INTRODUCTION — Kawasaki disease (KD), formerly called mucocutaneous lymph node syndrome, is one of the most common vasculitides of childhood [1]. It is typically a self-limited condition with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy. However, KD may cause cardiovascular complications, particularly coronary artery (CA) aneurysms. These, in turn, can lead to coronary occlusion and cardiac ischemia and result in significant morbidity or even mortality. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation".)
The frequency of CA aneurysm development and associated morbidity and mortality have dramatically decreased as a result of treatment with intravenous immune globulin (IVIG). This therapy is effective for preventing CA abnormalities, but the benefits in children who have already developed CA aneurysms are more equivocal. Thus, expeditious diagnosis and timely treatment are critical to achieve the optimal clinical outcome. The initial treatment of KD is discussed in this topic review. The clinical manifestations, diagnosis, cardiovascular sequelae, and treatment of refractory KD are reviewed elsewhere. (See "Refractory Kawasaki disease" and "Kawasaki disease: Clinical features and diagnosis" and "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation".)
IDENTIFICATION OF PATIENTS AT HIGH RISK FOR IVIG RESISTANCE — Once the diagnosis of KD has been made (algorithm 1), the next step is to determine the risk of intravenous immune globulin (IVIG) resistance since it is associated with a higher risk of coronary artery (CA) abnormalities (algorithm 2). Patients who do not respond to IVIG treatment may benefit from more aggressive initial therapy for KD.
The first retrospective study to look at risk factors for refractory KD used the database of the 2003 to 2004 nationwide survey of KD in Japan [2]. Of the 15,940 patients with KD, 20 percent did not respond to initial IVIG therapy. These nonresponders had a dramatically higher risk for CA aneurysms (odds ratio [OR] 10.38, 95% CI 6.98-15.45) and giant CA aneurysms (OR 54.06, 95% CI 12.84-227.65) compared with responders. One of the risk factors identified was initial treatment at or before the fifth day of illness (OR 1.89, 95% CI 1.66-2.15). However, a review of data from the 1997 to 2004 nationwide KD surveys suggests that earlier initial treatment might have reflected more clear-cut and therefore more severe disease at presentation [3]. Thus, the high incidence of retreatment among children initially treated before the sixth day of illness could simply support the impression that severe vasculitis requires more aggressive therapy.
No single risk factor identifies a majority of children likely to have an incomplete response to the initial dose of IVIG; therefore, scoring models based upon combinations of risk factors have been developed to predict initial response to IVIG therapy. Most such attempts, however, have been inadequate to use clinically, with sensitivities ranging from 86 to 33 percent and specificities from 87 to 62 percent [4-6]. In addition, risk factors are not necessarily transferable between populations. For example, the Kobayashi score effectively identified 95 percent of Japanese children in Japan likely to respond incompletely to the initial dose of IVIG [6]. When used in the United States, however, 64 percent of patients who were resistant to IVIG were not flagged as high risk by the Kobayashi score [7]. Three other Japanese risk scores that are sensitive and specific for identifying children in Japan at high risk of being resistant to the first dose of IVIG are similarly insensitive in American patients with KD [8].
Japanese children — Risk stratification has proven useful in identifying Japanese children treated in Japan for KD who are at high risk of IVIG resistance [4,6,9]. Further studies are needed to prospectively validate criteria for identifying high-risk patients in other populations [8]. The Japanese studies have led to the augmentation of initial therapy with glucocorticoids or other agents in certain patients at high risk for IVIG resistance (refractory KD). Extrapolating the data from Japanese children in Japan to other populations, including children of Japanese ethnicity in other countries, is increasingly common in view of the strength of the benefit in Japan [9]. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation", section on 'Risk factors' and "Refractory Kawasaki disease", section on 'Risk factors' and 'Glucocorticoids' below.)
The risk of IVIG resistance in Japanese children with KD can be ascertained using the Kobayashi score (figure 1) [6] or other similar validated scores [4,10]. These scores can be used to determine which patients might benefit from augmented initial therapy. The data are strongest for the addition of glucocorticoids to initial IVIG treatment in children at high risk of failing to respond to IVIG alone. As an example, the RAISE (Randomized controlled trial to Assess Immunoglobulin plus Steroid Efficacy for Kawasaki disease) trial examined the addition of glucocorticoids to initial IVIG in children with a Kobayashi score ≥5 [9]. In this randomized trial, 125 patients received IVIG and aspirin plus prednisolone, while 123 received IVIG and aspirin alone. The incidence of CA abnormalities was significantly lower in the group that received prednisolone (4 patients [3 percent] versus 28 patients [23 percent]). Serious adverse events were similar between both groups. The other risk scores have not yet been used in clinical trials for this purpose. (See 'Additional therapy for patients at high risk for IVIG resistance' below.)
The Kobayashi score includes the following risk factors [6]:
●Sodium ≤133 mmol/L (2 points) [6]
●Aspartate aminotransferase (AST) ≥100 int. units/L (2 points) [5,6]
●C-reactive protein (CRP) ≥10 mg/dL (≥100 mg/L) (1 point) [4,6]
●Neutrophils ≥80 percent of the white blood cell (WBC) count differential (2 points) [4,11]
●Platelet count ≤300,000/mm3 (1 point) [6]
●Early diagnosis, with initial treatment at or before the fourth day of illness (2 points) [2,4,6,12]
●Age ≤12 months (1 point) [4,6]
Additional risk factors for nonresponsiveness to initial IVIG therapy identified in retrospective studies include recurrent episodes of KD [2], male sex [2], elevated alanine aminotransferase (ALT) [4,5], and low serum albumin [13].
Non-Japanese children — Non-Japanese children are also at increased risk of failing to respond to initial therapy with IVIG alone when they fulfill risk scores (such as the Kobayashi score), but these scores have low sensitivity and poor negative predictive value outside of Japan [8]. In non-Japanese populations, different risk factors can identify children in whom significant CA dilatation is likely to occur despite treatment with IVIG. Extrapolating from the RAISE trial, some centers elect to treat such children with adjunct glucocorticoids because they believe that the potential benefits outweigh potential risks. It is important to stress, however, that limited data are available demonstrating that such an extrapolation is valid [14].
