Intravenous immunoglobulin for the treatment of Kawasaki disease

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To evaluate the efficacy and safety of IVIG in treating and preventing cardiac consequences of Kawasaki disease.

Background

Description of the condition

Kawasaki disease (KD) is an acute systemic vasculitis (inflammation of the blood vessels) first described in 1967 by Japanese paediatrician Tomisaku Kawasaki that mainly affects children (Kawasaki 1967; Yamaji 2019). The majority of cases are seen in children between six months and five years old, and more often in males than females (21 per 100,000 compared to 15 per 100,000, respectively) (Makino 2019). There is substantial ethnic variation, with the lowest rates seen amongst white children (13.7 per 100,000 children under five) and the highest rates seen in children of Asian descent (29.8 per 100,000 children under five) (Makino 2019), although a Japan‐wide survey reported that KD had increased between 2008 and 2015 (Makino 2015). Data are lacking for black/Hispanic ethnic groups due to too few cases being reported (Holman 2010; Maddox 2015).

There is no specific diagnostic test for KD, with diagnosis being made using clinical criteria and by excluding other possible diagnoses. To be diagnosed with KD, individuals must have five or more days of fever as well as four or more of the five principal clinical features (chapped lips, strawberry tongue; bulbar conjunctival injection; rash, redness, and swelling of hands and feet or skin peeling; and enlarged cervical lymph nodes) (see Table 1) (Rife 2020). Individuals who meet the criteria are said to have complete KD (also known as typical or classic KD). Individuals who do not meet all the criteria may be diagnosed as having incomplete KD (also known as atypical KD) (Kobayashi 2020; McCrindle 2017).

1. Diagnosis of classic Kawasaki disease*.

Diagnosis of classic Kawasaki disease

Classic KD is diagnosed in the presence of fever for at least 5 d (the day of fever onset is taken to be the first day of fever) together with at least 4 of the 5 following principal clinical features. In the presence of ≥ 4 principal clinical features, particularly when redness and swelling of the hands and feet are present, the diagnosis of KD can be made with 4 d of fever, although in rare cases experienced clinicians who have treated many patients with KD may establish the diagnosis with 3 d of fever. Erythema and cracking of lips, strawberry tongue, and/or erythema of oral and pharyngeal mucosa Bilateral bulbar conjunctival injection without exudate Rash: maculopapular, diffuse erythroderma, or erythema multiforme‐like Erythema and oedema of the hands and feet in acute phase and/or periungual desquamation in subacute phase Cervical lymphadenopathy (≥ 1.5‐centimetre diameter), usually unilateral

A careful history may reveal that ≥ 1 principal clinical features were present during the illness but resolved by the time of presentation.

Patients who lack full clinical features of classic KD are often evaluated for incomplete KD. If coronary artery abnormalities are detected, the diagnosis of KD is considered confirmed in most cases.

Laboratory tests typically reveal normal or elevated white blood cell count with neutrophil predominance and elevated acute phase reactants such as C‐reactive protein and erythrocyte sedimentation rate during the acute phase. Low serum sodium and albumin levels, elevated serum liver enzymes, and sterile pyuria can be present. In the second week after fever onset, thrombocytosis is common.

Other clinical findings may include the following:

Cardiovascular

Myocarditis, pericarditis, valvular regurgitation, shock

Coronary artery abnormalities

Aneurysms of medium‐sized non‐coronary arteries

Peripheral gangrene

Aortic root enlargement

Respiratory

Peribronchial and interstitial infiltrates on chest x‐ray

Pulmonary nodules

Musculoskeletal

Arthritis, arthralgia (pleocytosis of synovial fluid)

Gastrointestinal

Diarrhoea, vomiting, abdominal pain

Hepatitis, jaundice

Gallbladder hydrops

Pancreatitis

Nervous system

Extreme irritability

Aseptic meningitis (pleocytosis of cerebrospinal fluid)

