Steroid pulse therapy for Kawasaki disease unresponsive to additional immunoglobulin therapy

Abstract

Résumé

Kawasaki disease (KD), the most common cause of acquired heart disease in children in developed nations, is an acute systemic vasculitis of childhood, primarily affecting the coronary arteries. Approximately 10% to 20% of patients do not become afebrile after standard therapy with intravenous immunoglobulin (IVIG) and oral acetylsalicylic acid, and are at an increased risk for the development of coronary artery lesions (CAL) (1–6). Such patients generally receive additional treatment with IVIG (1–5), which may prevent CAL if administered promptly (6); however, not all patients respond. Other treatment options, including corticosteroids, cyclosporine, plasma exchange and infliximab, have been reported to be effective in some cases (1–5,7). Although corticosteroids are widely used, the indications and dosage for patients with KD remain controversial. Some physicians avoid corticosteroids because of the potential risk of exacerbating CAL, but no study, including the classical work by Kato et al (8), has demonstrated a significant relationship between the use of corticosteroids and CAL.

Intravenous methylprednisolone pulse (IVMP) therapy rapidly resolves fever associated with refractory KD and is, thus, expected to prevent CAL. In small, open-label, randomized controlled studies performed by us (9) and Hashino et al (10), the prevalence of CAL was similar in patients with KD unresponsive to initial IVIG therapy who received IVMP and patients who received additional IVIG. In our study, IVMP induced faster resolution of fever, but caused more adverse effects, such as bradycardia, than did additional IVIG; however, the total antipyretic potency of these treatments was similar because fever recurred after the completion of IVMP therapy (9). In a double-blind, randomized controlled study, Newburger et al (11) reported that the addition of a single dose of IVMP to initial IVIG did not reduce the prevalence of CAL or the total length of the hospital stay; nonetheless, the initial period of hospitalization was shorter for all patients with KD who received IVMP, and the prevalence of CAL was significantly lower in patients unresponsive to IVIG who received IVMP, compared with patients who received placebo. These findings may reflect the prompt and short antipyretic activity of IVMP, and suggest that IVMP may prevent CAL in patients with severe KD.

During the past five years, we treated KD patients who were unresponsive to additional IVIG with IVMP followed by oral prednisolone to prevent recurrent fever. We now report the extremely low prevalence of CAL among the approximately 400 patients with KD managed using this treatment regimen.

METHODS

The present study prospectively evaluated a protocol for the treatment of patients with acute KD. In brief, nonresponders to initial treatment with IVIG received additional IVIG, and patients who still did not respond to additional IVIG were given IVMP followed by oral prednisolone. The subjects were consecutive patients with KD who were given IVIG in the hospital within nine days after disease onset from July 2003 through November 2008. Since December 2008, the hospital has participated in the Randomized controlled trial to Assess Immunoglobulin plus Steroid Efficacy for Kawasaki disease (RAISE) study. Acetylsalicylic acid was given orally (30 mg/kg/day to 50 mg/kg/day) until two or three days after fever cessation, followed by 5 mg/kg/day until no CAL were evident as of eight weeks after the onset of illness. Exclusion criteria were incomplete KD, acetylsalicylic acid therapy alone, initiation of IVIG treatment 10 or more days after the onset of disease, and previous treatment with IVIG or corticosteroids within two weeks before admission.

According to the protocol, an additional dose of IVIG (2 g/kg/24 h) was given to patients who had persistent or recurrent fever 48 h after completion of the initial IVIG infusion. Fever was defined as an axillary body temperature of 37.5°C or higher. Patients in whom fever did not resolve within 24 h after completion of the additional IVIG infusion received IVMP (30 mg/kg/day of methylprednisolone for three days) combined with a continuous infusion of heparin (15 units/kg/h to 20 units/kg/h). Then, oral prednisolone (1 mg/kg/day to 2 mg/kg/day) was given for one week and the dose was tapered over the following week. If fever recurred during this period, the dose of prednisolone was increased and tapered again, thereby extending prednisolone therapy. The subjects also received famotidine orally (0.5 mg/kg/day) during IVMP and prednisolone therapy to prevent gastrointestinal ulcers. The study was approved by the Human Research Ethics Committee of the hospital. Informed consent was obtained from the parents or guardians of the children for all treatments.