One risk model appears to successfully predict risk factors for developing CA aneurysms despite initial treatment with IVIG in children in the United States with KD [15]. The development database retrospectively analyzed 903 patients with KD from Boston and San Diego, and the validation cohort consisted of 185 well-characterized subjects in a Pediatric Heart Network clinical trial at eight North American centers. The final score used several of the same risk factors that are central to the Japanese models, with the unique addition of enlarged CAs at presentation (Z-score >2). Predictors of CA aneurysms at two to eight weeks were baseline Z-score of left anterior descending or right CA ≥2.0, age <6 months, any Asian race, and CRP >13 mg/dL. Each of the variables is given 1 point, except 2 points for baseline Z-score of left anterior descending or right CA >2.0. Patients are grouped into low (0 to 1 points), moderate (2 points), or high (3 to 5 points) risk. The odds of developing aneurysms (Z-score >2.5) two to eight weeks after onset of KD was 40-fold greater in high- than low-risk groups in the validation cohort (OR 44.0, 95% CI 10.8-180).
●Children with enlarged CAs at presentation, prior to IVIG treatment – A retrospective study of 500 children with CA aneurysms found that CA Z-scores at presentation were highly predictive of outcomes [16,17]. The suggested cutoff for initial Z-scores ranges from 2.0 to 3.0, depending upon the desired balance between minimizing unnecessary use of glucocorticoids versus minimizing development of CA aneurysms in the greatest number of children [7]. A subsequent retrospective study of 121 children with CA aneurysms (Z-score ≥2 to <10) at the time of diagnosis who were treated with glucocorticoids plus IVIG (n = 30), infliximab plus IVIG (n = 58), or IVIG alone (n = 33) found that children treated with glucocorticoids were 31 percent less likely to have progression of CA aneurysm size compared with IVIG alone [18]. In addition, no children treated with glucocorticoids needed additional treatment due to persistent fever compared with 21 percent treated with IVIG alone.
Another retrospective study of 157 European children of mixed ethnic backgrounds with KD found that the presence of any echocardiographic abnormality on the initial echocardiogram (CA dilatation, CA aneurysm, pericardial effusion, perivascular brightness of the CAs, left ventricular dysfunction) was strongly associated with IVIG resistance and development of CA lesions within the first six weeks [19]. These findings are relatively subjective and difficult to quantify. Thus, further studies are needed before other echocardiogram abnormalities are included as a criterion for addition of glucocorticoids.
●Young infants with KD – Children under six months of age have up to a 35 percent risk of developing CA aneurysms despite timely treatment with IVIG, and children from 6 to 12 months of age are also at higher risk of failing to respond to IVIG [20,21]. Young age is included in many risk scores, including the Kobayashi score, and is the most sensitive marker of increased CA risk. Accordingly, it is used by some centers as an independent indication for augmentation of initial therapy with glucocorticoids.
●Children with KD associated with shock – Though the literature consists mostly of case reports and case series, children with KD who present with shock are at higher risk of failing to respond to IVIG. Studies have not been performed to determine whether adjuvant glucocorticoids improve CA outcomes, but they may have other benefits in nonseptic shock, such as decreasing capillary leak and other manifestations of shock [22].
●Children with KD presenting with macrophage activation syndrome (MAS) – From 1 to 5 percent of patients with KD develop MAS, with cytokine storm, cytopenias, hepatic dysfunction, and risk of thrombosis. These patients have a higher rate of failing to respond to IVIG and an increased mortality rate. Outcomes are poor in children with KD and MAS whose diagnosis and treatment are delayed. Thus, augmentation of initial IVIG is an attractive option even though it is not clear whether addition of glucocorticoids alone affects outcomes [23]. (See "Kawasaki disease: Complications", section on 'Macrophage activation syndrome' and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
INITIAL THERAPY — Our approach to the treatment of patients who are diagnosed with KD is consistent with American Heart Association (AHA) and American Academy of Pediatrics (AAP) guidelines [14,24]. The recommended initial therapy includes intravenous immune globulin (IVIG; 2 g/kg) administered as a single infusion over 8 to 12 hours. All published guidelines also include aspirin (30 to 50 mg/kg daily divided into four doses) with IVIG as initial treatment of KD (algorithm 2) unless it is contraindicated (see 'Aspirin' below). Risk of IVIG resistance should also be determined prior to initiating therapy (see 'Identification of patients at high risk for IVIG resistance' above). Patients who are at high risk for IVIG resistance are additionally treated with systemic glucocorticoids [9].
Children who meet partial criteria (incomplete KD) (table 1 and algorithm 1) are treated no differently from children who fulfill diagnostic criteria for KD. A review of almost 16,000 cases enrolled in the 17th Japanese nationwide survey of KD found that 16.1 percent of children with coronary artery (CA) abnormalities had incomplete KD, meeting fewer than five diagnostic criteria [25]. A retrospective review evaluated 195 patients with KD who developed CA aneurysms at four centers in the United States from 1981 to 2006, 53 (27 percent) of whom were not treated for KD, because they did not fulfill diagnostic criteria [26]. Application of the 2004 AHA/AAP guidelines [27] would have resulted in the administration of IVIG therapy to all but three of these children (98 percent).
Patients are usually observed for 24 hours (minimum 12 hours) following completion of initial IVIG therapy to confirm resolution of fever. Recommendations concerning the timing of follow-up of children discharged after responding to IVIG depend upon whether CAs are normal or dilated and the patient's risk factors for ultimately failing to respond to IVIG (see 'Monitoring for fever' below). Refractory KD is defined as persistent or recurrent fever of any magnitude between 36 hours to approximately two weeks after the start of treatment and is discussed in detail separately. (See "Kawasaki disease: Clinical features and diagnosis" and "Incomplete (atypical) Kawasaki disease" and 'Identification of patients at high risk for IVIG resistance' above and "Refractory Kawasaki disease".)
Treatment for all patients — Theoretically, it should be possible to stratify therapy for KD according to disease severity defined by the likelihood of developing CA aneurysms. However, no criteria have been developed that can reliably distinguish children who are not at risk of developing severe disease at the time of initial presentation. Thus, all children diagnosed with KD or incomplete KD are treated with IVIG and also aspirin, unless contraindicated, at the time of diagnosis (algorithm 2) [1].