Facial nerve palsy

Sensorineural hearing loss

Genitourinary

Urethritis/meatitis, hydrocele

Other

Desquamating rash in groin

Retropharyngeal phlegmon

Anterior uveitis by slit lamp examination

Erythema and induration at BCG inoculation site

The differential diagnosis includes other infectious and non‐infectious conditions, including the following:

Measles

Other viral infections (e.g. adenovirus, enterovirus)

Staphylococcal and streptococcal toxin‐mediated diseases (e.g. scarlet fever and toxic shock syndrome)

Drug hypersensitivity reactions, including Stevens Johnson syndrome

Systemic onset juvenile idiopathic arthritis

With epidemiologic risk factors:

Rocky Mountain spotted fever or other rickettsial infections

Leptospirosis

*American Heart Association guidelines (McCrindle 2017).

BCG: Bacillus Calmette‐Guerin (used in vaccine for prevention of tuberculosis)
KD: Kawasaki disease

Kawasaki disease is usually triphasic with an acute, subacute, and convalescent phase. The acute phase is characterised by high fevers (lasting from seven to 14 days if untreated), and systemic inflammation in the medium‐sized arteries, multiple organs and tissues, resulting in the following common clinical findings: liver (hepatocyte damage), lung (interstitial pneumonitis), gastrointestinal tract (abdominal pain, vomiting, diarrhoea, gallbladder hydrops), meninges (aseptic meningitis, irritability), heart (myocarditis, pericarditis, valvulitis), urinary tract (pyuria), pancreas (pancreatitis), and lymph nodes (lymphadenopathy) (McCrindle 2017). Inflammation of the coronary arteries causes the most serious complication of the disease, that is coronary artery abnormalities (CAAs), which include dilatations and aneurysms. Close monitoring of CAA is important, as ischaemic symptoms or myocardial infarction (MI) due to thrombosis or stenosis can occur. In Japan between 2017 and 2018, coronary artery dilatation, aneurysm, and giant aneurysm (lumen size ≥ 8 mm) within 30 days after KD onset were reported to occur in 7.64%, 0.95%, and 0.11% of patients, respectively (Ae 2020). Kawasaki disease is believed to be a leading cause of acquired heart disease in children from high‐income countries, with male patients or those resistant to initial intravenous immunoglobulin (IVIG) treatment at increased risk of CAAs (Newburger 2004; Uehara 2003).

The subacute phase is often asymptomatic, lasting approximately four weeks. During this time there may be peeling of the skin of the hands and feet, joint pain, and abnormal clinical findings such as thrombocytosis (increase in the number of platelets) or joint pain. This is also when the patient is at greatest risk of developing a coronary artery aneurysm. The convalescent phase is typically asymptomatic, four to eight weeks after onset.

Echocardiography is the standard imaging technique used to evaluate coronary abnormalities, with coronary arteries classified according to size. In children less than five years old, a coronary artery lumen diameter of 3 mm or more is abnormal, whilst in children five years or older, 4 mm or more is considered to be abnormal (JMHW 1984). Coronary artery lesions (CAL) are classified using Z scores (the coronary artery dimensions adjusted for body surface area as dimensions will change with the size of the child) (Dallaire 2010; JMHW 1984; Kobayashi 2016; Olivieri 2008).

The prognosis for children with KD is highly dependent on the severity of coronary artery involvement. The fatality rate in the USA and Japan is reported as less than 0.2%, with MI from coronary occlusion being the main cause of death (Hayasaka 2003).　

Description of the intervention

It is thought that KD may be caused by activation of the immune system after infection with an unknown agent, such as a virus, in a genetically susceptible child. This results in an inflammatory cascade where both the innate and adaptive arms of the immune system are activated (Franco 2010; Gedalia 2007; Rowley 1997). However, no infectious cause has yet been identified. A genetic role is indicated by the ethnic relationships and by increased incidence in children whose parents or siblings have also had KD (Uehara 2003; Yashiro 2004), as well as by polymorphisms identified in different genes and gene regions by family linkage and genome studies (Onouchi 2008; Onouchi 2010; Onouchi 2012).

The primary treatments for KD are IVIG and acetylsalicylic acid (ASA) (Newburger 2004; Rife 2020).

