Guidelines for medical treatment of acute Kawasaki disease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version).

Abstract

The primary purpose of practical guidelines is to contribute to timely and appropriate diagnosis and treatment of a given disease or condition, in addition to providing current medical information on pathogenesis and treatment, as determined by specialists in the field. Guidelines, however, should not be considered procedure manuals that limit the treatment options of practitioners, because treatment modalities other than those recommended in such guidelines are often required. Such treatment choices are the result of comprehensive analysis of all medical circumstances, including patient condition, treatment option, and disease severity. Furthermore, certain drugs shown to be useful in studies conducted in other countries may not yet have been approved for use here in Japan. The results of clinical research (including randomized controlled trials) must be verified in subsequent research, and the safety and effectiveness of a particular treatment may take several months to confirm. Recent clinical guidelines typically provide evidence levels based on study design and reported effectiveness. These are defined as follows: class Ia, systematic reviews, meta-analyses; class Ib, randomized controlled trials; class IIa, non-randomized controlled trials; class IIb, other quasi-experimental studies; class III, non-experimental reports (comparative studies, correlation studies, case studies); and class IV, opinions of committees of experts and authorities. These are given as follows: grade A, highly recommended; grade B, recommended; grade C, recommended, but evidence is uncertain; and grade D, contraindicated. The present guidelines will use these classification systems in reviewing the available evidence for the various treatments. In July 2003, the Scientific Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery published its Treatment Guidelines for Acute Kawasaki Disease (KD). These guidelines were designed to present, in a clinically relevant manner, the findings of Ministry of Health research done from 1998 through 2000 by the Onishi group at Kagawa Medical University (working under the official title, “The Pediatric Pharmaceutical Investigation Research Group”). This research had been published as “Research designed to identify and solve problems in the suitable use of pharmaceuticals for pediatric medical treatment: pharmaceuticals in cardiology” and had originally been conducted to provide clinical data for the approval of single-use i.v. immunoglobulin (IVIG). During the 9 years that have passed since the publication of the previous guideline, new data have been collected, and reports on new drug treatments have been published. Members of the International Kawasaki disease Symposium have been waiting for a revision of the previous Japanese guideline. Thus, the Scientific Committee was restructured and assigned the task of revising the guideline. Data on IVIG that have accumulated since it was approved and first marketed have confirmed the efficacy and safety of single-use IVIG therapy. In addition, the incidence of coronary artery lesions (CAL) has gradually decreased every year since IVIG treatment was introduced in Japan.1 The incidence of giant coronary artery aneurysms (CAA), however, has remained almost unchanged, which highlights the importance of timely use of second- and third-line treatments for IVIG-resistant patients. In developing the present guideline, we carefully reviewed the most recent available literature, classified evidence and efficacy, and revised suggested treatment methods, including procedures for selecting first-, second- and third-line medications, with a special focus on off-label uses. For example, the previous guideline did not mention new therapeutic agents such as infliximab (IFX), cyclosporin A (CsA), or methotrexate (MTX). In the present edition, risk/benefit considerations are also clearly presented, based on data collected in and outside Japan. Despite the publication of almost 200 reports every year on KD, there is still no universally accepted treatment for IVIG resistance. This is also the case, however, for many other disorders, such as autoimmune disease and rheumatoid conditions, given that no single medication will benefit all patients in the same way. Thus, to ensure optimal outcome, physicians must treat each patient individually. In the published results of the 21st Nationwide Survey of KD by Jichi Medical School a total of 23 730 cases of KD were reported in Japan during the 2 year period 2009–2010.1 Diagnosis of KD follows the criteria outlined in the fifth edition of the diagnosis guidelines for KD,2 which requires that at least five of the following six principal symptoms are present: (i) fever persisting ≥5 days (including fever that subsides before the fifth day in response to therapy); (ii) bilateral conjunctival congestion; (iii) changes