Pulsed Corticosteroid Therapy No Bonus in Kawasaki's

BOSTON, Feb. 14 -- For children with Kawasaki's disease, a single pulsed dose of intravenous methylprednisolone added to conventional therapy has drawn a therapeutic blank.

The addition of methylprednisolone to conventional primary therapy for Kawasaki's disease did not reduce the risk of coronary-artery abnormalities, according to a report in the Feb. 15 issue of the New England Journal of Medicine.

The data from this multicenter randomized, double-blind, controlled trial do not provide support for the addition of corticosteroid therapy to the routine primary treatment of children with Kawasaki's disease, said Jane Newburger, M.D., of Children's Hospital and Harvard here, and colleagues.

In the two-year trial, 199 children in the Pediatric Heart Network were recruited from eight centers in North America from December 2002 through December 2004. Of 199 children, 101 with 10 or fewer days of fever were randomly assigned to receive intravenous methylprednisolone (30 mg/kg of body weight) while 98 patients were randomized to placebo.

All patients received conventional therapy with intravenous immune globulin (2 g/kg) as well as aspirin (80 to 100 mg/kg per day) until they were afebrile for 48 hours and 3 mg/kg to 5 mg/kg per day thereafter.

Two-dimensional echocardiography was used to measure the internal lumen diameters of the left-main coronary artery,

the proximal and distal left-anterior-descending coronary arteries, and the circumflex, posterior descending, and proximal and distal right coronary arteries.

At week one and week five after randomization, patients in the two study groups had similar coronary dimensions, expressed as z scores adjusted for body-surface area, absolute dimensions, and changes in dimensions, the researchers reported.

Compared with patients receiving placebo, patients treated with intravenous methylprednisolone had a somewhat shorter initial period of hospitalization (P = 0.05) and at week one, a lower erythrocyte sedimentation rate (P = 0.02), and a tendency toward a lower C-reactive protein level (P = 0.07).

However, the researchers said, the two groups had similar numbers of total days spent in the hospital, numbers of days of fever, rates of retreatment with intravenous immune globulin, and number of adverse events.

The effect of IV methylprednisolone on coronary-artery outcomes at five weeks was consistent across predetermined subgroups, sex, age, presence or absence of coronary-artery abnormalities at baseline, and number of days of illness as randomization, the researchers said.

In a post-hoc subgroup analysis of children with persistent fever who were retreated with intravenous immune globulin, coronary outcomes were better in the methylprednisolone group than in the placebo group.

This suggests, the researchers said, that children at highest risk for resistance to immune globulin and for coronary abnormalities may benefit from corticosteroid treatment. Nevertheless, they added, the post-hoc nature of this analysis and practical limitations in prospectively identifying these patients are important caveats to this conclusion. Nonetheless, the treatment is not indicated for routine primary treatment of all children with Kawasaki's disease, the investigators emphasized.

Addressing other study limitations, the researchers noted that they studied only a single dose of methylprednisolone and the trial did not preclude the efficacy of other corticosteroid regimens. Furthermore, the anatomical site of temperature measurement was not standardized, and data were not collected beyond five weeks. Still, they said, new coronary aneurysms rarely develop after the first month of illness.

In summary, Dr. Newburger and her colleagues said that although pulsed corticosteroid therapy was associated with more rapid resolution of serum inflammatory markers and a somewhat shorter initial length of stay in the hospital than placebo, it did not improve coronary-artery outcomes or reduce the number of adverse events, total days in the hospital, or days of fever. Therefore, they said, it is not recommended for routine primary treatment in these children.

However, the researchers added, because the post-hoc subgroup analysis suggested that primary therapy with intravenous methylprednisolone might benefit children with persistent fever after treatment with intravenous immune globulin, future prospective studies should explore the usefulness of corticosteroid or other immunomodulatory therapies in children at highest risk for resistance to intravenous immune globulin.

In a commentary bringing perspective to the riddle of Kawasaki's disease, Jane Burns, M.D., of the University of California, San Diego, wrote that the finding that corticosteroids failed to benefit these patients underscores the difference between Kawasaki's and other chronic vasculitides for which corticosteroids are the foundation of most treatment strategies.

Commenting on the Kawasaki's puzzle, she wrote, "How can an illness look like an infection but not have a recoverable agent; look like an immune-mediated vasculitis, but not be easily treated with corticosteroids; and look like a benign, self-limited illness but be the leading cause of acquired heart disease in children? The answers to the riddle continue to elude us."

Despite the existence of an effective treatment, great challenges remain in the diagnosis and care of these children. For example, a four-decade search for causative agents had yielded only a long list of ruled-out pathogens, she said.

This self-limiting vasculitis, Dr. Burns said, affords a unique opportunity to study acute endothelial-cell injury, aneurysm formation, and vascular-wall remodeling in young children still free of the effects of aging and environmental insults.

"The lessons to be learned from Kawasaki's disease are likely to have relevance for the study of chronic conditions involving vascular injury, including atherosclerosis and abdominal aortic aneurysm," Dr. Burns wrote.

"Progress toward understanding genetic influences, refining treatment, developing diagnostic tests, and understanding the best management practices for children with coronary-artery damage can come only through adequately powered, multicenter, collaborative studies such as the clinical trial by Newburger et al," she concluded.

Dr. Burns reported receiving consulting fees from Bristol-Myers Squibb and grant support from Centocor.