Echocardiograms were obtained before the start of the initial IVIG infusion, and two weeks, four weeks and one year after the onset of KD. The internal lumen diameters of the left main coronary artery (LMCA), the left anterior descending coronary artery (LAD), the left circumflex coronary artery and the proximal right coronary artery (RCA) were measured. The presence or absence of CAL was evaluated according to the criteria of the Japanese Ministry of Health and Welfare (JMHW [12]; previously named the Japanese Ministry of Health, Labour and Welfare) and those of the American Heart Association (AHA [3]). The JMHW criteria consider CAL to be present if the luminal diameter is greater than 3 mm in children younger than five years of age, or greater than 4 mm in children five years of age or older; if the internal diameter of a segment measures at least 1.5 times that of an adjacent segment; or if the coronary lumen is clearly irregular (12). The AHA criteria consider CAL to be present if the z score of the internal diameter is at least 2.5 for the LAD or proximal RCA (3). In addition, systolic dysfunction of the left ventricle, defined as a shortening fraction of less than 29%, regurgitation of the mitral and aortic valves, and pericardial effusion were evaluated.

Adverse effects of IVMP followed by oral prednisolone therapy were studied, especially hypothermia, arrhythmias, hypertension, thrombosis, femoral head necrosis, convulsions, secondary infections and gastrointestinal bleeding (9). Hypothermia was defined as an axillary body temperature below 35.0°C; bradycardia as a heart rate below the second percentile of the normal standard (13); and hypertension as a systolic or diastolic blood pressure higher than the 95th percentile of the normal standard (14). As for corticosteroid-related changes in laboratory data, hyperglycemia (fasting blood glucose greater than 6.99 mmol/L) and serum electrolyte imbalance (hyponatremia [lower than 135 mmol/L] and hyperkalemia [greater than 5.5 mmol/L]) were also assessed.

RESULTS

During the study period, 469 cases of KD in 461 Japanese patients, including eight recurrent cases, were admitted to study hospital. The following cases were excluded: incomplete KD (n=35), treated with acetylsalicylic acid alone (n=7), IVIG started 10 days or more after disease onset (n=3), and those previously treated with IVIG therapy before transfer to the hospital (n=12). A total of 412 cases of complete KD in 404 patients, including eight recurrent cases that initially received IVIG and acetylsalicylic acid within nine days after disease onset, fulfilled the inclusion criteria. A total of 227 male and 177 female patients were one to 158 months of age (median 23 months; interquartile range 12 to 45 months) at the onset of KD. The initial IVIG infusion was started two to nine days (median five days; interquartile range four to six days) after disease onset. Underlying diseases were detected in nine patients: ventricular septal defect (n=3), corrected transposition of the arteries (n=1), Down syndrome with ventricular septal defect (n=1), Niikawa-Kuroki syndrome with a double-outlet right ventricle (n=1), Williams syndrome with supra-aortic valvular stenosis (n=1), Sotos syndrome with a bicuspid aortic valve (n=1) and diabetes mellitus (n=1).

