Effect of breastfeeding for 6 months on disease outcomes in patients with Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a systematic vasculitis that occurs predominantly in young children, and is the leading cause of acquired heart disease in children younger than five-years-old in developed countries. Although the etiology of KD is unknown, it is believed to be an inflammatory disease resulting from abnormal immune responses to possible environmental or infectious stimuli in genetically predisposed individuals. Breast milk contains numerous anti-inflammatory factors which may protect against allergic and autoimmune diseases. In this study we tried to examine the effect of breastfeeding for 6 months or more on disease outcomes in patients with Kawasaki disease. METHODS: A retrospective cohort study of 249 KD patients admitted from 1999- 2013 who were older than 6 months at time of diagnosis and had data regarding breastfeeding in the first 6 months of life. Demographic, clinical and laboratory data was collected by chart review. Continuous data was compared using Student's t-test and categorical variables were compared using Chi-square. Stepwise multivariate regression of all demographic factors was performed. RESULTS: Breastfeeding for 6 months or more was associated with a shorter total duration of fever (5.980± 1.405 Vs. 6.910 ± 2.573 days, p = 0.001) and a lower risk of developing persistent coronary artery lesions (CALs) (7.8% Vs. 20.2%, p-value = 0.039) on univariate analysis. Multivariate regression of all factors associated with CALs including breastfeeding for 6 months found that only the presence of CALs at baseline (ß-coefficient = 0.065, p < 0.001) and white blood count (ß-coefficient = 0.065, p = 0.018) remained significant after regression analysis. CONCLUSIONS: Breastfeeding for 6 months or more was associated with a shorter duration of fever and a lower risk of persistent CAL formation in patients with KD on univariate analysis, although this effect may be modest when other factors such as the presence of CALs at baseline and white blood cell count are also taken into consideration.

Impact of Social Distancing on Kawasaki Disease-associated Hospitalization, South Korea.

We conducted a cohort study to estimate the impact of social distancing on incidence of Kawasaki disease (KD) in Korean children, using the nationally representative data. The KD-related hospitalization rate has declined significantly from -38.8% (April) to 81.7% (June). The decrease in diagnosis of KD adds clue for infectious etiology of KD and the establishment of preventive measures.

Association between breastfeeding and Kawasaki disease: a case-control study.

The association between breastfeeding and Kawasaki disease is not fully understood. We performed a case-control study to examine the association between breastfeeding and Kawasaki disease. In this study, 389 children diagnosed with Kawasaki disease and 426 gender- and age-matched controls were identified at Renmin Hospital of Wuhan University between November 2013 and March 2019. Demographic and clinical data were collected from a structured telephone interview and medical record database. Odds ratio and 95% confidence interval for risk of Kawasaki disease were estimated. Children who were breastfed exclusively had a decrease in developing Kawasaki disease (adjusted odds ratios and 95% confidence intervals 0.53 (0.38-0.74). Although the risk reduction was not statistically different, partial breastfeeding also provided a protective effect (adjusted odds ratios and 95% confidence intervals 0.70 (0.48-1.01). In the stratified analysis, we still observed that exclusive breastfeeding was inversely associated with the development of complete Kawasaki disease (adjusted odds ratios and 95% confidence intervals 0.52 (0.31-0.88) and incomplete Kawasaki disease (adjusted odds ratios and 95% confidence intervals 0.54 (0.38-0.77). However, there was no significant association between exclusive breastfeeding and the intravenous immunoglobulin treatment response (adjusted odds ratios and 95% confidence intervals 0.69 (0.27-1.69) and the risk of coronary artery lesions (adjusted odds ratios and 95% confidence intervals 0.79 (0.49-1.31) in Kawasaki disease.Conclusion: Our analysis suggests that exclusive breastfeeding was inversely associated with the development of Kawasaki disease and that breastfeeding might be a potential protective factor against Kawasaki diseaseWhat is known• Previous studies have demonstrated that breastfeeding has been shown to potentially confer protection against several autoimmune disorders of childhood.• The association between breastfeeding and Kawasaki disease is not fully understood.What is newThe first study to evaluate the association between breastfeeding and the development of Kawasaki disease in China with a large sample size.• Exclusive breastfeeding was inversely associated with the development of Kawasaki disease and breastfeeding might be a potential protective factor against Kawasaki disease.

