Treatment of Kawasaki disease by different doses of immunoglobulin: a meta analysis of efficacy and safety
Review Article

Treatment of Kawasaki disease by different doses of immunoglobulin: a meta analysis of efficacy and safety

Jing Chen, Bin Ma, Li-Xing Lin, Yi-Ming Xue

Department of Pediatrics, First Clinical Medical College of Lanzhou University, Lanzhou 730000, China

Correspondence to: Li-Xing Lin. Department of Pediatrics, First Clinical Medical College of Lanzhou University, Lanzhou 730000, China. Email: lxlin.lzu@163.com.

Objective: To assess the efficacy and safety of different doses of immunoglobulin in the treatment of Kawasaki disease (KD).

Methods: The papers related to the treatment of KD were electronically searched in the databases including PubMed, EMBASE, Cochrane Library, CNKI, VIP and Wanfang. Randomized clinical trials (RCT) on the treatment of KD with different doses of immunoglobulin were included and assessed for quality. A Mata analysis was performed by RevMan 5.0.

Results: Twenty-eight RCTs involving 2,596 cases were included. The results of Meta analysis showed that there were no significant differences in the incidences of coronary artery injuries at various phases, adverse reactions, and fever disappearance time between the immunoglobulin treatment groups at the doses of 1 g/(kg•d) for 1-2 days or 2 g/(kg•d) for single use. The fever disappearance time in the immunoglobulin treatment group at the dose of 1 g/(kg•d) for 1-2 days was significantly shorter than that in the immunoglobulin treatment group at the dose of 400 mg/(kg•d) for 4-5 days, but there were no significant differences in the incidences of coronary artery injuries at the acute phase and 6 months after treatment and in the adverse effects between the two groups. The incidence of coronary artery injuries at the acute phase and 6 months after treatment was significantly lower and the fever disappearance time was significantly shorter in the immunoglobulin treatment group at the dose of 2 g/(kg•d) for single use than those in the immunoglobulin treatment group at the dose of 400 mg/(kg•d) for 4-5 days, but there were no significant differences in the incidences of coronary artery injuries at the subacute phase and 12 months after treatment and adverse effects between the two groups.

Conclusions: There are similar efficacy for KD between the immunoglobulin treatment groups at the doses of 1 g/(kg•d) for 1-2 days and 2 g/(kg•d) for single use. The fever disappearance time in the two groups is shorter than that in the treatment group at the dose of 400 mg/(kg•d) for 4-5 days.

Keywords: Immunoglobulin; Kawasaki disease; meta analysis; child

Submitted Mar 06, 2012. Accepted for publication Mar 23, 2012.

doi: 10.3978/j.issn.2224-4336.2012.04.05

Kawasaki disease (KD), an acute exanthematous disease characterized by systemic vasculitis, has shown an increasing trend of incidence over the past years (1). From the epidemiological viewpoint, it is known that this disease is more frequently found in Asiatic, and principally in Japanese, population. In North America, the highest number of cases are reported annually in the U.S. (2,3). The etiology includes very diverse bacterial and viral agents, chemical substances and acaros (dermatophagoides) without fully convincing evidence (4-6).

KD is a systemic vasculitis that occurs most commonly in children younger than 5 years of age (7). The inflammation involves small and medium-sized arteries, and the most severe problems arise from coronary artery inflammation. Coronary inflammation results in damage to the coronary arteries and may lead to artery aneurysms, arterial stenosis, and myocardial infarction (1,8). Such injuries may lead to serious problems in former patients during middle age. Research has shown that 15-26% of KD children will develop coronary artery aneurysms (9). Therefore, the aim of KD treatment is the prompt termination of systemic inflammation as early as possible and inhibition of the development of systemic vasculitis. Standard treatment for KD includes intravenous immunoglobulin (IVIG) and oral aspirin (ASA). Although the use of immunoglobulin has improved the prognosis for KD and dramatically lowered the incidences of cardiovascular diseases. However, some childern show persistent or recrudescent fever despite treatment with high-dose IVIG. And the doses of immunoglobulin and their efficacies and safety profiles remain controversial (10). Indicating that current alternative treatments are required for different patients.