Among the subjects, 338 cases in 336 patients, including two recurrent cases, demonstrated defervescence within 72 h after the start of IVIG treatment and remained afebrile (Figure 1). Fever persisted 48 h after the completion of initial IVIG treatment in 53 cases and recurred after defervescence in 21. Consequently, an additional IVIG infusion was used to treat 74 cases (18.0%) in 72 patients, including two recurrent cases. The additional IVIG infusion was started six to 19 days (median seven days) after disease onset and before day nine in 55 cases (74.3%). Despite the second IVIG infusion, 18 cases had persistent fever and three had recurrent fever. These 21 cases (28.4% of the cases treated by additional IVIG; 5.1% of the total cases) in 20 patients, including one recurrent case, were treated by IVMP therapy followed by oral prednisolone. The clinical characteristics of the cases treated with corticosteroids are shown in Table 1. IVMP was started seven to 12 days (median eight days) after disease onset and before day 10 in 17 cases (81.0% of the 21 cases treated by IVMP followed by prednisolone). Body temperature fell rapidly soon after the start of IVMP therapy in all cases and remained below 37.5°C during the two weeks of prednisolone therapy and, subsequently, in 14 cases (66.7%). Because of recurrent low-grade fever during tapering of prednisolone, the dose was adjusted in the remaining seven cases, and the duration of prednisolone therapy was prolonged to three weeks in four cases, four weeks in two cases, and six weeks in one case. None of the subjects required other treatments such as a third course of IVIG, cyclosporine, plasma exchange or infliximab.

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Figure 1)

Flowchart showing treatment results and coronary artery lesions. Numbers in parentheses represent percentages. Numbers beside the boxes indicate the number of cases of coronary artery lesions four weeks after disease onset according to the criteria of the Japanese Ministry of Health and Welfare (JMHW) and the American Heart Association (AHA). IVIG Intravenous immunoglobulin; IVMP Intravenous methylprednisolone pulse

Figure 1 and Table 2 show cardiac complications including CAL, ventricular systolic dysfunction, mitral and aortic valvular regurgitation, and pericardial effusion. Before starting the initial IVIG infusion, four cases (1.0%) had CAL according to the JMHW criteria and 15 (3.7%) had CAL according to the AHA criteria among the 410 cases for which echocardiographic studies were available. Four weeks after disease onset, CAL were diagnosed according to the JMHW criteria in one of 338 cases (0.3%) responsive to initial IVIG, zero of 53 responsive (0.0%) to additional IVIG, and two of 21 (9.5%) responsive to corticosteroids; CAL were diagnosed according to the AHA criteria in six (1.8%), zero (0.0%) and two (9.5%) cases, respectively (Figure 1). In total, CAL were present in two of 74 cases (2.7%) unresponsive to initial IVIG and in three of all 412 cases (0.7%), according to the JMHW criteria, compared with two (2.7%) and eight (1.9%), respectively, according to the AHA criteria. The prevalence of CAL eight weeks after disease onset was similar to that four weeks after disease onset.

Among three cases of CAL at four weeks, according to both the AHA and the JMHW criteria, one that responded to initial IVIG had a lesion that was 3.4 mm in diameter (z score = 2.3) in the LMCA and a 3.0 mm lesion (z score = 3.3) in the LAD; one of the two cases that responded to corticosteroids had a 4.9 mm lesion (z score = 7.9) in the RCA and a 3.4 mm lesion (z score = 5.1) in the LAD, and the other case had a 3.4 mm lesion (z score = 3.0) in the LMCA and a 2.5 mm (z score = 2.6) lesion in the LAD. All five cases of CAL according to the AHA criteria, but not the JMHW criteria, responded to initial IVIG; z scores were at least 2.5 for RCA lesions in two cases (2.6 and 2.9) and for LAD lesions in three cases (2.6, 3.0 and 3.5). One year after disease onset, CAL completely regressed in all eight cases; consequently, none of the 384 cases (0.0%), including all 21 cases treated by corticosteroids for which echocardiographic studies were available, had CAL according to the JMHW criteria. Catheter angiography was performed six months after disease onset to evaluate the coronary arteries in two cases responding to corticosteroids, and it also showed regression of CAL. However, according to the AHA criteria, CAL were newly detected in the LAD in two other cases (0.5%) one year after disease onset: one responsive to initial IVIG had a lesion 2.7 mm in diameter (z score = 2.6) and one responsive to additional IVIG had a 2.7 mm lesion (z score = 2.7). Twenty-two patients (5.7%) had mitral regurgitation, but not CAL, one year after disease onset; the severity was trivial in 16 patients, mild in five and moderate in one.

