Analysis of Plasmablasts From Children With Kawasaki Disease Reveals Evidence of a Convergent Antibody Response to a Specific Protein Epitope.

BACKGROUND: Kawasaki disease (KD) is a febrile illness of young childhood that can result in coronary artery aneurysms and death. Coronavirus disease 2019 (COVID-19) mitigation strategies resulted in a marked decrease in KD cases worldwide, supporting a transmissible respiratory agent as the cause. We previously reported a peptide epitope recognized by monoclonal antibodies (MAbs) derived from clonally expanded peripheral blood plasmablasts from 3 of 11 KD children, suggesting a common disease trigger in a subset of patients with KD. METHODS: We performed amino acid substitution scans to develop modified peptides with improved recognition by KD MAbs. We prepared additional MAbs from KD peripheral blood plasmablasts and assessed MAb characteristics that were associated with binding to the modified peptides. RESULTS: We report a modified peptide epitope that is recognized by 20 MAbs from 11 of 12 KD patients. These MAbs predominantly use heavy chain VH3-74; two-thirds of VH3-74 plasmablasts from these patients recognize the epitope. The MAbs were nonidentical between patients but share a common complementarity-determining region 3 (CDR3) motif. CONCLUSIONS: These results demonstrate a convergent VH3-74 plasmablast response to a specific protein antigen in children with KD, supporting one predominant causative agent in the etiopathogenesis of the illness.

Epidemiological and Clinical Features of Kawasaki Disease During the COVID-19 Pandemic in the United States.

Importance: Public health measures implemented during the COVID-19 pandemic had widespread effects on population behaviors, transmission of infectious diseases, and exposures to environmental pollutants. This provided an opportunity to study how these factors potentially influenced the incidence of Kawasaki disease (KD), a self-limited pediatric vasculitis of unknown etiology. Objectives: To examine the change in KD incidence across the United States and evaluate whether public health measures affected the prevalence of KD. Design, Setting, and Participants: This multicenter cohort study included consecutive, unselected patients with KD who were diagnosed between January 1, 2018, and December 31, 2020 (multicenter cohort with 28 pediatric centers), and a detailed analysis of patients with KD who were diagnosed between January 1, 2002, and November 15, 2021 (Rady Children's Hospital San Diego [RCHSD]). Main Outcomes and Measures: For the multicenter cohort, the date of fever onset for each patient with KD was collected. For RCHSD, detailed demographic and clinical data as well as publicly available, anonymized mobile phone data and median household income by census block group were collected. The study hypothesis was that public health measures undertaken during the pandemic would reduce exposure to the airborne trigger(s) of KD and that communities with high shelter-in-place compliance would experience the greatest decrease in KD incidence. Results: A total of 2461 KD cases were included in the multicenter study (2018: 894; 2019: 905; 2020: 646), and 1461 cases (median [IQR] age, 2.8 years [1.4-4.9 years]; 900 [61.6%] males; 220 [15.1%] Asian, 512 [35.0%] Hispanic, and 338 [23.1%] White children) from RCHSD between 2002 and 2021 were also included. The 28.2% decline in KD cases nationally during 2020 (646 cases) compared with 2018 (894 cases) and 2019 (905 cases) was uneven across the United States. For RCHSD, there was a disproportionate decline in KD cases in 2020 to 2021 compared with the mean (SD) number of cases in earlier years for children aged 1 to 5 years (22 vs 44.9 [9.9]; P = .02), male children (21 vs 47.6 [10.0]; P = .01), and Asian children (4 vs 11.8 [4.4]; P = .046). Mobility data did not suggest that shelter-in-place measures were associated with the number of KD cases. Clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were decreased during 2020 compared with the baseline period (strawberry tongue: 39% vs 63%; P = .04; enlarged lymph node: 21% vs 32%; P = .09; periungual desquamation: 47% vs 58%; P = .16). School closures, masking mandates, decreased ambient pollution, and decreased circulation of respiratory viruses all overlapped to different extents with the period of decreased KD cases. KD in San Diego rebounded in the spring of 2021, coincident with lifting of mask mandates. Conclusions and Relevance: In this study of epidemiological and clinical features of KD during the COVID-19 pandemic in the United States, KD cases fell and remained low during the period of masking and school closure. Mobility data indicated that differential intensity of sheltering in place was not associated with KD incidence. These findings suggest that social behavior is associated with exposure to the agent(s) that trigger KD and are consistent with a respiratory portal of entry for the agent(s).

Current Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome in Children.

