Piotr Buda
Joanna Friedman-Gruszczyńska2
Janusz Książyk- 1Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland
- 2Department of Pediatric and Congenital Heart Surgery, The Children's Memorial Health Institute, Warsaw, Poland
Kawasaki disease (KD), an acute, generalized vasculitis, is associated with an increased risk of coronary heart disease and is the most common cause of acquired heart disease in childhood. The incidence of KD is increasing worldwide. There are numerous international treatment guidelines. Our study aims to perform the first one so far comparison of them. While the gold standard therapy remains still the same (intravenous immunoglobulins and aspirin), there is currently a lack of evidence for choosing optimal treatment for high-risk patients and refractory KD. In this review, we also discuss the treatment of complications of KD and Kawasaki-like phenotypes, present an anti-inflammatory treatment in the light of new scientific data, and present novel potential therapeutic targets for KD.
Introduction
Kawasaki disease (KD) is an acute, systemic, vasculitis, most commonly occurring in children under 5 years of age. KD, firstly described in Japan in 1967 is the present most common cause of acquired heart disease in childhood (1, 2). The incidence ranges from 138–322/100,000 in Asia, to 4.5–25/100,000 in Europe and the United States of America (3–6). In Great Britain, the number of new cases has doubled in recent years and is now 8.1/100,000 (7, 8). The immunopathogenic mechanism for KD is not completely understood. The epidemiological observations suggest that in genetically predisposed children an environmental agent causes an abnormal hyperactivation of the immune system which results in damage of vascular endothelial cells and systemic vasculitis (8). Many genes responsible for susceptibility to KD have been identified through genome-wide association studies, however they differ within populations (9–15).
The diagnosis of KD should be considered in any child with a febrile exanthematous illness and presence of inflammation, particularly if it persists longer than 4–5 days. The diagnosis of KD is based on clinical criteria, established by the Japanese Ministry of Health Research Committee and adopted by the American Heart Association (16–18). Classic KD is defined as the presence of fever of ≥5 days plus at least ≥4 of the following diagnostic criteria: oral mucosal changes, non-suppurative conjunctival injection, polymorphous skin rash, peripheral changes, including erythema and/or edema of hands and feet, and cervical lymphadenopathy. The incidence of atypical form is increasing. It is more common in infants younger than 6–12 months, the only clinical sign could be fever and abnormalities in laboratory tests, which can cause diagnostic errors. Currently, the diagnosis of KD is only based on clinical and laboratory criteria, interestingly, Wright V et al. found that molecular patterns could enable earlier diagnosis and treatment of KD and reduce inappropriate treatment in those with other diagnoses (19). Although the acute febrile and exanthematous illness may be self-limiting, some patients develop serious complications that are associated with an increased risk of coronary heart disease. The main complication of the disease are coronary artery abnormalities (CAL), however extra coronary complications can occur. The coronary artery aneurysms occur in around 20–30% of untreated cases (19, 20). Coronary artery events (thrombosis, stenosis, intervention, myocardial infarction, death) occurrs in 1–48% of patients with CAL, the incidence depends on the aneurysm Z score <10 and on the absolute dimension (21). Up to 4% of cases of untreated KD with CAL will progress to sudden death during the acute phase of the illness as a result of aneurysmal thrombosis formation, myocardial infarction or dysrhythmia (22). In properly treated patients, the risk of permanent changes in coronary arteries decreases significantly (4%) (20, 23, 24). Patients without coronary artery abnormalities have no symptoms or events during follow-up. Medium to long term prognosis after Kawasaki disease is excellent (25). Recurrence of KD has been previously described. It varies between 0.8% in the united states of America to 3% in Japan (5, 26). The proportion of patients suffering from a recurrence increases with age, majority of recurrence occurs within 2 years of the initial presentation (26). In rare cases (0.2%), patient can suffer multiple recurrences (26).
The preliminary understanding of immunogenetic influences the disease susceptibility has already led to treatment with various regimens. The main goal of therapy is to reduce systemic inflammation as early as possible to prevent coronary artery damage.
There are many diagnostic and therapeutic strategies, the aim of this paper is to compare current guidelines and to discuss anti-inflammatory treatment of KD, complications of KD, Kawasaki-like phenotypes and to discuss new potential targets based on new scientific data.
Treatment Guidelines
There are differences in the scope of the procedure, depending on the recommendations of individual countries.
Most of them are listed below:
– (2014) Guidelines for medical treatment of acute Kawasaki disease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version) (17).
– (2017) Scientific Statement, which serves as an update to the 2004 American Heart Association guidelines for the diagnosis, treatment, and long-term management of Kawasaki disease (16).
– (2018) European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease—the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative (27).
– (2021) Revised recommendations of the Italian Society of Pediatrics about the general management of Kawasaki disease (28).
The comparison of various treatment regimens is shown in Tables 1, 2.
Table 1. Comparison of guidelines for the treatment of Kawasaki disease.
Table 2. Treatment options for IVIG-resistant KD patients and refractory KD.
There are also guidelines on the long-term management of patients who have vascular complications of KD. This therapy is individualized, it usually consists of medicines for heart conditions (antithrombotic therapy, statins, beta-blockers, interventional cardiology, cardiac surgery), though this topic exceeds the aim of this paper.
– (2020) Japanese Circulation Society Working Group 2020 Guideline on Diagnosis and Management of Cardiovascular Sequelae in Kawasaki Disease (29).
– (2020) Expert consensus statement “Lifetime cardiovascular management of patients with previous Kawasaki disease” (30).
It is also worth to mention that in 2020 Japan Pediatric Society presented the revision of guidelines for Kawasaki disease (6th revised edition) but only in the context of the diagnosis.
– (2020) Japan Pediatric Society: Revision of diagnostic guidelines for Kawasaki disease (6th revised edition) (18).
Standard Treatment of Kawasaki Disease
All above mentioned management guidelines are consistent with the first-line treatment. Treatment of acute illness with intravenous immunoglobulin (IVIG) and acetylosalic acid (ASA) is now the gold standard recommendation. Differences concerning aspirin dose are presented in Table 1.
Intravenous Immunoglobulins (IVIG)
Currently, the most effective anti-inflammatory treatment for KD is an early transfusion of intravenous immunoglobulins. Randomized clinical trials performed in the 1980s suggested that IVIG reduced the prevalence of persistent coronary artery lesions (CAL) (21, 31). The systematic review by the Cochrane Collaboration states that CAL development can be reduced by a single dose of 2 g/kg IVIG given before the 10th day after onset, thus, high-dose IVIG is still the first-line treatment of KD according to all current guidelines (Table 1) (24).
The molecular mechanisms of IVIG for anti-inflammation in KD remain unclear. Potential mechanisms include the blockade of the Fc receptor, neutralization of the pathogenic products of unknown infectious agents, immune-modulatory effects, stimulation of suppressor activity, and modulation of the cytokines (9, 14, 32–34). Multiple studies show that ~10–28% of patients are resistant to first-line treatment (no resolution of fever, recurrent fever, no / slight decrease in inflammation parameters) (20, 34). The definition of IVIG resistance varies according to different recommendations (Table 1). Many studies have been conducted to identify predictive factors of resistance to IVIG therapy. Xuan Li et al. performed a meta-analysis of 4,442 children with KD and identified the clinical features and laboratory factors: the initial administration of IVIG ≤ 4.0 days after the onset of symptoms, increased erythrocyte sedimentation rate (ESR) and decreased hemoglobin and platelet counts, oral mucosa alterations, cervical lymphadenopathy, swelling of extremities, and polymorphous rash (35). Yan et al. in their systematic review and meta-analysis confirmed that gender, IVIG resistance, IVIG treatment beyond 10 days of onset of symptoms and increased C-reactive protein (CRP) level are all significant risk factors for CAL (36). Zheng et al. performed the first meta-analysis that revealed the strongest association between the incidence of CAL and IVIG resistance (37). There is currently no universally accepted classification system to evaluate KD severity. Many predictive models that were designed to evaluate the possibility of IVIG resistance were proposed (38–47). Scoring systems (Kobayashi, Sano, Egami) most commonly used in clinical practice include following parameters: hyponatremia, prolonged illness duration, elevated C-reactive protein, aspartate transaminase, alanine transaminase (ALT), bilirubin, neutrophil ratio, low count of platelets. The problem is that there are no such predictive instruments or scores outside Japan, the effectiveness of such scores has not been confirmed in large-scale prospective cohort studies or meta-analyses. Kuo et al. used a novel approach by conducting a genomewide association analysis to develop a risk score for IVIG resistance (48). However, it is unknown whether one universal prediction model can be developed for all populations or population-specific prediction models will be required (49). Recently, Piram et al. identified predictors of IVIG resistance and presented a new score with good sensitivity and acceptable specificity in a non-Asian population (50). Predictors of secondary treatment after initial IVIG were hepatomegaly, ALT level ≥30 IU/L, lymphocyte count <2,400/mm3 and time to treatment <5 days. These findings have not yet been used to current guidelines.
