Annette L. Baker

Gamma-globulin treatment of acute myocarditis in the pediatric population.

BACKGROUND Myocardial damage in myocarditis is mediated, in part, by immunological mechanisms. High-dose intravenous gamma-globulin (IVIG) is an immunomodulatory agent that is beneficial in myocarditis secondary to Kawasaki disease, as well as in murine myocarditis. Since 1990, the routine management of presumed acute myocarditis at Childrens Hospital, Boston, and Childrens Hospital, Los Angeles, has included administration of high-dose IVIG. METHODS AND RESULTS We treated 21 consecutive children presenting with presumed acute myocarditis with IVIG, 2 g/kg, over 24 hours, in addition to anticongestive therapies. A comparison group comprised 25 recent historical control patients meeting identical eligibility criteria but not receiving IVIG therapy. Left ventricular function was assessed during five time intervals: 0 to 7 days, 1 to 3 weeks, 3 weeks to 3 months, 3 to 6 months, and 6 to 12 months. At presentation, the IVIG and non-IVIG groups had comparable left ventricular enlargement and poor fractional shortening. Compared with the non-IVIG group, those treated with IVIG had a smaller mean adjusted left ventricular end-diastolic dimension and higher fractional shortening in the periods from 3 to 6 months (P = .008 and P = .033, respectively) and 6 to 12 months (P = .072 and P = .029, respectively). When adjusting for age, biopsy status, intravenous inotropic agents, and angiotensin-converting enzyme inhibitors, patients treated with IVIG were more likely to achieve normal left ventricular function during the first year after presentation (P = .03). By 1 year after presentation, the probability of survival tended to be higher among IVIG-treated patients (.84 versus .60, P = .069). We observed no adverse effects of IVIG administration. CONCLUSIONS These data suggest that use of high-dose IVIG for treatment of acute myocarditis is associated with improved recovery of left ventricular function and with a tendency to better survival during the first year after presentation.

Treatment of immune globulin-resistant Kawasaki disease with pulsed doses of corticosteroids

We describe four children with Kawasaki disease resistant to treatment with intravenously administered immune globulin who were treated with high doses of methylprednisolone. All four patients apparently responded with normalization of symptoms, and none had significant progression of coronary artery abnormalities or adverse events. We recommend pulse methylprednisolone therapy (30 mg/kg per day) during a 1- to 3-day period for patients with Kawasaki disease who do not respond to intravenous immune globulin therapy or who have recrudescent disease after adequate therapy.

Evaluation of Kawasaki Disease Risk-Scoring Systems for Intravenous Immunoglobulin Resistance

OBJECTIVES To assess the performance of 3 risk scores from Japan that were developed to predict, in children with Kawasaki disease, resistance to intravenous immunoglobulin (IVIG) treatment. STUDY DESIGN We used data from a randomized trial of pulsed steroids for primary treatment of Kawasaki disease to assess operating characteristics of the 3 risk scores, and we examined whether steroid therapy lowers the risk of coronary artery abnormalities in patients prospectively classified as IVIG resistant. RESULTS For comparability with published cohorts, we analyzed the data of 99 patients who were not treated with steroids (16% IVIG-retreated) and identified male sex, lower albumin level, and higher aspartate aminotransferase level as independent risk factors for IVIG resistance. The Kobayashi score was similar in IVIG-resistant and -responsive patients, yielding a sensitivity of 33% and specificity of 87%. There was no interaction of high-risk versus low-risk status by treatment received (steroid versus placebo) with any of the 3 risk score algorithms. CONCLUSION Risk-scoring systems from Japan have good specificity but low sensitivity for predicting IVIG resistance in a North American cohort. Primary steroid therapy did not improve coronary outcomes in patients prospectively classified as being at high-risk for IVIG resistance.