Standard regimen of the primary treatment consists of a single infusion of high‐dose IVIG (2 g/kg) together with ASA (Newburger 1991). IVIG is most effective when administered within 10 days of the onset of fever, and has been reported to reduce the risk of coronary artery aneurysm formation from 20% to 25%, to 3% to 5% (Newburger 1986). As many as 20% of children are considered to be IVIG resistant (or refractory), as they develop recurrent or persistent fevers after primary treatment (Ashouri 2008; Mori 2004; Newburger 2004). Adjunctive therapy may benefit those patients who are at higher risk of coronary artery aneurysms. Adjuvant treatments may include the use of corticosteroids and tumour necrosis factor‐alpha (TNF‐alpha) blockers such as etanercept and infliximab. Corticosteroids have been shown to reduce the incidence of CALs in KD and decrease fever, duration of hospitalisation, and time to normalisation of C‐reactive protein (CRP) levels (Wardle 2017). Recent American Heart Association (AHA) guidelines state that giving high‐risk or IVIG‐resistant patients a longer course of corticosteroids should be considered as primary adjunctive therapy (McCrindle 2017). Compared with no treatment or additional treatment with IVIG, TNF‐alpha blockers may have beneficial effects on treatment resistance and the unwanted 'infusion reaction' after treatment initiation for KD (Yamaji 2019).　

Other agents include interleukin‐1 (IL‐1) receptor inhibitors (Kone‐Paut 2018), calcineurin inhibition therapy (ciclosporin) (Hamada 2019), cyclophosphamide, methotrexate (Lee 2008), rituximab (Sauvaget 2012), and plasma exchange (Hokosaki 2012), but their use is not widespread due to a lack of evidence (Rife 2020). Statins are also undergoing investigation due to their effects on inflammation, platelet aggregation, coagulation, and endothelial function (Tremoulet 2019).

How the intervention might work

Exactly how IVIG works as a treatment of KD is unknown, but it has a general anti‐inflammatory effect, probably by modulating cytokine and antibody production and by increasing regulatory T‐cell activity (Burns 2015). Acetylsalicylic acid has anti‐inflammatory activity in high dose or antiplatelet activity in low dose, but it does not appear to prevent the development of coronary abnormalities (Baumer 2006). The remaining adjunctive and additional therapeutic agents also act by suppressing the widespread immune response characterised in KD with the aim of minimising symptoms and preventing cardiac abnormalities (Zhang 2020).

Why it is important to do this review

Kawasaki disease is an important cause of acquired heart disease in children in high‐income countries, with the majority of deaths resulting from damage to the coronary arteries. In addition, unexpected death from MI can happen many years later, with incidences of non‐fatal and fatal MI in young adults sometimes thought to result from 'missed' KD in childhood (Burns 1996; Daniels 2012). The primary aim of an accurate diagnosis is to help prevent these complications with quick and effective treatment, and IVIG is widely used for this purpose. In 2020, with the SARS‐CoV‐2 pandemic, increased numbers of KD symptoms have been reported (Verdoni 2020). This review will replace an earlier Cochrane Review on the same topic (Oates‐Whitehead 2003). A new review is planned due to significant changes in Cochrane methodology since the previous review was published. We also aim to include all currently available evidence for IVIG for the treatment of KD in children to aid decision‐making for healthcare providers internationally.

Objectives

To evaluate the efficacy and safety of IVIG in treating and preventing cardiac consequences of Kawasaki disease.

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomised controlled trials (RCTs) investigating the use of IVIG for the treatment of KD. We will include studies involving treatment for initial or refractory KD, or both.

Types of participants

We will include studies involving participants diagnosed with KD using Japanese or AHA guidelines (see Table 1) (Ayusawa 2005; McCrindle 2017).

Types of interventions

We will include studies using IVIG to treat participants with KD. We will include all doses and types of IVIG. We will include studies with the following comparisons.

• IVIG versus placebo or no treatment.

• IVIG versus ASA.

• IVIG versus TNF‐alpha blockers.

