Microvascular changes on nailfold capillaroscopy in acute stage of Kawasaki disease: a new diagnostic paradigm for an enigmatic condition.

OBJECTIVES: Kawasaki disease (KD) is a medium vessel vasculitis with a predilection to involve coronary arteries. However, there is a paucity of literature on microvascular changes in patients with KD. METHODS: Children diagnosed with KD based on American Heart Association guidelines 2017 were enrolled prospectively. Demographic details and echocardiographic changes in coronaries were recorded. Nailfold capillaries were assessed using Optilia Video capillaroscopy and data were analysed using Optilia Optiflix Capillaroscopy software at acute (prior to IVIG administration) and subacute/convalescent phase. RESULTS: We enrolled 32 children with KD (17 boys) with a median age of 3 years. Nailfold capillaroscopy (NFC) was performed in 32 patients in the acute phase (compared with 32 controls) and in 17 during the subacute/convalescent phase at a median follow-up of 15 (15-90) days after IVIG treatment. The following findings were seen in NFC in the acute phase of KD: reduced capillary density (n = 12, 38.6%), dilated capillaries (n = 3, 9.3%), ramifications (n = 3, 9.3%) and capillary haemorrhages (n = 2, 6.2%). Capillary density was reduced significantly in the acute phase of KD (38.6%) as compared with the subacute/convalescent phase (25.4%) (P-value <0.001) and controls (0%) (P-value = 0.03). We observed no correlation between coronary artery involvement and mean capillary density (P = 0.870). CONCLUSION: Results show that patients with KD have significant nailfold capillary changes in the acute phase. These findings may provide a new diagnostic paradigm for KD and a window to predict coronary artery abnormalities.

Expression of PCT, BNP and Inflammatory Factors in Children with Kawasaki Disease and Their Correlation with Coronary Artery Lesions.

Background: Kawasaki disease (KD), as one of the most common vascular diseases in children, will cause the risk of coronary artery lesions (CAL) without treatment. This study is to explore the expression of procalcitonin (PCT), brain natriuretic peptide (BNP), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and interleukin-6 (IL-6) in children with KD and their correlation with CAL. Methods: 86 KD children in Baoding Hospital of Beijing Children's Hospital were selected as the study subjects from January 2020 to June 2021. According to whether CAL occurred, they were divided into the CAL group (n=30) and NCAL group (n=56). The clinical data of the two groups were collected from the medical record system. The levels of PCT and BNP were detected by chemiluminescence microparticle assay, the CRP level was detected by immunoturbidimetry, and the levels of TNF-α and IL-6 were detected by flow immunofluorescence method. The relationship of PCT, BNP, and inflammatory factors with CAL in KD children was explored by Pearson correlation analysis. Results: The comparative result of clinical data showed no overt difference in gender, disease types, age and blood routine indexes between the two groups, except for coronary artery diameter (P >.05). The levels of PCT, BNP, CRP, TNF-α and IL-6 in CAL group were (1.70±0.39) µg/L, (289.21±29.78) ng/L, (83.16±17.35) mg/L, (9.38±1.23) pg/mL and (59.97±0.97) ng/mL, respectively. The levels of PCT, BNP, CRP, TNF-α and IL-6 in NCAL group were (1.04±0.18) µg/L, (170.85±23.58) ng/L, (69.70±16.64) mg/L, (6.32±0.73) pg/mL and (44.16±11.97) ng/mL, respectively. The levels of each index in the CAL group were notably higher than in the NCAL group (P < .001). Pearson correlation analysis revealed that PCT, BNP, CRP, TNF-α and IL-6 were positively correlated with CAL in KD children (r=0.829, 0.865, 0.823, 0.894, 0.784, P < .001). Conclusion: The increase of PCT, BNP, and inflammatory factors has a certain warning effect on CAL in KD children. In clinical practice, health care professionals should strengthen the detection of PCT, BNP and inflammatory factors in KD children, carry out early monitoring of CAL in children with high expression of biomarkers, and formulate personalized preventive intervention based on the disease progress, so as to reduce the risk of cardiovascular disease. However, due to the limitations of research conditions and methods, the sample size of this study is small, which may affect the reliability and representativeness of the conclusion. In order to provide a new direction for the clinical prevention and treatment of the disease, future work will improve the research design, expand the sample size, and carry out more in-depth exploration on the prediction of CAL in KD children.

