Edited by: Silvia Piantoni, ASST-Spedali Civili and University of Brescia, Italy
Reviewed by: Cristina Pamfil, Iuliu Haţieganu University of Medicine and Pharmacy, Romania; Lucia Maria Arruda Campos, Universidade de São Paulo, Brazil
This article was submitted to Rheumatology, a section of the journal Frontiers in Medicine
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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.
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 (
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 (
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.
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) (
– (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 (
– (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 (
– (2021) Revised recommendations of the Italian Society of Pediatrics about the general management of Kawasaki disease (
The comparison of various treatment regimens is shown in
Comparison of guidelines for the treatment of Kawasaki disease.
IVIG | High-dose IVIG (2 g/kg given as a single infusion) within 10 days of illness onset but as soon as possible after diagnosis | IVIG (2 g/kg given as a single infusion) | IVIG (2 g/kg), preferably given within the 10th day, better if within the 7th day of illness, but as soon as possible after diagnosis | IVIG—single use (2 g/kg per day) orIVIG—modified single use (1 g/kg per day for 1 or 2 days continuously) or IVIG –divided dosing (200–400 mg/kg per day, over 3–5 days) |
IVIG resistance—definition | Persistent or recrudescent fever at least 36 hours and <7 days after completion of first IVIG infusion | Ongoing fever and/or persistent inflammation or clinical signs ≥ 48 h after receiving IVIG as a single dose of 2 g/kg.Laboratory values that can be important in assessing risk stratification for IVIG resistance: low sodium, raised bilirubin, raised ALT, low platelet count, high CRP, low albumin | Failure in the response to IVIG—recrudescent fever reoccurring or persisting 36–48 h after IVIG infusion | Persistent fever after 48 h of starting IVIG |
High-risk patients—definition | Not defined criterias for high-risk children outside Japan. In Japan patients at high risk for non-response to IVIG are defined by scoring systems (Kobayashi, Sano) | Patients with severe KD: IVIG-resistant (see above), Kobayashi score ≥5, features of HLH, shock, children under the age of 1 year, children with coronary and/or peripheral aneurysms | Children <12 months or those having CRP higher than 200 mg/l, severe anemia at disease onset, albumin level below 2.5 g/dl, liver disease, overt coronary artery aneurysms, macrophage activation syndrome or septic shock | According to representative scoring systems for evaluating potential IVIG resistance (Kobayashi, Egami, Sano) |
ASA moderate-high dose | Administration of moderate (30–50 mg/kg) to high-dose (80–100 mg/kg) ASA is reasonable until the patient is afebrile, although there is no evidence that it reduces coronary artery aneurysms. There are no data to suggest that either dose of ASA is superior | All patients diagnosed with KD who are treated with IVIG should be treated with aspirin at a dose of 30–50 mg/kg/day until fever has settled for 48 h, clinical features are improving, and CRP levels are falling | Treatment of KD is completed by ASA given at a daily dosage of 30–50 mg/kg in the acute phase of KD until 48 h after the disappearance of fever, then switched to the anti-platelet dose (3–5 mg/kg once daily). When GCS are given in patients classified as high risk, ASA is given in low dose (3–5 mg/kg) | Febrile period: oral dose of 30–50 mg/kg/day, in 3 divided doses |
ASA low dose | Reducing the ASA dose after the child has been afebrile for 48–72 h. Other clinicians continue high-dose ASA until the 14th day of illness and at least 48–72 h after cessation of fever | The dose of aspirin should subsequently be reduced to an antiplatelet dose of 3–5 mg/kg once daily when fever and inflammation have subsided | Low-dose ASA must be continued until 6–8 weeks in children without CAL and continued in children with CAL until the resolution of coronary artery lesions | 48–72 h after defervescence, dosage can be reduced to one dose of 3–5 mg/kg per day |
Treatment options for IVIG-resistant KD patients and refractory KD.