• IVIG versus corticosteroids.

• IVIG versus IVIG (i.e. dose versus dose).

• IVIG versus any combination of the above providing IVIG is the only difference between the groups, and any treatment effect is not confounded with another co‐treatment.

Types of outcome measures

We aim to record the time points of outcomes as reported by the included studies, but those of most interest are during the acute phase (up to two weeks) and convalescent phase (four weeks or later after initial treatment).

Primary outcomes

• Incidence of CAAs diagnosed by echocardiography or coronary angiography defined by absolute diameter, JMHW 1984, or Z‐scores.

• Incidence of any adverse effects after treatment initiation.

Secondary outcomes

• Acute coronary syndrome, such as MI or coronary thrombus.

• Duration of fever (days).

• Need for additional treatment.

• Length of hospital stay (days).

• Mortality (all‐cause).

Search methods for identification of studies

Electronic searches

The Cochrane Vascular Information Specialist aims to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress).

The Information Specialist will search the following databases for relevant trials:

• Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS‐Web);

• Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO);

• Medline (Ovid MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE) (1946 onwards);

• Embase Ovid (from 1974 onwards);

• CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature) (from 1982 onwards).

The Information Specialist has devised a draft search strategy for RCTs for MEDLINE (see Appendix 1), which will be used as the basis for search strategies for the other databases listed.

The Information Specialist will search the following trials registries:

• World Health Organization International Clinical Trials Registry Platform (who.int/trialsearch);

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov).

Searching other resources

We will check the reference lists of all included studies and review articles to identify other ongoing or published studies. We will search relevant manufacturers' websites for trial information. Manufacturers include Kaketsuken‐Teijin Pharma Limited, Nihon Pharmaceutical‐Takeda Pharmaceutical, Japan Blood Products Organization‐Mitsubishi Tanabe Pharma, and Japan Blood Products Organization‐Japan Red Cross Society.

Data collection and analysis

Selection of studies

We will use Covidence software (Covidence), to screen all reports identified by the Information Specialist. One of two review authors will assess reports by title or abstract (CB, SK), with any articles clearly not meeting the inclusion criteria (e.g. non‐RCTs) considered as 'not relevant'. We will obtain the full‐text reports of all studies deemed potentially relevant, which two of three authors (CB, SK, TK) will independently assess for inclusion in the review. Any disagreements will be resolved by discussion. We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will illustrate the study selection process in a PRISMA diagram (Liberati 2009). We will list all articles excluded after full‐text assessment in a 'Characteristics of excluded studies' table and provide the reasons for their exclusion.

Data extraction and management

We will use a data collection form based on the form provided by Cochrane Vascular to record study characteristics and outcome data. One of three review authors (CB, SK, MS) will extract study characteristics from the included studies. We will extract the following study characteristics.

• Methods (study design, number of participants, exclusions postrandomisation, losses to follow‐up, intention‐to‐treat analysis, duration of study).

• Participants (country, setting, age, sex, inclusion and exclusion criteria).

• Interventions (intervention, comparison, concomitant medications).

• Outcomes (primary and secondary outcomes specified and collected, and time points reported).

• Funding source and declaration of interest of the study authors.

Two of three review authors (CB, SK, MS) will independently extract outcome data from the included studies. Where multiple trial arms are reported in a single trial, we will include only the relevant arms. Any disagreements will be resolved by consensus or by involving a third review author (SI). One review author (CB) will transfer data into Review Manager Web (RevMan Web 2021). We will double‐check that data are entered correctly by comparing the data presented in the systematic review with the study reports. In the case of unclear or incomplete information or data, we will contact the study authors to request clarification.

Assessment of risk of bias in included studies

Two of three review authors (CB, SK, MS) will independently assess the risk of bias of each included study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreements will be resolved by discussion or by involving another review author (TK). We will assess risk of bias according to the following domains.