in lips and oral cavity: reddening of lips, strawberry tongue, diffuse injection of oral and pharyngeal mucosa; (iv) polymorphous exanthema; (v) changes in peripheral extremities: reddening of palms and soles, indurative edema (initial stage); membranous desquamation from fingertips (convalescent stage); and (vi) acute non-purulent cervical lymphadenopathy. Kawasaki disease, however, may also be diagnosed when only four of the aforementioned symptoms are present, if during the period of illness either 2-D echocardiography or coronary angiography shows CAA, including dilation of coronary artery, and other causes of CAA can be excluded. A diagnosis of KD is possible even if five or more of the principal symptoms are not present, if other conditions can be excluded and KD is suspected – a condition known as incomplete KD. Indeed, approximately 15–20% of KD patients have incomplete KD. But, even if a patient has four or fewer of the principal symptoms, the illness should not be regarded as less severe, because cardiovascular abnormalities are not rare in patients with incomplete KD. For this reason, even patients with fewer than five of the aforementioned symptoms should be evaluated for KD. Early treatment is essential, particularly when fever is present, because CAL development in such cases is not uncommon. Diagnosis of incomplete KD is not a simple matter of adding up the number of overt KD symptoms: the importance and individual characteristics of each symptom of the illness must be correctly assessed. For example, redness and crusting at a bacille Calmette–Guérin (BCG) inoculation site in infants younger than 1 year and multilocular cervical lymphadenopathy in children aged ≥4 years are characteristic features of KD. The 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides defines KD as an arteritis associated with mucocutaneous lymph node syndrome, predominantly affecting medium and small arteries.3 There is very little damage to veins. The location of pathological changes clearly differentiates KD from other vasculitis syndromes, given that the principal danger of KD is inflammatory vasculitis of the coronary arteries. Edematous lesions develop in the intima media, and vascular fragility increases due to partial rupture of the internal and external elastic lamina. As a result, the arterial wall can no longer withstand its internal pressure, particularly diastolic pressure, and becomes distended and deformed, leading in severe cases to aneurysm formation. Only a few other diseases cause distension of coronary arteries. These include vasculitis resulting from Epstein–Barr virus infection, lupus, classical periarteritis nodosa, and atherosclerotic lesions. Calcification can also occur in rare cases and affect coronary arteries, for example in cases of renal dialysis in adults and herpes infection in newborns. Patients with KD may develop multiple lesions in the proximal region and vessels branching out from it. As aneurysms begin to calcify, further pathological distension or development of aneurysms and intimal thickening may develop 2–3 years later in areas with previously disrupted internal and external elastic lamina.4 The principal characteristics of KD are dilation of coronary arteries and CAA. Most CAA occur in the proximal region and its branches, and arteries with a CAA measuring ≥8 mm in diameter are very unlikely to regain their normal morphology. Right CAA may lead to occlusion or recanalization, and left CAA may progress to stenotic lesions. Rupture of the internal elastic lamina in the intima media of the dilated area weakens the artery wall, and coronary arterial pressure then becomes the direct mechanical cause of distension. In rare cases, aneurysms may develop in branches of the axillary or celiac arteries. During acute KD, vasculitis worsens during the first 7 days after disease onset. In patients with mild illness, the vasculature returns to normal by the second or third week. The principal objective in treating acute KD is minimizing the risk of developing CAL. In practice, this means quickly suppressing the acute-phase inflammatory reaction caused by KD. Except in cases of very mild KD, IVIG should be started before illness day 7. Histological studies have shown that arteritis typically develops by 8 or 9 days after KD onset. Therefore, treatment should begin before this point, to suppress arteritis and hasten resolution of fever and normalization of inflammation markers. In patients with incomplete KD, IVIG should also be begun as soon as possible after a diagnosis of KD, especially if fever is present. In approximately 80% of cases, fever should be lowered to ≤37.5°C within 48 h of starting IVIG. In 40% of IVIG-resistant patients, fever can be reduced to ≤37.5°C with additional IVIG of 1 g/kg. Persistent fever after 48 h of starting IVIG should be regarded as evidence of IVIG-resistant KD. Prevention of CAA in such patients may largely depend on the selection of subsequent