The development of CAL despite IVIG treatment ranges from 19 to 42% (51, 52). A genetic contribution to CAL is likely as before effective therapy with IVIG was introduced, only 25–30% of affected children developed CAL (22, 53). Many genes and chromosomal regions have been identified through genome-wide association studies to have an association with KD and CAL formation (10, 14, 53, 54). Genes responsible for susceptibility and CAL formation may be different between populations. The neutrophil antigen 1 allotype in the extracellular domain 1 of FcγR3B has been identified as a major risk factor for IVIG refractoriness and persistent CAL (32). In the future, risk scores may include genetic testing for high-risk small nucleotide polymorphisms (SNPs).
Acetylsalicylid Acid (ASA)
Aspirin (ASA, aspirin) inhibits platelet function through irreversible inhibition of cyclooxygenase (COX) activity and blocks the synthesis of prostaglandins. The mechanism of action of aspirin depends on dosage, medium-high doses are usually given to obtain the anti-inflammatory effect, low doses inhibit platelet aggregation. ASA has been used in the treatment of KD for many years and is approved for all patients with KD. High-dose (80–100 mg/kg) and medium dose (30–50 mg/kg) acetylsalicylic acid have been recommended as standard treatment during the acute febrile phase by the American Heart Association and Japanese Society of Pediatric Cardiology and Cardiac Surgery, respectively (16, 18). The optimal dose of ASA remains controversial, however. Although high-dose aspirin shortens fever duration, researchers of many recent studies found that the use of medium- or higher-dose ASA in acute Kawasaki disease did not prevent CAL (54–58). Considering the risk of drug toxicity and the lack of evidence for prevention of CALs, the role of aspirin in the acute phase of KD needs to be reassessed and a future randomized controlled trial is needed to determine the optimum dose of ASA. Clinical trials comparing the efficacy of IVIG alone and IVIG plus high-dose aspirin in KD are ongoing. The duration of high-dose ASA administration varies across institutions. Some physicians recommend conversion to an antiplatelet dose of ASA after the child has been afebrile for 48–72 h. Others continue high-dose ASA until the 14th day of illness. Low-dose ASA is continued until the patient has no evidence of CAL by 6–8 weeks after onset of fever. For children who develop CAL, ASA may be continued indefinitely (16).
It is unclear what dose (anti-inflammatory vs. anti-platelet) of aspirin should be used with simultaneous supply of glucocorticosteroids (GCS) and whether to give aspirin at all (since GCS are anti-inflammatory and the combined use of both drugs increases their side effects).
Interestingly, only Italian guidelines indicate that patients treated with GCS as a first-line treatment need to be treated simultaneously with low dose ASA instead of high-dose ASA. Such strategy is reasonable but some authors concluded that in the absence of comparative studies, it is practiced to use both drugs.
Second-Line Treatment
Patients who are at increased risk of CAL, unresponsive to IVIG may be treated with second dose of IVIG, glucocorticosteroids, infliximab or other immunosuppressive agents. To date, there have been no robust clinical trials comparing second-line treatment options for IVIG resistant KD. Treatment choice varies according to different recommendations (Tables 1, 2).
Glucocorticosteroids (GCS)
GCS inhibit the transcription of most pro-inflammatory cytokines (IL-1, IL-2, IL-6, IL-8, interferon-γ, and tumor necrosis factor-α) (59). They also inhibit the proliferation of T and B lymphocytes, Langerhans cells, decrease adhesive molecule expression. Because of their effects on a broad range of innate and adaptive responses and effect on multiple types of immune cells, GCS are remarkable helpful in managing many of autoinflammatory and autoimmune diseases (60, 61). Corticosteroids are usually administered in all vasculitides due to their anti-inflammatory effect, but the use of GCS in children with KD is still controversial and varies depending on individual recommendations (16, 27, 28). In 2007, a multi-center prospective randomized, placebo-controlled, double-blinded study found no significant difference in coronary z scores or in the duration of fever in those treated with corticosteroids in addition to IVIG (62). Subsequent Japanese studies have shown that the addition of corticosteroids significantly decreases the risk of CAL; however, these studies included only patients classified as patients with a high risk of IVIG resistance based on Asian risk scores (63–66). In 2016 meta-analyses showed that the frequency of CAL was significantly lower in children that received GCS with IVIG than IVIG therapy only (67). Sixteen comparative studies were analyzed. It is worth noting that most included studies were conducted in Japan. Whether these results are applicable to other countries remains to be elucidated. Others found that long-term steroid treatment should be considered in all children diagnosed with the disease (68). Yang et al. stated that GCS treatment, combined with IVIG, reduces the incidence of coronary aneurysms, but only in Japanese patients, which was not observed in other nations' patients (69). Thus, these studies' conclusions should not be extrapolated to non-Asian populations due to the possible influence of various environmental, genetic, and economic factors on the effects of therapy (70). The current American Heart Association guidelines do not recommend routine use of adjunctive corticosteroids, but rather consideration for high-risk patients. The administration of a longer course of corticosteroids together with IVIG and ASA may be considered for treatment of high-risk patients, when they can be classified before initiation of treatment. Administration of high-dose pulse steroids may be considered as an alternative to the second infusion of IVIG or for retreatment of patients with KD who have had recurrent or recrudescent fever after additional IVIG (16). According to the SHARE guidelines, adjunctive primary GCS treatment should be given to children: who are IVIG resistant, have a Kobayashi score ≥4 or developed MAS/HLH and/or shock. The panel of experts defined additional ‘high-risk groups’ who might benefit from primary adjunctive GCS: infants <1 year of age and children presented with coronary and/or peripheral aneurysms at diagnosis. It is unclear whether corticosteroids should be used in children with less severe KD, and the optimal corticosteroid dosing regimen to use is uncertain. Italian and Japanese guidelines indicate the use of GCS for patients suspected of being IVIG resistant on the basis of clinical symptoms and laboratory findings and for patients found to be IVIG resistant after first-line IVIG (18, 28). The problem is that there are no predictive instruments or scores for reliable identification of high-risk children outside Japan, further research is needed to test the efficacy of GCS in this population. KD-CAAP is a multi-center, randomized trial comparing the effectiveness of corticosteroids with standard treatment vs. standard treatment alone to prevent KD heart complications. The study is ongoing.
Infliximab
Monoclonal antibodies may target the presumed key-cytokines involved in KD pathogenesis, particularly tumor necrosis factor (TNF)-α and interleukin (IL)-1 (71, 72). Elevated serum TNF-alpha is elevated in patients with KD and it correlates with the development of CAL. Infliximab is a chimeric murine/human IgG1 monoclonal antibody that binds specifically to TNF-alpha with high affinity and neutralizes the biological activity of soluble TNF-α (73). Among monoclonal antibodies, infliximab is the most widely tested drug in KD. It is safe and well-tolerated drug that reduces fever duration and inflammation, but the addition of infliximab to primary treatment in acute Kawasaki disease did not reduce treatment resistance. No trials have evaluated its use as adjunctive therapy in patients with early evidence of CAL (74). Thus, current guidelines supports the use of infliximab, as a rescue therapy at a single intravenous dose (5 mg/kg of body weight given in 2 h) for IVIG- and corticosteroid resistant KD patients.
The efficacy of another tumor necrosis factor-α receptor blocker (etanercept) was also evaluated (75, 76). However, the disadvantage of etanercept is that it only binds to circulating and not cell-bound TNF-alpha which could potentially impair its efficacy (77).