Purpose of Review: We highlight the new clinical entity multisystem inflammatory syndrome in children (MIS-C), the progress in understanding its immunopathogenesis, and compare and contrast the clinical and immunologic features of MIS-C with Kawasaki disease (KD). Recent Findings: Studies show immune dysregulation in MIS-C including T lymphocyte depletion and activation, T cell receptor Vbeta skewing, elevated plasmablast frequencies, increased markers of vascular pathology, and decreased numbers and functional profiles of antigen-presenting cells. Summary: MIS-C is a late manifestation of infection with SARS-CoV-2 associated with marked immune activation and many potential mechanisms of immunopathogenesis. MIS-C and KD have clinical similarities but are distinct. Myocardial dysfunction with or without mild coronary artery dilation can occur in MIS-C but generally corrects within weeks. In contrast, the coronary arteries are the primary target in KD, and coronary artery sequelae can be lifelong. Supportive care and anti-inflammatory therapy appear to hasten improvement in children with MIS-C, and there is hope that vaccines will prevent its development.

Cardiovascular magnetic resonance imaging in children after recovery from symptomatic COVID-19 or MIS-C: a prospective study.

BACKGROUND: Cardiac evaluations, including cardiovascular magnetic resonance (CMR) imaging and biomarker results, are needed in children during mid-term recovery after infection with SARS-CoV-2. The incidence of CMR abnormalities 1-3 months after recovery is over 50% in older adults and has ranged between 1 and 15% in college athletes. Abnormal cardiac biomarkers are common in adults, even during recovery. METHODS: We performed CMR imaging in a prospectively-recruited pediatric cohort recovered from COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We obtained CMR data and serum biomarkers. We compared these results to age-matched control patients, imaged prior to the SARS-CoV-2 pandemic. RESULTS: CMR was performed in 17 children (13.9 years, all ≤ 18 years) and 29 age-matched control patients without SARS-CoV-2 infection. Cases were recruited with symptomatic COVID-19 (11/17, 65%) or MIS-C (6/17, 35%) and studied an average of 2 months after diagnosis. All COVID-19 patients had been symptomatic with fever (73%), vomiting/diarrhea (64%), or breathing difficulty (55%) during infection. Left ventricular and right ventricular ejection fractions were indistinguishable between cases and controls (p = 0.66 and 0.70, respectively). Mean native global T1, global T2 values and segmental T2 maximum values were also not statistically different from control patients (p ≥ 0.06 for each). NT-proBNP and troponin levels were normal in all children. CONCLUSIONS: Children prospectively recruited following SARS-CoV-2 infection had normal CMR and cardiac biomarker evaluations during mid-term recovery. Trial Registration Not applicable.

The Impact of Social Distancing for COVID-19 Upon Diagnosis of Kawasaki Disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mitigation policies have been associated with profound decreases in diagnoses of common childhood respiratory infections. A leading theory of etiology of Kawasaki disease (KD) is that it is triggered by presently unidentified ubiquitous respiratory agent. We document that mitigation policies instituted in mid-March 2020 were associated with strikingly fewer diagnoses of KD in April-December 2020 compared with the same period in the previous 8 years (P = .01), a >67% decline. This finding supports the hypothesis that KD is caused by a respiratory-transmitted agent.

A Protein Epitope Targeted by the Antibody Response to Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is the leading cause of childhood acquired heart disease in developed nations and can result in coronary artery aneurysms and death. Clinical and epidemiologic features implicate an infectious cause but specific antigenic targets of the disease are unknown. Peripheral blood plasmablasts are normally highly clonally diverse but the antibodies they encode are approximately 70% antigen-specific 1-2 weeks after infection. METHODS: We isolated single peripheral blood plasmablasts from children with KD 1-3 weeks after onset and prepared 60 monoclonal antibodies (mAbs). We used the mAbs to identify their target antigens and assessed serologic response among KD patients and controls to specific antigen. RESULTS: Thirty-two mAbs from 9 of 11 patients recognize antigen within intracytoplasmic inclusion bodies in ciliated bronchial epithelial cells of fatal cases. Five of these mAbs, from 3 patients with coronary aneurysms, recognize a specific peptide, which blocks binding to inclusion bodies. Sera from 5/8 KD patients day ≥ 8 after illness onset, compared with 0/17 infant controls (P < .01), recognized the KD peptide antigen. CONCLUSIONS: These results identify a protein epitope targeted by the antibody response to KD and provide a means to elucidate the pathogenesis of this important worldwide pediatric problem.

Microbiology of Pediatric Orbital Cellulitis and Trends in Methicillin-Resistant Staphylococcus aureus Cases.