Maternal Serum Folic Acid Levels and Onset of Kawasaki Disease in Offspring During Infancy.

Importance: Kawasaki disease is an acute systemic vasculitis that primarily affects infants and young children. No reproducible risk factors have yet been identified, but a possible association between maternal folic acid supplementation and Kawasaki disease has been reported previously. Objective: To investigate the associations of exposure to maternal serum folic acid levels and maternal folic acid supplementation with onset of Kawasaki disease during infancy among offspring. Design, Setting, and Participants: This cohort study used data from the Japan Environment and Children's Study, a nationwide birth cohort, which has enrolled children since 2011. This study used the data set released in October 2019, and analysis was performed in January 2023. Exposures: Maternal serum folic acid levels (≥10 ng/mL classified as exposed) during the second and third trimesters and the frequency of maternal folic acid supplementation during the first trimester and during the second and third trimesters of pregnancy (once a week or more was classified as exposed). Main Outcomes and Measures: The primary outcome was onset of Kawasaki disease in offspring up to age 12 months. Odds ratios (ORs) for each exposure were estimated, and propensity score-adjusted logistic regression was conducted on the basis of the sets of variables. Results: The study population comprised 87 702 children who were followed-up for 12 months. Of these, 336 children developed Kawasaki disease. Mothers who took folic acid supplements (31 275 mothers [35.7%]; mean [SD] age, 32 [5] years) had higher serum folic acid levels than those who did not take supplements. Higher maternal serum folic acid levels were associated with a significantly lower risk of Kawasaki disease in offspring than lower levels (folic acid ≥10 vs <10 ng/mL, 56 of 20 698 children [0.27%] vs 267 of 64 468 children [0.41%]; OR, 0.68; 95% CI, 0.50-0.92). Children whose mothers took folic acid supplementation during the first trimester had a lower prevalence of Kawasaki disease than children whose mothers did not take folic acid (131 of 39 098 children [0.34%] vs 203 of 48 053 children [0.42%]), although the difference was not statistically significant (OR, 0.83; 95% CI, 0.66-1.04). Supplementation during the second and third trimesters was associated with a significantly lower risk of Kawasaki disease compared with no supplementation (94 of 31 275 children [0.30%] vs 242 of 56 427 children [0.43%]; OR, 0.73; 95% CI, 0.57-0.94). Conclusions and Relevance: In this cohort study, higher serum folic acid levels (≥10 ng/mL) and maternal folic acid supplementation more than once a week during the second and third trimesters were associated with reduced risk of Kawasaki disease in offspring during infancy.

Protective Roles of Xijiao Dihuang Tang on Coronary Artery Injury in Kawasaki Disease.