treatment. In addition to CAL, other cardiovascular complications may develop in patients with acute KD, including myocarditis, pericardial effusion, valvular regurgitation, and, rarely, arrhythmia. Specific treatment may be required for these sequelae, as well as for cardiac dysfunction or heart failure. Furthermore, other symptom-specific treatment may be required for systemic complications such as edema, hypoalbuminemia, electrolyte imbalances (i.e. hyponatremia), paralytic ileus, hepatic dysfunction, cholecystitis, impaired consciousness, convulsions, anemia, diarrhea, vomiting, and dehydration. Particularly during high-dose IVIG infusion, care must be taken to prevent volume overload so as to protect the patient from complications such as heart failure. There is currently no universally accepted classification system to evaluate KD severity and need for IVIG use, although many such scoring systems have been proposed. Initial attempts were made by Asai and Kusakawa,5 which were followed by the Iwasa score6 and Harada score.7 More recently, predictive models designed to evaluate the possibility of IVIG resistance were proposed, including the Kobayashi score,8 Egami score,9 and Sano score.10 In general, such predictive models consider factors such as age, gender, days of illness, white blood cell count, %neutrophils, hematocrit, platelet count, C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, sodium, and albumin. Recently, a randomized controlled trial found that IVIG plus steroid as initial therapy for patients predicted to be at high risk for IVIG resistance improved clinical and coronary arterial outcomes.11-13 The effectiveness of such predictive models, however, has not been confirmed in large-scale prospective cohort studies or meta-analyses, and controversy remains as to whether initial therapy with IVIG plus steroids is the optimal treatment. Several second-line treatment options are available if fever persists or has reappeared at 24 h after first-line treatment. The efficacy of these second-line treatments for resistance to first-line treatment is currently being investigated by researchers in many countries, but evidence remains limited due to the lack of randomized controlled trials. Options for second-line treatment include additional IVIG, i.v. methylprednisolone pulse (IVMP), prednisolone (PSL), IFX, ulinastatin (UTI), CsA, MTX, and plasma exchange (PE). The decision to use any of these treatments requires careful consideration of patient characteristics. At present, the most commonly used second-line treatment is additional IVIG,1 which is sometimes given in combination with other medications. As for steroids, a retrospective study noted a high incidence of giant aneurysms.14 That small uncontrolled case study reported that several patients had received steroids before rupture of coronary arteries, which suggests that physicians should carefully consider the decision to use steroids for patients with KD if CAA are already present. When steroids, biologics, or immunosuppressants are given to infants, there is also a risk of long-term side-effects, and questions remain regarding the general safety of such medications. Thus, a careful risk/benefit evaluation should be done to consider the likelihood of such adverse effects versus the possibility of CAA formation. To decrease the risks of first-line IVIG resistance and CAA, it seems reasonable to consider risk stratification using predictive models and to select more-aggressive initial treatment for patients at high risk of IVIG resistance. Such patients should be treated with 2 g/kg of IVIG in combination with either 2 mg/kg per day PSL or 30 mg/kg per day IVMP. If the patients fail to respond to these treatments, a third-line treatment will be upgraded to a second-line treatment. Because few studies have assessed the efficacy of medications other than IVIG retreatment, it is impossible at this time to assign an objective order of these treatment options. The present guidelines, however, offer evidence levels and grades to assist physicians in selecting appropriate alternatives. Various methods of calculating KD patient risk scores and, thereby, estimating KD severity have been developed at a number of institutions by different physicians, based on their particular experience with KD.8-10 The Japanese Society of Pediatric Cardiology and Cardiac Surgery does not intend to limit the treatment options available to clinicians, especially when such options have already received ethics committee approval at their institution. Instead, the judgment of physicians in selecting treatments should be respected, for practical reasons as well. Such treatments may be given after a physician has established a sufficient basis for selecting a given treatment and received informed consent/assent from the family/patient (Fig. 1). Algorithm for the treatment of acute Kawasaki disease (KD). ASA, acetyl salicylic acid; CRP, C-reactive