Studies have shown that the dose of 2 g/(kg•d) for single use can effectively reduce the coronary artery lesions and shorten the fever disappearance time (11,12). However, other authors believed 2 g/(kg•d) for single use will result in the sudden increase of the plasma osmotic pressure of immunoglobulin, and thus destablize the homeostasis, increase the serum viscosity, and decrease blood flow velocity, which ultimately will facilitate the formation of blood clots and increase the incidence of stroke in the adulthood (13,14). In addition, some authors also believed that the dose of 1 g/(kg•d) for 1-2 days had equal efficacy as 2 g/(kg•d) for single use (15). Therefore, a comprehensive evaluation of different dosages of immunoglobulin in treating KD will be helpful to clarify their effectiveness and safety.

Subjects and methods

Inclusion and exclusion criteria of the studies

Randomized controlled trials, whether adopting blinding methods or allocation concealment, were enrolled in this analysis.

The inclusion criteria of subjects were as follows: (I) Pediatric patients confirmed to be with KD; and (II) patients who had received immunoglobulin therapy and at least undergone echocardiography within two weeks after treatment. Patients with other exanthematous diseases were excluded.

Interventions were compared as follows: Immunoglobulin 1 g/(kg•d) for 1-2 days vs. 2 g/(kg•d) for single use; immunoglobulin 1 g/(kg•d) for 1-2 days vs. 400 mg/(kg•d) for 4-5 days; and immunoglobulin 2 g/(kg•d) for single use vs. 400 mg/(kg•d) for 4-5 days.

The primary measures included: the incidences of coronary artery lesions (coronary artery dilatation and/or coronary aneurysm) in the acute phase (week 1-3), subacute phase (week 3-6), and follow-up (month 6 and 12 after treatment). The secondary indicators included adverse reactions (e.g., chills, rash, shock, irritability, and palpitation) and fever disappearance time.

Search strategy

Literature was searched using the pre-determined strategy based on thesaurus terms and free-text terms. Using the searching terms including gamma globulin, gamma-globulins, Y globulin, immunoglobulin, immunoglobulins, Kawasaki disease, mucocutaneous lymph node syndrome, and their Chinese counterparts, we electronically searched the databases including PubMed, EMBASE, Cochrane Library, CNKI, VIP and Wanfang.

Data extraction and quality evaluation

Two reviewers independently conducted searching based on the searching strategy and retrieved the data using a pre-determined data extraction form. The quality of the included studies was evaluated using the criteria (16) recommended by the Cochrane Handbook for Systematic Reviews of Interventions 5.0 in terms of randomization method, assignment concealment, blinding method, integration of result data, selective reporting of data and results; and other sources of bias. Disagreement between them was resolved through discussion or by consulting a third party.

Statistical analysis

Statistical analysis was performed using the Cochrane Collaboration’s software RevMan 5.0. Efficacy analysis was based on relative risk (RR) and weighted mean differences (MD). A 95% confidence interval was applied for each effect size. The heterogeneity among the enrolled studies were analyzed using chi square test, and a fixed effects model was applied when P>0.1 and I square (I2) <50%; If there was significant heterogeneity (P<0.1, I2>50%), the causes of such heterogeneity was searched, and subgroup analysis or sensitivity analysis was performed based on the clinical and methodological heterogeneity factors; if no clinical or methodological heterogeneity was found among the studies, random effect model was used.

Results

Search results

The initial search yielded 2,227 articles, which included 612 articles from PubMed, 90 from EMbase, 65 from Cochrane Library, 49 from VIP, 1,488 from CNKI, and 33 from Wangfang. Then, 110 duplicate reports were excluded. By reviewing the titles and abstracts, we ruled out 2,103 articles that did not meet the inclusion criteria. The full text of the remaining 124 potentially eligible articles were read; finally, 96 of them were excluded and 28 RCT (17-30) entered the final analysis (31-44).

Ten RCT (18,21,23,28-30,34,42-44) reported the use of 1 g/(kg•d) for 1-2 d vs. 2 g/(kg•d) for single sue, 16 (22,24,25,26-32,39-42) reported the use of 1 g/(kg•d) for 1-2 days vs. 400 mg/(kg•d) for 4-5 days, and 13 (17,19,20, 25,29,30,33,35,37,38,40,41,44) reported the use of 2 g/(kg•d) for single use vs. 400 mg/(kg•d) for 4-5 days. There were 3 studies (17,19,20) and 25 domestic studies (18,21-44) (Table 1).