We reviewed medical records of children with orbital cellulitis with positive cultures at a tertiary institution from 2005 to 2018 to identify microbiology trends and features associated with methicillin-resistant Staphylococcus aureus (MRSA) cases. Cultures obtained from the orbits (n = 33), sinuses (n = 31), and dural cavities (n = 4) had yields of 66.7%, 61.3%, and 75%, respectively, compared with 17.6% of blood cultures (n = 69). Fifty-five patients had positive culture results. Staphylococcus aureus was the most common pathogen isolated (n = 19), followed by Streptococcus species, most commonly Streptococcus anginosus (n = 8). The most frequently prescribed antibiotic combination regimen was ampicillin-sulbactam followed by amoxicillin-clavulanate. There were 8 cases of MRSA. MRSA was associated with an age of presentation <1 year old (P = .034). Other clinical features were similar between MRSA and non-MRSA cases. In infants and neonates, or those with epidemiologic risk factors, MRSA should also be considered.

The Kawasaki Disease Comparative Effectiveness (KIDCARE) trial: A phase III, randomized trial of second intravenous immunoglobulin versus infliximab for resistant Kawasaki disease.

BACKGROUND: Although intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease (KD), the most common cause of acquired heart disease in children, 10-20% of patients are IVIG-resistant and require additional therapy. This group has an increased risk of coronary artery aneurysms (CAA) and there has been no adequately powered, randomized clinical trial in a multi-ethnic population to determine the optimal therapy for IVIG-resistant patients. OBJECTIVES: The primary outcome is duration of fever in IVIG-resistant patients randomized to treatment with either infliximab or a second IVIG infusion. Secondary outcomes include comparison of inflammatory markers, duration of hospitalization, and coronary artery outcome. An exploratory aim records parent-reported outcomes including signs, symptoms and treatment experience. METHODS: The KIDCARE trial is a 30-site randomized Phase III comparative effectiveness trial in KD patients with fever ≥36 h after the completion of their first IVIG treatment. Eligible patients will be randomized to receive either a second dose of IVIG (2 g/kg) or infliximab (10 mg/kg). Subjects with persistent or recrudescent fever at 24 h following completion of the first study treatment will cross-over to the other treatment arm. Subjects will exit the study after their first outpatient visit (5-18 days following last study treatment). The parent-reported outcomes, collected daily during hospitalization and at home, will be compared by study arm. CONCLUSION: This trial will contribute to the management of IVIG-resistant patients by establishing the relative efficacy of a second dose of IVIG compared to infliximab and will provide data regarding the patient/parent experience of these treatments.

Coronary artery aneurysms are more severe in infants than in older children with Kawasaki disease.

OBJECTIVE: We aimed to compare the severity of coronary artery abnormalities in Kawasaki disease between infants and older children. METHODS: We retrospectively reviewed and compared coronary artery dilation and aneurysm severity in infants <1 year of age with Kawasaki disease at our centre over a 10-year period with that observed in children ≥1 year of age in the Pediatric Heart Network Trial of Pulse Steroid Therapy in Kawasaki Disease. Coronary artery abnormalities were defined by z-scores according to American Heart Association guidelines. RESULTS: Of the 93 infants identified during the study period, 80 were treated with intravenous gamma globulin within the first 10 days of illness and were included for comparison to 170 children ≥1 year of age treated in the same time frame from the Pediatric Heart Network public database. The mean maximum z-score was significantly higher in infants compared with older children (3.37 vs 2.07, p<0.001). A higher incidence of medium and giant aneurysms was observed in infants compared with children ≥1 year of age (11% vs 3% for medium aneurysms, p=0.015; 8% vs <1% for giant aneurysms, p=0.005). CONCLUSIONS: Infants with Kawasaki disease have more severe coronary artery dilation compared with older children, and a higher prevalence of medium and giant aneurysms. Because adverse outcomes are closely linked to the maximal coronary artery diameter in Kawasaki disease, patients diagnosed as infants require very close long-term monitoring for cardiac complications.

The Epidemiology and Pathogenesis of Kawasaki Disease.