• Random sequence generation

• Allocation concealment

• Blinding of participants and personnel

• Blinding of outcome assessment

• Incomplete outcome data

• Selective outcome reporting

• Other bias

We will grade each domain as low, high, or unclear and provide a statement to justify our judgement in the risk of bias table. We will summarise the risk of bias judgements across different studies for each of the domains listed and report this in the review. Where necessary, we will consider blinding separately for outcomes (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality should be considered differently than a patient‐reported outcome).

Measures of treatment effect

We will analyse dichotomous data as odds ratios (OR) with 95% confidence intervals (CI) and continuous data as mean difference (MD) with 95% confidence intervals (CI). If the same outcome is reported but different measurement scales are used, we will use standardised mean difference (SMD).

Unit of analysis issues

We plan to use each individual participant as the unit of analysis. We will ensure there are no unit of analysis issues with double‐counting of controls if included studies used multiple intervention arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) are combined in the same meta‐analysis, we will halve the control group to avoid double‐counting. We plan to use intention‐to‐treat analysis.

Dealing with missing data

We will contact study authors to obtain missing study characteristics or outcome data when necessary. Where this is not possible, and the missing data are sufficient to possibly introduce bias, we will explore the impact of including such studies by sensitivity analysis. We will consider missing data sufficient to introduce bias if the missing data are imbalanced between study arms or are potentially a result of the intervention.

Assessment of heterogeneity

We will assess heterogeneity visually by inspecting forest plots. We will also use the Chi² and I² statistics and Tau² in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). We will interpret the I² value approximately as follows:

• 0 to 40%: might not be important;

• 30 to 60%: may represent moderate heterogeneity;

• 50 to 90%: may represent substantial heterogeneity;

• 75 to 100%: considerable heterogeneity.

When assessing the importance of the observed value of I², we will consider (i) the magnitude and direction of effects and (ii) the strength of evidence for heterogeneity (e.g. P value from the Chi² test, or a CI for I²) in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). If we detect heterogeneity, we will further explore the reasons for it through subgroup analysis.

Assessment of reporting biases

If more than 10 studies can be pooled for any given outcome, we will create a funnel plot to explore possible small‐study and publication biases.

Data synthesis

We will undertake data synthesis using Review Manager Web (RevMan Web 2021). We will use a fixed‐effect model when there are no concerns about heterogeneity; in the case of substantial heterogeneity (I² > 50%), we will use a random‐effects model instead. We will only undertake meta‐analyses where doing so is meaningful, that is if the treatments, participants, and the underlying clinical question are similar enough for pooling to make sense. If meta‐analysis is not possible, we will report the results using a narrative synthesis.

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses for the primary outcomes where sufficient data are available.

• Different types of IVIG (produced by different manufacturers).

• Initial or refractory (rescue) IVIG treatment.

• Single or multiple dose.

• Varying timing of IVIG treatment (day of treatment).

• Geographical distribution of trial participants.

• Study risk of bias.

• Age.

• Weight/body mass index (BMI).

If only limited data are available, we will consider if it is appropriate to conduct subgroup analysis, as results may reflect a lack of information rather than a true effect (Deeks 2021). We will use the formal test for subgroup interactions in Review Manager Web (RevMan Web 2021).

Sensitivity analysis

We plan to carry out sensitivity analyses to check if the results are robust by excluding studies at high risk of bias from the analysis. We will define studies as high risk of bias if they are assessed as being at high risk of selection bias (i.e. high risk in either sequence generation or allocation sequence concealment).

Summary of findings and assessment of the certainty of the evidence

We will create a summary of findings table to present the evidence for the review with the following outcomes.

• Incidence of coronary artery abnormalities (CAAs).

• Incidence of any adverse effects after treatment initiation.

• Acute coronary syndrome such as MI or coronary thrombus.

• Duration of fever after treatment.

• Need for additional treatment.

• Length of hospital stay.

• Mortality (all‐cause).

We will include one table for each comparison. We will use the five GRADE considerations (risk of bias, inconsistency, imprecision, indirectness, and publication bias) to assess the certainty of the evidence as it relates to the studies which contribute data to the meta‐analyses for the prespecified outcomes (Atkins 2004). We will use the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021; Schünemann 2021), employing GRADEpro GDT software (GRADEpro GDT). We will justify all decisions to downgrade the certainty of evidence using footnotes and will make comments to aid the reader's understanding of the review where needed. A draft summary of findings table is shown in Table 2.