PURPOSE: Xijiao Dihuang Tang (XJDHT) is a classical formula of traditional Chinese medicine constituted of Cornu Bubali, Rehmannia glutinosa (Gaertn.) DC., Paeonia lactiflora Pall., and Paeonia suffruticosa Andrews. It was first mentioned in the medical classic "Beiji Qianjin Yaofang" written by Simiao Sun in Tang Dynasty. It shows very strong antipyretic and anticoagulant effects and has been clinically applied to treat various type of blood loss, purple and black spots, heat stroke, and glossitis. Kawasaki disease (KD) is considered as a kind of acute febrile illness in children with systemic vasculitis as the main lesions. The aim of this research is to clarify whether XJDHT can play a protective role in KD. METHODS: A mouse model of Candida albicans water-soluble fraction (CAWS)-induced coronary arteritis and a KD cell model with tumor necrosis factor (TNF)-α induction were employed to investigate the potential effect and mechanism of XJDHT on coronary artery injury in KD. RESULTS: Data showed that XJDHT remarkably alleviated the coronary artery injury of KD mice, as evidenced by reduced inflammation and downregulated expression of pro-inflammatory cytokines interleukin (IL)-1ß and TNF-α. In vitro investigation showed that XJDHT could promote cell proliferation, inhibit cell apoptosis, and improve mitochondrial functions. Subsequent studies demonstrated that XJDHT rescued endothelial cell injury by PI3K/Akt-NFκB signaling pathway. Component analysis of XJDHT detected thirty-eight chemically active ingredients, including paeoniflorin, albiflorin, and paeoniflorigenone, which in in vitro experiments exhibited significant rescue effects on TNF-α-mediated endothelial cell injury. CONCLUSION: Our findings demonstrated that XJDHT mitigated coronary artery injury of KD through suppressing endothelial cell damage via PI3K/Akt-NFκB signaling.

Risk scores for Kawasaki disease, a management tool developed by the KAWA-RACE cohort.

INTRODUCTION/OBJECTIVES: Asian scores developed to predict unresponsiveness to intravenous immunoglobulin (IVIG) or development of coronary artery aneurysms (CAA) in patients with Kawasaki disease (KD) are not appropriate in Western populations. The purpose of this study is to develop 2 scores, to predict unresponsiveness to IVIG and development of CAA, appropriate for Spanish population. METHOD: Data of 625 Spanish children with KD collected retrospectively (2011-2016) were used to identify variables to develop the 2 scores of interest: unresponsiveness to IVIG and development of CAA. A statistical model selected best variables to create the scores, and scores were validated with data from 98 patients collected prospectively. RESULTS: From 625 patients of the retrospective cohort, final analysis was performed in 439 subjects: 37 developed CAA, and 212 were unresponsive to IVIG. For the score to predict CAA, a cutoff ≥ 8 was considered for high risk, considering a score system with a different weight for each of the eight variables. External validation showed a sensitivity of 22% and a specificity of 75%. The score to predict unresponsiveness to IVIG established a cutoff ≥ 8 for high risk, considering a score system with a different weight for each of the nine variables. External validation showed a sensitivity of 78% and a specificity of 50%. CONCLUSIONS: Two risk scores for KD were developed from Spanish population, to predict development of CAA and unresponsiveness to IVIG; validation in other cohorts could help to implement these tools in the management of KD in other Western populations.

Ambient Air Pollution and Kawasaki Disease in Korean Children: A Study of the National Health Insurance Claim Data.

Background Kawasaki disease (KD) is a systemic vasculitis of unknown etiology that primarily affects children under 5 years of age. Some researchers suggested a potential triggering effect of air pollution on KD, but the findings are inconsistent and limited by small sample size. We investigated the association between ambient air pollution and KD among the population of South Korea younger than 5 years using the National Health Insurance claim data between 2007 and 2019. Methods and Results We obtained the data regarding particulate matter ≤10 or 2.5 µm in diameter, nitrogen dioxide, sulfur dioxide, carbon monoxide, and ozone from 235 regulatory monitoring stations. Using a time-stratified case-crossover design, we performed conditional logistic regression to estimate odds ratios (OR) of KD according to interquartile range increases in each air pollutant concentration on the day of fever onset after adjusting for temperature and relative humidity. We identified 51 486 children treated for KD during the study period. An interquartile range increase (14.67 µg/m3) of particulate matter ≤2.5 µm was positively associated with KD at lag 1 (OR, 1.016; 95% CI, 1.004-1.029). An interquartile range increase (2.79 ppb) of sulfur dioxide concentration was associated with KD at all lag days (OR, 1.018; 95% CI, 1.002-1.034 at lag 0; OR, 1.022; 95% CI, 1.005-1.038 at lag 1; OR, 1.017; 95% CI, 1.001-1.033 at lag 2). Results were qualitatively similar in the second scenario of different fever onset, 2-pollutant model and sensitivity analyses. Conclusions In a KD-focused national cohort of children, exposure to particulate matter ≤2.5 µm and sulfur dioxide was positively associated with the risk of KD. This finding supports the triggering role of ambient air pollution in the development of KD.