Anakinra
The IL-1 signaling pathway seems to be key to the pathogenesis of KD, especially in the development of coronary artery aneurysms (78). Upregulated IL-1 pathway genes and elevated IL-1 concentrations have been demonstrated in the peripheral blood of KD patients during the acute phase of the disease (79, 80). Weng et al. showed that polymorphisms in the genes coding for IL-1 (-31 CC and−511 TT) were associated with a greater risk of resistance to IVIG treatment (81). The use of IL-1 inhibitors in patients with KD has been reported, but data are largely limited to small case series. Ferrara et al. summarized the scientific literature related to the use of anakinra, analyzing preclinical and clinical data (82). Reasons for using anakinra are as followed: Kawasaki disease shock syndrome, macrophage activation syndrome, persistent fever and laboratory abnormalities, worsening of coronary aneurysms, coronary aneurysms and increased proBNP levels. The dose ranged from 1 to 10 mg/kg/day; the duration ranged from 6 days to 6 months (83–88). According to compared recommendations only IPS mentioned about the duration of treatment for an overall period of 15 days or for a longer period, depending on the specific clinical scenery (28, 89). In the largest study concerning anakinra (KAWAKINRA), starting doses were 2 mg/kg of anakinra (4 mg/kg in patients who were age <8 months and who weighed ≥5 kg), and the dose was increased up to 6 mg/kg every 24 h if the patient's was febrile. Treatment duration was 2 weeks. Almost all patients (sixteen patients included) received a clinical benefit (reducing fever, markers of systemic inflammation, and coronary artery dilatation), and no relevant side effects were noted. Authors concluded that anakinra may be considered as an option after the failure of the first IVIG infusion, especially in patients with coronary involvement (90). Mastrolia MV et al. have recently reported two cases of children, diagnosed with KD, non-responsive to two doses of intravenous immunoglobulins, successfully treated with ANA, without prior use of steroids (91). Further studies are planned/ongoing to reveal its clinical significance (ANACOMP, ANAKID) and to better define the place of IL-1 blockade in KD step-up treatment.
Interestingly, other anti-IL drugs could be regarded as an alternative treatment. Canakinumab is a human monoclonal antibody targeted at IL-1β, with no cross-reactivity with other members of the IL-1 family. It has been authorized for the treatment of systemic juvenile idiopathic arthritis and different hereditary autoinflammatory syndromes. According to ISP guidelines using a single subcutaneous injection of 4 mg/kg/dose of canakinumab may be also a future option for cases of IVIG-resistant and corticosteroid-resistant KD (28).
Cyclosporin A
Cyclosporin A is a calcineurin inhibitor that exerts its immunosuppressive effects through the down-regulation of NFAT (nuclear factor of activated T cells) transcription factor, and suppresses cytokine production such as IL-2 by inhibiting nuclear factor of activated T cells (17, 92). It has been studied as both a second-line therapy and as rescue therapy for KD.
The largest study (KAICA trial) was conducted on Japanese participants. Hamada et al. found that combined primary therapy with IVIG and cyclosporin was safe and effective for favorable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG (93). Despite this CsA is reserved only for refractory KD according to current guidelines (including Japanese) (16, 17, 27, 28).
Other Treatment
Cyclophosphamide, methotrexate, ulinastatin have also been used in refractory-KD however according to all current guidelines these medicaments should only be considered in severe refractory cases because of potential adverse reactions and better experience with previously mentioned medicaments (77, 94–97). Plasma exchange (PE) could act via mechanical removal of inflammatory cytokines and was used in patients with refractory KD (17, 98, 99). The largest series reported to date included 125 patients who were resistant to IVIG and treated with plasma exchange (100). Authors conclude that outcomes of PE for Kawasaki disease refractory to IVIG are favorable, although not statistically significant. Because PE is a high-risk procedure and there are no controlled clinical trials it could be considered only in extreme cases of refractory KD.
Treatment of Other Clinical Conditions Related to KD
Macrophage Activation Syndrome (MAS)
Macrophage Activation Syndrome (MAS) is a form of secondary hemophagocytic lymphohistiocytosis (HLH). It is a life-threatening systemic extreme-inflammatory syndrome caused by multifactorial immune dysregulation and pathological hyperactivation of the immune system. The most common form of HLH is MAS in the course of systemic-onset juvenile idiopathic arthritis (so-JIA) but it could also occur as the manifestation of Kawasaki disease (101, 102). Macrophage activation syndrome is characterized by fever, hepato- and/or splenomegaly, non-characteristic skin lesions, lymphadenopathy, coagulopathy, central nervous system dysfunction. Symptoms of the respiratory system and heart failure could also be present. Uncharacteristic clinical symptoms often mistakenly suggest sepsis, are accompanied by more characteristic additional diagnostic work-up. Cytopenias, hypofibrinogenemia, hypertriglyceridemia, hyperferritinemia are the most common findings. MAS may be frequently under-recognized in children with KD because there are no distinct criteria for MAS complicating KD (103). Some authors recommend that Histiocyte Society criteria may be used for the diagnosis of MAS in KD (104, 105). The MAS criteria are validated for systemic juvenile idiopathic arthritis, but they are commonly used by other physicians for other systemic autoinflammatory diseases such as Kawasaki disease (106, 107). KD patients with MAS show high intravenous immunoglobulin (IVIG) resistance and coronary complications, they usually present with hepatosplenomegaly, cytopenia, liver dysfunction, hyperferritinemia, elevated serum LDH, hypofibrinogenemia, hypertriglyceridemia (103, 104).
The main goal of the therapy of MAS is to stop “cytokine storm,” the treatment should be implemented as soon as possible. The antimicrobial therapy usually is necessary because of fact that each form of HLH is triggered by an infectious agent. The chemotherapy protocol (HLH-2004) including etoposide, cyclosporine, dexamethasone, and transplantation of hematopoietic stem cells is widely used in primary HLH. For patients with acquired HLH there are no recommendations and guidelines. Glucocorticosteroids, intravenous immunoglobulins and cyclosporine A are commonly used. Anti-cytokines antibodies, cyclophosphamide, vincristine, anti-thymocyte globulin, granulocyte-colony stimulating factor, plasma exchange or hemofiltration could be used in severe and refractory HLH (102, 108–110). Some authors start with HLH-2004 protocol for secondary HLH (102, 105). Inappropriate treatment such as immunosuppression monotherapy and a delay in the start of treatment may be one of the main unfavorable prognostic factors in patients with MAS. The combined immunosuppression (high-dose GCS in combination with CsA and IVIG) is usually given as the initial therapy for patients with secondary HLH (102, 108, 109, 111). The commonly used treatment in children with MAS and KD is combination therapy with GCS, IVIG, cyclosporine, IL-1 blockers (103, 104, 112). Furthermore, in MAS there is a high risk of thrombosis because of the massive activation of the coagulation cascade. In cases of highly elevated level of D-dimers (seen especially in MAS and other hyperinflammatory conditions like pediatric inflammatory multisystem syndrome-temporally associated with SARS-CoV-2) the use of anticoagulant drugs (e.g., enoxaparin) could be required.
Appropriate treatment of MAS requires the collaboration of pediatric, infectious disease, and intensive care unit specialists with other experts such as rheumatologists, immunologists, hematologists.
Pediatric Inflammatory Multisystem Syndrome-Temporally Associated With SARS-CoV-2 (PIMS-TS)
Since late April 2020, many articles have been published describing the increasing incidence of Kawasaki-like disease after the beginning of the SARS-CoV-2 epidemic (107, 113–117). The new entity was proposed so-called Pediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2 (PIMS-TS). Multisystem inflammatory syndrome in children (MIS-C) is an alternative name proposed in the United States of America (USA) and adopted by the World Health Organization (WHO). Whether this is a particular form of KD triggered by SARS-CoV-2 or a different entity is still a matter of debate. Some of the clinical manifestations of PIMS-TS mimic KD and MAS. Children with PIMS-TS are usually older at disease onset, classic mucocutaneous symptoms are less common, gastrointestinal and respiratory symptoms are more frequently observed. Patients are at higher risk to develop myocarditis with heart insufficiency and require longer time in the hospital and ICU admittance, for the occurrence of shock, need of vasoactive agents, and invasive ventilation. Many treatment protocols recommends the use of IVIG and aspirin with/without high-dose corticosteroids as first-line therapy. Indications for the use of GCS and dosing depends on the phenotype of the disease and differs in many medical centers. Approximately 30–80% of patients do not respond to IVIG alone and may require adjunctive immunomodulatory therapy to control inflammation. This is in contrast to classic KD where IVIG resistance has been seen in <15% of patients. Anakinra is the most common anticytokine drug used in a subgroup of children with PIMS-TS in many medical institutions, given in cases of persistent severe inflammatory state despite previous treatment (113, 116, 118–121). Treatment with tocilizumab (humanized anti-IL-6 receptor antibody, inhibiting IL-6) or infliximab was also initiated in patients with PIMS-TS with a favorable outcomes. The effect of immunomodulatory therapy needs further evaluation in both observational and trial settings to determine the influence on inflammation (116, 118, 122).