Bifidobacterium plays a protective role in TNF-α-induced inflammatory response in Caco-2 cell through NF-κB and p38MAPK pathways.

Kawasaki disease is an immune-mediated acute, systemic vasculitis and is the leading cause of acquired heart disease in children in the developed world. Bifidobacterium (BIF) is one of the dominant bacteria in the intestines of humans and many mammals and is able to adjust the intestinal flora disorder. The Caco-2 cell monolayers were treated with tumor necrosis factor-α (TNF-α) at 10 ng/ml for 24 h to induce the destruction of intestinal mucosal barrier system. Cells viability was detected through Cell Counting Kit-8 assay. Cell apoptosis was measured by flow cytometry and the expression of apoptosis related proteins was also detected through Western blot. The level of pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8 was detected through ELISA, Western blot and qRT-PCR, respectively. Transepithelial electrical resistance (TEER) assay was conducted to value the barrier function of intestinal mucosa. Cell autophagy and NF-κB and p38MAPK pathways associated proteins were examined through Western blot. In the absence of TNF-α treatment, cell viability and apoptosis showed no significant change. TNF-α decreased cell viability and increased cell apoptosis and BIF treatment mitigated the TNF-α-induced change. Then, we found that BIF treatment effectively suppressed TNF-α-induced overexpression of IL-6 and IL-8. Besides, the results of TEER assay showed that barrier function of intestinal mucosa which was destroyed by TNF-α was effectively recovered by BIF treatment. In addition, TNF-α induced autophagy was also suppressed by BIF. Moreover, TNF-α activated NF-κB and p38MAPK signal pathways were also blocked by BIF, SN50 and SB203580. Our present study reveals that BIF plays a protective role in TNF-α-induced inflammatory response in Caco-2 cells through NF-κB and p38MAPK pathways.

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.

Aneurismas coronarios gigantes en lactantes con enfermedad de Kawasaki / Kawasaki giant coronary aneurysms in infants with Kawasaki disease

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Health impact of childhood and adolescent soy consumption.

Soyfoods have been intensely researched, primarily because they provide such abundant amounts of isoflavones. Isoflavones are classified as both plant estrogens and selective estrogen receptor modulators. Evidence suggests that these soybean constituents are protective against a number of chronic diseases, but they are not without controversy. In fact, because soyfoods contain such large amounts of isoflavones, concerns have arisen that these foods may cause untoward effects in some individuals. There is particular interest in understanding the effects of isoflavones in young people. Relatively few studies involving children have been conducted, and many of those that have are small in size. While the data are limited, evidence suggests that soy does not exert adverse hormonal effects in children or affect pubertal development. On the other hand, there is intriguing evidence indicating that when soy is consumed during childhood and/or adolescence, risk of developing breast cancer is markedly reduced. Relatively few children are allergic to soy protein, and most of those who initially are outgrow their soy allergy by 10 years of age. The totality of the available evidence indicates that soyfoods can be healthful additions to the diets of children, but more research is required to allow definitive conclusions to be made.

Preventing coronary artery lesions in Kawasaki disease.

A form of systemic vasculitis that affects mostly small and medium-sized vessels, Kawasaki disease (KD) is most commonly found in children under the age of 5 years old. Though its etiology is unknown, KD has been the most frequent acquired heart disease in developing countries. Its incidence has increased over recent decades in many centuries, including Japan, Korea, and China. The most severe complications of KD are coronary artery lesions (CAL), including dilation, fistula, aneurysm, arterial remodeling, stenosis, and occlusion. Aneurysm formation has been observed in 20-25% of KD patients that do not receive intravenous immunoglobulin (IVIG) treatment, and in 3-5% that do receive it. Coronary artery dilation has been found in about 30% of KD patients in the acute stage, although mostly in the transient form. Diminishing the occurrence and regression of CAL is a vital part of treating KD. In this review article, I demonstrate the clinical method to prevent CAL formation used at the Kawasaki Disease Center in Taiwan.

Quercetin Inhibits Inflammasome Activation by Interfering with ASC Oligomerization and Prevents Interleukin-1 Mediated Mouse Vasculitis.