Integrative treatment of herbal medicine with western medicine on coronary artery lesions in children with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a major cause of coronary artery lesions (CALs) in children. Approximately 10% to 20% of children treated with intravenous immunoglobulin are intravenous immunoglobulin-resistant. This study evaluated the efficacy and safety of adding herbal medicine to conventional western medicines versus conventional western medicines alone for CALs in children with KD. METHODS: This study searched 9 electronic databases until August 31, 2021. The inclusion criteria were the randomized controlled trials (RCTs) that assessed the CALs in children with KD and compared integrative treatment with conventional western treatments. Two authors searched independently for RCTs, including eligible articles that fulfilled the inclusion criteria, extracted data, and assessed the methodological quality using the Cochrane risk of bias tool. Meta-analysis was conducted using Cochrane Collaboration's Review Manager 5.4 software. The effect size was presented as the risk ratio (RR), and the fixed-effect models were used to pool the results. RESULTS: The finally selected 12 studies included a total of 1030 KD patients. According to a meta-analysis, the integrative treatment showed better results than the conventional treatment in the CAL prevalence rate (RR = 2.00; 95% confidence interval [CI], 1.49-2.71; P < .00001), CAL recovery rate (RR = 1.27; 95% CI, 1.05-1.54; P = .02), and total effective rate (RR = 1.17; 95% CI, 1.11-1.23; P < .00001). Only 2 studies referred to the safety of the treatment. The asymmetrical funnel plot of the CAL prevalence rate indicated the possibility of potential publication bias. CONCLUSIONS: This review found the integrative treatment to be more effective in reducing the CAL prevalence rate and increasing the CAL recovery rate and total effective rate in KD patients than conventional western treatment. However, additional well-designed RCTs will be needed further to compensate restrictions of insufficient trials on safety, methodological quality, and publication bias.

Yersinia pseudotuberculosis Infection Accompanied by Intussusception and Incomplete Kawasaki Disease in a 7-year-old Girl.

Infection with Yersinia pseudotuberculosis, a known causal pathogen of human bacterial gastroenteritis, causes various symptoms and complications. A previously healthy 7-year-old girl was admitted because of fever and gastrointestinal symptoms. She was initially diagnosed with intussusception by abdominal ultrasonography. Although the patient was successfully treated by air enema, the fever persisted. The patient was then diagnosed with incomplete Kawasaki disease based on the presence of four principal clinical features. Intravenous immunoglobulin and oral aspirin were initiated. The patient defervesced and the other symptoms subsided after the treatment. Cardiac ultrasound results showed normal coronary arteries. Because of the gastrointestinal symptoms, stool samples were cultured repeatedly, only to yield normal flora. However, serum levels of anti-Y. pseudotuberculosis-derived mitogen antibody were elevated between the 7th and 18th days of the disease, thereby confirming Y. pseudotuberculosis infection. Because Y. pseudotuberculosis infection results in various clinical manifestations, we must be aware of each symptom and address them systematically.