Intravenous immune globulin — Since the first report of IVIG therapy in patients with KD in 1983 [28], randomized, controlled studies and meta-analyses have confirmed that IVIG started within 10 days of fever onset reduces the risk of CA aneurysms from approximately 25 to <5 percent [27,29-34]. IVIG has additional beneficial effects in KD, such as rapid resolution of the almost universal lymphocytic myocarditis seen in the disease. The recommended IVIG dose for treating patients who are newly diagnosed with KD is based upon the superiority of a single 2 g/kg dose in a randomized control trial compared with five daily doses of 400 mg/kg/day [31]. Treatment is most effective if given within the first 7 to 10 days of the illness but is still given after 10 days in patients with persistent fever, ongoing signs of systemic inflammation, and/or CA abnormalities. IVIG is given as a single infusion over 8 to 12 hours. (See 'Aspirin' below.)
The mechanism of the beneficial effect of IVIG remains unknown. IVIG appears to have a generalized anti-inflammatory effect, with reduction of fever and acute-phase reactants such as C-reactive protein (CRP) and fibrinogen. However, the erythrocyte sedimentation rate (ESR) may rise further after IVIG because positively charged proteins such as immunoglobulins increase the sedimentation of red blood cells, regardless of the degree of inflammation [35]. Possible mechanisms by which IVIG improves outcomes in KD include modulating cytokine levels and production, augmenting T cell suppressor activity, downregulating antibody synthesis, and providing anti-idiotypic antibodies [36-38].
Cost-benefit analysis reveals that IVIG treatment of KD is one of the most cost-effective medical therapies available, leading to tremendous short- and long-term savings [39].
Efficacy and dose — IVIG with aspirin is effective in decreasing the risk of CA aneurysms. There is a dose-response effect of IVIG (the highest dose studied is 2 g/kg), but several meta-analyses have shown that CA outcomes are not affected by addition of aspirin [27,29-34]. In addition, treatment with IVIG usually results in faster resolution of fever and more rapid normalization of acute-phase reactants, serum lipoprotein profiles, and myocardial contractility [40]. (See 'Efficacy and dose' below.)
A meta-analysis reported decreasing risk of CA aneurysms with increasing doses of IVIG [34]. The duration of fever also decreased with increasing IVIG dosing. The relative risks (RRs) of developing CA aneurysms 30 days after receiving varying doses of IVIG plus aspirin, compared with aspirin alone, were:
●IVIG dose of 1 g/kg, RR 0.81 (95% CI 0.43-1.50)
●IVIG dose of 1.2 g/kg, RR 0.51 (95% CI 0.29-0.92)
●IVIG dose of 1.6 g/kg, RR 0.35 (95% CI 0.15-0.83)
The dose-response effect of IVIG implies that additional modifications of this treatment regimen might lead to further improvement in outcome. There are no data, however, documenting effects of treating patients with doses greater than 2 g/kg. Further dose increases are limited by the cost and availability of IVIG, as well as by potential side effects. There is also concern for the large volume that is administered to patients who may not be able to tolerate the fluid load, although, in clinical practice, this has not been a significant problem in patients with KD. Also unclear is the potential for additional benefit with the prevalence rate for CA complications already reduced fivefold with IVIG standard therapy. Nevertheless, the dose response to IVIG provides the theoretical basis for the practice of IVIG retreatment of patients who have persistent or recrudescent fever after initial IVIG therapy. (See 'Adverse effects' below and "Refractory Kawasaki disease".)
There are no randomized, controlled studies comparing IVIG therapy alone with combined IVIG and aspirin therapy. In one retrospective report from Taiwan, IVIG 2 g/kg was administered initially to patients without concomitant aspirin treatment [41]. Low-dose aspirin (as an antiplatelet agent) was subsequently prescribed following resolution of fever. In 128 of 162 patients (80 percent), fever resolved within 24 hours of completion of IVIG therapy. At the time of diagnosis, 10 percent of patients had CA aneurysms. Subsequent CA aneurysms formed in 3 percent of patients whose fever normalized within 24 hours of completing IVIG therapy. These results are comparable with those seen in studies of children treated initially with both IVIG and aspirin. (See 'Aspirin' below.)
Administration — IVIG is most effective when administered in a single infusion given over 8 to 12 hours. This is illustrated by the following studies:
●A randomized trial of 549 patients with KD demonstrated that a single dose of IVIG (2 g/kg), compared with a four-day treatment regimen (400 mg/kg for four consecutive days), led to a more rapid resolution of fever, normalization of laboratory evidence of acute inflammation, and lower risk of CA abnormalities [31].
●In the previously mentioned meta-analysis, two studies demonstrated that a single infusion of IVIG (2 g/kg), compared with a regimen of 400 mg/kg per day for five days, was more effective at reducing the frequency of CA aneurysms (RR 0.22, 95% CI 0.08-0.65) [34]. In addition, the duration of fever and the length of hospital stay also were decreased.
Timing of therapy — The effectiveness of IVIG therapy is best established for patients treated within the first 7 to 10 days of illness [27]. There are few data on the efficacy of IVIG therapy administered more than 10 days after the onset of KD in preventing CA aneurysms. The AHA and AAP guidelines recommend that IVIG be administered to children with KD within the first 10 days of illness and, if possible, within the first seven days of illness because the rate at which children with KD develop aneurysms increases significantly after the ninth day of illness. Nonetheless, IVIG should still be administered to patients with KD who present after the 10th day of illness if they have persistent fever without another explanation, aneurysms, or evidence of ongoing systemic inflammation (eg, elevated CRP or ESR) [27].
Two retrospective studies reported a lower incidence of cardiac sequelae and a shorter duration of clinical symptoms (eg, fever) for patients treated before day 5 or 6 of illness [42,43]. On the other hand, in the nationwide surveys of KD in Japan, there was no difference in the incidence of CA aneurysms between 4731 patients treated early (≤day 4 of illness) and 4020 patients treated between days 5 and 9. However, patients treated early were more likely to require retreatment with IVIG [2,4,6,12]. (See "Refractory Kawasaki disease".)
In one report of 16 children with CA aneurysms, patients treated after a mean of 17 days of illness appeared to benefit with improvement in echocardiographic abnormalities already present at the time of treatment [44]. A case-control study of 150 children treated with IVIG 10 to 20 days (cases) or 4 to 8 days (controls) after the onset of illness found that the rate of coronary artery lesions (CALs; dilatation or aneurysm) during the convalescent period was significantly higher in cases (27 percent) versus controls (1 percent) [45]. However, the effectiveness of IVIG treatment after 10 days was unclear because approximately one-half of patients in the late group had already developed CALs before receiving IVIG. In fact, among patients without CALs before treatment with IVIG, the percentage developing de novo CALs after treatment was 8 percent in both the early- and late-treated groups.