Perspectives
KD and SoJIA
Systemic-onset juvenile idiopathic arthritis (so-JIA) is a systemic inflammatory disease classified as a subtype of juvenile idiopathic arthritis. It is associated with dysregulation of the innate immune system, suggesting that it belongs to the spectrum of autoinflammatory disorders. KD and so-JIA share many common clinical and laboratory features. So-JIA can be initially diagnosed as KD and vice versa (123–125). CAL can be also found in soJIA. Most children with soJIA and coronary artery dilatations are classified initially as KD and treated with multiple doses of IVIG. Although KD and so-JIA could mimic each other at the presentation, the follow-up is quite different. Non-responsiveness to standard therapy with GCS and classical disease-modifying antirheumatic drugs is not uncommon in children with so-JIA. Recently, biologic agents that specifically inhibit the cytokines interleukin (IL)-1 and IL-6 have demonstrated remarkable clinical effectiveness and confirmed the importance of these cytokines in the process of so-JIA (126). The three IL-1 blockers that have been tested so far (anakinra, canakinumab, and rilonacept) have all been proven effective and safe, although only canakinumab is currently approved for use in so-JIA (127–130). IL-18 is another proinflammatory cytokine elevated in so-JIA and may represent a pathogenic link between so-JIA and MAS (131). Based on this, some authors suggested using exogenous IL-18BP (IL-18 binding protein) as a novel therapeutic approach for inflammatory diseases (132). A recent Phase II trial of recombinant IL-18BP (tadekinig alfa) showed promising results for adult-onset Still's disease (133). Some authors found that it could be useful in resistant systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome (134). Interestingly, IL-18 is also elevated in the acute phase of KD and may be protective for those at high-risk for treatment failure (135). Above mentioned findings warrant future research on these drugs as a promising therapeutic option also in Kawasaki disease.
Potential Therapeutic Target
Many recent studies found novel immunobiological pathways involved in KD and allowed to identify potential therapeutic targets for KD, they are listed in Table 3 (15, 37, 136–147). Literature data indicate that researchers focused especially on JAK / STAT pathway in the context of vasculitis, thus it could be regarded as a most promising potential target.
Table 3. Potential therapeutic target for Kawasaki disease.
Conclusions
IVIG and ASA are now the gold standard recommendation for the treatment of Kawasaki disease according to all guidelines. However new scientific data indicate that in the future this regimen can change. Definition of high-risk patients, as well as the indication for additional treatment in these patients, varies depending on the national recommendations. Stratification of patients and optimalization of the second-line therapy is the most urgent issue in Kawasaki disease and the effect of immunomodulatory therapy needs further evaluation in carefully designed observational and trial settings to determine the effect on inflammation. There is currently a lack of evidence for choosing optimal treatment for refractory KD.
The use of glucocorticosteroids in children with KD is still controversial. Monoclonal antibodies are currently regarded as a rescue therapy, althought some data could indicate that anakinra and infliximab may be considered as an option after the failure of the first IVIG infusion. Other medicaments should only be considered in severe refractory cases because of potential adverse reactions. Results of many ongoing studies are awaited and may provide changes in the future management of KD patients.
So-JIA overlaps clinical and immunological presentation with KD and these findings could encourage to perform further studies based on previous results on so-JIA and other autoinflammatory syndromes. Many recently described immunobiological pathways could serve as a promising potential therapeutic target.
Author Contributions
PB have made a substantial contribution to the concept or design of the article, or the acquisition, analysis, or interpretation of data for the article, and drafted the article. JF-G and JK revised the article critically for important intellectual content and approved the version to be published. All authors reviewed the results and approved the final version of the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Japanese J Allergol. (1967) 16:178–222.
2. Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics. (1974) 3:271–76.
3. Gardner-Medwin JMM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch-Schönlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet. (2002) 360:1197–202. doi: 10.1016/S0140-6736(02)11279-7
4. Nakamura Y, Yashiro M, Uehara R, Oki I, Kayaba K, Yanagawa H. Increasing incidence of Kawasaki disease in Japan: nationwide survey. Pediatr Int. (2008) 50:287–90. doi: 10.1111/j.1442-200X.2008.02572.x
5. Bell DM, Morens DM, Holman RC, Hurwitz ES, Hunter MK. Kawasaki syndrome in the United States 1976 to 1980. Am J Dis Child. (1983) 137:211–14. doi: 10.1001/archpedi.1983.02140290003001
6. Holman RC, Curns AT, Belay ED, Steiner CA, Schonberger LB. Kawasaki syndrome hospitalizations in the United States, 1997 and 2000. Pediatrics. (2003) 112:495–501. doi: 10.1542/peds.112.3.495
7. Harnden A, Alves B, Sheikh A. Rising incidence of Kawasaki disease in England: analysis of hospital admission data. BMJ. (2002) 324:1424–25. doi: 10.1136/bmj.324.7351.1424
8. Eleftheriou D, Levin M, Shingadia D, Tulloh R, Klein NJ, Brogan PA. Management of Kawasaki disease. Arch Dis Child. (2014) 99:74–83. doi: 10.1136/archdischild-2012-302841
9. Kuo HC, Chang WC. Genetic polymorphisms in Kawasaki disease. Acta Pharmacol Sin. (2011) 32:1193–8. doi: 10.1038/aps.2011.93
10. Kuo HC Li SC, Guo MMH, Huang YH Yu HR, Huang FC, et al. Genome-wide association study identifies novel susceptibility genes associated with coronary artery aneurysm formation in Kawasaki disease. PLoS ONE. (2016) 11:e0154943. doi: 10.1371/journal.pone.0154943
11. Onouchi Y, Ozaki K, Buns JC, Shimizu C, Hamada H, Honda T, et al. Common variants in CASP3 confer susceptibility to Kawasaki disease. Hum Mol Genet. (2010) 19:2898–906. doi: 10.1093/hmg/ddq176
12. Onouchi Y. The genetics of Kawasaki disease. Int J Rheum Dis. (2018) 21:26–30. doi: 10.1111/1756-185X.13218
13. Onouchi Y, Gunji T, Burns JC, Shimizu C, Newburger JW, Yashiro M, et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet. (2008) 40:35–42. doi: 10.1038/ng.2007.59
14. Khor CC, Davila S, Breunis WB, Lee YC, Shimizu C, Wright VJ, et al. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat Genet. (2011) 43:1241–6. doi: 10.1038/ng.981
15. Buda P, Chyb M, Smorczewska-Kiljan A, Wieteska-Klimczak A, Paczesna A, Kowalczyk-Domagała M, et al. Association between rs12037447, rs146732504, rs151078858, rs55723436, and rs6094136 polymorphisms and Kawasaki Disease in the population of polish children. Front Pediatr. (2021) 9:624798. doi: 10.3389/fped.2021.624798
16. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. (2017) 135:927–99. doi: 10.1161/CIR.0000000000000484
17. Saji T. Guidelines for medical treatment of acute Kawasaki disease: Report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version). Pediatr Int. (2014) 56:135–58. doi: 10.1111/ped.12317
18. Kobayashi T, Ayusawa M, Suzuki H, Abe J, Ito S, Kato T, et al. Revision of diagnostic guidelines for Kawasaki disease (6th revised edition). Pediatr Int. (2020) 62:1135–8. doi: 10.1111/ped.14326
19. Wright VJ, Herberg JA, Kaforou M, Shimizu C, Eleftherohorinou H, Shailes H, et al. diagnosis of Kawasaki Disease using a minimal whole-blood gene expression signature. JAMA Pediatr. (2018) 172:e182293. doi: 10.1001/jamapediatrics.2018.2293
20. Kato H, Akagi T, Sugimura T, Sato N, Kazue T, Hashino K, et al. Kawasaki disease. Coron Artery Dis. (1995) 6:194–206.