Aspects épidémiologiques et thérapeutiques de la maladie de Kawasaki à Libreville de 2014 à 2021

Introduction.Kawasaki disease (KD) is an acute multi-systemic vasculitis of young children and infants. It is the first cause of acquired cardiac disease in children and remains poorly described in Gabon. We therefore wanted to describe the epidemiological and therapeutic aspects of this disease in two hospitals in Libreville. Patients and methods.We conducted a retrospective, descriptive study from 2014 to 2021 at the Akanda University Hospital and the El Rapha polyclinic in Libreville. All records of patients hospitalised in paediatrics for MK were included. Results.Thirty three cases of MK were retrieved, giving ahospital prevalence of0.6%. The mean age of patients was 20.4 months, the proportion of patients <18 months was 60.6% and the sex ratio was 1.7. The symptoms were observed mainly during the dry season (69.7%). Fever (100%), conjunctivitis (78.8%) and desquamation (72.7%) were the main reasons for consultation. In 24.2% of cases, a traditional medicine was administered. The average time between the onset of symptoms and hospitalization was 11 days. Once hospitalized, the diagnosis of MK was evoked within an average of 3 days. The typical form was observed in 57.6% of cases. In 100% of cases, the hemoglobin level was <12g/dl and the CRP was >15mg/l. Echocardiography was abnormal in 5 patients. Acetylsalicylic acid was the only treatment with a mean time to apyrexia of 3 days after administration. No deaths were recorded. Conclusion:the MK is relatively present in Libreville. It is important to mention it in the event of a fever of more than 5 days.

Eyelid ptosis and muscle weakness in a child with Kawasaki disease: a case report.

BACKGROUND: Kawasaki disease (KD) is an acute febrile vasculitis that often occurs in children under 5 years. Ptosis and muscle weakness associated with KD are rarely documented. CASE PRESENTATION: We present a case of KD with eyelid ptosis and muscle weakness in a 3-year-old boy. At admission, grade IV and grade III muscle strength were recorded for upper and lower limbs, respectively. Diminished patellar tendon reflex was noted. Laboratory evaluation showed hypokalemia with the serum potassium concentration of 2.62 mmol/L. Intravenous immunoglobulin (IVIG) and aspirin were initiated immediately accompanied with methylprednisolone for adjunctive therapy. Potassium supplement was administered at the same time, which resulted in the correction of hypokalemia on the 2nd day of admission but no improvement in ptosis and muscle weakness. Neostigmine testing, lumber puncture, electromyography, and cerebral and full spine MRI were performed, which, however, did not find evidence for neural and muscle diseases. On the 5th day, the fever was resolved. On the 6th day, eyelid ptosis disappeared. And on the 14th day, the muscle strength and muscle tension returned to normal, patellar tendon reflex could be drawn out normally, and the boy regained full ambulatory ability. CONCLUSIONS: KD might affect the neural and muscular systems, and KD complicated with eyelid ptosis and muscle weakness is responsive to the standard anti-inflammatory treatment plus adjunctive corticosteroid therapy.

Leukocyte proteomics coupled with serum metabolomics identifies novel biomarkers and abnormal amino acid metabolism in Kawasaki disease.

Kawasaki disease (KD) is a systemic vasculitis that can lead to severe cardiovascular complications, whereas the development and clinical usage of specific biomarkers might help diagnose KD and avoid certain complications. To this end, the molecular profiles of acute KD patients with coronary artery lesions (CAL) were first investigated through leukocyte proteomics and serum metabolomics assays. A total of 269 differentially abundant proteins and 35 differentially abundant metabolites with the top fold-changed levels were identified in acute KD patients compared to those in the healthy controls. Among them, several highly promising candidate marker proteins and metabolites indicative of KD progression were further analysed, such as the increased proteins ALPL, NAMPT, and S100P, as well as the decreased proteins C1QB and apolipoprotein family members. Moreover, metabolites, including succinic acid, dGMP, hyaluronic acid, L-tryptophan, propionylcarnitine, inosine, and phosphorylcholine, were found to be highly accurate at distinguishing between KD patients and healthy controls. Interestingly, the abnormal expression levels of a distinct set of proteins and metabolites in acute KD patients can be restored to normal levels upon intravenous immunoglobulin (IVIG) treatment. Overall, this work has revealed novel biomarkers and abnormal amino-acid metabolism as a prominent feature involved in KD patients with CAL. SIGNIFICANCE: KD is frequently concomitant with the development of life-threatening coronary vasculitis. Here, the profiles of leukocyte proteomics and serum metabolomics in acute KD patients with CALs were first investigated, and several hub molecules identified here could be used as supplemental biomarkers for KD diagnosis. Moreover, the metabolomic abnormalities especially the amino acids are particularly prominent in KD patients. Interestingly, the abnormal expression levels of a distinct set of proteins and metabolites in acute KD patients can be restored to normal levels upon IVIG treatment. Therefore, these findings might help understand the IVIG activities and also the underlying mechanisms of IVIG-resistant patients, thereby providing a new perspective for the exploration of mechanisms related to KD.