Interleukin-1ß (IL-1ß) is a highly inflammatory cytokine that significantly contributes to both acute and chronic inflammatory diseases. The secretion of IL-1ß requires a unique protease, caspase-1, which is activated by various protein platforms called inflammasomes. Data suggests a key role for mitochondrial reactive oxygen species for inflammasome activation. Flavonoids constitute a group of naturally occurring polyphenolic molecules with many biological activities, including antioxidant effects. In this study, we investigated the effect of three flavonoids, quercetin (QUC), naringenin, and silymarim on inflammasome activation. We found that QUC inhibits IL-1ß secretion by both the NLRP3 and AIM2 inflammasome in a dose dependent manner, but not the NLRC4 inflammasome. QUC inhibition of the inflammasome was still observed in Atg16l1 knockout macrophages, indicating that QUC's effect was autophagy independent. Since QUC inhibited both NLRP3 and AIM2 inflammasomes but not NLRC4, we assessed ASC speck formation. QUC reduced ASC speck formation and ASC oligomerization compared with controls. Additionally, QUC inhibited IL-1ß in Cryopyrin-Associated Periodic Syndromes (CAPS) macrophages, where NLRP3 inflammasome is constitutively activated. In conclusion, QUC inhibits both the NLRP3 and AIM2 inflammasome by preventing ASC oligomerization and may be a potential therapeutic candidate for Kawasaki disease vasculitis and other IL-1 mediated inflammatory diseases.

Breastfeeding and Risk of Kawasaki Disease: A Nationwide Longitudinal Survey in Japan.

BACKGROUND AND OBJECTIVES: Kawasaki disease (KD) is the most common cause of childhood-acquired heart disease in developed countries. However, the etiology of KD is not known. Aberrant immune responses are considered to play key roles in disease initiation and breastfeeding can mature immune system in infants. We thus examined the association between breastfeeding and the development of KD. METHODS: We used a nationwide population-based longitudinal survey ongoing since 2010 and restricted participants to a total of 37 630 children who had data on their feeding during infancy. Infant feeding practice was queried at 6 to 7 months of age, and responses to questions about hospital admission for KD during the period from 6 to 30 months of age were used as outcome. We conducted logistic regression analyses controlling for child and maternal factors with formula feeding without colostrum as our reference group. RESULTS: A total of 232 hospital admissions were observed. Children who were breastfed exclusively or partially were less likely to be hospitalized for KD compared with those who were formula fed without colostrum; odds ratios for hospitalization were 0.26 (95% confidence interval: 0.12-0.55) for exclusive breastfeeding and 0.27 (95% confidence interval: 0.13-0.55) for partial breastfeeding. Although the risk reduction was not statistically significant, feeding colostrum only also provided a protective effect. CONCLUSIONS: We observed protective effects of breastfeeding on the development of KD during the period from 6 to 30 months of age in a nationwide, population-based, longitudinal survey in Japan, the country in which KD is most common.

Suppressive influence of seasonal influenza epidemic on Kawasaki disease onset.

  Kawasaki disease (KD) is an acute systemic vasculitis presenting as an infantile febrile disease. In Japan, the widespread cedar plantation commenced in 1945 has been correlated with the increased incidences of both KD and allergic rhinitis (pollinosis) since the early 1960s. We previously showed that KD was a pollen-induced, delayed-type hypersensitivity that displays biphasic peaks in both summer and winter. KD incidences decrease suddenly around February, particularly after influenza epidemics. Here we investigated the reason for a drastic decrease in KD onsets directly before spring pollen release following rapid increase after autumn pollen release leading to the biphasic pattern. We separately analyzed weekly incidences of KD and influenza in Tokyo (1987-2010) and Kanagawa (1991-2002). Repeated measures for the analysis of variance followed by Bonferroni's multiple comparison tests were performed to compare KD incidence over 3 consecutive weeks, including the weeks when the mean KD prevalence showed the steepest decrease. Next, the week with peak influenza incidence was reset for each year. KD incidence over 3 consecutive weeks, including the new origin week (adjusted week 0), was similarly analyzed. In Tokyo and Kanagawa, KD incidence significantly decreased only after resetting the influenza peak time. These findings suggested that influenza epidemics suppressed KD onset.

Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group.