21. Ogata S, Tremoulet AH, Sato Y, Ueda K, Shimizu C, Sun X, et al. Coronary artery outcomes among children with Kawasaki disease in the United States and Japan. Int J Cardiol. (2013) 168:3825–8. doi: 10.1016/j.ijcard.2013.06.027
22. Dhillon R, Newton L, Rudd PT, Hall SM. Management of Kawasaki disease in the British Isles. Arch Dis Child. (1993) 69:631–8. doi: 10.1136/adc.69.6.631
23. Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. (1986) 315:341–7. doi: 10.1056/NEJM198608073150601
24. Oates-Whitehead RM, Baumer JH, Haines L, Love S, Maconochie IK, Gupta A, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane database Syst Rev. (2003) 2003:CD004000. doi: 10.1002/14651858.CD004000
25. de La Harpe M, di Bernardo S, Hofer M, Sekarski N. Thirty Years of Kawasaki disease: a single-center study at the University Hospital of Lausanne. Front Pediatr. (2019) 7:11. doi: 10.3389/fped.2019.00011
26. Yanagawa H, Yashiro M, Nakamura Y, Hirose K, Kawasaki T. Nationwide surveillance of Kawasaki disease in Japan, 1984 to 1993. Pediatr Infect Dis J. (1995) 14:69–71. doi: 10.1097/00006454-199501000-00017
27. De Graeff N, Groot N, Ozen S, Eleftheriou D, Avcin T, Bader-Meunier B, et al. European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease-the SHARE initiative. Rheumatol. (2019) 58:672–82. doi: 10.1093/rheumatology/key344
28. Marchesi A, Rigante D, Cimaz R, Ravelli A, Tarissi de Jacobis I, Rimini A, et al. Revised recommendations of the Italian Society of Pediatrics about the general management of Kawasaki disease. Ital J Pediatr. (2021) 47:1–12. doi: 10.1186/s13052-021-00962-4
29. Fukazawa R, Kobayashi J, Ayusawa M, Hamada H, Miura M, Mitani Y, et al. JCS/JSCS 2020 Guideline on diagnosis and management of cardiovascular sequelae in Kawasaki disease. Circ J. (2020) 84:1348–407. doi: 10.1253/circj.CJ-19-1094
30. Brogan P, Burns JC, Cornish J, Diwakar V, Eleftheriou D, Gordon JB, et al. Lifetime cardiovascular management of patients with previous Kawasaki disease. Heart. (2020) 106:411–20. doi: 10.1136/heartjnl-2019-315925
31. Furusho K, Kamiya T, Nakano H, Kiyosawa N, Shinomiya K, Hayashidera T, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet. (1984) 2:1055–8. doi: 10.1016/S0140-6736(84)91504-6
32. Shrestha S, Wiener H, Shendre A, Kaslow RA, Wu J, Olson A, et al. Role of activating FcγR gene polymorphisms in Kawasaki disease susceptibility and intravenous immunoglobulin response. Circ Cardiovasc Genet. (2012) 5:309–16. doi: 10.1161/CIRCGENETICS.111.962464
33. Kuo H-C, Yang Y-L, Chuang J-H, Tiao M-M, Yu H-R, Huang L-T, et al. Inflammation-induced hepcidin is associated with the development of anemia and coronary artery lesions in Kawasaki disease. J Clin Immunol. (2012) 32:746–52. doi: 10.1007/s10875-012-9668-1
34. Wang Y, Wang W, Gong F, Fu S, Zhang Q, Hu J, et al. Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease. Arthritis Rheum. (2013) 65:805–14. doi: 10.1002/art.37815
35. Li X, Chen Y, Tang Y, Ding Y, Xu Q, Sun L, et al. Predictors of intravenous immunoglobulin-resistant Kawasaki disease in children: a meta-analysis of 4442 cases. Eur J Pediatr. (2018) 177:1279–92. doi: 10.1007/s00431-018-3182-2
36. Yan F, Pan B, Sun H, Tian J, Li M. Risk factors of coronary artery abnormality in children with Kawasaki disease: a systematic review and meta-analysis. Front Pediatr. (2019) 7:374. doi: 10.3389/fped.2019.00374
37. Zheng X, Li J, Yue P, Liu L, Li J, Zhou K, et al. Is there an association between intravenous immunoglobulin resistance and coronary artery lesion in Kawasaki disease?-Current evidence based on a meta-analysis. PLoS ONE. (2021) 16:e0248812. doi: 10.1371/journal.pone.0248812
38. Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. (2006) 113:2606–12. doi: 10.1161/CIRCULATIONAHA.105.592865
39. Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr. (2006) 149:237–40. doi: 10.1016/j.jpeds.2006.03.050
40. Harada K. Intravenous gamma-globulin treatment in Kawasaki disease. Acta Paediatr Jpn Overseas Ed. (1991) 33:805–10. doi: 10.1111/j.1442-200X.1991.tb02612.x
41. Sano T, Kurotobi S, Matsuzaki K, Yamamoto T, Maki I, Miki K, et al. Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr. (2007) 166:131–7. doi: 10.1007/s00431-006-0223-z
42. Lin M-T, Chang C-H, Sun L-C, Liu H-M, Chang H-W, Chen C-A, et al. Risk factors and derived formosa score for intravenous immunoglobulin unresponsiveness in Taiwanese children with Kawasaki disease. J Formos Med Assoc. (2016) 115:350–5. doi: 10.1016/j.jfma.2015.03.012
43. Wu S, Liao Y, Sun Y, Zhang C-Y, Zhang Q-Y, Yan H, et al. Prediction of intravenous immunoglobulin resistance in Kawasaki disease in children. World J Pediatr. (2020) 16:607–13. doi: 10.1007/s12519-020-00348-2
44. Yang S, Song R, Zhang J, Li X, Li C. Predictive tool for intravenous immunoglobulin resistance of Kawasaki disease in Beijing. Arch Dis Child. (2019) 104:262–7. doi: 10.1136/archdischild-2017-314512
45. Tan X-H, Zhang X-W, Wang X-Y, He X-Q, Fan C, Lyu T-W, et al. A new model for predicting intravenous immunoglobin-resistant Kawasaki disease in Chongqing: a retrospective study on 5277 patients. Sci Rep. (2019) 9:1722. doi: 10.1038/s41598-019-39330-y
46. Kanai T, Takeshita S, Kawamura Y, Kinoshita K, Nakatani K, Iwashima S, et al. The combination of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as a novel predictor of intravenous immunoglobulin resistance in patients with Kawasaki disease: a multicenter study. Heart Vessels. (2020) 35:1463–72. doi: 10.1007/s00380-020-01622-z
47. Kaya Akca U, Arslanoglu Aydin E, Aykan HH, Serin O, Sag E, Demir S, et al. Comparison of IVIG resistance predictive models in Kawasaki disease. Pediatr Res. (2021) 22. doi: 10.1038/s41390-021-01459-w
48. Kuo H-C, Wong HS-C, Chang W-P, Chen B-K, Wu M-S, Yang KD, et al. Prediction for intravenous immunoglobulin resistance by using weighted genetic risk score identified from genome-wide association study in Kawasaki disease. Circ Cardiovasc Genet. (2017) 10:e001625. doi: 10.1161/CIRCGENETICS.116.001625
49. Portman MA, Shrestha S. One size does not fit all: genetic prediction of Kawasaki disease treatment response in diverse populations. Circ Cardiovasc Genet. (2017) 10:e001917. doi: 10.1161/CIRCGENETICS.117.001917
50. Piram M, Darce Bello M, Tellier S, Di Filippo S, Boralevi F, Madhi F, et al. Defining the risk of first intravenous immunoglobulin unresponsiveness in non-Asian patients with Kawasaki disease. Sci Rep. (2020) 10:3125. doi: 10.1038/s41598-020-59972-7
51. Tulloh RMR, Mayon-White R, Harnden A, Ramanan A V, Tizard EJ, Shingadia D, et al. Kawasaki disease: a prospective population survey in the UK and Ireland from 2013 to 2015. Arch Dis Child. (2019) 104:640–6. doi: 10.1136/archdischild-2018-315087
52. Baer AZ, Rubin LG, Shapiro CA, Sood SK, Rajan S, Shapir Y, et al. Prevalence of coronary artery lesions on the initial echocardiogram in Kawasaki syndrome. Arch Pediatr Adolesc Med. (2006) 160:686–90. doi: 10.1001/archpedi.160.7.686
53. Hoggart C, Shimizu C, Galassini R, Wright VJ, Shailes H, Bellos E, et al. Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease. Eur J Hum Genet. (2021) doi: 10.1038/s41431-021-00838-5
54. Onouchi Y, Ozaki K, Burns JC, Shimizu C, Terai M, Hamada H, et al. A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat Genet. (2012) 44:517–21. doi: 10.1038/ng.2220
55. Ho LGY, Curtis N. What dose of aspirin should be used in the initial treatment of Kawasaki disease? Arch Dis Child. (2017) 102:1180–2. doi: 10.1136/archdischild-2017-313538
56. Amarilyo G, Koren Y, Brik Simon D, Bar-Meir M, Bahat H, Helou MH, et al. High-dose aspirin for Kawasaki disease: outdated myth or effective aid? Clin Exp Rheumatol. (2017) 35:209–12.