Síndrome Inflamatorio Sistémico Pediátrico Asociado a SARS-CoV-2 / Pediatric Systemic Inflammatory Syndrome Associated with SARS-CoV-2

La infección por SARS-CoV-2 es poco frecuente en niños, niñas y adolescentes, con manifestaciones clínicas leves o asintomáticos, pero desde abril del 2020, se han reportado niños gravemente enfermos en las zonas de mayor incidencia de infecciones por coronavirus, caracterizado por fiebre, síntomas gastrointestinales y marcadores de inflamación sistémica, compromiso cardiovascular importante (shock, disfunción miocárdica o miocarditis), con semejanzas a la Enfermedad de Kawasaki, tormenta de citoquinas y síndrome de activación macrofágica, denominado Síndrome Inflamatorio Multisistémico Pediátrico (PIMS/MIS-C). La patogénesis no se conoce exactamente, pero una respuesta inmune innata y adaptativa alterada asociada a autoinmunidad podría ser el mecanismo. Si bien no existe una guía terapéutica estandarizada, la mayoría de los pacientes reciben gamaglobulina intravenosa y corticoides sistémicos, y en algunos casos se requiere el uso inhibidores de interleuquinas. Se ha reportado una buena respuesta y mejoría en casi todos los niños, con una baja letalidad de 1,7-2%.

SARS-CoV-2 infection is rare in children and adolescents, with mild or asymptomatic clinical manifestations, but since April 2020, seriously ill children have been reported in areas with the highest incidence of coronavirus infections, characterized by fever, gastrointestinal symptoms and markers of systemic inflammation, significant cardiovascular compromise (shock, myocardial dysfunction or myocarditis), with similarities to Kawasaki disease, cytokine storm and macrophage activation syndrome, called Pediatric Multisystemic Inflammatory Syndrome (PIMS / MIS-C) ). The pathogenesis is not exactly known, but an altered innate and adaptive immune response associated with autoimmunity could be the mechanism. Although there is no standardized therapeutic guide, most patients receive intravenous gamma globulin and systemic corticosteroids, and in some cases the use of interleukin inhibitors is required. A good response and improvement has been reported in almost all children, with a low fatality rate of 1.7-2%.

Adjuvant herbal therapy for targeting susceptibility genes to Kawasaki disease: An overview of epidemiology, pathogenesis, diagnosis and pharmacological treatment of Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a self-limiting acute systemic vasculitis occur mainly in infants and young children under 5 years old. Although the use of acetylsalicylic acid (AAS) in combination with intravenous immunoglobulin (IVIG) remains the standard therapy to KD, the etiology, genetic susceptibility genes and pathogenic factors of KD are still un-elucidated. PURPOSE: Current obstacles in the treatment of KD include the lack of standard clinical and genetic markers for early diagnosis, possible severe side effect of AAS (Reye's syndrome), and the refractory KD cases with resistance to IVIG therapy, therefore, this review has focused on introducing the current advances in the identification of genetic susceptibility genes, environmental factors, diagnostic markers and adjuvant pharmacological intervention for KD. RESULTS: With an overall update in the development of KD from different aspects, our current bioinformatics data has suggested CASP3, CD40 and TLR4 as the possible pathogenic factors or diagnostic markers of KD. Besides, a list of herbal medicines which may work as the adjunct therapy for KD via targeting different proposed molecular targets of KD have also been summarized. CONCLUSION: With the aid of modern pharmacological research and technology, it is anticipated that novel therapeutic remedies, especially active herbal chemicals targeting precise clinical markers of KD could be developed for accurate diagnosis and treatment of the disease.