A predictive instrument for coronary artery aneurysms in Kawasaki disease

To construct a predictive instrument for developing coronary artery abnormalities in patients with acute Kawasaki disease treated with aspirin and intravenous gamma globulin within the first 10 days of illness, data available from a multicenter database of patients with acute Kawasaki disease were analyzed. A development data set (n = 212) was used to construct a sequential risk classification instrument based on easily measured baseline laboratory test results and temperature. The instrument was then validated in 3 test data sets (n = 192, 264, and 92, respectively). Risk factors used in the sequential classification instrument included baseline neutrophil and band counts, hemoglobin concentration, platelet count, and temperature on the day after infusion of intravenous gamma globulin. In the development data set, the instrument classified 123 of 212 patients (58%) as low risk; none developed coronary artery abnormalities. Among 89 patients classified as high risk, 3 of 36 female (8.3%) and 9 of 53 male patients (17.0%) developed coronary artery abnormalities. The instrument performed similarly in the 3 test data sets; no patient in any data set classified as low risk developed coronary artery abnormalities. This simple instrument allows the clinician to identify within 1 day of treatment low-risk children in whom extensive and frequent cardiac testing may be unnecessary, as well as high-risk children who require closer monitoring and may be candidates for additional therapies.

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.

Gamma globulin re-treatment in Kawasaki disease.

We retrospectively reviewed the effects of intravenous gamma-globulin (IVGG) re-treatment of 13 children with Kawasaki disease and persistent or recrudescent fever. Fever and mucocutaneous inflammation resolved within 48 hours in nine patients; fever abated in two other children after a third course of IVGG. We conclude that IVGG re-treatment of Kawasaki disease appears to be safe and may improve the clinical course.

Treatment of Kawasaki Disease: Analysis of 27 US Pediatric Hospitals From 2001 to 2006

OBJECTIVES: We sought to analyze trends in admissions and to describe therapies used for acute Kawasaki disease over a 6-year period. METHODS: The Pediatric Health Information System provides patient data including demographic variables, International Classification of Diseases, Ninth Revision codes, and services billed to patients. Patient identifiers enable tracking of medication use in and across multiple admissions within a center. We analyzed data for patients with (1) a diagnosis code for Kawasaki disease, (2) intravenously administered immunoglobulin treatment during hospitalization, and (3) discharge between January 1, 2001, and December 30, 2006, from 27 hospitals contributing complete data over the study period. RESULTS: During the study period, 5197 Kawasaki disease admissions were identified for 4811 patients; numbers increased 32.6% from 2001 (n = 678) to 2006 (n = 899). Retreatment with intravenous immunoglobulin was administered to 712 patients (14.8%) over the study period. Other antiinflammatory therapies included intravenously administered methylprednisolone (5.8%), orally administered prednisone (2.8%), and infliximab (1%). Use of infliximab steadily increased from 0.0% (0 of 678 patients) in 2001 to 2.3% (21 of 899 patients) in 2006. Coronary artery aneurysms were coded for 3.3% of patients. Male patients, patients <1 year of age, and Hispanic patients were significantly more likely to have coding for coronary artery aneurysms. CONCLUSIONS: Our report provides the first large multicenter description of agents used in the treatment of intravenously administered immunoglobulin-resistant Kawasaki disease in the United States. Trends include increased numbers of admissions attributable to Kawasaki disease and increased usage of infliximab.

Infliximab for Intravenous Immunoglobulin Resistance in Kawasaki Disease: A Retrospective Study

OBJECTIVE To test the hypothesis that first re-treatment with infliximab, compared with intravenous immunoglobulin (IVIG), might improve outcomes in IVIG-resistant Kawasaki disease. STUDY DESIGN In a two-center retrospective review from January 2000 to March 2008, we compared duration of fever and coronary artery dimensions in patients with IVIG-resistance whose first re-treatment was with IVIG compared with infliximab given for fever ≥38.0°C beyond 36 hours after first IVIG completion. RESULTS Patients in the IVIG group (n = 86, 2 g/kg) and infliximab group (n = 20, 5 mg/kg) were similar in demographics, days of fever at diagnosis, and baseline coronary artery dimensions. Patients had similar coronary dimensions 6 weeks after diagnosis, both in univariate and multivariate analysis. The infliximab group had fewer days of fever (median 8 days versus10 days, P = .028), and in a multivariate analysis, the infliximab group had 1.2 fewer days of fever (P = .033). Patients who received infliximab had shorter lengths of hospitalization (median 5.5 days versus 6 days, P = .040). Treatment groups did not differ significantly in adverse events (0% versus 2.3%, P = 1.0). CONCLUSIONS In our retrospective study, patients with IVIG-resistant Kawasaki disease whose first re-treatment was with infliximab, compared with IVIG, had faster resolution of fever and fewer days of hospitalization. Coronary artery outcomes and adverse events were similar; the power of the study was limited.