protein; IFX, infliximab; IVIG, i.v. immunoglobulin; IVMP, i.v. methylprednisolone pulse; PSL, prednisolone; UTI, ulinastatin. Currently, the most effective anti-inflammatory treatment for KD is early IVIG.15-17 The latest systematic review by the Cochrane Collaboration states that CAL development can be reduced by a single dose of 2 g/kg IVIG given before the 10th day after onset.18 Because the causes of KD are unknown, the mechanisms underlying the therapeutic benefits of IVIG remain speculative. Table 1 lists the hypothesized mechanisms of action.19-22 I.v. immunoglobulin is suitable for almost all cases of typical acute KD, that is, when KD is diagnosed based on the presence of the principal symptoms specified in the criteria of the diagnostic guideline for KD2 and the patient is at risk for CAL. For patients with symptoms that only partially fulfill the diagnostic criteria, incomplete KD may be diagnosed – if other diseases or conditions can be excluded – after which IVIG should be started as quickly as possible due to the risk of CAL.17 In cases of less severe KD or spontaneous defervescence, clinicians may refrain from IVIG, in accordance with the considerations detailed in the Ministry of Health Group Committee guidelines for IVIG (Harada score)7 and disease severity standards established at the physician's institution. Data from the 21st Nationwide Survey of KD show that IVIG was given to 89.5% of patients.1 I.v. immunoglobulin should be started on or before the seventh day after KD onset. It is essential to quickly reduce inflammation and duration of fever, definitely before illness day 8 or 9, when CAL begin to appear. Markers of systemic inflammation, for example CRP and neutrophil count, should be lowered as well. One study compared patients receiving IVIG on the fifth of illness day or earlier with those who received IVIG on the sixth through ninth days of illness. Although duration from treatment onset to defervescence was slightly longer overall among those receiving IVIG earlier, total duration of fever was shorter. Moreover, the groups did not differ in incidence of fever recurrence or additional IVIG treatment, or in number of days of hospitalization. Furthermore, 1 year after appearance of symptoms, those who had received IVIG earlier had a lower incidence of CAL.23 The suggested IVIG dosage for acute KD is 2 g/kg per day (single use), 1 g/kg per day for 1 or 2 days continuously (modified single use), or 200–400 mg/kg per day, over 3–5 days (divided dosing). Studies in a number of countries have shown that, as compared with divided-dose regimens, a single dose of 2 g/kg per day significantly reduced CAL incidence, more quickly normalized inflammation markers, and was more effective in reducing fever.4, 5 As for 1 g/kg/day use, if clinical efficacy is seen on the first day, it might not be necessary to continue treatment into the second day. The 21st Nationwide Survey of KD found that a single dose of 2 g/kg per day IVIG was used in 85% of reported cases and that 1 g/kg per day was given for 1 or 2 days in 6.2% and in 7.7% of cases, respectively.1 There is no consensus in Japan as to whether older/larger children should be treated with 2 g/kg IVIG or a lower dose. As for 2 g/kg regimen, the treatment rate varies slightly for different products, although IVIG is typically given over a period of approximately 12 h in North America. In Japan, one product permits use within a similar 12 h period, but the total volume of 2 g/kg IVIG is usually given over a period of 24 h. Because volume overload might occur when the treatment rate is too fast, which can lead to cardiac dysfunction, it is important to adhere to the recommended treatment rate and carefully observe patient hemodynamics. At present, four brands of IVIG are approved for KD in Japan (Table 2): two are processed with polyethylene glycol (PEG), one is sulfonated, and one is processed to ensure a pH of 4 (acidic). No major differences in efficacy have been reported. Table 2 lists the characteristics of these products, as described in their respective product inserts. Sulfonated human immunoglobulin G Glycin Human plasma albumin D-mannitol Sodium chloride 2500 mg 1125 mg 125 mg 500 mg 450 mg Polyethylene glycol treated human immunoglobulin G D-mannitol Glycin Sodium chloride 2500 mg 750 mg 225 mg 450 mg Human immunoglobulin G D-sorbitol Sodium hydroxide Hydrochloric acid 2500 mg 2500 mg Suitable amount Suitable amount Human immunoglobulin G Maltose hydrate Hydrochloric acid Sodium hydroxide 2500 mg 5000 mg Suitable amount Suitable amount Treatment speed: 1) On the first day, the first 30 min should be at a rate of 0.01–0.02 mL/kg/min. If no side-effects or other abnormalities are observed, treatment speed may gradually be increased to 0.03–0.06 mL/kg/min. From the second day onward, the patient may be started at the highest rate tolerated on the previous day. 2) In cases of 1-time treatment of 2000 mg (40 mL)/kg to KD patients, treatment rates in 1) above should basically be adhered to, and the i.v. infusion should given over a period of at least 12 h. Treatment speed: As there is the possibility of shock or other serious side-effects during the first hour of treatment on the first day, and also when treatment speed is increased, the patient must be carefully monitored during these times. 