Large- and medium-sized arterial aneurysms in two patients with SMAD4-related juvenile polyposis syndrome.

Germline SMAD4 pathogenic variants (PVs) cause juvenile polyposis syndrome (JPS), which is known for an increased risk of gastrointestinal juvenile polyps and gastrointestinal cancer. Many patients with SMAD4 PV also show signs of hereditary hemorrhagic telangiectasia (HHT) and some patients have aneurysms and dissections of the thoracic aorta. Here we describe two patients with a germline SMAD4 PV and a remarkable clinical presentation including multiple medium-sized arterial aneurysms. More data are needed to confirm whether the more extensive vascular phenotype and the other described features in our patients are indeed part of a broader JPS spectrum.

Treatment and Coronary Artery Aneurysm Formation in Kawasaki Disease: A Per-Day Risk Analysis.

OBJECTIVE: To assess whether 'treatment day' is a significant predicting factor in Kawasaki disease and imposes a risk for coronary artery aneurysms (CAAs) in a per-day analysis. CAA formation can be reduced from 25% to 10% when treated with intravenous immunoglobulin (IVIG). STUDY DESIGN: Patient data from (n = 1016) a single center were collected for an observational cohort study. After exclusions, we retrospectively analyzed 776 patients in total. A multivariate analysis was performed with treatment day as a continuous variable (n = 691). Patients were categorized as no enlargement, small CAA, medium CAA, and giant CAA. RESULTS: Late treatment per-day was a significant predicting factor for the development of larger CAAs. ORs for medium and giant CAAs per delayed day were 1.1 (95% CI 1.1-1.2) P < .05 and 1.2 (95% CI 1.1-1.2) P < .05, respectively. CONCLUSION: We showed that every day of delay in treatment of patients with Kawasaki disease inherently carries a risk of medium and giant aneurysm formation. There was no cut-off point for treatment day that could mark a safe zone.

Myocardial infarction due to thrombotic occlusion despite anticoagulation in Kawasaki disease - a case report.

BACKGROUND: Kawasaki disease (KD) is a pediatric vasculitis. Mainly the coronary arteries become affected due to acute inflammation and formation of coronary artery aneurysms (CAAs) can occur. The larger the CAA, the higher the risk for clinical complications and major adverse cardiac events, as the blood flow changes to vortex or turbulent flow facilitating thrombosis. Such patients may develop life threatening thrombotic coronary artery occlusion and myocardial ischemiaunless anti-platelet and anti-coagulation therapy is timely initiated. CASE PRESENTATION: We present a unique case of a 5-year-old girl with KD associated giant CAAs suffering from myocardial ischemia due to acute progressive thrombus growth despite intensive anticoagulation treatment (acetylsalicylic acid, acenocoumarol and clopidogrel) after 21 months of onset of disease. Thrombus growth continued even after percutaneous coronary intervention (PCI) with thrombolytic treatment and subsequent systemic thrombolysis, finally causing lasting myocardial damage. Acute coronary artery bypass grafting (CABG) was performed, although technically challenging at this very young age. Whereas myocardial infarction was not prevented, follow-up fortunately showed favorable recovery of heart failure. CONCLUSIONS: Anticoagulation and thrombolysis may be insufficient for treatment of acute coronary syndrome in case of impending thrombotic occlusion of giant coronary aneurysms in KD. Our case demonstrates that a thrombus can still continue to grow despite triple anticoagulation therapy and well-tailored cardiovascular follow-up, which can be most likely attributed to the state of low blood flow inside the aneurysm.

[Kawasaki disease or SARS-CoV-2 related MIS-C? How to discriminate between these hyperinflammatory syndromes in children?] / Ziekte van Kawasaki of SARS-CoV-2-gerelateerde MIS-C?

Increasing waiting lists and a structural staff shortage are putting pressure on the health system. Because care production is lower than care demand, there is no longer competition. Competition is over and we are beginning to see the contours of the new health system. The new system takes health instead of care as its starting point by legally embedding health goals in addition to the duty of care. The new system is based on health regions, but does not require a regional health authority. It is based on health manifestos that include agreements about cooperation in good and bad times.

Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease.