57. Lee G, Lee SE, Hong YM, Sohn S. Is high-dose aspirin necessary in the acute phase of kawasaki disease? Korean Circ J. (2013) 43:182–6. doi: 10.4070/kcj.2013.43.3.182
58. Kim GB, Yu JJ, Yoon KL, Jeong SI, Song YH, Han JW, et al. Medium- or higher-dose acetylsalicylic acid for acute Kawasaki disease and patient outcomes. J Pediatr. (2017) 184:125–9.e1. doi: 10.1016/j.jpeds.2016.12.019
59. Brattsand R, Linden M. Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. Aliment Pharmacol Ther. (1996) 10:81–2. doi: 10.1046/j.1365-2036.1996.22164025.x
60. Vandewalle J, Luypaert A, De Bosscher K, Libert C. Therapeutic mechanisms of glucocorticoids. Trends Endocrinol Metab. (2018) 29:42–54. doi: 10.1016/j.tem.2017.10.010
61. Alijotas-Reig J, Esteve-Valverde E, Belizna C, Selva-O'Callaghan A, Pardos-Gea J, Quintana A, et al. Immunomodulatory therapy for the management of severe COVID-19 Beyond the anti-viral therapy: A comprehensive review. Autoimmun Rev. (2020) 19:102569. doi: 10.1016/j.autrev.2020.102569
62. Newburger JW, Sleeper LA, McCrindle BW, Minich LL, Gersony W, Vetter VL, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med. (2007) 356:663–75. doi: 10.1056/NEJMoa061235
63. Ogata S, Ogihara Y, Honda T, Kon S, Akiyama K, Ishii M. Corticosteroid pulse combination therapy for refractory Kawasaki disease: a randomized trial. Pediatrics. (2012) 129:e17–23. doi: 10.1542/peds.2011-0148
64. Miyata K, Kaneko T, Morikawa Y, Sakakibara H, Matsushima T, Misawa M, et al. Efficacy and safety of intravenous immunoglobulin plus prednisolone therapy in patients with Kawasaki disease (Post RAISE): a multicentre, prospective cohort study. Lancet Child Adolesc Heal. (2018) 2:855–62. doi: 10.1016/S2352-4642(18)30293-1
65. Kobayashi T, Saji T, Otani T, Takeuchi K, Nakamura T, Arakawa H, et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet. (2012) 379:1613–20. doi: 10.1016/S0140-6736(11)61930-2
66. Okada K, Hara J, Maki I, Miki K, Matsuzaki K, Matsuoka T, et al. Pulse methylprednisolone with gammaglobulin as an initial treatment for acute Kawasaki disease. Eur J Pediatr. (2009) 168:181–5. doi: 10.1007/s00431-008-0727-9
67. Chen S, Dong Y, Kiuchi MG, Wang J, Li R, Ling Z, et al. Coronary artery complication in Kawasaki disease and the importance of early intervention : a systematic review and meta-analysis. JAMA Pediatr. (2016) 170:1156–63. doi: 10.1001/jamapediatrics.2016.2055
68. Wardle AJ, Connolly GM, Seager MJ, Tulloh RM. Corticosteroids for the treatment of Kawasaki disease in children. Cochrane database Syst Rev. (2017) 1:CD011188. doi: 10.1002/14651858.CD011188.pub2
69. Yang T-J, Lin M-T, Lu C-Y, Chen J-M, Lee P-I, Huang L-M, et al. The prevention of coronary arterial abnormalities in Kawasaki disease: a meta-analysis of the corticosteroid effectiveness. J Microbiol Immunol Infect. (2018) 51:321–31. doi: 10.1016/j.jmii.2017.08.012
70. Dong Y, Chen S. Caution in generalizing the use of adjunctive primary corticosteroids in Kawasaki disease to unselected non-Japanese populations-reply. JAMA Pediatr. (2017) 171:398–9. doi: 10.1001/jamapediatrics.2016.5154
71. Leung DY, Cotran RS, Kurt-Jones E, Burns JC, Newburger JW, Pober JS. Endothelial cell activation and high interleukin-1 secretion in the pathogenesis of acute Kawasaki disease. Lancet. (1989) 2:1298–302. doi: 10.1016/S0140-6736(89)91910-7
72. Hui-Yuen JS, Duong TT, Yeung RSM. TNF-alpha is necessary for induction of coronary artery inflammation and aneurysm formation in an animal model of Kawasaki disease. J Immunol. (2006) 176:6294–301. doi: 10.4049/jimmunol.176.10.6294
73. Matsubara T, Furukawa S, Yabuta K. Serum levels of tumor necrosis factor, interleukin 2 receptor, and interferon-gamma in Kawasaki disease involved coronary-artery lesions. Clin Immunol Immunopathol. (1990) 56:29–36. doi: 10.1016/0090-1229(90)90166-N
74. Burns JC, Best BM, Mejias A, Mahony L, Fixler DE, Jafri HS, et al. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr. (2008) 153:833–8. doi: 10.1016/j.jpeds.2008.06.011
75. Portman MA, Dahdah NS, Slee A, Olson AK, Choueiter NF, Soriano BD, et al. Etanercept with IVIg for acute Kawasaki disease: a randomized controlled trial. Pediatrics. (2019) 143:e20183675. doi: 10.1542/peds.2018-3675
76. Burgner DP, Newburger JW. Etanercept as adjunctive primary therapy in Kawasaki disease. Pediatrics. (2019) 143:e20190912. doi: 10.1542/peds.2019-0912
77. Duignan S, Doyle SL, Mcmahon CJ. Refractory Kawasaki disease : diagnostic and management challenges. Pediatric Health Med Ther. (2019) 10:131–9. doi: 10.2147/PHMT.S165935
78. Burns JC, Koné-Paut I, Kuijpers T, Shimizu C, Tremoulet A, Arditi M. Review: found in translation: international initiatives pursuing interleukin-1 blockade for treatment of acute Kawasaki disease. Arthritis Rheumatol. (2017) 69:268–76. doi: 10.1002/art.39975
79. Hoang LT, Shimizu C, Ling L, Naim ANM, Khor CC, Tremoulet AH, et al. Global gene expression profiling identifies new therapeutic targets in acute Kawasaki disease. Genome Med. (2014) 6:541. doi: 10.1186/s13073-014-0102-6
80. Suzuki H, Uemura S, Tone S, Iizuka T, Koike M, Hirayama K, et al. Effects of immunoglobulin and gamma-interferon on the production of tumour necrosis factor-α and interleukin-1β by peripheral blood monocytes in the acute phase of Kawasaki disease. Eur J Pediatr. (1996) 155:291–6. doi: 10.1007/BF02002715
81. Weng K-P, Hsieh K-S, Ho T-Y, Huang S-H, Lai C-R, Chiu Y-T, et al. IL-1B polymorphism in association with initial intravenous immunoglobulin treatment failure in Taiwanese children with Kawasaki disease. Circ J. (2010) 74:544–51. doi: 10.1253/circj.CJ-09-0664
82. Ferrara G, Giani T, Caparello MC, Farella C, Gamalero L, Cimaz R. Anakinra for treatment-resistant Kawasaki disease: evidence from a literature review. Pediatr Drugs. (2020) 22:645–52. doi: 10.1007/s40272-020-00421-3
83. Cohen S, Tacke CE, Straver B, Meijer N, Kuipers IM, Kuijpers TW, et al. child with severe relapsing Kawasaki disease rescued by IL-1 receptor blockade and extracorporeal membrane oxygenation. Ann Rheum Dis. (2012) 71:2059–61. doi: 10.1136/annrheumdis-2012-201658
