Intravenous Immunoglobulin in Kawasaki Disease: History
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Pallavi L. Nadig
,
Vibhu Joshi
,
Rakesh Kumar Pilania
,
Rajni Kumrah
,
Jayakanthan Kabeerdoss
,
Saniya Sharma
,
Deepti Suri
,
Amit Rawat
,
Surjit Singh

Kawasaki disease (KD) is an acute vasculitis of childhood that affects the medium vessels with a special predilection to the involvement of coronary arteries. The major morbidity of this disease is due to coronary artery aneurysm, which occurs in about 25–30% of untreated cases. Intravenous immunoglobulin (IVIg) has consistently been shown to reduce the risk of CAAs to less than 5%. However, the mechanism of immunomodulation remains unclear. Several studies on the role of IVIg in the modulation of toll-like receptor pathways, autophagy, and apoptosis of the mononuclear phagocytic system, neutrophil extracellular trap, and dendritic cell modulation suggest a modulatory effect on the innate immune system. Similarly, certain studies have shown its effect on T-cell differentiation, cytokine release, and regulatory T-cell function.

  • Kawasaki disease
  • treatment
  • intravenous immunoglobulin
  • pathogenesis
  • coronary artery abnormalities
  • innate immunity
  • adaptive immunity

1. Background

Kawasaki disease (KD) is the commonest medium vessel vasculitis in children. KD is one of the commonest causes of acquired heart disease in children in developed countries. The most critical complication of KD is the development of coronary artery abnormalities (CAAs) [1]. The incidence of CAA is observed up to 25% in untreated patients, effectively reduced to <5% with timely treatment. Intravenous immunoglobulin (IVIg) remains the standard of care in all children with KD. Approximately 10–20% of patients with KD remain refractory to IVIg and require additional therapy.

2. History of the Evolution of IVIg as a Treatment for KD

After the initial description of the disease in 1957 by Dr. Tomisaku Kawasaki, aspirin and prednisolone were used extensively for treating KD [2]. In 1979, Kato et al. showed that aspirin reduced the incidence of CAAs (11%); however, the use of steroids was associated with increased chances of CAAs (64.7%) in KD [3]. Following this study, the usage of corticosteroids in KD halted, which paved the way for exploring newer options. One such option was IVIg.
Furusho et al. [4], in 1984, carried out a landmark study on the use of IVIg in patients with KD [5]. They performed a multicentric controlled trial of IVIg with aspirin versus aspirin alone. The control group received aspirin at a dose of 10–30 mg/kg/day for 3 months, while the treatment group received IVIg at a dose of 400 mg/kg/day for 5 days within 7 days of onset of illness. The study results showed that none of the patients in the IVIg group developed CAAs during the follow-up period, while 17% of the patients in the control group developed CAAs. Additionally, the IVIg group experienced early resolution of fever compared to the control group. These were significant findings because they first time demonstrated the efficacy of IVIg in preventing the development of CAAs in KD [5]. As a result of this study, IVIg became an important component of therapy in KD.
In 1990, a randomized controlled trial involving 105 Japanese children with KD considered to be at high risk of developing CAAs was randomized between 1 g/kg single dose and 2 g/kg single dose, demonstrating higher efficacy with the latter [6]. Results of this study showed that a higher dose (2 g/kg) was more effective in preventing the development of CAAs than those who received 1 g/kg. Later in 1991, a large multicentric randomized control trial in the United States by Newburger et al. compared the efficacy of daily infusions of 400 mg/kg/day for 4 consecutive days versus IVIg as a single 2 g/kg infusion over 10 h [7]. The study showed that children treated with a single high dose (2 g/kg) of IVIg infusion had several advantages over four consecutive daily infusions protocol. There was early defervescence with a shorter mean duration of fever in the single high dose infusion group—29.3% of children were febrile on day 3 in four consecutive day infusions group compared to 19.1% in the single infusion group; p = 0.028. Further, the single high-dose infusion group had lower systemic inflammation in the form of lower C-reactive protein (CRP) (p = 0.017), higher serum albumin (p = 0.002), and lower alpha-1 antitrypsin (p = 0.007) at 2 weeks of follow-up. More importantly, the single high-dose infusion group had a lower prevalence of CAAs when compared to the four-day infusion group (4.6% vs. 9.1% at 2 weeks follow-up, p= 0.042; 3.9% vs. 7.2% at 7 weeks follow-up, p = 0.098). Among the 4-day infusion group, it was noted that lower IgG levels on day 4 were associated with a higher prevalence of CAAs (p = 0.002) and a greater degree of systemic inflammation [7]. The mechanisms underlying the effectiveness of a single large dose of IVIg in KD treatment are not fully understood. However, two possible explanations were suggested by Newburger et al.; one possibility is the neutralization of superantigens that bind nonspecifically to receptors on antigen-presenting cells. Another possibility is the binding of gamma globulin to FcγR1, leading to the rapid downregulation of the cytokine storm. Nonetheless, a single high dose of IVIg emerged as a mainstream treatment following this study.