Table 1
Table 1 The general characteristics of the enrolled studies
Full table

Results of quality assessment for the enrolled studies

All the enrolled 28 RCT mentioned “randomization”; however, only two studies (19,34) applied random digits table for randomization, two clearly (17,42) stated that they used sealed envelopes for concealed allocation, and two (17,42) used single-blind method (blind physician). Three studies (18,22,24) mentioned lost to follow-up, but failed to state whether intention-to-treat was applied (Table 2).

Table 2
Table 2 Quality assessment for the enrolled studies
Full table

Comparison of the efficacy

Immunoglobulin 1 g/(kg•d) for 1-2 days vs. 2 g/(kg•d) for single use

Nine studies (19,21,23,29,30,34,42-44) reported the incidence of coronary artery injuries at the acute phase and two (23,30) reported the incidence of coronary artery injuries at the sub-acute phase; Meta analysis showed that these two dosages showed no significant difference in terms of the incidences of coronary artery injuries at the acute and sub-acute phases (P>0.05). Two studies (29,30) reported the incidence of coronary artery injuries at the 6-month follow-up and four (18,29,34,44) reported that at 1-year follow-up; Meta analysis showed that these two dosages showed no significant difference in terms of the incidences of coronary artery injuries at 6-month and 1-year follow-up (P>0.05). Four studies (18,29,34,44) reported the adverse reactions of immunoglobulin; analysis showed that the incidences of adverse reactions showed no significant differences between these two groups (P>0.05). Five studies (18,21,30,34,44) reported the fever disappearance time after the use of immunoglobulin; analysis showed that the fever disappearance time was not significantly different between these two groups (P>0.05) (Table 3).

Table 3
Table 3 Meta analysis of 1 g/(kg•d) for 1-2 days vs. 2 g/(kg•d) for single use
Full table

Immunoglobulin 1 g/(kg•d) for 1-2 days vs. 400 mg/(kg•d) for 4-5 days

Eleven studies (22,24,26,28-32,36,37,42) reported the incidence of coronary artery injuries at the acute phase and one study (25) reported the incidence of coronary artery injuries at the sub-acute phase; Meta analysis showed that these two dosages showed no significant difference in terms of the incidences of coronary artery injuries at the acute and sub-acute phases (P>0.05). Four studies (28-30,39) reported the incidence of coronary artery injuries at the 6-month follow-up and three studies (22,24,44) reported the incidence of coronary artery injuries at the 1-year follow-up; Meta analysis showed that these two dosages showed no significant difference in terms of the incidences of coronary artery injuries at 6-month follow-up (P>0.05); One study (44) showed that the incidence of coronary artery injuries at 1-month follow-up was not significantly different between these two groups (P>0.05). Seven studies (27-29,32,36,39,44) reported adverse reactions. The incidences of adverse reactions showed no significant differences between these two groups (P>0.05). Ten studies (22,24,25,27,28,30-32,36,44) reported the fever disappearance time after the use of immunoglobulin; Meta analysis showed that the fever disappearance time was significantly shorter in the 1 g/(kg•d) for 1-2 days group than in 400 mg/(kg•d) for 4-5 days group (P<0.001) (Table 4).

Table 4
Table 4 Meta analysis of 1 g/(kg•d) for 1-2 days vs. 400 mg/(kg•d) for 4-5 days
Full table

Immunoglobulin 2 g/(kg•d) for single use vs. 400 mg/(kg•d) for 4-5 days

Nine studies (17,19,26,29,30,33,35,37,44) reported the incidence of coronary artery injuries at the acute phase and one study (30) reported the incidence of coronary artery injuries at the sub-acute phase. Meta analysis showed that the incidence of coronary artery injuries at the acute phase was significantly lower in the 2 g/(kg•d) for single use group than in 400 mg/(kg•d) for 4-5 days group (P<0.05), although that at the sub-acute phase showed no significant difference between these two groups (P>0.05). Four studies (29,30,38,40) and one study (44), respectively, reported the incidence of coronary artery injuries at the 6- and 12-month follow-up. Meta analysis showed that the incidence of coronary artery injuries was significantly lower in the 2 g/(kg•d) for single use group than in 400 mg/(kg•d) for 4-5 days group at the 6-month follow-up (P=0.009), although it showed no significant different at 12-month follow-up (P=0.90). Five studies (17,19,26,29,44) reported the adverse reactions of immunoglobulin; the incidences of adverse reactions showed no significant differences between these two groups (P>0.48). Eleven studies (17,19,20,25,33, 35,37,38,40,41,44) reported the fever disappearance time after the use of immunoglobulin; Meta analysis showed that the fever disappearance time was significantly shorter in the 2 g/(kg•d) for single use group than in 400 mg/(kg•d) for 4-5 days group (P<0.001) (Table 5).