84. Shafferman A, Birmingham JD, Cron RQ. High dose Anakinra for treatment of severe neonatal Kawasaki disease: a case report. Pediatr Rheumatol Online J. (2014) 12:26. doi: 10.1186/1546-0096-12-26
85. Sánchez-Manubens J, Gelman A, Franch N, Teodoro S, Palacios JR, Rudi N, et al. A child with resistant Kawasaki disease successfully treated with anakinra: a case report. BMC Pediatr. (2017) 17:4–6. doi: 10.1186/s12887-017-0852-6
86. Guillaume MP, Reumaux H, Dubos F. Usefulness and safety of anakinra in refractory Kawasaki disease complicated by coronary artery aneurysm. Cardiol Young. (2018) 28:739–42. doi: 10.1017/S1047951117002864
87. Blonz G, Lacroix S, Benbrik N, Warin-Fresse K, Masseau A, Trewick D, et al. Severe late-onset kawasaki disease successfully treated with anakinra. J Clin Rheumatol. (2020) 26:e42–3. doi: 10.1097/RHU.0000000000000814
88. Kone-Paut I, Cimaz R, Herberg J, Bates O, Carbasse A, Saulnier JP, et al. The use of interleukin 1 receptor antagonist (anakinra) in Kawasaki disease: a retrospective cases series. Autoimmun Rev. (2018) 17:768–74. doi: 10.1016/j.autrev.2018.01.024
89. Vitale A, Insalaco A, Sfriso P, Lopalco G, Emmi G, Cattalini M, et al. A snapshot on the on-label and off-label use of the interleukin-1 inhibitors in Italy among rheumatologists and pediatric rheumatologists: a nationwide multi-center retrospective observational study. Front Pharmacol. (2016) 7:380. doi: 10.3389/fphar.2016.00380
90. Koné-Paut I, Tellier S, Belot A, Brochard K, Guitton C, Marie I, et al. Phase II open label study of anakinra in intravenous immunoglobulin-resistant Kawasaki disease. Arthritis Rheumatol. (2021) 73:151–61. doi: 10.1002/art.41481
91. Mastrolia MV, Abbati G, Signorino C, Maccora I, Marrani E, Pagnini I, et al. Early anti IL-1 treatment replaces steroids in refractory Kawasaki disease: clinical experience from two case reports. Ther Adv Musculoskelet Dis. (2021) 13:1759720X211002593. doi: 10.1177/1759720X211002593
92. Amasaki Y. Calcineurin inhibitors and calcineurin-NFAT system. Nihon Rinsho Meneki Gakkai Kaishi. (2010) 33:249–61. doi: 10.2177/jsci.33.249
93. Hamada H, Suzuki H, Onouchi Y, Ebata R, Terai M, Fuse S, et al. Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (KAICA): a randomised con. Lancet. (2019) 393:1128–37. doi: 10.1016/S0140-6736(18)32003-8
94. Lee MS, An SY, Jang GC, Kim DS. A case of intravenous immunoglobulin-resistant Kawasaki disease treated with methotrexate. Yonsei Med J. (2002) 43:527–32. doi: 10.3349/ymj.2002.43.4.527
95. Wallace CA, French JW, Kahn SJ, Sherry DD. Initial intravenous gammaglobulin treatment failure in Kawasaki disease. Pediatrics. (2000) 105:E78. doi: 10.1542/peds.105.6.e78
96. Lee TJ, Kim KH, Chun J-K, Kim DS. Low-dose methotrexate therapy for intravenous immunoglobulin-resistant Kawasaki disease. Yonsei Med J. (2008) 49:714–8. doi: 10.3349/ymj.2008.49.5.714
97. Ahn SY, Kim DS. Treatment of intravenous immunoglobulin-resistant Kawasaki disease with methotrexate. Scand J Rheumatol. (2005) 34:136–9.
98. Mori M, Imagawa T, Katakura S, Miyamae T, Okuyama K-I, Ito S, et al. Efficacy of plasma exchange therapy for Kawasaki disease intractable to intravenous gamma-globulin. Mod Rheumatol. (2004) 14:43–7. doi: 10.3109/s10165-003-0264-3
99. Imagawa T, Mori M, Miyamae T, Ito S, Nakamura T, Yasui K, et al. Plasma exchange for refractory Kawasaki disease. Eur J Pediatr. (2004) 163:263–4. doi: 10.1007/s00431-003-1267-y
100. Hokosaki T, Mori M, Nishizawa T, Nakamura T, Imagawa T, Iwamoto M, et al. Long-term efficacy of plasma exchange treatment for refractory Kawasaki disease. Pediatr Int. (2012) 54:99–103. doi: 10.1111/j.1442-200X.2011.03487.x
101. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr. (2007) 166:95–109. doi: 10.1007/s00431-006-0258-1
102. Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol. (2013) 160:275–87. doi: 10.1111/bjh.12138
103. Wang W, Gong F, Zhu W, Fu S, Zhang Q. Macrophage activation syndrome in Kawasaki disease: more common than we thought? Semin Arthritis Rheum. (2015) 44:405–140. doi: 10.1016/j.semarthrit.2014.07.007
104. Han SB, Lee S-Y. Macrophage activation syndrome in children with Kawasaki disease: diagnostic and therapeutic approaches. World J Pediatr. (2020) 16:566–74. doi: 10.1007/s12519-020-00360-6
105. Henter JI, Horne AC, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. (2007) 48:124–31. doi: 10.1002/pbc.21039
106. Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, et al. Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborat. Arthritis Rheumatol. (2016) 68:566–76. doi: 10.1002/art.39332
107. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. (2020) 395:1771–8. doi: 10.1016/S0140-6736(20)31103-X
108. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. (2011) 118:4041–52. doi: 10.1182/blood-2011-03-278127
109. Castillo L, Carcillo J. Secondary hemophagocytic lymphohistiocytosis and severe sepsis/ systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr Crit care Med. (2009) 10:387–92. doi: 10.1097/PCC.0b013e3181a1ae08
110. Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. (2016) 44:275–81. doi: 10.1097/CCM.0000000000001402
111. Buda P, Gietka P, Ksiazyk JB, Machaczka M. The influence of various therapeutic regimens on early clinical and laboratory response and outcome of children with secondary hemophagocytic lymphohistiocytosis. Arch Med Sci. (2018) 14:138–50. doi: 10.5114/aoms.2015.56325
112. Crayne C, Cron RQ. Pediatric macrophage activation syndrome, recognizing the tip of the Iceberg. Eur J Rheumatol. (2019) 7:1–8. doi: 10.5152/eurjrheum.2019.19150
113. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. (2020) 395:1607–8. doi: 10.1016/S0140-6736(20)31094-1
114. Sancho-Shimizu V, Brodin P, Cobat A, Biggs CM, Toubiana J, Lucas CL, et al. SARS-CoV-2-related MIS-C: a key to the viral and genetic causes of Kawasaki disease? J Exp Med. (2021) 218:e20210446.