1) On the first day, the treatment speed should be 0.01 mL/kg/min during the first hour. When the absence of side-effects and other problems has been confirmed, the speed may be gradually increased. However, it should not exceed 0.03 mL/kg/min. On the second day and later, treatment may be started at the highest rate tolerated on the previous day. 2) In the cases of 1-time treatment of 2000 mg (40 mL)/kg i.v. to KD patients, the rates in 1) should basically be adhered to, with careful attention to sudden increases in circulatory blood volume. The i.v. should be given over a period of at least 20 h. Treatment speed: As there is a possibility of shock or other serious side-effects during the first hour of treatment on the first day, and also when treatment speed is increased, the patient must be carefully monitored during these times. 1) On the first day, the treatment speed should be 0.01 mL/kg/min during the first hour. When the absence of side-effects and other problems has been confirmed, the rate may gradually be increased. However, it should not exceed 0.03 mL/kg/min. On the second day and thereafter, treatment may be started at the highest rate tolerated on the previous day. 2) In the case of 1-time treatment of 2000 mg (40 mL)/kg i.v. to KD patients, the rates in 1) should basically be adhered to, with careful attention to sudden increases in circulating blood volume. The i.v. should be given over a period of at least 20 h. Treatment speed: 1) On the first day, the drug should be delivered at a rate of 0.01–0.02 mL/kg/min during the first 30 min. If no side-effects or other abnormalities are observed, the rate may gradually be increased to 0.03–0.06 mL/kg/min. From the second day onward, the patient may be started at the highest speed tolerated on the previous day. 2) In the case of 1-time treatment of 2000 mg (40 mL)/kg to KD patients, the treatment rates in 1) above should basically be adhered to. The i.v. should be given over a period of at least 12 h. Shock, anaphylactic symptoms (<0.1%) Hepatic dysfunction, jaundice (incidence unknown) Aseptic meningitis (incidence unknown) Acute renal failure (incidence unknown) Thrombocytopenia (incidence unknown) Pulmonary edema (incidence unknown) Thromboembolism (incidence unknown) Heart failure (incidence unknown) Shock, anaphylactic symptoms (0.1% to <5%) Hepatic dysfunction, jaundice (incidence unknown) Aseptic meningitis (incidence unknown) Acute renal failure (incidence unknown) Thrombocytopenia (incidence unknown) Pulmonary edema (incidence unknown) Thromboembolism (incidence unknown) Heart failure (incidence unknown) Shock, anaphylactic symptoms (0.1 to <5%) Hepatic dysfunction (0.1 to <5%), jaundice (incidence unknown) Aseptic meningitis (0.1 to <5%) Acute renal failure (incidence unknown) Thrombocytopenia (incidence unknown) Pulmonary edema (incidence unknown) Thromboembolism (incidence unknown) Heart failure (incidence unknown) Shock, anaphylactic symptoms (0.1 to <5%) Hepatic dysfunction, jaundice (0.1 to <5%) Aseptic meningitis (incidence unknown) Acute renal failure (incidence unknown) Thrombocytopenia (incidence unknown) Thromboembolism (incidence unknown) Heart failure (incidence unknown) Avoid co-treatment with other medications. Do not use any preparation that is not completely dissolved. Once dissolved, the medication should be used as soon as possible. Any liquid remaining after treatment should not be reused, due to the possibility of bacterial contamination. Avoid co-treatment with other medications. Do not use product if it appears incompletely dissolved or there is excessive turbidity. Administer only after returning to room temperature. Any liquid remaining after treatment should not be reused, due to the possibility of bacterial contamination. Avoid co-treatment with other medications. Do not use product if it appears incompletely dissolved or there is excessive turbidity. Do not use the product if it has been frozen. Any liquid remaining after treatment should not be reused, due to the possibility of bacterial contamination. When administering the product i.v., ensure that none of the medication leaks out of the blood vessel (in infants, if there is leakage during i.v. treatment, the skin near the insertion point may become ulcerated; cases of skin necrosis have been reported) The sulfonated product (Kenketsu Venilon-I; Teijin, Tokyo, Japan) contains serum albumin, and its sodium concentration is identical to that of saline (154 mEq/L). The two products processed with PEG come in freeze-dried (Kenketsu Glovenin-I; Nihon Shinyaku, Kyoto, Japan) and liquid (Venoglobulin IH; Japan Blood Products