BACKGROUND: Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C. Therefore, we explored the immunological response, presence of ACAAs and disease correlates in both disorders. METHODS: Eighteen inflammatory plasma protein levels and seven ACAAs were measured in KD (n = 216) and MIS-C (n = 56) longitudinally by Luminex and/or ELISA. Levels (up to 1 year post-onset) of these proteins were related to clinical data and compared with healthy paediatric controls. FINDINGS: ACAAs were found in both patient groups. The presence of ACAAs lagged behind the inflammatory plasma proteins and peaked in the subacute phase. ACAAs were mostly directed against IFN-γ (>80%) and were partially neutralising at best. KD presented with a higher variety of ACAAs than MIS-C. Increased levels of anti-IL-17A (P = 0·02) and anti-IL-22 (P = 0·01) were inversely associated with ICU admission in MIS-C. Except for CXCL10 in MIS-C (P = 0·002), inflammatory plasma proteins were elevated in both KD and MIS-C. Endothelial angiopoietin-2 levels were associated with coronary artery aneurysms in KD (P = 0·02); and sCD25 (P = 0·009), angiopoietin-2 (P = 0·001), soluble IL-33-receptor (ST2, P = 0·01) and CXCL10 (P = 0·02) with ICU admission in MIS-C. INTERPRETATION: Markers of endothelial activation (E-selectin, angiopoietin-2), and innate and adaptive immune responses (macrophages [CD163, G-CSF], neutrophils [lipocalin-2], and T cells [IFN-γ, CXCL10, IL-6, IL-17]), are upregulated in KD and MIS-C. ACAAs were detected in both diseases and, although only partly neutralising, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation. FUNDING: The Kawasaki study is funded by the Dutch foundation Fonds Kind & Handicap and an anonymous donor. The sponsors had no role in the study design, analysis, or decision for publication.

Practical Workflow for Cardiovascular Assessment and Follow-Up in Kawasaki Disease Based on Expert Opinion.

Background: Approximately 25% of the patients with a history of Kawasaki disease (KD) develop coronary artery pathology if left untreated, with coronary artery aneurysms (CAA) as an early hallmark. Depending on the severity of CAAs, these patients are at risk of myocardial ischemia, infarction and sudden death. In order to reduce cardiac complications it is crucial to accurately identify patients with coronary artery pathology by an integrated cardiovascular program, tailored to the severity of the existing coronary artery pathology. Methods: The development of this practical workflow for the cardiovascular assessment of KD patients involve expert opinions of pediatric cardiologists, infectious disease specialists and radiology experts with clinical experience in a tertiary KD reference center of more than 1000 KD patients. Literature was analyzed and an overview of the currently most used guidelines is given. Conclusions: We present a patient-specific step-by-step, integrated cardiovascular follow-up approach based on expert opinion of a multidisciplinary panel with expertise in KD.

Corrigendum: CT Angiography or Cardiac MRI for Detection of Coronary Artery Aneurysms in Kawasaki Disease.

[This corrects the article DOI: 10.3389/fped.2021.630462.].

Corrigendum: Lower CMV and EBV Exposure in Children With Kawasaki Disease Suggests an Under-Challenged Immune System.

[This corrects the article DOI: 10.3389/fped.2020.627957.].

CT Angiography or Cardiac MRI for Detection of Coronary Artery Aneurysms in Kawasaki Disease.

Background: Kawasaki disease (KD) is an acute vasculitis that mainly affects the coronary arteries. This inflammation can cause coronary artery aneurysms (CAAs). Patients with KD need cardiac assessment for risk stratification for the development of myocardial ischemia, based on Z-score (luminal diameter of the coronary artery corrected for body surface area). Echocardiography is the primary imaging modality in KD but has several important limitations. Coronary computed tomographic angiography (cCTA) and Cardiac MRI (CMR) are non-invasive imaging modalities and of additional value for assessment of CAAs with a high diagnostic yield. The objective of this single center, retrospective study is to explore the diagnostic potential of coronary artery assessment of cCTA vs. CMR in children with KD. Methods and Results: Out of 965 KD patients from our database, a total of 111 cCTAs (104 patients) and 311 CMR (225 patients) have been performed since 2010. For comparison, we identified 54 KD patients who had undergone both cCTA and CMR. CMR only identified eight patients with CAAs compared to 14 patients by cCTA. CMR missed 50% of the CAAs identified by cCTA. Conclusions: Our single center study demonstrates that cCTA may be a more sensitive diagnostic tool to detect CAAs in KD patients, compared to CMR.

Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease.

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.

Lower CMV and EBV Exposure in Children With Kawasaki Disease Suggests an Under-Challenged Immune System.

Background: Kawasaki Disease (KD) is a pediatric vasculitis of which the pathogenesis is unclear. The hypothesis is that genetically pre-disposed children develop KD when they encounter a pathogen which remains most often unidentified or pathogen derived factors. Since age is a dominant factor, prior immune status in children could influence their reactivity and hence the acquisition of KD. We hypothesized that systemic immune responses early in life could protect against developing KD. With this study we tested whether the incidence of previous systemic cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection is lower in children with KD compared to healthy age-matched controls. Methods and Results: We compared 86 KD patients with an age-matched control group regarding CMV and EBV VCA IgG measurements (taken before or 9 months after IVIG treatment). We found that both CMV and EBV had an almost 2-fold lower seroprevalence in the KD population than in the control group. Conclusions: We suggest that an under-challenged immune system causes an altered immune reactivity which may affect the response to a pathological trigger causing KD in susceptible children.