Epidemiologic and clinical features of Kawasaki Disease (KD) strongly support an infectious etiology. KD is worldwide, most prominently in Japan, Korea, and Taiwan, reflecting increased genetic susceptibility among Asian populations. In Hawaii, KD rates are 20-fold higher in Japanese ethnics than in Caucasians, intermediate in other ethnicities. The age distribution of KD, highest in children < 2 yo, lower in those < 6 months, is compatible with infection by a ubiquitous agent resulting in increasing immunity with age and with transplacental immunity, as with some classic viruses. The primarily winter-spring KD seasonality and well-documented Japanese epidemics with wave-like spread also support an infectious trigger. We hypothesize KD pathogenesis involves an RNA virus that usually causes asymptomatic infection but KD in a subset of genetically predisposed children. CD8 T cells, oligoclonal IgA, and upregulation of cytotoxic T cell and interferon pathway genes in the coronaries in fatal KD also support a viral etiology. Cytoplasmic inclusion bodies in ciliated bronchial epithelium identified by monoclonal antibodies made from oligoclonal IgA heavy chains also supports a viral etiology. Recent availability of "second generation" antibodies from KD peripheral blood plasmablasts may identify a specific viral antigen. Thus, we propose an unidentified ("new") RNA virus infects bronchial epithelium usually causing asymptomatic infection but KD in a subset of genetically predisposed children. The agent persists in inclusion bodies, with intermittent respiratory shedding, entering the bloodstream via macrophages targeting coronaries. Antigen-specific IgA plasma cells and CD8 T cells respond but coronaries can be damaged. IVIG may include antibody against the agent. Post infection, 97-99% of KD patients are immune to the agent, protected against recurrence. The agent can spread either from those with asymptomatic primary infection in winter-spring or from a previously infected contact who intermittently sheds the agent.

Is Kawasaki disease an infectious disorder?

Although the etiology of Kawasaki disease (KD) is largely unknown, a large body of clinical, epidemiologic, immunologic, pathologic and ultrastructural evidence suggests that an infectious agent triggers a cascade that causes the illness. However, this elusive infectious agent remains unidentified at present. Increasingly sensitive molecular methods for identifying microbial nucleic acids and proteins in tissue samples continue to rapidly emerge, and these methods should be utilized in studies on KD etiology as they become available. Identifying the etiology of this enigmatic disease remains the single most important research goal in the field, and accomplishing this goal is the best means to improve diagnosis, treatment and prevention of this potentially fatal childhood disease.

Allograft Inflammatory Factor-1 Links T-Cell Activation, Interferon Response, and Macrophage Activation in Chronic Kawasaki Disease Arteritis.

BACKGROUND: Kawasaki disease (KD) is widely viewed as an acute arteritis. However, our pathologic studies show that chronic coronary arteritis can persist long after disease onset and is closely linked with arterial stenosis. Transcriptome profiling of acute KD arteritis tissues revealed upregulation of T lymphocyte, type I interferon, and allograft inflammatory factor-1 (AIF1) genes. We determined whether these immune responses persist in chronic KD arteritis, and we investigated the role of AIF1 in these responses. METHODS: Gene expression in chronic KD and childhood control arteries was determined by real-time reverse-transcriptase polymerase chain reaction, and arterial protein expression was determined by immunohistochemistry and immunofluorescence. Allograft inflammatory factor-1 small-interfering ribonucleic acid macrophage treatment was performed to investigate the role of AIF1 in macrophage and T lymphocyte activation. RESULTS: Allograft inflammatory factor-1 protein was highly expressed in stenotic KD arteries and colocalized with the macrophage marker CD68. T lymphocyte and interferon pathway genes were significantly upregulated in chronic KD coronary artery tissues. Alpha interferon-induced macrophage expression of CD80 and major histocompatibility complex class II was dependent on AIF1, and macrophage expression of AIF1 was required for antigen-specific T lymphocyte activation. CONCLUSIONS: Allograft inflammatory factor-1, originally identified in posttransplant arterial stenosis, is markedly upregulated in KD stenotic arterial tissues. T lymphocyte and type I interferon responses persist in chronic KD arteritis. Allograft inflammatory factor-1 may play multiple roles linking type I interferon response, macrophage activation, and antigen-specific T lymphocyte activation. These results suggest the likely importance of lymphocyte-myeloid cell cross-talk in the pathogenesis of KD arteritis and can inform selection of new immunotherapies for clinical trials in high-risk KD children.

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.

BACKGROUND: Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries. METHODS AND RESULTS: To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis, treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and long-term outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up. CONCLUSIONS: These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances.

Hyponatremia Is a Feature of Kawasaki Disease Shock Syndrome: A Case-Control Study.

Kawasaki disease (KD) shock syndrome (KDSS) is hypotension with KD. We compared children with KDSS and matched control children with KD. Children with KDSS more often were female, had a lower platelet count and sodium concentration, had a condition refractory to immunoglobulin, and had abnormal echocardiography results. KDSS is a unique subset of KD.