pediatric population. The significant differences found between symptoms at presentation, demographics, and laboratory findings will aide health-care providers in distinguishing the two disease entities.

Multidisciplinary Guidance Regarding the Use of Immunomodulatory Therapies for Acute Coronavirus Disease 2019 in Pediatric Patients.

BACKGROUND: Immune-mediated lung injury and systemic hyperinflammation are characteristic of severe and critical coronavirus disease 2019 (COVID-19) in adults. Although the majority of severe acute respiratory syndrome coronavirus 2 infections in pediatric populations result in minimal or mild COVID-19 in the acute phase of infection, a small subset of children develop severe and even critical disease in this phase with concomitant inflammation that may benefit from immunomodulation. Therefore, guidance is needed regarding immunomodulatory therapies in the setting of acute pediatric COVID-19. This document does not provide guidance regarding the recently emergent multisystem inflammatory syndrome in children (MIS-C). METHODS: A multidisciplinary panel of pediatric subspecialty physicians and pharmacists with expertise in infectious diseases, rheumatology, hematology/oncology, and critical care medicine was convened. Guidance statements were developed based on best available evidence and expert opinion. RESULTS: The panel devised a framework for considering the use of immunomodulatory therapy based on an assessment of clinical disease severity and degree of multiorgan involvement combined with evidence of hyperinflammation. Additionally, the known rationale for consideration of each immunomodulatory approach and the associated risks and benefits was summarized. CONCLUSIONS: Immunomodulatory therapy is not recommended for the majority of pediatric patients, who typically develop mild or moderate COVID-19. For children with severe or critical illness, the use of immunomodulatory agents may be beneficial. The risks and benefits of such therapies are variable and should be evaluated on a case-by-case basis with input from appropriate specialty services. When available, the panel strongly favors immunomodulatory agent use within the context of clinical trials. The framework presented herein offers an approach to decision-making regarding immunomodulatory therapy for severe or critical pediatric COVID-19 and is informed by currently available data, while awaiting results of placebo-controlled randomized clinical trials.