Retrospective study of the course, treatment and long-term follow-up of Kawasaki disease: a single-center experience from Poland.

Kawasaki disease (KD) is an acute, self-limited, systemic vasculitis and the most common cause of acquired coronary artery disease in pediatric population in the developed countries. It occurs mostly in Asian countries; however, due to better access to diagnostic and imaging tests, it is more frequently diagnosed among pediatric patients in Poland. The aim of this study was to describe the clinical course with special interest in cardiac involvement, treatment and follow-up of Polish patients with KD. It is a single-center retrospective study. Clinical features (including coronary involvement), laboratory results and treatment were evaluated. In our study group, we observed elevated levels of indicators of inflammation: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), leukocytosis, platelet count, fibrinogen, D-dimer and ferritin. We also noticed changes in lipid profile and liver enzymes. Twenty-four patients were diagnosed with coronary artery abnormalities. Mean day of treatment equaled 9th day of the disease. Kawasaki disease should be suspected in all pediatric patients who have fever lasting 5 days, or more particularly those under 5 years of age. It is very important to apply treatment within the first 10 days of disease due to the high risk of cardiovascular complications. Each child should have echocardiography on admission, around 14th day of the disease, after 4-6 weeks from the onset of symptoms, as well as long-term observation at least once a year due to the fact that the inflammatory process and changes in the lipid profile increase the risk of atherosclerosis. Children with coronary aneurysms should undergo check-ups every 6 months.

Breastfeeding and vitamin D supplementation reduce the risk of Kawasaki disease in a German population-based case-control study.

BACKGROUND: In Kawasaki disease (KD), a vasculitis of unknown etiology, the most serious complication is the development of coronary artery aneurysm (CAA). To date, the exact pathomechanism of KD is unknown. Both environmental and genetic factors seem to be associated with the development of the disease. METHODS: Data on KD patients recruited from the population-based German Pediatric Surveillance Study during 2012-2014 were used to evaluate the impact of various factors from the perinatal and infancy period on the development of KD. The study design was a matched case-control study with respect to age, sex and place of residence (n = 308 KD cases, n = 326 controls). All KD patients were individually re-evaluated; all fulfilled the international diagnostic KD criteria. A standardized questionnaire was used to review breastfeeding practices, vitamin D supplementation and birth characteristics. Logistic regression analyses were performed to obtain odds ratios (OR) for various risk factors among the case-control pairs. Simple measures of association were used to assess the impact of these factors on the clinical course. RESULTS: There was no difference in lengths of gestation, birth weight or parturition between KD patients and controls, but independently from each other vitamin D supplementation and breastfeeding were negatively associated with KD, even when adjusted for age, place of residence and sex. The duration of vitamin D was significantly shorter among children with KD than among children without KD (p = 0.039, OR = 0.964, 95% CI: 0.931-0.998), as was the duration of breastfeeding (p = 0.013, OR = 0.471, 95% CI: 0.260-0.853). Comparing KD patients with and without breastfeeding and/or vitamin D supplementation, there were no differences regarding developing CAA, being refractory to intravenous immunoglobulin treatment, age at onset of the disease and levels of inflammatory laboratory values. CONCLUSION: Our findings indicate breastfeeding and vitamin D supplementation to have protective effects in association with KD in our study population; however, these seem not to influence the natural course of the disease. Although the overall effects were relatively small, they nevertheless underline the overall benefit of both interventions. TRIAL REGISTRATION: Clinical Trial Registration: German clinical trial registration, http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00010071 . Date of registration was 26. February 2016. The trial was registered retrospectively.