Type of intravenous immune globulin — IVIG is a biologic product pooled from donor plasma that undergoes a number of manufacturing procedures including different methods of sterilization. These processes may result in variable efficacy in treating patients with KD among the different brands of IVIG. However, data are not sufficient to identify a brand of IVIG that is most efficacious in the treatment of KD [34,46,47].
Adverse effects — Despite its advantages, IVIG is an expensive and potentially toxic intervention. Adverse effects include aseptic meningitis, hemolytic anemia, and transmission of bloodborne pathogens.
Significant hemolysis requiring transfusion can occur within 5 to 10 days of infusion due to isoagglutinins in the IVIG products [24]. The risk of hemolysis is dose related and is particularly increased in patients who receive more than one dose of IVIG. Children with non-type O blood are also at increased risk of developing significant hemolysis following IVIG therapy.
The greatest long-term concern with any blood product is the potential transmission of bloodborne pathogens. As an example, more than 100 cases of hepatitis C occurred in recipients of a single brand of IVIG in 1994 (none were in children with KD) [48]. Since that time, manufacturers have introduced a variety of elaborate sterilization procedures including lyophilization, pasteurization, and addition of solvent detergents. These are generally effective in rendering the product free of at least lipid-soluble viruses so that transmission of hepatitis C is no longer a risk. However, other pathogens, such as parvovirus, might escape neutralization by these procedures [49]. Other stages of the purification of IVIG may inactivate detergent-resistant viruses, and confirmed reports of transmission of viruses are rare with available preparations of IVIG [50]. Clinicians should remain cognizant of such risks, but significant toxicity is rare, and the benefits outweigh risks in children with confirmed KD. The adverse effects of IVIG are discussed in detail separately. (See "Intravenous immune globulin: Adverse effects".)
Aspirin — Aspirin was one of the first treatments used for KD because of its anti-inflammatory effects (eg, reduction in the duration of fever) and antiplatelet effects [51]. However, it is unclear if the addition of aspirin provides greater anti-inflammatory effects than does IVIG alone. Several meta-analyses have shown that aspirin does not affect aneurysm formation [32,33]. The question of whether the benefits of aspirin warrant its continued use in KD is unlikely to be answered since all prospective studies that have demonstrated the effectiveness of IVIG in treating KD also employed moderate to high doses of aspirin.
The dose of aspirin used to achieve an anti-inflammatory effect during the acute phase of illness is relatively high, with a recommended range of 30 to 100 mg/kg per day in four divided doses [1,27,52,53]. We use 30 to 50 mg/kg per day (maximum 4 g/day), the lower end of the dose range recommended by the AHA and AAP guidelines [14,24], because higher doses have an increased potential for adverse effects without confirmed benefits. We do not hesitate to hold the aspirin for any contraindication, particularly infection with, or exposure to, varicella or influenza. Once fever has been absent for 48 hours, patients are generally switched to a low dose of aspirin, 3 to 5 mg/kg per day, for its antiplatelet effect. This low-dose aspirin regimen is continued until laboratory markers of ongoing inflammation (eg, platelet count and ESR) return to normal, unless CA abnormalities are detected by echocardiography. The antithrombotic regimen for patients with persistent CA aneurysms is reviewed in greater detail separately. (See "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Antithrombotic therapy'.)
CRP usually normalizes within one to two weeks of IVIG treatment; however, normalization of ESR typically takes an additional one to two months. Thus, aspirin therapy generally is complete within two months of the onset of disease in children with no CA abnormalities. Alternative regimens, such as treatment with high-dose aspirin until the 14th day after fever onset [30,31] or low-dose aspirin (ASA; 3 to 5 mg/kg) from the start of therapy [54], are used by other practitioners. Other anti-inflammatory agents, such as ibuprofen, may be used if the patient has prolonged arthritis and is not taking high-dose aspirin.
Efficacy and dose — There are no randomized, controlled studies comparing only high-dose aspirin (>80 mg/kg per day) with moderate-dose aspirin (≤50 mg/kg per day) in resolving the signs and symptoms of inflammation in KD [52]. A review of six randomized, controlled studies, which evaluated varying doses of IVIG and aspirin and aspirin alone using blinded echocardiographic assessment to detect CA aneurysms, demonstrated no difference in the prevalence of CA aneurysms between patients receiving moderate-dose aspirin (30 to 50 mg/kg per day) and those receiving high-dose aspirin (80 to 120 mg/kg) [33]. The prevalence of CA aneurysms at respective subacute (30 days) and convalescent (>60 days) time points based upon IVIG dose was as follows:
●Aspirin alone, 26 and 18 percent
●IVIG dose of <1 g/kg and aspirin, 18 and 14 percent
●IVIG dose of 1 to 1.2 g/kg and aspirin, 16 and 10 percent
●IVIG dose of 1.6 g/kg and aspirin, 9 and 6 percent
●IVIG dose of 2 g/kg and aspirin, 4 and 4 percent
The risk of CA aneurysms was only dependent upon IVIG dose. For each IVIG dose, the risk of CA aneurysms was the same in each of the aspirin subgroups when evaluated at 30 days (subacute) and 60 days (convalescent) after diagnosis. This suggests that aspirin at any dose does not affect the incidence of CA changes.
Several retrospective studies have examined different aspirin doses, with no differences seen in the rate of CA abnormalities [54-57]. In a retrospective study from Taiwan, children with KD received either >30 mg/kg/day of aspirin until the fever resolved and then 3 to 5 mg/kg/day of aspirin (n = 305) or low-dose aspirin (3 to 5 mg/kg/day) from the onset of initial treatment (n = 546). There were no significant differences between the groups with regard to IVIG resistance rate, CA lesion formation, or duration of hospitalization. The group on initial moderate-to-high-dose aspirin had significantly lower levels of hemoglobin and higher levels of CRP and hepcidin compared with the low-dose aspirin group [55].
