Kawasaki Disease: Add Corticosteroids to Initial IVIG

Diana Swift

October 21, 2016

Pediatric patients with Kawasaki disease (KD), especially those resistant to intravenous immunoglobulin (IVIG), appear to benefit from early adjunctive corticosteroids, according to a small meta-analysis published online October 17 in JAMA Pediatrics.

"Corticosteroids combined with IVIG as an initial therapy showed a more protective effect compared with conventional IVIG therapy, and the efficacy was more pronounced in high-risk patients at the initiation of intervention, indicating that an early and aggressive initial anti-inflammation therapy for high-risk patients may be beneficial to improve coronary outcomes," the researchers write.

The findings point to the role of prompt adjunctive treatment in preventing potential coronary artery abnormalities (CAA) such as aneurysm and ectasia, researchers Shaojie Chen, MD, MM, PhD, a cardiologist at Shanghai General Hospital in China, and colleagues write.

Adding corticosteroids to IVIG, either as initial or rescue therapy, was associated with an overall relative risk reduction of 58% in the rate of CAA compared with IVIG alone (odds ratio [OR], 0.424; 95% confidence interval [CI], 0.270 - 0.665; P < .001).

The effect was more pronounced in patients deemed at high risk for IVIG resistance at baseline, with a relative risk reduction of 76% vs IVIG alone (OR, 0.240; 95% CI, 0.123 - 0.467, P < .001).

"Corticosteroid therapy strategy was also correlated with a more rapid resolution of fever, and the merit of corticosteroids was conferred without an increased risk of adverse events as relative to IVIG therapy," the researchers write.

KD, an acute febrile vasculitis of unknown etiology, is estimated to affect as many as 3500 US children annually. As a common cause of acquired heart disease in children, KD has serious public health implications, the authors note.

Their analysis involved 16 moderately heterogeneous studies, conducted mainly by Japanese researchers from 1999 to 2013 and including a total of 2746 children ranging in age from 2.2 to 5.4 years. More than half the patients were male. There were 1885 participants in the IVIG-only group and 861 in the adjunctive corticosteroid group. Meta-regression based on known patient variables found that the overall efficacy of corticosteroids was negatively correlated with longer duration of illness before therapy (P < .001).

In subgroup analysis, initial adjunctive therapy was also more effective than IVIG alone for CAA prevention (OR, 0.320; 95% CI, 0.183 - 0.560; P < .001), which was a benefit not observed in a subgroup of studies that administered corticosteroids as rescue therapy.

The authors note that 30% to 50% of patients in the meta-analysis developed transient coronary artery dilatation in the acute stage, and about a quarter subsequently developed serious abnormalities such as aneurysm and ectasia. Untreated CAAs carry a risk for thrombus, stenosis, myocardial infarction, and sudden death years after the acute illness, they write.

"Should all patients with KD receive corticosteroids as a part of initial treatment, or only a selected group of patients with high risk of poor prognosis?" the authors ask, referring to the superior benefit seen in patients deemed high risk for IVIG resistance. If the latter, "further questions one might raise are how best to early identify patients who are at high risk for IVIG resistance and what the strong risk factors are for the development of CAA," the researchers write.

Current risk-scoring systems for IVIG resistance need to be improved, they write, adding, "A more efficient diagnosis and treatment system is urgently needed by both clinicians and patients."

In an accompanying editorial, Robert Sundel, MD, a pediatric rheumatologist at Boston Children's Hospital in Massachusetts, outlines the changing attitudes over time to corticosteroids in KD, with sentiment fluctuating "between the extremes, from indispensable to proscribed, even as the roles of [IVIG] and aspirin have been defined."

Dr Sundel notes that steroids were long considered contraindicated in KD, a view based largely on a small 1979 observational study that reported a higher incidence of coronary artery aneurysm in patients receiving corticosteroids vs no treatment.

Recent studies, however, "are finally lending some clarity to when steroids can be beneficial in KD," he writes. Among these, "the meta-analysis of Chen et al does an excellent job of bringing together the most important KD clinical trials involving corticosteroids and of highlighting the actionable findings."

In Dr Sundel's view, although the pooled data argue strongly for the initial use of adjuvant corticosteroids in high-risk children, he cautioned that the study excluded the bulk of published reports on the grounds of low quality. Hence, "the data are not adequate to answer questions about other situations in which steroids may be effective," he said. "Analyzing the same deficient information, no matter how carefully or creatively, will not answer the numerous questions that remain."

Addressing timing of administration and initial vs rescue corticosteroid therapy, Dr Sundel took issue with the authors' view that corticosteroids are probably most beneficial when started at KD diagnosis, rather than at IVIG failure. "This conclusion is based on six studies involving 383 patients, only 167 of whom were treated with steroids, and using widely disparate therapeutic protocols," he writes. "Is this really sufficient experimental evidence to obviate late treatment with steroids when no clear alternatives are available?"

He doubts whether the findings warrant precluding steroid salvage therapy when initial therapy fails. "This is where the small number of evaluable studies (16 in all) and the heterogeneity between treatment groups impose intractable limitations on the ability of a meta-analysis to extend our knowledge," Dr Sundel writes. As in other inflammatory diseases, early steroids are better than late, he concedes, but "this does not preclude the possibility that salvage therapy with steroids might have some benefit."

He cites the need for research to identify the characteristics of IVIG-resistant children of various ethnic groups who are likely to respond to initial adjunctive therapy. Clinical trials or comparative effectiveness studies are needed to determine optimal dose, formulation, and a circumstance-appropriate regimen.

"Chen et al move us forward, but although they confirm 1 important indication for steroids in KD, they do not define the full extent or limitations of their role," Dr Sundel writes.

The authors and the editorial commentator have disclosed no relevant financial relationships.

JAMA Pediatr. Published online October 17, 2016. Article full text, Editorial full text

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