BACKGROUND: The purpose of this statement is to update the recommendations by the American Heart Association (AHA) for the prevention of infective endocarditis that were last published in 1997. METHODS AND RESULTS: A writing group was appointed by the AHA for their expertise in prevention and treatment of infective endocarditis, with liaison members representing the American Dental Association, the Infectious Diseases Society of America, and the American Academy of Pediatrics. The writing group reviewed input from national and international experts on infective endocarditis. The recommendations in this document reflect analyses of relevant literature regarding procedure-related bacteremia and infective endocarditis, in vitro susceptibility data of the most common microorganisms that cause infective endocarditis, results of prophylactic studies in animal models of experimental endocarditis, and retrospective and prospective studies of prevention of infective endocarditis. MEDLINE database searches from 1950 to 2006 were done for English-language papers using the following search terms: endocarditis, infective endocarditis, prophylaxis, prevention, antibiotic, antimicrobial, pathogens, organisms, dental, gastrointestinal, genitourinary, streptococcus, enterococcus, staphylococcus, respiratory, dental surgery, pathogenesis, vaccine, immunization, and bacteremia. The reference lists of the identified papers were also searched. We also searched the AHA online library. The American College of Cardiology/AHA classification of recommendations and levels of evidence for practice guidelines were used. The paper was subsequently reviewed by outside experts not affiliated with the writing group and by the AHA Science Advisory and Coordinating Committee. CONCLUSIONS: The major changes in the updated recommendations include the following: (1) The Committee concluded that only an extremely small number of cases of infective endocarditis might be prevented by antibiotic prophylaxis for dental procedures even if such prophylactic therapy were 100% effective. (2) Infective endocarditis prophylaxis for dental procedures is reasonable only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis. (3) For patients with these underlying cardiac conditions, prophylaxis is reasonable for all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. (4) Prophylaxis is not recommended based solely on an increased lifetime risk of acquisition of infective endocarditis. (5) Administration of antibiotics solely to prevent endocarditis is not recommended for patients who undergo a genitourinary or gastrointestinal tract procedure. These changes are intended to define more clearly when infective endocarditis prophylaxis is or is not recommended and to provide more uniform and consistent global recommendations.

Kawasaki disease: infection, immunity and genetics.

Kawasaki disease is an acute multisystem vasculitic syndrome of unknown etiology occurring mostly in infants and children younger than 5 years of age. In developed countries, Kawasaki disease is currently the leading cause of acquired heart diseases in children. However, it is still a mysterious disease. In this article, we reviewed and summarized from the aspects based on infection agents, host immune dysregulation and genetic background intended to establish a feasible infection-immunogenetic pathogenesis for this mysterious disease and also provided the rational strategy to explore optimal treatment of this disease.

Maternal antibody against toxic shock syndrome toxin-1 may protect infants younger than 6 months of age from developing Kawasaki syndrome.

The symptoms of Kawasaki syndrome (KS) suggest a possible relationship between KS and superantigen(s). The infrequent occurrence of KS among young infants may be due to a passive maternal antibody. We investigated the antibody titers for superantigens (toxic shock syndrome toxin [TSST]-1, staphylococcal exotoxin B, and streptococcal pyrogenic exotoxins C and A) in 15 patients with KS who were <6 months of age prior to gamma globulin therapy and in 10 mothers of patients with KS <6 months of age. Significant findings were observed for only TSST-1 among the 4 anti-superantigens. The proportion of patients with KS who had high anti-TSST-1 titers was significantly higher than that among infant control subjects (33% vs. 5%, respectively; P=.031). The mean anti-TSST-1 titer for the mothers was significantly lower than that of adult control subjects (P=.021). Among infants <6 months of age, TSST-1 may be related to KS, and a maternal antibody may protect infants from developing KS.

Suppression of coronary vasculitis in a murine model of Kawasaki disease using an angiogenesis inhibitor.

Coronary arteritis can be induced in C57BL/6 mice with a single intraperitoneal (ip) injection of Lactobacillus casei cell fragments. Histologic sections resemble the vasculitis and aneurysms observed in the medium-sized coronary arteries of children with Kawasaki disease. Since endothelial cells could play an important role in the development of vasculitis, a recently described angiogenesis inhibitor that is not an immunosuppressive agent, AGM-1470 (derived from Aspergillus fumigatus), was used to evaluate its therapeutic potential in this model. A total of 32 mice were administered 0.5 mg of sterile L. casei preparation ip on day 0 and randomized to either a treatment (AGM-1470, 27mg/kg sc alternate days) or a control (vehicle only) protocol. Hearts were harvested on day 14 (early disease) or at the end of the study on day 28 (established disease). Histologic sections were scored blindly for vasculitis. Day 14 sections from both protocols manifested only minimal disease, indicating that the vasculitis had not yet matured. By day 28, the AGM-1470 group had significantly less coronary vasculitis than the control group (0.7 vs 2.6, p < 0.005, respectively). These studies suggest that endothelial cells may play an active role in this pathologic process and that angiogenesis inhibitors, such as AGM-1470, could be useful tools for the treatment and understanding of vasculitis.