3. Mechanisms of Action of IVIg

The study conducted by JC Burns and colleagues investigated the effect of high doses of IVIg on natural killer (NK) cell activity in peripheral blood in patients with KD [8]. The authors demonstrated that IVIg could inhibit the interaction between NK cells and endothelial cells, suggesting a potential mechanism for its therapeutic effects in KD [8]. Mouthon L et al. in 1995 provided an elaborate description of the mechanisms of action of IVIg in immune-mediated disorders [9]. High-dose IVIg has been used in various autoimmune and inflammatory disorders, and it is hypothesized to exert its immunomodulatory role in both Fab-dependent and Fab-independent manners. The immunomodulatory effects of IVIg involve interactions with different components of the immune and vascular systems, leading to the downregulation of inflammation. IVIg can target various cell types, including endothelial cells and cells involved in both innate and adaptive immunity [9]. In the following discussion, the researchers summarize the possible mechanisms of the immunomodulatory role of high-dose IVIg. Proposed mechanisms involve the provision of the anti-idiotypic antibodies, clearance of autoantibodies by binding with Fc receptors, blockade of adhesion molecules, and activation of the inhibitory Fc receptor (i.e., FcγRIIB) on macrophages. IVIg has the potential to neutralize the cytokines and superantigens as well as augment the T-cell suppressor activity.

4. IVIg Refractory KD

Most children with KD respond to the initial dose of IVIg infusion. Those who develop a recrudescent or persistent fever at least 36 h after the end of their IVIg infusion are termed IVIg-resistant KD. The prevalence of IVIg-resistant KD is between 10 and 20% [10]. It constitutes a significant risk factor for the development of CAAs. These children require additional treatment with infliximab, corticosteroids, cyclosporine, or anakinra [10]. Genome-wide association studies (GWAS) studies have shown single nucleotide polymorphisms (SNPs) in genes of IFN-gamma, DC-SIGN, IL-1B, FcγR, MRP4, BAZ1A, STX1B, high mobility group box 1 (HMGB1), and P2Y12 (P2RY12) have been associated with risk of IVIg unresponsiveness [11][12][13][14][15][16]. Numerous scoring systems have been developed for the prediction of IVIg resistance. These include the Kobayashi score, Sano score, and Egami score [17][18][19]. However, these scoring systems have failed to show accurate predictions in other ethnic groups [20]. Nevertheless, age < 1 year, hypoalbuminemia, elevated transaminases, and neutrophilic leukocytosis have been consistently associated with a higher risk of IVIg resistance and the development of CAAs [10]. A meta-analysis by Li et al. has shown that the risk of IVIg resistance increases with elevated acute phase reactants (erythrocyte sedimentation rate, C-reactive protein, polymorphonuclear leucocytes), total bilirubin, transaminases, pro-Brain natriuretic peptide (pro-BNP), and lower platelet count, hemoglobin and serum sodium [21]. Patients with severe KD show lower levels of serum IgG, which may be related to IVIg resistance and increased incidence of CAAs [17][22]. Recently echocardiographic abnormalities such as coronary artery dilatation, perivascular brightness, presence of pericardial effusion, left ventricular (LV) insufficiency, and mitral insufficiency in the initial period of illness have been associated with a higher risk of IVIg resistance and CAAs [23][24][25][26][27]

