Low- versus high-concentration intravenous immunoglobulin for children with Kawasaki disease in the acute phase

Purpose: Few studies have compared the effects of low-concentration (5%) and high-concentration (10%) intravenous immunoglobulin (IVIG) preparations for patients with Kawasaki disease (KD) in the acute phase. The purpose of this study was to compare outcomes between low- and high-concentration IVIG preparations in children with KD, using a national inpatient database in Japan. Method: We used the Diagnostic Procedure Combination database to identify patients with KD treated with IVIG from April 2012 to March 2020. We identied those receiving high- and low-concentration IVIG preparations as an initial treatment. The outcomes included the proportions of patients with coronary artery abnormalities (CAAs) and IVIG resistance, length of stay, and medical costs. Propensity score-matched analyses were conducted to compare the outcomes between the two groups. Instrumental variable analyses were performed to conrm the results. Result: We identied 48,046 patients with KD and created 4:1 propensity score-matched pairs between the low- and high-concentration IVIG groups. There was a signicant difference in the percentage with IVIG resistance between the two groups (20.6% vs 24.1%; risk difference, 3.5% [95% condence interval, 2.3-4.7]; p < 0.001). However, there was no signicant difference in CAAs (1.6% vs 1.6%; risk difference, 0.013% [95% condence interval, −0.34 to 0.37]; p = 0.953). The instrumental variable analyses showed similar results. Conclusions: The proportion of CAAs did not differ signicantly between those receiving low- and high-concentration IVIG. To conrm the results of this study, prospective studies adjusting for duration of IVIG administration and duration of observation are needed. studies have performed comparisons to determine which preparation of IVIG is superior. present ndings suggest that the proportion of coronary artery abnormalities did not differ signicantly between those receiving low- and high-concentration IVIG.


Introduction
Kawasaki disease (KD), which is acute systemic vasculitis, is the most common cause of acquired heart disease in children in developed countries. 1 Previously, 5% intravenous immunoglobulin (IVIG) preparations were used in Japan. Since January 2013, 10% IVIG preparations began to be used in Japan to treat patients with KD in the acute phase. In the United States, 10% IVIG preparations are already mainstream. Several previous studies have shown that halving the dose and duration of treatment for patients with KD in the acute phase may lead to earlier detection of IVIG resistance because of reduced volume load and shorter treatment duration. [2][3][4] Additionally, more intense treatments can be used to suppress in ammation faster in patients with KD in the acute phase. No studies have evaluated the proportion of patients with IVIG resistance or coronary artery abnormalities (CAAs), length of stay, medical costs, or complications by different concentrations of IVIG. The purpose of this study was to compare the outcomes of children with KD treated with low-concentration (5%) and high-concentration (10%) IVIG preparations, using a national inpatient database in Japan.

Data source
For this retrospective cohort study, we used data derived from the Diagnosis Procedure Combination database. 5 All 82 academic hospitals in Japan are obliged to participate in the database. Each year, data are collected on about eight million hospitalized patients of all ages, which is equivalent to about 50% of all acute-care hospitalizations in Japan. The database includes the following information: unique identi ers of hospitals; baseline patient characteristics; and diagnosis at admission, comorbidities at admission, and complications after admission recorded as text data in Japanese and using International Classi cation of Diseases, Tenth Revision (ICD-10) codes. The database also contains information on medical procedures and treatments (including drug administrations, device use, and surgical and nonsurgical procedures) based on the original Japanese codes; length of stay; discharge status; and medical costs during hospitalization. The attending physicians have to con rm the recorded patient data for all diagnoses and comorbidities with reference to medical records. Furthermore, because accurate reporting is linked with the payment system in Japan, the attending physicians and hospitals are required to accurately report diagnoses and comorbidities. The present study was approved by the Institutional Review Board of The University of Tokyo (approval number: 3501-(3); December 25, 2017). The requirement for informed consent was waived because of the anonymous nature of the data.

Participants
We used the database to identify patients who were diagnosed with KD (ICD-10 code: M303) from April 2012 to March 2020. We included patients whose rst IVIG treatment was started within 3 days of hospitalization and who received at least 2 g/kg of IVIG within 3 days of starting their initial IVIG treatment. We checked the Japanese text describing the detailed diagnoses in each case to include patients with atypical KD and exclude patients with "suspected" KD. We also excluded patients aged > 6 years because the appropriate IVIG dose for older patients with KD remains controversial. We further excluded patients weighing < 3 kg, those with missing data, and those with inadequate treatment (< 2 g/kg IVIG). The included children with KD in the acute phase were divided into two groups depending on whether they had a 5% or 10% IVIG preparation as their initial treatment. We excluded patients who received both 5% and 10% IVIG preparations.