115. Toubiana J, Cohen JF, Brice J, Poirault C, Bajolle F, Curtis W, et al. Distinctive features of Kawasaki disease following SARS-CoV-2 infection: a controlled study in Paris, France. J Clin Immunol. (2021) 41:526–35. doi: 10.1007/s10875-020-00941-0
116. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. (2020) 324:259–69. doi: 10.1001/jama.2020.10369
117. Okarska-Napierała M, Ludwikowska KM, Szenborn L, Dudek N, Mania A, Buda P, et al. Pediatric Inflammatory Multisystem Syndrome (PIMS) did occur in Poland during months with low COVID-19 prevalence, preliminary results of a nationwide register. J Clin Med. (2020) 9:3386. doi: 10.3390/jcm9113386
118. Davies P, Evans C, Kanthimathinathan HK, Lillie J, Brierley J, Waters G, et al. Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study. Lancet Child Adolesc Heal. (2020) 2:1–9. doi: 10.1016/S2352-4642(20)30215-7
119. Grimaud M, Starck J, Levy M, Marais C, Chareyre J, Khraiche D, et al. Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children. Ann Intensive Care. (2020) 10:69. doi: 10.1186/s13613-020-00690-8
120. Chiotos K, Bassiri H, Behrens EM, Blatz AM, Chang J, Diorio C, et al. Multisystem inflammatory syndrome in children during the coronavirus 2019 pandemic: a case series. J Pediatric Infect Dis Soc. (2020) 9:393–8. doi: 10.1093/jpids/piaa069
121. Belhadjer Z, Méot M, Bajolle F, Khraiche D, Legendre A, Abakka S, et al. Acute heart failure in multisystem inflammatory syndrome in children in the context of global SARS-CoV-2 pandemic. Circulation. (2020) 142:429–36. doi: 10.1161/CIRCULATIONAHA.120.048360
122. Nozawa T, Imagawa T, Ito S. Coronary-artery aneurysm in tocilizumab-treated children with Kawasaki's disease. N Eng J Med. (2017) 377:1894–6. doi: 10.1056/NEJMc1709609
123. Dong S, Bout-Tabaku S, Texter K, Jaggi P. Diagnosis of systemic-onset juvenile idiopathic arthritis after treatment for presumed Kawasaki disease. J Pediatr. (2015) 166:1283–8. doi: 10.1016/j.jpeds.2015.02.003
124. Kumar S, Vaidyanathan B, Gayathri S, Rajam L. Systemic onset juvenile idiopathic arthritis with macrophage activation syndrome misdiagnosed as Kawasaki disease: case report and literature review. Rheumatol Int. (2013) 33:1065–9. doi: 10.1007/s00296-010-1650-8
125. Saez-de-Ocariz M, Gámez-González LB, Rivas-Larrauri F, Castaño-Jaramillo LM, Toledo-Salinas C, Garrido-García LM, et al. Kawasaki disease mimickers. Pediatr Int. (2020) doi: 10.1111/ped.14561
126. Tarp S, Amarilyo G, Foeldvari I, Christensen R, Woo JMP, Cohen N, et al. Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: a systematic review and meta-analysis of randomized trials. Rheumatology. (2016) 55:669–79. doi: 10.1093/rheumatology/kev382
127. Toplak N, Blazina Š, Avčin T. The role of IL-1 inhibition in systemic juvenile idiopathic arthritis: current status and future perspectives. Drug Des Devel Ther. (2018) 12:1633–43. doi: 10.2147/DDDT.S114532
128. Colafrancesco S, Manara M, Bortoluzzi A, Serban T, Bianchi G, Cantarini L, et al. Management of adult-onset Still's disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts. Arthritis Res Ther. (2019) 21:275. doi: 10.1186/s13075-019-2021-9
129. Song GG, Lee YH. Comparison of the efficacy and safety of biological agents in patients with systemic juvenile idiopathic arthritis: a Bayesian network meta-analysis of randomized controlled trials. Int J Clin Pharmacol Ther. (2021) 59:239–46. doi: 10.5414/CP203791
130. Malcova H, Milota T, Strizova Z, Cebecauerova D, Striz I, Sediva A, et al. Interleukin-1 blockade in polygenic autoinflammatory disorders: where are we now? Front Pharmacol. (2020) 11:619273. doi: 10.3389/fphar.2020.619273
131. Shimizu M, Nakagishi Y, Yachie A. Distinct subsets of patients with systemic juvenile idiopathic arthritis based on their cytokine profiles. Cytokine. (2013) 61:345–8. doi: 10.1016/j.cyto.2012.11.025
132. Canna SW, Girard C, Malle L, de Jesus A, Romberg N, Kelsen J, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol. (2017) 139:1698–701. doi: 10.1016/j.jaci.2016.10.022
133. Gabay C, Fautrel B, Rech J, Spertini F, Feist E, Kötter I, et al. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease. Ann Rheum Dis. (2018) 77:840–7. doi: 10.1136/annrheumdis-2017-212608
134. Yasin S, Solomon K, Canna SW, Girard-Guyonvarc'h C, Gabay C, Schiffrin E, et al. IL-18 as therapeutic target in a patient with resistant systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome. Rheumatology. (2020) 59:442–5. doi: 10.1093/rheumatology/kez284
135. Weng K-P, Hsieh K-S, Huang S-H, Ou S-F, Lai T-J, Tang C-W, et al. Interleukin-18 and coronary artery lesions in patients with Kawasaki disease. J Chin Med Assoc. (2013) 76:438–45. doi: 10.1016/j.jcma.2013.04.005
136. Li S-C, Tsai K-W, Huang L-H, Weng K-P, Chien K-J, Lin Y, et al. Serum proteins may facilitate the identification of Kawasaki disease and promote in vitro neutrophil infiltration. Sci Rep. (2020) 10:15645. doi: 10.1038/s41598-020-72695-z
137. Zhang Y, Wang Y, Zhang L, Xia L, Zheng M, Zeng Z, et al. Reduced platelet miR-223 induction in Kawasaki disease leads to severe coronary artery pathology through a miR-223/PDGFRβ vascular smooth muscle cell axis. Circ Res. (2020) 127:855–73. doi: 10.1161/CIRCRESAHA.120.316951
138. Weng H, Peng Y, Pei Q, Jing F, Yang M, Yi Q. Decreased serum Annexin A1 levels in Kawasaki disease with coronary artery aneurysm. Pediatr Res. (2021) 89:569–73. doi: 10.1038/s41390-020-0898-2
139. Anzai F, Watanabe S, Kimura H, Kamata R, Karasawa T, Komada T, et al. Crucial role of NLRP3 inflammasome in a murine model of Kawasaki disease. J Mol Cell Cardiol. (2020) 138:185–96. doi: 10.1016/j.yjmcc.2019.11.158
140. Wu W, You K, Zhong J, Ruan Z, Wang B. Identification of potential core genes in Kawasaki disease using bioinformatics analysis. J Int Med Res. (2019) 47:4051–8. doi: 10.1177/0300060519862057
141. Takada Y, Ye X, Simon S. The integrins. Genome Biol. (2007) 8:215. doi: 10.1186/gb-2007-8-5-215
142. Huang L, Jian Z, Gao Y, Zhou P, Zhang G, Jiang B, et al. RPN2 promotes metastasis of hepatocellular carcinoma cell and inhibits autophagy via STAT3 and NF-κB pathways. Aging. (2019) 11:6674–90. doi: 10.18632/aging.102167
143. Bursi R, Cafaro G, Perricone C, Riccucci I, Calvacchi S, Gerli R, et al. Contribution of janus-kinase/signal transduction activator of transcription pathway in the pathogenesis of vasculitis: a possible treatment target in the upcoming future. Front Pharmacol. (2021) 12:635663. doi: 10.3389/fphar.2021.635663
144. Régnier P, Le Joncour A, Maciejewski-Duval A, Desbois A-C, Comarmond C, Rosenzwajg M, et al. Targeting JAK/STAT pathway in Takayasu's arteritis. Ann Rheum Dis. (2020) 79:951–9. doi: 10.1136/annrheumdis-2019-216900
145. Burgner D, Davila S, Breunis WB, Ng SB Li Y, Bonnard C, et al. A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki disease. PLoS Genet. (2009) 5:e1000319. doi: 10.1371/journal.pgen.1000319
146. Nanke Y, Yago T, Kotake S. The Role of Th17 Cells in the Pathogenesis of Behcet's Disease. J Clin Med. (2017) 6:74. doi: 10.3390/jcm6070074
Keywords: Kawasaki disease, vasculitis, guidelines, anti-inflammatory treatment, coronary artery aneurysm, SARS-CoV-2, PIMS-TS, MIS-C
Citation: Buda P, Friedman-Gruszczyńska J and Książyk J (2021) Anti-inflammatory Treatment of Kawasaki Disease: Comparison of Current Guidelines and Perspectives. Front. Med. 8:738850. doi: 10.3389/fmed.2021.738850
Received: 09 July 2021; Accepted: 04 November 2021;
Published: 30 November 2021.
Edited by:
Silvia Piantoni, ASST-Spedali Civili and University of Brescia, ItalyReviewed by:
Cristina Pamfil, Iuliu Haţieganu University of Medicine and Pharmacy, RomaniaLucia Maria Arruda Campos, Universidade de São Paulo, Brazil
Copyright © 2021 Buda, Friedman-Gruszczyńska and Książyk. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Piotr Buda, cC5idWRhJiN4MDAwNDA7aXBjemQucGw=