Performance of 2004 American Heart Association Recommendations for Treatment of Kawasaki Disease

OBJECTIVE: The 2004 American Heart Association (AHA) statement included a clinical case definition and an algorithm for diagnosing and treating suspected incomplete Kawasaki disease (KD). We explored the performance of these recommendations in a multicenter series of US patients with KD with coronary artery aneurysms (CAAs). METHODS: We reviewed retrospectively records of patients with KD with CAAs at 4 US centers from 1981 to 2006. CAAs were defined on the basis of z scores of >3 or Japanese Ministry of Health and Welfare criteria. Our primary outcome was the proportion of patients presenting at illness day ≤21 who would have received intravenous immunoglobulin (IVIG) treatment by following the AHA guidelines at the time of their initial presentation to the clinical center. RESULTS: Of 195 patients who met entry criteria, 137 (70%) met the case definition and would have received IVIG treatment at presentation. Fifty-three patients (27%) had suspected incomplete KD and were eligible for algorithm application; all would have received IVIG treatment at presentation. Of the remaining 5 patients, 3 were excluded from the algorithm because of fever for <5 days at presentation and 2 because of <2 clinical criteria at >6 months of age. Two of these 5 patients would have entered the algorithm and received IVIG treatment after follow-up monitoring. Overall, application of the AHA algorithm would have referred ≥190 patients (97%) for IVIG treatment. CONCLUSIONS: Application of the 2004 AHA recommendations, compared with the classic criteria alone, improves the rate of IVIG treatment for patients with KD who develop CAAs. Future multicenter prospective studies are needed to assess the performance characteristics of the AHA algorithm in febrile children with incomplete criterion findings and to refine the algorithm further.

Transforming Growth Factor-β Signaling Pathway in Patients With Kawasaki Disease

Background—Transforming growth factor (TGF)-&bgr; is a multifunctional peptide that is important in T-cell activation and cardiovascular remodeling, both of which are important features of Kawasaki disease (KD). We postulated that variation in TGF-&bgr; signaling might be important in KD susceptibility and disease outcome. Methods and Results—We investigated genetic variation in 15 genes belonging to the TGF-&bgr; pathway in a total of 771 KD subjects of mainly European descent from the United States, the United Kingdom, Australia, and the Netherlands. We analyzed transcript abundance patterns using microarray and reverse transcriptase–polymerase chain reaction for these same genes, and measured TGF-&bgr;2 protein levels in plasma. Genetic variants in TGFB2, TGFBR2, and SMAD3 and their haplotypes were consistently and reproducibly associated with KD susceptibility, coronary artery aneurysm formation, aortic root dilatation, and intravenous immunoglobulin treatment response in different cohorts. A SMAD3 haplotype associated with KD susceptibility replicated in 2 independent cohorts and an intronic single nucleotide polymorphism in a separate haplotype block was also strongly associated (A/G, rs4776338) (P=0.000022; odds ratio, 1.50; 95% confidence interval, 1.25 to 1.81). Pathway analysis using all 15 genes further confirmed the importance of the TGF-&bgr; pathway in KD pathogenesis. Whole-blood transcript abundance for these genes and TGF-&bgr;2 plasma protein levels changed dynamically over the course of the illness. Conclusions—These studies suggest that genetic variation in the TGF-&bgr; pathway influences KD susceptibility, disease outcome, and response to therapy, and that aortic root and coronary artery Z scores can be used for phenotype/genotype analyses. Analysis of transcript abundance and protein levels further support the importance of this pathway in KD pathogenesis.