Intravenous immunoglobulin (IVIG) infusion is an effective therapy for acute Kawasaki disease (KD).1) Administration within a few days of illness of a single dose of IVIG, in combination with high-dose aspirin, ceases fever, rapidly resolves clinical signs and symptoms of inflammation, and reduces the incidence of coronary artery aneurysms.1)2) However, approximately 10% to 20% of KD patients have persistent or recrudescent fever, despite IVIG therapy.2)3)

When fever persists or recurs with signs of mucocutaneous inflammation after initial IVIG therapy, retreatment can be indicated. However, when the patients have fever with few clinical signs of ongoing inflammation, these patients pose a therapeutic dilemma. The KD patients who fail to respond to initial IVIG treatment should be reassessed to exclude the pos-sibility of a bacterial infection. Although current diagnostic criteria for KD require exclusion of infectious diseases before making a definite diagnosis, there are actually several reports of patients with typical features of KD, including coronary artery aneurysm, who also have had a documented infection.4)5) In addition, we have sometimes experienced KD patients who became afebrile with IVIG treatment, but shortly febrile again due to newly developed viral infection, pharyngotonsillitis, gastroenteritis, or urinary tract infection during hospitalization. In such cases, the values of acute phase reactants were usually within the normal range and fever subsided without the use of IVIG. In patients who remain febrile despite IVIG therapy, our institutional protocol requires that we always deliberate on the values of acute phase reactants, when a need for additional therapy is recognized. If the patients become afebrile after treatment, no laboratory test is performed. Most physicians clinically judge post-IVIG fever to be at-tributable to active KD, rather than to other causes,2)6) and tend to retreat this group of patients in the absence of the systemic evaluation required to guide the decision of treatment. We believe that there is a need for objective laboratory measures that identify KD patients who remain febrile after IVIG treat-ment and therefore need additional therapy.

Our goal was to determine from routine laboratory meas-ures the parameters that may serve to guide retreatment in KD patients who remained febrile after initial IVIG therapy.

During the study period between November 2008 and September 2010, a total of 129 children who met the diagnostic criteria for KD7) were prospectively enrolled. Subjects comprised 72 boys (55.8%) and 57 girls, aged 2 months to 11 years. All patients were treated with IVIG 2 g/kg for 2 to 9 days after the onset of disease, and were also given aspirin 80 to 100 mg/kg/day until defervescence, and then 5 mg/kg/day as a single daily dose. When the patients failed to defervesce after the first IVIG therapy, they were retreated with a second dose of IVIG (n=14). When they remained still febrile despite a second dose of IVIG therapy, then pulse methylprednisolone (30 mg/kg/day for 3 days) was administered (n=8).

We measured white blood cell (WBC), percentage of neutrophils in WBCs (% neutrophils), hematocrit, platelet counts, serum sodium, total bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), protein, albumin, C-reactive protein (CRP), and N-terminal pro-brain natriuretic peptide (NT-proBNP), before and 48 to 72 hours after IVIG treatment. For patients who failed to respond to the second dose of IVIG, laboratory measures were repeated before pulse steroid therapy. Coronary arteries were assessed by echocardiography performed at the time of diagnosis and at discharge, and repeated at weeks 2, 4, and 8 after treatment, and then as needed thereafter. Coronary artery lesions (CALs) were diagnosed according to the criteria of the Japanese Ministry of Health and Welfare.8) Patients who presented with CAL before the initial treatment were excluded from the study.

Subjects were divided into 2 groups according to responsiveness to IVIG treatment: IVIG-responsive patients (n=107) and IVIG-resistant patients (n=22). Laboratory measures before and after IVIG therapy were compared in each group. We selected the variables that showed a different change after IVIG therapy between the groups. Pre- and post-IVIG concentrations of each variable between the groups were compared. The value of the fractional change (FC) of each variable between the groups was also compared, as described previously.9) FC was defined as follows:

FC=(Y-X)/X

In which X represents data before IVIG treatment and Y represents data at 48 to 72 hours after IVIG treatment.

This study was approved by the Institutional Review Board of Ewha Womans University Mokdong Hospital (#ECT 230-2-28) and written informed consents were obtained from the parents of each patient.

Although IVIG plus aspirin therapy are effective for the treatment of acute KD,1) approximately 10% to 20% of patients ex-perience either persistent or recrudescent fever, despite initial IVIG treatment.2)3) These patients are at increased risk of developing coronary artery aneurysm.2)10)11) Therefore, it is important to determine the effectiveness of IVIG soon after therapy, especially in resistant cases, to recognize a need for additional therapy, such as a second dose of IVIG, steroids, or infliximab.12)13) However, no evaluation system currently exists to determine the effectiveness of IVIG therapy. Both fever resulting from cytokine release and increased CRP levels me-diated by interleukin-6 are clinically useful measures of systemic inflammation in KD. Post-IVIG fever, however, may arise from other causes (e.g., intercurrent infection), as well as from KD itself during hospitalization. Thus other adjuvant inflammatory markers may be required to more precisely assess the ongoing inflammation arising from KD and to support the decision for retreatment in patients who remain febrile after IVIG therapy. We investigated routine laboratory measures and propose herein CRP, NT-proBNP, and % neutrophils as independent parameters to guide the decision of retreatment in KD patients who are still febrile after initial IVIG therapy.