As for the adverse effects of IVMP, sinus bradycardia in 17 cases (81.0%) and hypertension in 17 (81.0%) were most prominent (Table 1). Hypothermia occurred in three cases (14.3%), hyperglycemia in seven (33.3%) and hyponatremia in four (19.0%). All of these adverse effects improved during the following course of prednisolone and finally resolved with no special treatment. No subject experienced thrombosis, femoral head necrosis, convulsions, secondary infection, gastrointestinal bleeding or severe arrhythmias such as atrial flutter, ventricular tachycardia and atrioventricular block.

DISCUSSION

The results of our study suggest that IVMP therapy followed by oral prednisolone is useful for the prevention of CAL and for defervescence in patients with KD unresponsive to an additional IVIG infusion. Four weeks after disease onset, CAL were present, according to both the AHA and the JMHW criteria, in only two cases (2.7% of 74 cases unresponsive to initial IVIG). The incidences of CAL were, thus, considerably lower than those previously reported for severe cases of KD, ie, 26.7% to 48.6% in cases unresponsive to initial IVIG, and 60.0% to 70.6% in cases unresponsive to additional IVIG (1,2,6,9–11). Furthermore, CAL in our two cases did not have a diameter of at least 5.0 mm or a z score of at least 8.0, and completely regressed within one year after disease onset. We believe that IVMP followed by prednisolone therapy, therefore, prevented CAL in cases unresponsive to additional IVIG, resulting in the extremely low prevalence of CAL in our study group as a whole, ie, 0.7% at four weeks and 0.0% one year after disease onset according to the JMHW criteria, and 1.9% and 0.5%, respectively, according to the AHA criteria. A nationwide survey of KD in Japan (15,16) reported that the prevalence of CAL according to the JMHW criteria was 3.2% to 3.8% four weeks after disease onset; the prevalence of giant coronary aneurysms was 0.25% to 0.35%. In an analysis performed at 27 paediatric hospitals in the United States (7), coronary artery aneurysms were diagnosed in 3.3% of patients with KD, although the criteria were not clearly described. We believe our results are very encouraging because we have almost reached the final goal of treatment for KD (ie, no patients with CAL).

Our indications for corticosteroid therapy are consistent with the AHA statement (3) that the use of corticosteroids should be restricted to patients with KD in whom two infusions of IVIG have been ineffective for alleviating fever and acute inflammation. At present, corticosteroids are not superior to IVIG in terms of experience, the prevention of CAL or possible adverse effects. We, therefore, do not recommend that corticosteroids be administered to all patients with KD as initial treatment (17) or to those not responding to initial IVIG therapy (18), although this policy may change if novel benefits of corticosteroid therapy are established, for example, by the ongoing RAISE study. When our strategy was used for treatment, only 5.1% of subjects received corticosteroid therapy.

Nonetheless, early administration of corticosteroids is essential for patients with severe KD unresponsive to IVIG because prolonged inflammation may induce CAL. Among cases responding to corticosteroids in our study, 81.0% were treated with IVMP therapy before 10 days after disease onset, when CAL become evident pathologically (19) and clinically (6,20). This early onset of IVMP therapy may have played an important role in the low prevalence of CAL. If fever resolves before 10 days after disease onset in patients with severe KD, early treatment for nonresponders to additional IVIG is necessary; the response was, therefore, evaluated 24 h after completion of the additional IVIG infusion. Corticosteroids are used in various regimens for the treatment of KD; however, we prefer IVMP rather than the conventionally used dosage to resolve fever rapidly because IVMP therapy is started approximately 10 days after disease onset in patients who do not respond to initial or additional infusions of IVIG. We previously reported that IVMP promptly induces defervescence, but fever rebounds in 54.5% of patients within four days after the completion of treatment (9). Indeed, the half-life of pulse methylprednisolone is short (3 h) and the duration of action is only two days (21). In the present study, subsequent administration of oral prednisolone prevented recurrence of fever after IVMP therapy, without the need for any other treatment; seven of 21 cases (33.3%) had low-grade fever during tapering of prednisolone, but all of these cases became and remained afebrile after adjusting the dose of prednisolone. Coincidentally, our strategy is similar to the report by Gong et al (22) with respect to the oral administration of corticosteroids after IVMP therapy given to patients not responding to an additional IVIG infusion.