5. Time to IVIg Administration since Onset of Fever—Early versus Late IVIg Treatment

Timely administration of IVIg in patients with KD is crucial in reducing the risk of developing CAAs. CAAs can occur in approximately 25% of untreated cases of KD, but the risk is significantly reduced to <5% with timely treatment. While there are no specific guidelines on the earliest possible timing for IVIg, initiating treatment as early as possible is generally recommended, ideally within the first 10 days of fever onset. The rationale behind this recommendation is to coincide with the peak of systemic inflammation, typically observed between 5–10 days in most studies [10]. Recent AHA guidelines suggest that the diagnosis of KD can be made as early as 3 days of fever by an expert if typical features are present, highlighting the importance of early diagnosis and timely treatment [28]. Few studies have found an association between early administration of IVIg (as early as day 4 of illness) and a higher requirement of additional treatment as well as the risk of relapse of fever after initial resolution [29]. However, it is possible that patients who receive IVIg early in the course of illness may have a more severe disease with a higher degree of inflammation and typical clinical signs leading to the early identification and treatment of KD and that these subsets of patients may be already at a higher risk of developing CAA despite early treatment. Cai et al., in a retrospective analysis, compared different timing groups of IVIg treatment, i.e., early (<5 days), conventional (5–7, 7–9 days), and late groups (>/= 10 days), and found no difference in rates of IVIg resistance between the groups and authors observed an increased rate of CAAs in the late group in comparison to conventional group [30]. A recent meta-analysis by Yan et al. suggests that early IVIg treatment (</= 5 days) did not significantly reduce the incidence of CAAs overall. However, the analysis found regional differences in the outcomes—Japan showed no significant difference in CAAs development (OR 1.27; p = 0.074); however, studies from the United States and China showed a reduced risk in the occurrence of CAAs with early IVIg treatment (OR 0.73; p = 0.000 and OR 0.50; p = 0.000, respectively) [31]. These regional variations may be attributed to differences in patient populations, disease severity, or other unidentified factors. These findings highlight the complexity of determining the optimal timing of IVIg administration in KD.

6. Data on the Duration of IVIg Infusion

The advantages of shortened infusion duration are that it shortens the hospital stay, allows earlier determination of the efficacy of the initial IVIg, and allows to decide on additional treatment earlier. Additionally, shorter infusion periods may reduce the inflammation rapidly however is associated with the risk of headache, vomiting, and thrombosis due to rapid infusion rate [32]. AHA 2017 guidelines recommend administering 2 g/kg IVIg over 10–12 h [10]. A multicentric randomized trial by Fukui et al. assessed the safety and efficacy of the infusion rates (12 h vs. 24 h) in patients with KD during the acute phase and found no statistically significant difference in fever duration (21 h versus 21.5 h, p = 0.325), the requirement of additional IVIg (36.8% vs. 30%, p = 0.741) or a third line treatment (21.1% versus 5%; p = 0.182) or any difference in serious adverse effects between the two groups. The requirement for additional third-line treatment was associated with the risk score at presentation, not the infusion rate. Two patients in the 12-h group (one at presentation and another on day 7 of illness) had small coronary aneurysms that regressed in follow-up. However, none in 24 h group had CAAs. Though the serum IgG levels increased in both the treatment arms by day 2, the levels were lower in the former compared to the latter (2414 mg/dL vs. 3037 mg/dL, p =<0.01). It may be hypothesized that serum IgG levels may fall rapidly after the shorter infusion, and the systemic inflammation may remain unsettled, resulting in the need for additional treatment by itself. On the other hand, a slower elevation of serum IgG level by 24 h infusion may maintain a more prolonged anti-inflammatory effect. However, this study was confounded by the difference in risk score between the 2 groups (lower sodium and IgG values in the 12-h group) at the baseline, and thus the superiority of 12-h infusion could not be proven [33]. However, further trials with better study designs are required to conclude the effects of shorter infusions.