In this study, IVIG-resistance occurred in 17% of KD patients. The clinical indications for retreatment were persistent fever in 14 patients and recrudescent fever in 8 patients. Of these 22 patients retreated with a second dose of IVIG, 14 patients (63.6%) achieved defervescence with this treatment. This finding was similar to results of other studies in which approximately two thirds of the initial non-responders eventually responded to a second dose of IVIG.3)6) In addition, although there was no statistical significance, persistent fever was likely to cease either by a second dose of IVIG or by steroid therapy, whereas recrudescent fever was more likely to cease by a second dose of IVIG only.

The optimal period to begin IVIG administration remains controversial. Some investigators reported that early treatment, i.e., before day 5 of illness, is associated with increased need for additional IVIG therapy.14) Contrarily, others advocated that earlier treatment would be better.15) In this study, we found no difference between the IVIG-responsive and IVIG-resistant group in the proportion of patients who were treated before day 5 of illness (62.0% vs. 77.3%, p=0.215) and also in the mean duration of fever until IVIG initiation. Thus neither group was affected by the time of IVIG administration in this study.

The patients who failed to defervesce after IVIG therapy were characterized by significantly higher values of post-IV-IG WBC, % neutrophils, CRP, and NT-proBNP, compared with IVIG-responsive patients. Thus, we demonstrated that WBC, % neutrophils, CRP, and NT-proBNP may be suitable parameters of retreatment after initial IVIG therapy. When assessed by multivariate analysis, the neutrophil counts and serum concentrations of CRP and NT-proBNP were found to be independent parameters of the response to IVIG therapy. Both the sensitivity and specificity of these 3 independent pa-rameters, as defined in this study, may allow clinicians to identify patients who remain febrile and need additional therapy after initial IVIG treatment. We are able to justify retreatment more reliably by measuring not only CRP, but also NT-proBNP and % neutrophils, rather than CRP alone.

Our results were similar to the findings of Mori et al.9) who demonstrated that increased WBC, neutrophil counts, and CRP after IVIG treatment are markers of treatment efficacy and also useful predictors of CALs. The role of neutrophils in acute KD has been elucidated. Neutrophil activation can occur by stimulation of increased granulocyte colony-stimulating factor and cytokines that are involved in coronary artery dilation.16)17) In the acute phase of disease, enhanced neutrophil function may contribute to the pathogenesis of coronary vascular endothelial injury through either production of elastase or expression of vascular endothelial growth factor.17)18) This was demonstrated in a pathologic study showing early infiltration of neutrophils in the CALs of patients who died 10 days after the onset of disease.19) Thus, it is natural that neutrophil is a marker of systemic inflammation. As a parameter in the multivariate analysis, the neutrophil count is interpreted to be more significant than WBC.

We proposed a CRP cutoff value of 3.68 mg/dL as a marker of ongoing inflammation after IVIG therapy. This value is similar to 4 mg/dL calculated as the upper limit of post-IVIG CRP (mean+2 SDs) in the responsive group, as shown in Table 4, but is still a little higher than the value of 3 mg/dL, proposed by the American Heart Association as a criterion for the evaluation of suspected incomplete KD.20)

We reported previously that NT-proBNP increases during the acute phase of KD, i.e., before IVIG treatment, and decrea-ses to within the normal range in the convalescent phase.21) The change in NT-proBNP according to the phase of KD is equivalent to that in CRP, suggesting that NT-proBNP may be used as a marker of systemic inflammation, as well as myocardial involvement, in acute KD. This finding is consistent with that of the other study.22) Moreover, the fact that, after IVIG administration, NT-proBNP was paradoxically elevated in nearly half of IVIG-resistant patients suggests that NT-proBNP may be a useful marker of ongoing inflammation after IVIG treatment as well. Thus we put an emphasis on the clinical significance of NT-proBNP as a marker of retreatment. A NT-proBNP cutoff value of 479 pg/mL, indicated as a marker of retreatment in the present study, was higher than both 260 pg/mL and 170 pg/mL proposed as a diagnostic test of acute KD in our previous study,21) and in the other study,22) respectively.

Using the defined parameters, here are our suggested guidelines of retreatment for KD patients who receive IVIG treatment: 1) Do necessarily retreat patients who remain febrile despite IVIG therapy and have high values of CRP, NT-proBNP and/or neutrophil counts; 2) When the patients become febrile and show normal lab measures (i.e., parameters), do not retreat for KD and observe for 1 to 2 days, with anticipation of defervescence. In these cases, fever is less likely to be caused by KD; 3) When the patients become afebrile and show abnormal lab values/parameters, do not retreat them and repeat laboratory tests; 4) Do not retreat patients who become afebrile and have normal parameters.

In conclusion, our study shows that, in KD patients who remain febrile despite IVIG treatment, additional therapy can be facilitated early by measuring CRP in combination with NT-proBNP and/or % neutrophils. Further study in a larger sample of patients is warranted to clarify our guidelines of retreatment for KD patients.