IVIG resistance—treatment | IVIG or IVIG + GCS or Infliximab It is reasonable to administer a second dose of IVIG (2 g/kg) to patients with persistent or recrudescent fever at least 36 h after the end of the first IVIG infusion | GCS +/– IVIGA second dose of IVIG is at the discretion of the treating physician | IVIG or IVIG + GCS In non-responder patients with KD treatment requires a second infusion of IVIG and—in case of failure—pulses of methylprednisolone (30 mg/kg/day) for 3 consecutive days, followed by oral prednisone (2 mg/kg/day, then gradually tapered) | IVIG + GCSIVIG in combination with either prednisolone or methyloprednisolone |
High-risk patients—first line treatment | IVIG + ASA +/− GCS. Administration of a longer course of corticosteroids (e.g., tapering over 2–3 weeks), together with IVIG 2 g/kg and ASA, may be considered for treatment of high-risk patients with acute KD, when such high risk can be identified in patients before initiation of treatment | IVIG + GCS + ASACorticosteroid treatment should be given to patients with severe KD.Treatment should not be delayed while awaiting echocardiography.Two regimens would be reasonable (see below) | IVIG + GCS + ASA |
IVIG + GCS + ASASuch patients should be treated with 2 g/kg of IVIG in combination with either 2 mg/kg per day prednisolone or 30 mg/kg per day intravenous methylprednisolone pulseIf the patients fail to respond to these treatments, a third-line treatment will be upgraded to a second-line treatment |
GCS | Single-dose pulse methylprednisolone should not be administered with IVIG as routine primary therapy for patients with KD. Administration of a longer course of corticosteroids (e.g., tapering over 2–3 weeks), together with IVIG 2 g/kg and ASA, may be considered for treatment of high-risk patients with acute KD, when such high risk can be identified in patients before initiation of treatment. Administration of high-dose pulse steroids (usually methylprednisolone 20–30 mg/kg intravenously for 3 days, with or without a subsequent course and taper of oral prednisone) may be considered as an alternative to a second infusion of IVIG or for retreatment of patients with KD who have had recurrent or recrudescent fever after additional IVIG. Administration of a longer (e.g., 2–3 weeks) tapering course of prednisolone or prednisone, together with IVIG 2 g/kg and ASA, may be considered in the retreatment of patients with KD who have had recurrent or recrudescent fever after initial IVIG treatment | Corticosteroid treatment should be given to patients with severe KD (see high-risk patients, |
In high risk patients. In case of failure treatment | In patients suspected of being IVIG resistant on the basis of clinical symptoms and laboratory findings.In patients found to be IVIG resistant after first-line IVIG treatment |
Treatment options for IVIG-Resistant KD patients and Refractory KD | IVIG |
IVIGGCSInfliximab—TNF-alpha blockade (e.g., infliximab) should be considered in KD patients with persistent inflammation despite IVIG, aspirin and corticosteroid treatment, after consultation with a specialist unit.The use of DMARDs such as cyclosporin, cyclophosphamide and methotrexate, along with anakinra and plasma exchange, cannot be recommended, except on an individual basis after consultation with a specialist unit | IVIG |
IVIGGCSInfliximabUlinastatinCsAMethotrexatePE— |
Prednisone/prednisolone | Prednisolone 2 mg/kg i.v. divided every 8 h until afebrile, then prednisone orally until CRP normalized, then taper over 2–3 weeks | – | After intravenours methylprednisolone treatment. Prednisone at the initial dose of 2 mg/kg/day, then tapered up to the resolution of symptoms and normalization of CRP | During fever: 2 mg/kg/day of prednisolone, i.v. in 3 divided dosesAfter defervescence: Once patient is no longer febrile and general status has improved, prednisolone is given orally. When CRP normalizes, the dose of prednisolone is tapered over 15 days, in 5 day steps, from 2 mg/kg/day in 3 divided doses to 1 mg/kg/day in 2 divided doses to 0.5 mg/kg/day in a single dose |
Methylprednisolone | Usually 20–30 mg/kg intravenously for 3 days, with or without a subsequent course and taper of oral prednisone | Regimen 1: methylprednisolone 2 ×0.8 mg/kg for 5–7 days or until CRP normalizes; then convert to oral prednisone/prednisolone 2 mg/kg/day and wean off over next 2–3 weeks.Regimen 2: methylprednisolone 10–30 mg/kg (up to maximum of 1 g/day) once daily for 3 days followed by oral prednisone/prednisolone 2 mg/kg per day until day 7 or until CRP normalizes; then wean over next 2–3 weeks | In high-risk patients with KD initial treatment should include: IVIG + single intravenous pulse of methylprednisolone (30 mg/kg/day) + low-dose aspirin (3–5 mg/kg/day). In case of failure treatment should be implemented with a further infusion of IVIG and three pulses of intravenous methylprednisolone (30 mg/kg/day, followed by prednisone: 2 mg/kg/day, then gradually tapered) + low-dose aspirin (3–5 mg/kg/day). In low-risk KD patients resistant to two previous infusions of IVIG: pulses of methylprednisolone (30 mg/kg/day) for 3 days. followed by oral prednisone (2 mg/kg/day, then gradually tapered) | When used in combination with first-line IVIG: 1 dose of 30 mg/kg methylprednisolone. When used to treat IVIG-resistant patients: 30 mg/kg methylprednisolone once a day, for 1–3 days. Some reports suggest additional prednisolone (started at 1–2 mg/kg/day and gradually tapered over a period of 1–3 weeks) after methylprednisolone |