7. Effect of the Strength of IVIg Concentration—5% versus 10%

A few studies have elucidated the efficacy and safety profile of 5% versus 10% IVIg concentrations for treatment in children with KD. Downie et al. showed that in Canadian children, a higher IVIg resistance rate was reported in patients who received 10% IVIg compared with those who received 5% IVIg. However, it was unclear whether the difference was solely due to the IVIg concentration or a change in the brand [34].
Oda et al. specifically compared the effectiveness of 5% and 10% IVIg from a single brand. The author reported that patients who received 10% IVIg had a shorter duration of infusion (half the infusion time than 5%) and fever compared to those who received 5% IVIg (10 vs. 13 h, p = 0.022). However, the two groups had no difference in adverse events, CAAs, or IVIg resistance. Among IVIg non-responders, the duration between initial IVIg and second-line treatment was significantly shorter in the 10% group (47 h vs. 49 h, p = 0.035), suggesting that early adjuvant therapy may help reduce CAAs [35]. A nationwide database from Japan compared the outcome between low and high concentrations of IVIg among 48,046 patients with KD and found that the resistance rate was higher in the 10% group compared to the 5% group (44.7% versus 21%, p = 0.008), but there were no statistically significant differences in duration of fever or CAAs noted between the two groups [36]. Similar findings were noted in another study by Han et al. [37]. To summarize, the choice of IVIg concentration may vary based on individual patient factors, local protocols, and the availability of specific brands. Further research and studies with standardized protocols are necessary to provide clearer recommendations on the optimal concentration of IVIg for KD treatment.

8. Recent Data on the Efficacy of Different Doses of IVIg in the Treatment of KD—1 g/kg versus 2 g/kg

Following the landmark study in 1991, a single high dose IVIg at a dose of 2 g/kg became the standard of care for KD. Recent AHA guidelines recommend 2 g/kg during the acute phase of KD. However, it adds up to higher medical costs and a financial burden to the family. A few earlier studies have shown that medium dose IVIg was equally effective and was sufficient in the majority in preventing CAAs [4][38][39][40].
Moving towards cost-effective options, few recent studies have compared a single dose of medium and high doses of IVIg during the acute phase of illness. Lan He et al. conducted a randomized controlled study comparing three treatment regimens—i.e., 1 g/kg once, 1 g/kg on 2 consecutive days, and 2 g/kg once in the treatment of KD. This study found no significant differences in duration of fever, time to defervescence, length of hospital stay, acute phase reactants (white blood cells, C-reactive protein), platelet count, and hemoglobin at 72 h after completion of initial IVIg infusion. More importantly, the incidence of IVIg resistance and CAAs at 2 weeks (15.2%, 15%, and 12.9%, p = 0.837) and up to 6 months following illness was comparable between the two treatment groups [41]. Similar results were found in a national-wide database from Japan [42]. Matsuura et al., based on their study, have suggested a more stratified therapy according to risk scores where treatment was guided by Kobayashi risk score and less high-risk score [43]. In this study, patients in the high-risk group (Kobayashi score ≥ 5 points) received 2 g/kg IVIg and prednisolone, whereas the moderate-risk group (Kobayashi score < 5 points and less high-risk score ≥ 2 points) received 2 g/kg IVIg and those in the low-risk group (Kobayashi score < 5 points and less high-risk score < 2 points) received 1 g/kg IVIg treatment. The study found no significant differences between the groups in terms of treatment response (defined as afebrile within 24 h of initial IVIg) or the rate of CAAs (7.3, 3.8, and 2.3% of patients in the high-, moderate-, and low-risk groups, respectively, p = 0.26) [44]. It is important to note that individual patient factors, local protocols, and clinical judgment should be considered when determining the appropriate IVIg dose for each patient. Further research and studies with larger sample sizes and standardized protocols are necessary to confirm these findings and provide more definitive recommendations on using medium-dose IVIg in KD treatment.

9. Side Effect Profile

High-dose IVIg infusion in children with KD largely has a good safety profile. Common adverse effects observed during or following the IVIg infusion include infusion-related reactions—mild flushing, rash, urticaria, chills, nausea, vomiting, and hypotension—that are transient and mild and do not require treatment cessation. Rarely, there have been adverse events such as aseptic meningitis, renal impairment, thrombosis [32], worsening of congestive cardiac failure, neutropenia, splenomegaly [7], pericardial effusion [45], derangement in liver functions [46], and hemolytic anemia [47].

This entry is adapted from the peer-reviewed paper 10.3390/diagnostics13142338

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