In another retrospective study, children with KD at two Canadian centers received either low-dose aspirin (3 to 5 mg/kg) from diagnosis or initial high-dose aspirin (80 to 100 mg/kg) used for a mean of 4.5 days [56]. The odds of IVIG resistance were greater in the low-dose aspirin group (odds ratio [OR] 3.2, 95% CI 1.1-9.1) in a multivariable logistic regression analysis, with a second dose of IVIG given in 28/122 patients (23 percent) in the low-dose group compared with 11/127 (7.3 percent) in the high-dose group. There was no significant difference in the rate of CA aneurysms in the subacute phase (2/117 or 1.7 percent in the low-dose group compared with 6/125 or 4.8 percent in the high-dose group). A retrospective, nonrandomized cohort study avoided some of the risks of other retrospective studies by comparing outcomes at three institutions that routinely used high-dose aspirin (80 mg/kg/day) to outcomes at three centers that used low-dose aspirin (3 to 5 mg/kg/day), rather than different doses used at the same institution (potential bias by indication) [54]. Overall, 1213 subjects were included, 848 receiving high-dose and 365 low-dose aspirin. There were no differences in the risk of CA abnormalities in the low-dose versus high-dose groups (22.2 versus 20.5 percent, 95% CI -4.5 to 5.0 percent). (See 'Intravenous immune globulin' above.)
Adverse effects — The risks of aspirin therapy are low and appear to be similar to those reported in other settings, including chemical hepatitis with elevated transaminases, transient hearing loss, dose-related hemolytic anemia [58], and, rarely, Reye syndrome. Theoretically, these risks may be increased in patients with KD. Aspirin-binding studies have suggested that the hypoalbuminemia of children with KD predisposes them to toxic levels of free salicylate despite measured (total) salicylate levels within the therapeutic range [59]. In addition, several cases of Reye syndrome in the setting of varicella or influenza infection have been documented in patients on high-dose aspirin therapy for KD [60,61]. The recommended therapeutic regimens are designed to maintain any potential beneficial effects of aspirin in KD while minimizing the risk of toxicity by lowering the dose to antiplatelet levels as soon as inflammation is improving. The result is that serious aspirin side effects are rare among children treated for KD [62]. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Clinical features' and "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.)
Additional therapy for patients at high risk for IVIG resistance — Patients who are at high risk for IVIG resistance (see 'Identification of patients at high risk for IVIG resistance' above) are at increased risk for CA abnormalities and therefore are usually treated with additional therapy.
Glucocorticoids — Glucocorticoids have been shown to decrease the rate of CA abnormalities in Japanese patients with KD at high risk for IVIG resistance [9,63-66], but findings regarding the benefits of glucocorticoids are variable in other patients with KD and with different glucocorticoid regimens [18,27,67-69]. We suggest adding glucocorticoids to the initial treatment regimen for KD in Japanese patients with a Kobayashi score ≥5 (figure 1) (or other positive, validated, high-risk score) [9]. We suggest the addition of glucocorticoids in non-Japanese children who meet one or more of the high-risk criteria for IVIG resistance outlined above, such as age <6 months or CA Z-score ≥3.0 [14,16]. (See 'Identification of patients at high risk for IVIG resistance' above.)
The protocol in Japan, where children are typically hospitalized longer than in the US, is to give children 2 mg/kg/day of intravenous prednisolone for five days, then switch to oral dosing starting with 2 mg/kg/day for five days, then 1 mg/kg/day for five days, and then finally 0.5 mg/kg/day for five days or until afebrile. A randomized, open-label, blinded-endpoints trial of 248 Japanese patients with severe KD at high risk for IVIG resistance found that CA abnormalities were significantly decreased in those treated according to the "RAISE" protocol with prednisolone in addition to IVIG and aspirin compared with IVIG and aspirin alone (3 versus 23 percent) [9]. The IVIG dose was 2 g/kg given over 24 hours. Aspirin was dosed at 30 mg/kg/day until the patient was afebrile and then decreased to a dose of 3 to 5 mg/kg/day.
At the author's institution in the US, patients receiving adjuvant glucocorticoids are given a total of 15 days of prednisone, five days each on 2 mg/kg, 1 mg/kg, and 0.5 mg/kg. Most patients defervesce quickly on intravenous glucocorticoids, and, if their echocardiograms are stable, they are switched to oral glucocorticoids before five days have passed. As long as fever or coronary vasculitis is not fully controlled, however, intravenous therapy is continued for at least five days to ensure that absorption of glucocorticoids is optimized. Patients are switched from intravenous to oral glucocorticoids 12 to 24 hours before expected discharge to allow time for monitoring the patient's condition on the oral regimen. CRP is measured two to three times per week until the concentration is ≤5 mg/L. Patients who fail glucocorticoid therapy should be reassessed to confirm that they have received the proper diagnosis.
Overall efficacy — A systematic review and meta-analysis that examined treatment with glucocorticoids plus IVIG compared with IVIG alone in both randomized trials and observational studies in Japanese and non-Japanese populations found a significantly lower rate of CA abnormalities in the combination therapy group (OR 0.42, 95% CI 0.27-0.66) [70]. This effect was more pronounced if glucocorticoids were given as part of initial therapy (OR 0.32, 95% CI 0.18-0.56) or if patients were predicted to be at high risk for IVIG resistance at baseline based upon criteria similar to those listed above (OR 0.24, 95% CI 0.12-0.47). Effects were less pronounced in patients who received glucocorticoids as rescue therapy two or more days after initial IVIG therapy. Similar results with regard to the efficacy of initial treatment with glucocorticoids were found in another systematic review and meta-analysis [71]. Therapeutic recommendations based upon these analyses are limited by the fact that different studies have used varying formulations (eg, oral prednisolone, intravenous prednisolone, intravenous methylprednisolone [IVMP], pulsed-dose IVMP), durations (eg, single dose, 5 days, 15 days), and doses (2 to 30 mg/kg/day) of glucocorticoids. (See "Refractory Kawasaki disease", section on 'Risk factors'.)
Adverse effects — Many studies support the utility of glucocorticoid treatment in children at high risk of failing IVIG therapy alone, but clinicians should be aware of potential toxicity of glucocorticoids. Though not well reported in the literature, rare patients with KD develop extremely high white blood cell (WBC) counts (>40,000/mm3), acute hepatomegaly and transaminitis, and even gastrointestinal hemorrhage due to the combination of aspirin and glucocorticoids. Bradycardia is the most common cardiovascular abnormality seen in patients with rheumatologic or immunologic disease who are treated with systemic glucocorticoids. In a retrospective Japanese cohort study of 176 patients with severe KD, the incidence of bradycardia (heart rate less than the first percentile for normal children) in patients who received initial therapy with IVIG plus prednisolone from February 2012 onward was significantly higher compared with those treated with IVIG alone prior to this date (79 versus 7 percent) [72]. Slowing the rate of the glucocorticoid infusion was effective at alleviating the bradycardia, and, in fact, bradycardia was associated with responsiveness to initial therapy. The other potential side effects of systemic glucocorticoids are discussed in greater detail separately. (See "Major side effects of systemic glucocorticoids".)