Outcomes
The primary outcome was the occurrence of CAAs at the time of discharge. CAAs were identi ed using the recorded diagnosis of CAAs (ICD-10 code: I254) and/or the appearance of "CAAs" in the Japanese language text data. The secondary outcomes were the proportion of patients with IVIG resistance, length of stay, and medical costs. IVIG resistance was de ned as the use of IVIG at a total dose of ≥ 4.0 g/kg and/or in combination with any steroid, in iximab, cyclosporine, and/or plasma exchange that was not performed at the same time as the initial IVIG treatment. We also examined adverse events occurring with IVIG, including hyperviscosity syndrome (ICD-10 code: R70.1) and congestive heart failure (ICD-10 code: I50.0).

Covariates
The included baseline characteristics included sex, age, weight, height, hospital days of illness at initial IVIG, type of hospital, complex chronic conditions, 6 activities of daily living at admission, Japan Coma Scale score at admission, transportation by ambulance, transportation from another hospital, scal year, additional treatments, and hospital volume. Assessments using the Japan Coma Scale have previously been shown to be highly correlated with assessments using the Glasgow Coma Scale. 7 Hospital volume was de ned as the annual number of all patients with KD at each hospital. We separated the included patients into hospital volume tertiles so that the numbers of patients in the groups were almost equal. Additional treatment was de ned as the use of any steroid, in iximab, and/or cyclosporine at the same time as or before the start of the initial IVIG treatment.
Propensity score-matched analysis We performed 4:1 propensity score-matched analyses to compare the outcomes between the two IVIG concentration groups. We estimated the propensity score using a logistic regression model in which 10% IVIG use was the dependent variable, with the covariates described above. For the propensity score matching, nearest-neighbor matching without replacement was performed. The caliper width was set at ≤ 0.2 of the pooled standard deviation of the evaluated propensity scores. We estimated the covariate balance between the two groups before and after propensity score matching using the absolute standardized difference. An absolute standardized difference of > 10% was regarded as imbalanced. 8

Instrumental variable analysis
Propensity score-matched analyses cannot exclude the effects of unmeasured confounders such as symptoms of KD, laboratory data, duration of illness, duration of fever from KD onset, duration of IVIG administration, and duration of observation after initial IVIG treatment. Thus, to con rm our propensity score-matched analyses, we performed instrumental variable analyses. The key assumptions for instrumental variable analysis are as follows: the instrumental variable (i) is highly correlated with the treatment assignment, (ii) is not correlated with other confounders, and (iii) does not affect patient outcomes except through the treatment. 9 In instrumental variable analyses, physician prescribing preference is commonly used as an instrumental variable. This variable re ects the notion that a physician's prescribing decision depends not only on the patient's characteristics but also on the physician's preference for each treatment. Physician's preference is mostly independent of patient characteristics and outcomes and can therefore be used as an instrumental variable. In the present study, we used prescription for previous patient as the instrumental variable. 10 When the prescription for the previous patient in the same institution was 10% IVIG, the current patient was assumed to be more likely to receive 10% IVIG. When the prescription for the previous patient in the same institution was 5% IVIG, the current patient was assumed to be more likely to receive 5% IVIG. Prescription for the previous patient is assumed to be independent of the current patient's characteristics and not directly related to their outcome. Therefore, this variable was considered to meet the three key requirements for an instrumental variable described above.
In this study, we employed a two-stage residual inclusion method for both continuous and binary outcome variables. 11,12 In the rst-stage model, we determined the row residual for each patient by calculating the difference between the model-predicted probability of receiving the treatment choice and the actual treatment received. These residuals were included as an additional covariate in the second-stage model, where the association between treatment choice and outcome was estimated in an unbiased manner after adjustment for covariates. We used a multivariable linear regression model for continuous outcome variables and a multivariable logistic regression model for binary outcome variables. All instrumental variable analyses were performed using robust standard errors. To assess the validity of the instrumental variable, we tested its association with our main predictor of actual treatment choice using the F-statistic (F-statistic > 10 is considered to re ect a valid instrumental variable). 13 We also determined that the instrumental variable was not associated with the patient background characteristics or outcomes. A twosided p < 0.05 was considered signi cant. All statistical analyses were conducted using Stata, version 17.0 (StataCorp LP, College Station, TX, USA).

Statistical analysis
Categorical variables, which are shown as numbers and percentages, were compared using Fisher's exact test. Continuous variables are shown as means and standard deviations or medians and interquartile ranges. The Mann-Whitney U test was used to compare non-normally distributed variables between the two groups. Speci cally, this test was used to compare length of stay and medical costs.
To allow for the meaningful interpretation of variables with skewed distributions, we calculated median differences with 95% con dence intervals (95% CIs) using the Hodges-Lehmann estimator. The chi-square test was used to compare the proportions of patients with CAAs and IVIG resistance between the two groups. We also estimated the risk differences with 95% CIs.
As a sensitivity analysis, CAAs were de ned as a diagnosis of CAAs and the use of anticoagulants such as warfarin or clopidogrel, or a diagnosis of CAAs and cardiac catheterization. The diagnosis of CAAs was de ned as the presence of a descriptive diagnosis of CAAs (ICD-10 code: I254) or the use of "CAAs" to describe the case in the Japanese text data.