Infliximab | Administration of infliximab (5 mg/kg) may be considered as an alternative to a second infusion of IVIG or corticosteroids for IVIG-resistant patients. Single infusion: 5 mg/kg IV given over 2 h | Infliximab should be considered in KD patients with persistent inflammation despite IVIG, aspirin and corticosteroid treatment, after consultation with a specialist unit | Current evidence supports the use of infliximab, a chimeric monoclonal antibody against TNF-α, as rescue therapy at a single intravenous dose of 5 mg/kg of body weight (given in 2 h) for IVIG- and corticosteroid resistant KD patients | i.v. drip infusion of 5 mg/kg (may only be given once) |
Anakinra | 2–6 mg/kg given by subcutaneous injection | The use of DMARDs such as ciclosporin, cyclophosphamide and methotrexate, along with anakinra and plasma exchange, cannot be recommended, except on an individual basis after consultation with a specialist unit | In children with a refractory KD, given subcutaneously at a daily dose of 4–8 mg/kg of body weight for an overall period of 15 days or for a longer period, depending on the specific clinical scenery | – |
Cyclosporin A | i.v.: 3 mg/kg divided every 12 h p.o.: 4–8 mg/kg divided every 12 h. Adjust dose to achieve trough 50–150 ng/mL; 2-h peak level 300–600 ng/mL | The use of DMARDs such as cyclosporin, cyclophosphamide and methotrexate, along with anakinra and plasma exchange, cannot be recommended, except on an individual basis after consultation with a specialist unit | 4 mg/kg/day in 2 doses p.o.; in case of persistence of fever the dosage can be increased to 5–8 mg/kg/day; administered until CRP normalization or for 10–14 days | Start on 2 divided oral doses (1 each before meal) of 4–5 mg/kg/dayTarget trough level: 60–200 ng/mL |
Plasma Exchange | Plasma exchange should be reserved for patients in whom all reasonable medical therapies have failed | The use of DMARDs such as cyclosporin, cyclophosphamide and methotrexate, along with anakinra and plasma exchange, cannot be recommended, except on an individual basis after consultation with a specialist unit | – | Displacing solution set at 5% albumin; 1–1.5 × the patient's circulating plasma volume is exchanged. Usually given for 3 continuous days (upper limit: 6 days) |
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 (
– (2020) Expert consensus statement “Lifetime cardiovascular management of patients with previous Kawasaki disease” (
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) (
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
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) (
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 (
The development of CAL despite IVIG treatment ranges from 19 to 42% (
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 (
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.
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 (
GCS inhibit the transcription of most pro-inflammatory cytokines
Monoclonal antibodies may target the presumed key-cytokines involved in KD pathogenesis, particularly tumor necrosis factor (TNF)-α and interleukin (IL)-1 (
The efficacy of another tumor necrosis factor-α receptor blocker (etanercept) was also evaluated (
The IL-1 signaling pathway seems to be key to the pathogenesis of KD, especially in the development of coronary artery aneurysms (
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 (
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 (
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 (
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 (
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 (
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 (
Appropriate treatment of MAS requires the collaboration of pediatric, infectious disease, and intensive care unit specialists with other experts such as rheumatologists, immunologists, hematologists.
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 (
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 (
Many recent studies found novel immunobiological pathways involved in KD and allowed to identify potential therapeutic targets for KD, they are listed in
Potential therapeutic target for Kawasaki disease.
S100A12 | One of serum protein-based biomarkers of KD (S100A12 promoted |
( |
Platelet miR-223 or VSMC PDGFRβ | Uptake of platelets and platelet-derived miRNAs influences vascular smooth muscle cell phenotype |
( |
ANXA1 | Annexin A1 (ANXA1) is an endogenous anti-inflammatory agent and pro-resolving mediator involved in inflammation-related diseases | ( |
NLRP3 | NLRP3 inflammasome is a large multiprotein complex that plays a key role in IL-1β-driven sterile inflammatory diseases | ( |
ITGAM | In KD coronary artery lesions, Integrin αM (ITGAM) might enhance subacute/chronic vasculitis, resulting in the transition of smooth muscle cells to myofibroblasts and their subsequent proliferation | ( |
JAK/STAT | RPN2 inhibits autophagy via STAT3 (signal transducer and activator of transcription-3) and NF-κB pathways STAT3 is activated by interleukin 6, a pro-inflammatory cytokine that is involved in early innate immune reactivity, and present in the acute phase of KD JAK1/STAT3 signaling pathway is activated in some systemic vasculitides through the activation of Th1/Th17-type cytokines such as IL-2, interferon (IFN-γ), IL-6, IL-17, and IL-23 | ( |
STING | Over-activation of the STING-pathway (Stimulator of interferon (IFN) genes), could increase the risk of delayed aneurysms in KD and COVID-19 vasculitis | ( |
KCa3.1 | KCa3.1 (calcium-activated potassium channel) blockade of macrophages suppresses inflammatory reaction leading to mouse coronary artery endothelial cell injury in a cell model of KD by hampering the activation of NF-κB and STAT3 signaling pathway | ( |
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.
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.
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.
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