Cyclosporine — Cyclosporine, a calcineurin inhibitor, has shown some efficacy for refractory KD and for initial therapy of KD in patients at high risk for IVIG resistance. A multicenter, randomized, open-label, blinded endpoints trial of 175 children in Japan at high risk for IVIG resistance based upon a Kobayashi score ≥5 found a lower incidence of CA abnormalities at any evaluation point between treatment day 3 and week 12 in the group treated with cyclosporine (5 mg/kg/day for five days) as part of the initial treatment regimen compared with placebo (14 versus 31 percent, respectively; risk ratio 0.46, 95% CI 0.25-0.86) [73]. The incidence of adverse events was similar between the two groups. This study had several limitations, including lack of blinding. Further studies are needed before cyclosporine can be recommended as additional therapy for patients with KD at high risk for IVIG resistance.
Therapies not recommended for initial treatment
Tumor necrosis factor inhibition — Elevated levels of tumor necrosis factor (TNF) alpha are identified in some patients with KD. As such, anti-TNF-alpha agents, such as etanercept or infliximab, have been studied as both adjuvant therapy for primary disease [18,74-76] and as monotherapy for refractory KD. (See "Refractory Kawasaki disease".)
A randomized trial of 201 patients at eight centers in North America that compared initial therapy with intravenous immune globulin (IVIG) plus etanercept versus IVIG plus placebo showed no significant overall difference in treatment resistance [76].
One trial randomly assigned 196 children with KD to a single intravenous dose of infliximab 5 mg/kg or placebo in addition to standard initial therapy [75]. No difference was seen between the two groups in the rate of treatment resistance, defined as a temperature of 38°C or higher at 36 hours to seven days after completion of the intravenous immune globulin (IVIG) infusion (11 percent for both). The median number of days with fever was shorter in the infliximab group compared with placebo (one versus two days), and IVIG reaction rates and some markers of inflammation were lower in the treatment group, but no effect on the incidence of coronary artery (CA) abnormalities was noted. A retrospective study that examined use of infliximab in addition to IVIG for initial therapy in patients with CA aneurysms is discussed above [18]. (See 'Non-Japanese children' above.)
A trial comparing infliximab versus IVIG for salvage therapy of IVIG-resistant KD is enrolling patients at 30 sites in North America, though smaller studies do not show clear benefits on CA outcomes from the addition of infliximab as augmented initial or salvage therapy. Accordingly, while awaiting further data, we do not endorse the routine use of TNF-alpha inhibitors in KD in view of the data supporting the benefits of glucocorticoids in IVIG-resistant KD. The use of anti-TNF-alpha agents in refractory KD is discussed in detail separately. (See "Refractory Kawasaki disease", section on 'TNF inhibition (infliximab)'.)
Other therapies — Ulinastatin, a medication available in only certain countries, is a urinary trypsin inhibitor that has anti-inflammatory effects. It may prevent tissue and organ damage, particularly neutrophil-mediated injury that is suspected to play a role in refractory KD. Ulinastatin was less effective as initial monotherapy than IVIG in a small, randomized trial in Japan [77]. A retrospective study suggests that it may have some benefit when used with IVIG and aspirin for initial therapy, but further studies are needed before ulinastatin can be recommended for treatment of KD [78].
REFRACTORY KD — Fever persists or returns in 10 to 15 percent of patients with KD who are initially treated with intravenous immune globulin (IVIG) and aspirin [1,24]. Persistent fever of any magnitude usually indicates ongoing vasculitis, although other causes of fever should be excluded. Barring extenuating circumstances, children are not usually retreated until at least 36 hours after the start of their initial IVIG infusion, as fever before this time may represent a reaction to the medication or slow response to therapy. In children with severe coronary artery (CA) involvement or other signs of active vasculitis and inflammation, rescue therapy need not be postponed for more than 18 to 24 hours after the first dose of IVIG.
It is extremely important not to dismiss mild temperature elevations in children with KD, because persistent or recrudescent fever is the single strongest risk factor for the development of CA aneurysms [79]. Thus, additional therapy is indicated in any patient with KD who does not respond fully to initial therapy. Indeed, this is the reason that researchers are focusing on augmented initial therapy for patients at high risk of failing to respond to the initial dose of IVIG. Evaluation for and treatment of refractory KD are discussed in detail separately. (See "Refractory Kawasaki disease".)
COMPLICATIONS — Complications in patients with KD primarily result from cardiovascular involvement and include coronary artery (CA) aneurysms, depressed myocardial contractility and heart failure, myocardial infarction, arrhythmias, and peripheral arterial occlusion. Noncardiac complications are generally uncommon and include shock and multiple organ dysfunction syndrome, macrophage activation syndrome (MAS), altered renal function, acute abdominal catastrophes, and sensorineural hearing loss. Patients with KD shock syndrome or MAS are at higher risk of failing to respond to IVIG and are therefore often given augmented initial therapy. (See 'Non-Japanese children' above and 'Additional therapy for patients at high risk for IVIG resistance' above.)
KD complications and their management are discussed in greater detail separately. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation" and "Kawasaki disease: Complications".)
PROGNOSIS — Mortality due to KD is rare among children treated with intravenous immune globulin (IVIG). Long-term morbidity is primarily related to the degree of coronary artery (CA) involvement. Recurrence of KD is uncommon.
Mortality — The reported mortality rate of KD is low (0.1 to 0.3 percent) since the advent of IVIG therapy [80,81]. The rare fatal outcomes from severe cardiac involvement in KD are generally the result of either myocardial infarction or arrhythmias, although aneurysm rupture can also occur. Mistaken or late diagnosis, or complete lack of IVIG treatment, is associated with potentially fatal outcomes [82].
