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Introduction
Kawasaki disease (KD) is an acute, idiopathic febrile vasculitis that usually occurs in young children with 15%-25% incidence of coronary artery abnormalities (CAAs)1-4). Intravenous immunoglobulin (IVIG), a current standard treatment for KD5), is thought to reduce systemic inflammation via controlling the production of cytokine or neutralizing toxins and preventing the occurrence of CAAs5-7). Among the adverse effects of IVIG, fever is the most common cause of stopping administration of IVIG, which is vital in controlling the inflammation. Therefore, fever control is important for initial treatment for KD.
Dexamethasone is a long-acting fluoridated glucocorticoid with a long half-life, and has anti-inflammatory and immunosuppressive effects without mineralocorticoid effects8,9). Anti-inflammatory potency of dexamethasone is 6.7 times higher than the equivalent dose of methylprednisolone8), which is used primarily in clinical trials to control inflammation.
We hypothesized that primary treatment for KD combined with single dose dexamethasone can have anti-inflammatory effects with relief from fever, proper IVIG administration, and early disease control. The purpose of this study was to investigate the impact of single dose dexamethasone as an adjunctive therapy for primary treatment on inflammation control of KD with a focus on the changes in values of inflammatory markers.
Methods
1. Study design and setting
From March 2016 through April 2017, 143 children were hospitalized for complete KD in the Kyungpook National University Children’s Hospital. Inclusion criteria were complete KD as a final diagnosis, a blood test before and 24 hours after the administration of IVIG, and agreement of the children’s guardians for the analysis of inflammatory markers using a serum left after the conventional tests. This study protocol was approved by the institutional review board (IRB no. KNUCH 2016-06-013). Written informed consents were obtained from the guardians of participating children.
IVIG was the primary treatment for all children. At the start of IVIG infusion, children without fever were immediately treated with IVIG whereas children with fever (> 38.8℃) received acetaminophen and/or ibuprofen for fever control before the infusion. If the fever control failed, single dose intravenous dexamethasone (0.1 mg/kg) was administered. IVIG-resistant KD was diagnosed when fever recurred or persisted for at least initial 36 hours after the initial infusion of IVIG. Children with IVIG-resistant KD received secondary treatment of additional IVIG and intravenous methylprednisolone (30 mg/kg). Acetylsalicylic acid was not being used as a primary treatment during the study period because the medication was not in use in the hospital due to an incident of acetylsalicylic acid-related Reye’s syndrome.
2. Variables of interest and inflammatory markers
As baseline characteristics, we obtained information regarding age (months), sex, the Kobayashi score (≥ 4; high-risk for IVIG resistance)10), length of hospital stay (day), duration of fever (total [day] and from administration of IVIG to defervescence [hour]), time required to IVIG administration (hour), use of the antipyretics, and implementation of the secondary treatment. Groups were designated as per the use of dexamethasone. Outcomes included CAAs, inotropic support, hospitalization to the intensive care units, and in-hospital mortality.
We have routinely performed blood tests on the day of hospitalization and 24 hours after IVIG administration. Inflammatory markers of interest included white blood cells, erythrocyte sedimentation rate, C-reactive protein (CRP), and interleukin (IL)-6, and IL-10. The other laboratory tests were counts of neutrophils and platelets, and concentrations of hemoglobin and aminotransferases. The ILs were analyzed using the remaining serum from the above-mentioned tests which was stored at −80°C. According to the manufacturer’s instruction, a multiplex assay on the Luminex 200 Total System (Luminex Corp., Austin, TX) was used for measuring the ILs. The changes in laboratory data and cytokine concentrations before and after primary treatment were presented as delta (Δ) scores.
3. Echocardiography
CAAs were evaluated by performing echocardiography twice during the hospitalization. We used the Z-score of size of the coronary artery based on aortic valve annular diameter for confirmation of CAAs11). The aortic valve annular diameters were measured with magnification in parasternal long-axis views from the inner edge of the proximal valve insertion hinge point within the arterial root to the inner edge of the opposite hinge point. Dilatation and aneurysm were defined as Z-scores of 2 to < 2.5 and ≥ 2.5, respectively5).