Table 5
Table 5 Meta analysis of 2 g/(kg•d) for single use vs. 400 mg/(kg•d) for 4-5 days
Full table

Discussion

Our analysis found that, compared with the immunoglobulin 2 g/(kg•d) for single use, immunoglobulin 1 g/(kg•d) for 1-2 days showed no significant differences in terms of the incidences of coronary artery injuries at the acute phase, sub-acute phase, 6-month follow-up, and 12-month follow-up, the fever disappearance time, and the incidences of adverse reactions. Although a study enrolling 1,052 pediatric patients indicated that the incidence of coronary artery injuries at the sub-acute phase was lower in the 2 g/(kg•d) for single use group (13), the study was a retrospective case-control study, which is inferior to RCT in controlling the selection bias, performance bias, and attrition bias. Our analysis also found that, compared with the immunoglobulin 400 mg/(kg•d) for 4-5 days, the immunoglobulin 1 g/(kg•d) for 1-2 days had significantly shorter fever disappearance time, although it showed no significant difference in terms of the incidences of coronary artery injuries at the acute phase, sub-acute phase, 6-month follow-up, and 12-month follow-up and the incidences of adverse reactions. Furthermore, although the 2 g/(kg•d) for single use group was non-superior to 400 mg/(kg•d) for 4-5 days group in terms of the incidences of coronary artery injuries at the sub-acute phase and 6-month follow-up and the incidences of adverse reactions, it showed certain advantages in the terms of the incidence of coronary artery injuries at the acute phase and 6-month follow-up and the fever disappearance time. Mofi et al. (45) found the 2 g/(kg•d) for single use had better efficacy, shorter fever disappearance time, and lower incidence of coronary artery injuries. In addition, our pooled analysis showed the fever disappearance time was highly heterogeneous (P<0.1, I2>50%), which may be explained by the different physical status and drug sensitivities of the individual patient.

Among the 28 enrolled RCT, only two described the correct randomization methods and two used single-blind method. Therefore, there was unavoidable case-selection bias.

Immunoglobulin can cause mild adverse reactions such as chills, rash, shock, irritability, and palpitation, and also may induce severe adverse reactions such as embolism and myocardial infarction (13,14). All the enrolled literature in this analysis mentioned mild adverse reactions; however, no literature mentioned these severe adverse reactions or the increased risk of stroke during adulthood due to the short follow-up period. For the long-term efficacy, only 6 studies mentioned the outcomes of coronary artery injuries that had been followed up for one year; in other words, few long-term follow-up has been conducted for these injuries. In their studies, Deng et al. (22) and Guo et al. (24) mentioned that some patients were lost during the 1-year follow-up; however, they did not report the numbers of patients lost to follow-up in the treatment group and control group separately, making it impossible to merge the data. Therefore, standardized data reporting should be emphasized in the future studies.

In summary, There are similar therapeutic effects for KD between the immunoglobulin treatment groups at the doses of 1 g/(kg•d) for 1-2 days and 2 g/(kg•d) for single use. All the indicaters show no remarkable difference between these two doses except that the dose of 2 g/(kg•d) for single use is superior to 400 mg/(kg•d) for 4-5 days in terms of the incidences of coronary artery injuries at the acute phase and 6-month follow-up while the dose of 1 g/(kg•d) for 1-2 days has shorter fever disappearance time than 400 mg/(kg•d) for 4-5 days. However, the long-term efficacy (especially for coronary artery abnormalities) and safety of immunoglobulin still require further investigation.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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Cite this article as: Chen J, Ma B, Lin LX, Xue YM. Treatment of Kawasaki disease by different doses of immunoglobulin: a meta analysis of efficacy and safety. Transl Pediatr 2012;1(2):99-107. doi: 10.3978/j.issn.2224-4336.2012.04.05

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