Corticosteroids may inhibit immune cells and inflammatory cytokines that cannot be completely suppressed by IVIG in patients with KD unresponsive to IVIG. Makata et al (23) showed that IVIG inhibits the activation of macrophages and coronary arterial endothelial cells more strongly than that of T cells in vitro, whereas dexamethasone inhibits the activation of all three cell types. CD8-positive T cells and macrophages infiltrate the tissue of coronary artery aneurysms in patients with fatal KD, and both of these cell types are speculated to play important roles in the pathogenesis of CAL (24). High concentrations of steroids intercalate into the plasma and mitochondrial membranes of immune cells, thereby altering their physicochemical properties and the activities of membrane-associated proteins (25), which are believed to contribute to rapid immunosuppression. Okada et al (26) reported that serum levels of inflammatory cytokines, such as interleukin 2 and interleukin 6, were significantly lower in patients with KD who initially received IVIG combined with prednisolone than in those who received IVIG alone. In our control study of patients with KD unresponsive to initial IVIG (9,27), plasma levels of tumour necrosis factor-alpha and monocyte chemoattractant protein-1 were reduced faster with IVMP therapy than by additional IVIG therapy. Hence, we believe that the mechanisms of corticosteroid therapy complement those of IVIG in refractory KD.

Despite the good outcomes in terms of CAL, our strategy has several shortcomings. An additional infusion of IVIG, an expensive biological product, was used to treat 18.0% of KD cases. The well-known adverse effects of corticosteroids can be induced by IVMP therapy followed by oral prednisolone for two weeks or longer. In our study group, sinus bradycardia, hypertension and hyperglycemia were the most prominent adverse effects, but did not require treatment. There were no severe complications such as thrombosis or gastrointestinal bleeding in any patient, in part because heparin and a histamine type 2 blocker were given prophylactically. We have used heparin with IVMP to prevent potential hypercoagulability and coronary thrombosis as recommended for steroid-resistant nephrotic syndrome in children (28).

The dose of acetylsalicylic acid used to treat acute KD differs from country to country, eg, 30 mg/kg/day to 50 mg/kg/day in Japan (4) and the United Kingdom (5), and 80 mg/kg/day to 100 mg/kg/day in the United States (3). Lower doses may exert lower anti-inflammatory activity than higher doses and, therefore, may have contributed to the rate of nonresponders to IVIG in the present study. However, Japanese physicians prefer lower doses because of a potentially better tolerance (ie, lower risks of liver dysfunction, gastrointestinal ulcers and other side effects). We believe that the dose of acetylsalicylic acid is unimportant because a meta-analysis conducted by Terai and Shulman (29) showed that the prevalence of CAL is strongly dependent on the IVIG dose, but independent of the acetylsalicylic acid dose.

Our study had several limitations. First, some biases may have been present because the study was noncontrolled and performed in a single centre; the effectiveness of IVMP followed by oral prednisolone should, therefore, be verified by a multicentre, controlled study. Second, echocardiographic studies were performed by several people, including paediatric cardiologists and technicians, and one-year follow-up studies were not completed in all 410 patients. Third, the z scores of coronary artery diameters derived from studies in American children (3) were applied to our Japanese subjects, and racial differences may be related to the low incidence of CAL in our study.

CONCLUSION

In cases of KD unresponsive to an additional infusion of IVIG, IVMP therapy induced prompt defervescence and subsequent treatment with oral prednisolone suppressed recurrent fever. This treatment strategy may have decreased the prevalence of CAL. Adverse effects caused by corticosteroid therapy were transient and nonsevere, although sinus bradycardia and hypertension occurred frequently.

Acknowledgments

Footnotes

REFERENCES