In Japan, a registry of 6576 patients with KD has been established for longitudinal evaluation of ongoing morbidity and mortality [80]. As of 1998, standardized mortality rates based upon Japanese vital statistics data demonstrated an increased mortality rate within the first two months of the disease, but, after the acute phase, the mortality rate was not increased compared with the general population. A subsequent follow-up of this cohort was published in 2013 [83]. Subjects at that time were 17 to 39 years of age, representing follow-up of 17 to 27 years. Overall age-adjusted mortality remained no higher than in the general Japanese population, and subjects with no cardiac sequelae actually had a decreased standardized mortality rate (SMR). However, the SMR was 1.86 for those with cardiac sequelae of KD, including 7 of 14 deaths among those with sequelae of KD definitely or presumptively ascribed to late effects of KD.
Long-term morbidity — Long-term morbidity for patients following KD depends upon the severity of CA involvement.
●Children without cardiovascular abnormalities detected in the acute and subacute phase (up to eight weeks after onset of disease) appear to be clinically asymptomatic 10 to 21 years later [84]. However, the long-term effect on cardiovascular health is unknown, and it is unclear whether these patients will be at increased risk for atherosclerotic heart disease as adults compared with those who never had KD.
●CA dilatation <8 mm generally regresses over time, and most aneurysms <6 mm in diameter fully resolve by echocardiogram [85]. Decreases in luminal diameter result from thrombi or myofibroblastic proliferation. Thrombi may calcify, though even grossly normal vessels without calcifications do not demonstrate normal vascular reactivity [86]. Thus, children with KD who develop CA dilation following the illness should be followed indefinitely after KD, a point highlighted by a report of sudden death in a 3.5-year-old child three months after dilated CAs had regained a normal echocardiographic appearance [87]. Autopsy revealed obliteration of the lumen of the left anterior descending CA because of fibrosis, with evidence of ongoing active inflammation in the epicardial arteries. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation", section on 'Coronary artery abnormalities'.)
●Patients with giant aneurysms (maximum diameter ≥8 mm) are at the greatest risk for myocardial infarction resulting from CA occlusion [88]. In these lesions, thrombogenesis is promoted by the combination of sluggish blood flow through the massively dilated vessel and the frequent development of stenoses at the proximal and/or distal ends of the aneurysms. One Korean case series suggested that mortality in such children is low (1 out of 47 patients after a mean duration of follow-up of 12.5 years), though morbidity is significant [89].
Recurrence — There appears to be a low rate of recurrence for KD, as illustrated by data from the 13th and 14th nationwide surveys of KD in Japan. After three years of follow-up, 2 percent of patients were reported to have a recurrence of KD with a rate of 6.9 per 1000 person-years [90]. The highest incidence was in children less than three years of age who had cardiac sequelae during the first episode. Recurrences most commonly occurred within the first 12 months after the initial episode of KD.
In this report, however, a recurrent episode was defined as rehospitalization of a patient who satisfied the diagnostic criteria for KD. In order to determine a true recurrence rate, follow-up studies must use a more precise definition of recurrence: a separate episode fulfilling KD criteria after an earlier occurrence has fully resolved, typically at least two months later. Episodes that occur sooner may well represent recrudescent or persistent KD and not truly recurrent disease. Nonetheless, patients with recurrent disease appear to be at increased risk for cardiac sequelae [91]. Consequently, practitioners should adopt a more conservative approach to possible recurrences of KD, including a lower threshold for using IVIG if the diagnosis is uncertain, and earlier use of salvage therapy for incomplete responses to IVIG.
FOLLOW-UP — Follow-up after discharge includes monitoring for recurrence of fever and repeat echocardiograms to assess for cardiac involvement. Live-virus vaccines are postponed due to decreased immunogenicity in children who have received intravenous immune globulin (IVIG) treatment [24].
Monitoring for fever — It is important that caregivers remain alert to mild temperature elevations in children treated for KD. In one study of 378 patients, those who remained febrile had an almost ninefold increased risk of developing coronary artery (CA) abnormalities compared with those who responded to initial IVIG (12.2 versus 1.4 percent) [92].
Accurate core temperature measurements are important for optimal management of KD patients in view of the strong association between elevated temperatures and CA abnormalities. Temperatures should be taken orally or rectally [93]. Inaccurate temperature measurement may explain the rare reports of development of CA abnormalities after children apparently became afebrile based upon axillary temperature measurement [94].
Caregivers are typically instructed to check the child's temperature every six hours until 48 hours after the last fever. At this point, the aspirin is decreased to 3 to 5 mg/kg once daily, and the temperature is taken daily before the aspirin dose. The temperature should also be taken if the child feels warm or recurrent clinical signs of KD seem to be developing. Such heightened vigilance continues until the next outpatient follow-up visit, which usually occurs 7 to 10 days after discharge. Any child who develops a fever should be evaluated for recurrence of other manifestations of inflammation, for interval CA dilatation on echocardiogram, and for other causes of fever. These patients should be retreated for presumed recrudescence of KD unless there is clear evidence of another explanation for fever. (See "Refractory Kawasaki disease".)
Cardiac evaluations — After the baseline echocardiogram is obtained at diagnosis, echocardiography is usually repeated at approximately two and six weeks of illness to evaluate for CA involvement. [27]. Children who remain clinically well following IVIG therapy and have a normal echocardiogram at two weeks seldom develop new abnormalities. Conversely, those with CA aneurysms, or those at higher risk for developing CA dilatation, warrant more frequent echocardiograms. Patients also should have repeated clinical evaluations during the first one to two months following diagnosis of KD to detect arrhythmias, heart failure, valvular insufficiency, or myocarditis. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation", section on 'Cardiac evaluation'.)
The relative risk for myocardial infarction based upon CA abnormalities detected by echocardiogram can be assessed at six to eight weeks after the onset of illness [14]. Based upon this risk, guidelines have been developed by the American Heart Association (AHA) and the American Academy of Pediatrics (AAP) for medical therapy, physical activity, and the schedule and content of follow-up visits (table 2) [14]. Children with CA abnormalities generally receive antithrombotic therapy with aspirin, warfarin, or other agents, as well as regular cardiac evaluation. (See "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Management'.)
Physical activity — Children generally do not feel completely well for several weeks after KD, and they therefore tend to limit their own activity level. Restrictions are dependent upon the risk of myocardial infarction and should be imposed only in children with increased risk of thrombosis during the convalescent stage of disease, particularly those with giant CA aneurysms (table 2). The restrictions should be determined in consultation with the child's cardiologist.