Study population
We identi ed a total of 48,046 patients with KD who met the inclusion criteria, including 42,133 patients with 5% IVIG and 5913 patients with 10% IVIG as the initial treatment in the acute phase (Fig. 1). The baseline characteristics before and after propensity score matching are shown in Table 1.   Table 3). The F-statistic was 10,140 (> 10), and the instrument was considered valid. There was no signi cant association between the instrument and patient background (Supplemental Table).

Discussion
Using a large nationwide inpatient database in Japan, this study showed that the proportion with CAAs did not differ signi cantly between patients with KD receiving 5% and 10% IVIG in the acute phase. This result was similar in the propensity score analysis and the instrumental variable analysis.
Numerous studies have shown insigni cant differences in outcomes between 5% and 10% IVIG for multifocal motor neuropathy, chronic in ammatory demyelinating polyradiculoneuropathy, primary immunode ciency, and vesiculobullous autoimmune diseases. [14][15][16][17][18][19] Previous small studies on KD have also shown no signi cant difference in the proportion with CAAs between 5% and 10% IVIG for patients with acute-phase KD. 2,4 In this study, 10% IVIG was shown to increase the proportion of IVIG resistance in patients with acute KD. According to the 2012 Japanese KD guidelines, the observation period for KD is 24 hours after the completion of the rst IVIG dose. 20 In general, it is recommended that 5% IVIG should be administered to patients with KD within 24 hours of starting IVIG and that 10% IVIG should be administered to these patients within 12 hours of starting IVIG. IVIG resistance can therefore be determined at 36 hours from the start of dosing for the 10% IVIG formulation and at 48 hours from the start of dosing for the 5% formulation, after which IVIG can be re-administered.
The increased proportion of IVIG resistance with the use of 10% IVIG in this study may be explained by this difference in the observation period. In Japan, the 2020 KD guidelines basically recommend a decision whether a patient is IVIG resistance 48 hours after the start of IVIG administration. 21 We believe that, in the future, as the new guidelines become more widespread and the follow-up period after IVIG lengthens, IVIG resistance resulting from the use of 10% IVIG may decrease.
In the propensity score analysis and the instrumental variable analysis, medical costs for the 10% IVIG group did not differ from those for the 5% IVIG group. A previous study showed that, in primary immunode ciency, the widespread use of 10% IVIG has reduced medical costs and patient physical burden. 17 If the proportion with IVIG resistance is modi ed according to the 2020 KD guidelines, the use of 10% IVIG may help to shorten length of stay and reduce medical costs for patients with KD.
In the sensitivity analyses, different results were obtained for the proportion of patients with CAAs in the propensity score analysis and the instrumental variable analysis. The propensity analysis does not adjust for unmeasured confounding factors such as laboratory ndings; if the 10% IVIG group had more severe KD with poorer laboratory results compared with the 5% IVIG group, the 10% IVIG group may have had an excessively high proportion of patients with CAAs. It is also possible that the instrumental variable analysis did not meet the requirement of no relationship between unmeasured confounders and the instrumental variable. In fact, the results showed a relatively high number of patients receiving the 10% formulation in high-volume hospitals, and the proportion with CAAs may have tended to be lower in the 10% IVIG group than in the 5% IVIG group because high-volume hospitals are accustomed to treating KD. This suggests that the difference between the results from the propensity score analysis and the instrumental variable analysis may not be explained by differences in the IVIG concentration; rather, these differences may be explained by the severity of KD. Further detailed study is needed in the future.

Limitations
We acknowledge several limitations in this study. First, our database lacked information on KD symptoms, laboratory ndings, and fever duration for patients with KD in the acute phase. The severity of KD was not identi ed clearly because bias still exists in the form of unmeasured confounders including laboratory ndings, time from KD onset to hospital admission, and duration of illness. To adjust for differences in the severity of KD between the two groups, we used baseline characteristics including Japan Coma Scale score and complex chronic conditions to evaluate the propensity score-matched analyses. Furthermore, we performed instrumental variable analyses and obtained similar results to those from the propensity scorematched analyses. Second, information on the severity of the CAAs caused by KD, such as diameters and Z-scores, were not included in our database. To ensure that the CAAs were not transient, we added a sensitivity analysis using history of cardiac catheterization and prescription history of anticoagulants in addition to aspirin. Third, the accuracy of the times of IVIG administration, observation time, and the duration of fever among patients with KD could not be evaluated using the database.