2. Example summary of findings table.

Intravenous immunoglobulin for the treatment of Kawasaki disease
Patient or population: children with KD Settings: hospital Intervention: IVIG Comparison: placebo or no treatment
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo or no treatment	Risk with IVIG
Incidence of CAAs [follow‐up]	Study population		OR [value] ([value] to [value])	[value] ([value])	⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
Incidence of any adverse effects after treatment initiation [follow‐up]	Study population		OR [value] ([value] to [value])	[value] ([value])	⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
Acute coronary syndrome (such as MI or coronary thrombus) [follow‐up]	Study population		OR [value] ([value] to [value])	[value] ([value])	⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
Duration of fever (days) [follow‐up]	The mean [outcome] ranged across control groups from [value][measure].	The mean [outcome] in the intervention groups was [value] [lower/higher] [(value to value lower/higher)].		[value] ([value])	⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
Need for additional treatment [follow‐up]	Study population		OR [value] ([value] to [value])	[value] ([value])	⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
Length of hospital stay (days) [follow‐up]	The mean [outcome] ranged across control groups from [value][measure]	The mean [outcome] in the intervention groups was [value] [lower/higher] [(value to value lower/higher)].		[value] ([value])	⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
Mortality (all‐cause) [follow‐up]	Study population		OR [value] ([value] to [value])	[value] ([value])	⊕⊝⊝⊝ very low ⊕⊕⊝⊝ low ⊕⊕⊕⊝ moderate ⊕⊕⊕⊕ high
	[value] per 1000	[value] per 1000 ([value] to [value])
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CAAs: coronary artery abnormalities; CI: confidence interval; IVIG: intravenous immunoglobulin; KD: Kawasaki disease; MI: myocardial infarction;OR: odds ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Notes

Parts of the Methods section of this protocol are based on a standard template established by Cochrane Vascular.

Appendices

Appendix 1. MEDLINE search strategy

1 Mucocutaneous Lymph Node Syndrome/

2 (mucocutan* adj syndrome*).ti,ab.

3 kawasaki*.ti,ab.

4 "Mucocutaneous Lymph Node Syndrome".ti,ab.

5 or/1‐4

6 exp Immunoglobulins, Intravenous/

7 immunoglobulin*.ti,ab.

8 Ig*.ti,ab.

9 IVIG.ti,ab.

10 (civacir or flebogamma or gamunex or carimune or gammagard or octagam or privigen).ti,ab.

11 or/6‐10

12 5 and 11

13 randomized controlled trial.pt.

14 controlled clinical trial.pt.

15 randomized.ab.

16 placebo.ab.

17 drug therapy.fs.

18 randomly.ab.

19 trial.ab.

20 groups.ab.

21 or/13‐20

22 exp animals/ not humans.sh.

23 21 not 22

24 12 and 23

Contributions of authors

CB: drafting of protocol
SK: drafting of protocol
MS: drafting of protocol
SI: drafting of protocol
TK: drafting of protocol

Sources of support

Internal sources

• No sources of support provided

External sources

• Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK

  The Cochrane Vascular editorial base is supported by the Chief Scientist Office.

Declarations of interest

CB: none known
SK: none known
MS: none known
SI: research grants: institution: Japan Blood Products Organization (JB), Tanabe Mistsubushi Pharma, Nihon Pharmaceutical Co Ltd, Teijin Pharma for basic research on Kawasaki disease. No conflicts with this review. Payment or honoraria for lectures about Kawasaki disease and rheumatic diseases: Japan Blood Products Organization (JB), Tanabe Mistsubushi Pharma, Nihon Pharmaceutical Co Ltd, Teijin Pharma, Novartis Pharma. No conflict with this review.
TK: declares that his institution received a scholarship grant from Japan Blood Products Organization (total amount JPY 300,000 in 2021). This does not conflict with his work on this review.

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