Organization, Tokyo, Japan) form. The suggested infusion rate for PEG-processed IG is slightly slower than that of the sulfonated product. Kenketsu Glovenin-I has a sodium concentration of 154 mEq/L. Because liquid preparations are usually refrigerated until use, they must be warmed to at least room temperature beforehand. The pH 4-processed IG (Nisseki Polyglobin-N; Japan Red Cross Society, Tokyo, Japan) comes in liquid form and should also be warmed to at least room temperature before use. During injection, it is essential that the liquid does not leak out of the vein, because this may cause necrosis of the skin. Furthermore, because the preparation contains maltose, the plasma glucose dehydrogenase method should not be used to measure blood sugar after injection, given that this method can be affected by the presence of maltose. Close monitoring and a slower infusion rate are required during the first 30–60 min, given that all the aforementioned products might result in anaphylaxis during treatment. If no adverse reactions occur during the first hour of treatment (rate, 0.01 mg/kg per min), the maximum rate (<0.03 mg/kg per min) of 2 g/kg may then be used over a course of 12–20 h. Although IVIG is the established first-line treatment for KD, approximately 15–20% of all KD patients (16.6% of patients in the 21st Nationwide Survey of KD1) have persistent or recrudescent fever after 2 g/kg of IVIG, and there has been considerable debate regarding the optimal second-line treatment for such patients. The 21st Nationwide Survey of KD reported that additional IVIG was given to a large majority (91.5%) of the 3231 IVIG-resistant patients reported during the survey period. Steroid was given together with IVIG in 29.0% of patients, IFX in 4.3%, immunosuppressants in 3.7%, and PE in 2.2% of patients. IVIG retreatment alone was effective in approximately half of the patients.24 In recent years, various scoring systems have been developed to evaluate the likelihood of IVIG resistance at the time of diagnosis. Representative scoring systems are listed in Table 3.8-10 If such scores suggest that patients are at high risk of IVIG resistance, more aggressive primary therapy in combination with the usual first-line treatment of 2 g/kg IVIG plus aspirin can be considered. In the RAISE study, Kobayashi et al. found that IVIG plus PSL, started at 2 mg/kg per day and halved every 5 days, was effective in preventing CAL formation and initial treatment failure.8, 13 In addition, Egami et al. and Ogata et al. as well as Sano et al. and Okada et al. reported the effectiveness of methylprednisolone (MP; 1–3 doses of 30 mg/kg of IVMP) in combination with IVIG.9-12 As compared with patients receiving only IVIG plus aspirin, defervescence was significantly more likely, and the incidence of CAL was significantly lower, among patients receiving IVIG plus steroids. Although further research is necessary, it seems advisable to adapt this risk-stratified strategy for severe cases so as to reduce the number of IVIG-resistant patients and further lower the incidence of CAL. I.v. immunoglobulin was found to be quite safe and, at present, has the greatest effectiveness. For these reasons, its effectiveness has been widely recognized both in Japan and in other countries, and it is also included in the recommendations of many relevant textbooks. The incidence of cardiac complications reported in the latest Nationwide KD survey decreased to approximately half that in 1997–1998, when patients only rarely received 2 g/kg IVIG. During the acute phase of the illness, that is, until approximately 1 month after disease onset, the incidence of cardiac complications was 9.3%, including dilation, 7.26%; valvular insufficiency, 1.19%; coronary aneurysm, 1.04%; giant coronary aneurysm, 0.24%; coronary artery stenosis, 0.03%; and myocardial infarction, 0.01%. Even during the convalescent phase, that is, >28 days after disease onset, complications persisted in 3.0% of patients, including dilation, 1.90%; aneurysm, 0.78%; valvular insufficiency, 0.29%; giant aneurysm, 0.22%; stenosis, 0.03%; and myocardial infarction, 0.02%. Furthermore, the number of deaths in Japan within 2 years of KD onset was 51 during the 10 year period 1991–2000, which decreased by more than 60% to 19 cases with the introduction of 2 g/kg IVIG during the subsequent 10 year period, 2001–2010 (Fig. 2).1 Incidence of coronary artery lesions (CAL) vs rate of 2 g/kg i.v. immunoglobulin (IVIG) treatment. , <30 days; , ≥30 days. I.v. immunoglobulin is derived from human plasma and is considered to have very few adverse effects and a high level of safety (Table 4). It is necessary, however, to carefully explain the possibilities of rare side-effects to patients and/or their families and to obtain their informed consent before treatment. In Japan, there have been no reports of viral contamination of any IVIG product. Donated blood is carefully screened to confirm the absence of HBs antigens, anti-HCV antibodies, an