Vaccinations — The administration of live-virus vaccines, including measles and varicella, should be postponed for at least 11 months in children who have been treated with IVIG. Passively acquired antibodies persist for an extended period of time (up to 11 months) following IVIG administration and may interfere with vaccine immunogenicity [24]. Patients may be vaccinated during a measles outbreak or after a varicella exposure as long as the vaccine is repeated at least 11 months after the administration of IVIG (unless there is serologic evidence of adequate immunity). Schedules for other routine childhood vaccinations do not need to be altered. (See "Post-exposure prophylaxis against varicella-zoster virus infection".)
Influenza immunization, recommended in all children over six months of age, is particularly important in those who require long-term high-dose aspirin therapy because of the possible increased risk of Reye syndrome [24,95]. In addition, we suggest giving the varicella vaccine to patients receiving long-term low-dose aspirin therapy, even though epidemiologic data only implicate high- and medium-dose aspirin in the development of Reye syndrome [95,96]. As of 2017, no cases of Reye syndrome had been reported in children receiving the influenza or varicella vaccines while on long-term low-dose aspirin therapy [97]. (See "Vaccination for the prevention of chickenpox (primary varicella infection)" and "Seasonal influenza in children: Prevention with vaccines".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kawasaki disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Kawasaki disease (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Rationale for treatment – Patients who fulfill the criteria for Kawasaki disease (KD) or incomplete KD (algorithm 1) require treatment (algorithm 2) because of the risk of cardiovascular complications that may result in significant morbidity and even mortality. (See "Kawasaki disease: Clinical features and diagnosis".)
●Determining risk of IVIG resistance
•Japanese children – For Japanese children, well-validated criteria, such as the Kobayashi criteria (figure 1) or similar, can be used to select patients at increased risk of intravenous immune globulin (IVIG) resistance. Such high-risk patients are most likely to benefit from adjuvant treatment with glucocorticoids in addition to IVIG. (See 'Japanese children' above.)
•Non-Japanese children – For non-Japanese patients, criteria for identifying at-risk children are not well validated. In these patients, the following may be used to select those who are most likely to benefit from augmented treatment with glucocorticoids in addition to initial IVIG: enlarged coronary arteries (CAs) at presentation (prior to IVIG treatment), age ≤12 months (and particularly age <6 months), KD associated with shock, and KD presenting with macrophage activation syndrome (MAS). (See 'Non-Japanese children' above.)
●Initial treatment in all patients
•IVIG – In patients with KD, we recommend a single dose of intravenous immune globulin (IVIG; 2 g/kg) administered over 8 to 12 hours (Grade 1A). IVIG is most effective if administered within the first 10 days of illness, before aneurysms typically develop. Nonetheless, IVIG should be administered even beyond this 10-day window in patients with evidence of persistent vasculitis or systemic inflammation (eg, persistent fever, elevated acute-phase reactants). (See 'Intravenous immune globulin' above.)
•Aspirin – In patients with KD, we suggest administering aspirin during the acute phase of illness (Grade 2C). The American Academy of Pediatrics (AAP) and American Heart Association (AHA) have recommended a broad range of aspirin doses (30 to 100 mg/kg/day), but it is not clear that any amount of aspirin has long-term benefits. We administer a total daily aspirin dose of 30 to 50 mg/kg/day in four divided doses (maximum dose 4 g per day) but do not hesitate to hold the aspirin for any contraindication, particularly exposure to varicella or influenza. The dose of aspirin is decreased to 3 to 5 mg/kg/day 48 hours after the resolution of fever. Aspirin is continued until laboratory markers of ongoing inflammation (eg, platelet count and erythrocyte sedimentation rate [ESR]) return to normal, unless coronary artery (CA) abnormalities are detected by echocardiography, in which case aspirin therapy is continued. (See 'Aspirin' above and "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Antithrombotic therapy'.)
●Additional treatment in patients at increased risk of IVIG resistance – In children with KD who are determined to be at increased risk of IVIG resistance, we suggest adding glucocorticoids to initial IVIG therapy (Grade 2C). We typically give a total of 15 days of prednisone/prednisolone (five days each of 2 mg/kg, 1 mg/kg, and 0.5 mg/kg), starting with an intravenous formulation and switching to oral glucocorticoids 12 to 24 hours before expected discharge. A reasonable alternative, particularly in non-Japanese patients, is to treat with IVIG and aspirin alone since most children with KD recover with standard therapy and have a low risk of CA aneurysms or other complications. (See 'Glucocorticoids' above and 'Identification of patients at high risk for IVIG resistance' above.)
●Prognosis – Prognosis is based upon the severity of CA involvement as a marker of risk for myocardial infarction. After the baseline echocardiogram is obtained at diagnosis, echocardiography is usually repeated at approximately two and six weeks of illness to evaluate for CA involvement. Examinations and echocardiograms are repeated more frequently in children with CA abnormalities. Children also should be monitored carefully for any signs of persistent illness during the first two weeks after treatment, as those with ongoing inflammation, particularly fever of any degree, are at highest risk of developing CA abnormalities. Patients without any cardiovascular abnormalities appear to be clinically healthy at long-term follow-up (range, 10 to 21 years). However, it is unknown whether they are at increased risk for atherosclerotic heart disease. (See 'Prognosis' above.)
●Follow-up – Guidelines have been developed by the AHA and AAP for subsequent therapy, physical activity, and follow-up visits (schedule and content) based upon the relative risk for myocardial infarction (table 2). (See 'Prognosis' above and 'Follow-up' above.)
●Vaccinations – We suggest postponing administration of live-virus vaccines (eg, measles, varicella) for at least 11 months in children who have been treated with IVIG because passively acquired antibodies can interfere with vaccine immunogenicity (Grade 2C). One exception to this postponement is in children residing in communities experiencing an outbreak of a vaccine-preventable disease. Another exception is children on long-term aspirin therapy. We suggest that children who are ≥12 months of age and are on long-term, moderate- or high-dose aspirin therapy (30 to 100 mg/kg/day) receive the varicella vaccine because of the increased risk of Reye syndrome (Grade 2C). In situations where vaccination is not postponed, the vaccine should be repeated at least 11 months after the administration of IVIG. Influenza immunization, recommended in all children over six months of age, is also particularly important in those who require long-term high-dose aspirin therapy because of the possible increased risk of Reye syndrome. (See 'Vaccinations' above.)