Probable role of Streptococcus pyogenes in Kawasaki disease.

Over the past 25 years, the clinical course of Kawasaki disease has been defined, the prevalence and nature of the cardiovascular effects widely understood, and pathological changes in the most severe cases well described. However, the aetiology and pathogenesis of this puzzling disease have remained unclear, thus specific therapy is not yet available. Because of some close clinical similarities between this disease and streptococcal scarlet fever, particular attention has been paid to the possible role of Streptococcus pyogenes as an aetiological agent in this illness. Until now, however, group A beta-haemolytic streptococci have never been consistently isolated from any patients; in addition, the titre of anti-streptolysin 0 is not raised, and lack of response to antibiotics is a feature of this disease. Our long series of investigations over more than 10 years, which will be covered in the present review, were performed in an attempt at elucidating causative agent(s) of Kawasaki disease. This has led to our firm belief in the probable role of S. pyogenes in the pathogenesis of this disease, despite the lack of fulfillment of Koch's postulates, on the basis of the following findings. Patients with Kawasaki disease recovering from the acute, febrile phase of the illness exhibited an exaggerated cell-mediated reactivity, as measured by the macrophage migration inhibition test, to group A beta-haemolytic streptococci, their pyrogenic exotoxin and streptolysin 0 as well as to several mammalian muscle cell extracts which are allegedly related antigenically to the cell wall and/or cytoplasmic membrane of S. pyogenes. Protoplast-like "spherical bodies" varying in diameter from 0.5 to 1.5 microns, and devoid of cell walls, were detected in the buffy coats of peripheral blood from patients with this disease, and stained distinctly by immuno-electron microscopy using, as a primary antibody, a rabbit antiserum to S. pyogenes- derived protoplasts, and followed by absorption with protoplasts from Staphylococcus aureus and Escherichia coli. Newborn mice infected with S. pyogenes having no capacity to confer cell-mediated immunity even in adult murine hosts, and reinfected 4-6 weeks later with another strain of the same species of bacteria which is able to elicit cellular immunity, showed a lack of humoral response to streptococcal antigens, leaving intact cell-mediated immunity. Such a biased immunological characteristic is an exact counterpart of that of Kawasaki disease patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Possible role of Streptococcus pyogenes in mucocutaneous lymph node syndrome. XV. Potential utility of streptococcal pyrogenic exotoxin toxoid for the prophylaxis and treatment of MCLS.

Mice made tolerant to streptococcal pyrogenic exotoxin (SPE) by neonatal inoculation with SPE emulsified in incomplete Freund's adjuvant demonstrated early thrombocytopenia followed by thrombocytosis. This state is the perfect counterpart of patients with mucocutaneous lymph node syndrome (MCLS). We have hypothesized that by inducing tolerance to SPE, the biological activities of the toxin might play leading roles in the pathogenesis of MCLS. In the present investigations, the efficacy of SPE on the prophylaxis and treatment of diseases caused by Streptococcus pyogenes (including MCLS) were monitored using the murine model system accompanied with a platelet-counting technique. The mice, rendered tolerant due to neonatal SPE inoculation and followed by immunization with SPE toxoid about 1 month prior to the provocative injections with SPE, demonstrated an almost complete lack of response to the provocation, keeping platelet counts within the normal range of values (except for a marginally significant thrombocytosis 7 days postprovocation). Moreover, anti-SPE titers of the sera from the mice sacrificed on day 35, at which point the observation was terminated, were proved to be markedly elevated when compared with controls. These findings seem to suggest that immunization with the toxoid could overcome tolerance, resulting in the production of an antitoxin. In a second experiment that examined the effect of administration with rabbit antiserum raised against the toxoid, the antiserum-treated mice demonstrated a transitory thrombocytosis on 7 days postprovocation with SPE, followed by an abrupt decrease in the number of platelets from day 10 onward.(ABSTRACT TRUNCATED AT 250 WORDS)