4. Statistical analysis
All statistical analyses were performed with IBM SPSS for Windows, version 25.0 (IBM Corp., Armonk, NY). Statistics were presented as medians (interquartile ranges) or numbers (%). The Mann-Whitney U-tests were used to compare the changes in values of the inflammatory markers as per the use of dexamethasone, and before and after the primary treatment. For this purpose, paired t-test and Wilcoxon signed-rank test were used. A P < 0.05 was considered statistically significant.
Results
1. Baseline characteristics
A total of 42 children were enrolled and divided into the 2 groups according to the use of dexamethasone as an adjunctive therapy for primary treatment: 18 children in the dexamethasone group and 24 in the control group. No differences were found between the groups in the baseline characteristics (Table 1). There were no children with CAAs, inotropic support, hospitalization to the intensive care units or in-hospital mortality.
2. Inflammatory markers
Table 2 lists the changes in values of the inflammatory markers and the other laboratory tests. In both groups, all tests but platelet counts showed significant changes before and after the primary therapy. Among the markers with the significant changes in both groups, white blood cells, CRP, and the ILs decreased. The delta scores of CRP, IL-6, and IL-10 were significantly higher in the dexamethasone group than the control group (Table 3). The scores of the other laboratory findings showed no significant differences between the 2 groups.
Discussion
The present study suggests single dose dexamethasone as an adjunctive therapy for primary treatment for KD may lead to (1) significant reduction of values of inflammatory markers, such as CRP, IL-6, and IL-10, but (2) no direct effect of reducing fever duration and shortening the length of hospital stay.
Corticosteroids have been used during the acute phase of KD as an adjunctive therapy for primary treatment combined with IVIG for selected cases, such as KD shock syndrome, clinical myocarditis, or high-risk for IVIG resistance or CAAs5). For these cases, intravenous methylprednisolone has been considered the major corticosteroid. Intravenous methylprednisolone combined with IVIG as the primary treatment is associated with a shorter fever duration and length of hospital stay, and faster reduction in concentrations of inflammatory markers and conventional clinical markers, in comparison with IVIG alone12-14). Dexamethasone is 25-30 times more potent than hydrocortisone in anti-inflammatory effect, and has a 36-72 hours duration of action15). This strength of dexamethasone makes its indications for acute and serious diseases, such as croup, acute exacerbations of asthma, and anaphylaxis15). Dexamethasone in KD may attenuate the cytokine reactions in vivo13), and inhibit the activation of monocytes, macrophages, coronary arterial endothelial cells, and T cells in vitro16).
A combination of dexamethasone (0.3 mg/kg/day for 3 days) and IVIG as the primary treatment in KD shows more favorable disease course compared to IVIG alone as demonstrated by: (1) shorter duration of fever and length of hospital stay, (2) refractoriness to primary treatment, and (3) lower concentration of CRP after IVIG treatment17,18). The present study using the 0.1 mg/kg single dose dexamethasone did not show benefits of febrile duration, length of hospital stay or refractoriness to primary treatment. This disparity might be related to the lower dose of dexamethasone in this present study. The larger decreases in the concentrations of CRP, IL-6, and IL-8 in the dexamethasone group suggest an anti-inflammatory effect of the single dose dexamethasone.
The use of dexamethasone as an adjunctive therapy for primary treatment for KD may prevent the adverse effects of IVIG via anti-inflammatory effect, reduce the number of additional uses of antipyretics, and stabilize administration of IVIG without a fever-related delay in infusion. In this study, the time required for IVIG infusion was about 13 hours in both groups without a difference in the use of antipyretics. The time interval included the time required for fever control before and during IVIG administration. Single dose of dexamethasone was helpful in the dexamethasone group, which had fever at the start of IVIG infusion even after the initial antipyretic therapy.
This study had limitations, including the small size of the study population and absence of comparison among various doses of dexamethasone.
In conclusion, single dose dexamethasone as an adjunctive therapy for primary treatment may have an anti-inflammatory effect in children with KD without effects in shortening the duration of fever and the length of hospital stay.
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