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Kawasaki disease: guidelines of ItalianSociety of Pediatrics, part II - treatment ofresistant forms and cardiovascularcomplications, follow-up, lifestyle andprevention of cardiovascular risksAlessandra Marchesi1*, Isabella Tarissi de Jacobis1, Donato Rigante2, Alessandro Rimini3, Walter Malorni4,Giovanni Corsello5, Grazia Bossi6, Sabrina Buonuomo1, Fabio Cardinale7, Elisabetta Cortis8, Fabrizio De Benedetti1,Andrea De Zorzi1, Marzia Duse9, Domenico Del Principe10, Rosa Maria Dellepiane11, Livio D’Isanto12,Maya El Hachem1, Susanna Esposito13, Fernanda Falcini14, Ugo Giordano1, Maria Cristina Maggio5,Savina Mannarino6, Gianluigi Marseglia6, Silvana Martino15, Giulia Marucci1, Rossella Massaro16,Christian Pescosolido16, Donatella Pietraforte4, Maria Cristina Pietrogrande11, Patrizia Salice11, Aurelio Secinaro1,Elisabetta Straface4 and Alberto Villani1

Abstract

This second part of practical Guidelines related to Kawasaki disease (KD) has the goal of contributing to promptdiagnosis and most appropriate treatment of KD resistant forms and cardiovascular complications, including non-pharmacologic treatments, follow-up, lifestyle and prevention of cardiovascular risks in the long-term through a setof 17 recommendations.Guidelines, however, should not be considered a norm that limits the treatment options of pediatricians andpractitioners, as treatment modalities other than those recommended may be required as a result of peculiarmedical circumstances, patient’s condition, and disease severity or individual complications.

Keywords: Kawasaki disease, Coronary artery abnormalities, Intravenous immunoglobulin, Aspirin, Personalizedmedicine, Innovative biotechnologies, Child

BackgroundIn 2008 the first Italian Kawasaki disease (KD) Guide-lines were published. During the subsequent years newdata have been collected and updated treatment reportshave been published.Kawasaki: Linee Guida italiane.

ScopeScope of these revised Guidelines is to update evidenceon the following topics:

� efficacy of therapy in the chronic phase of the illnessand in its sequelae;

� short- and long-term follow-up;� lifestyle and prevention of cardiovascular risks.

UsersThese Guidelines are directed to pediatricians who workin hospital, family pediatricians, and general practi-tioners who work with children affected by KD and forfamilies of KD patients.

Note for usersThe clinical management of each KD patient requiresthe application of these recommendations based on the

* Correspondence: [email protected] Gesù Children’s Hospital, Piazza S. Onofrio n. 4, 00165 Rome, ItalyFull list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Marchesi et al. Italian Journal of Pediatrics (2018) 44:103 https://doi.org/10.1186/s13052-018-0529-2

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peculiar patient’s condition. We are pleased to publishupdated diagnostic and therapeutic indications for bothmedical and paramedical staff as well as the most accur-ate information for families.

SponsorshipsNo person who participated in the drafting of theseGuidelines has been sponsored.

DisseminationThe text has been initially discussed during the Consen-sus Conference “Kawasaki Disease Italian Guidelines” inRome during September 2015. The same text has beenrediscussed in the 71st National Congress of the ItalianSociety of Pediatrics in Rome during June 2015, and fi-nally approved in the 73th National Congress of theItalian Society of Pediatrics in Naples during June 2017.

UpdatesFuture updates are planned within the next five years, orsooner, if the medical literature will reveal evidencesshowing that these Guidelines have become obsolete.

MethodsDifferent experts in general pediatric medicine, cardiology,infectious diseases, rheumatology, immuno-allergology,dermatology, radiology, or biologists experts in cell oxida-tive stress have participated in writing these Guidelines.They have been supported by representatives of family as-sociations. The team has been requested to systematicallyanalyze the present literature about KD to define the fol-lowing evidences about efficacy of therapies in the chronicphase and in its sequelae, and efficacy of short-term andlong-term follow-up for KD patients.The basic document was the previous Italian KD

Guidelines, which were published in 2008 (MarchesiA et al. Malattia di Kawasaki: Linee-Guida Italiane.Prospettive in Pediatria. 2008;38:266–83). Additionally,further references from the last 8 years were considered,using PubMed and Cochrane databases.The following key-words were used: “child”, “Kawasaki

disease or Kawasaki syndrome”, “coronary arteriesaneurysm and ectasia”, “echocardiography”, “multi-slidecomputed tomography”, “angiography”, “intravenous im-munoglobulin”, “aspirin”, “corticosteroids”, “biologicaldrugs”, “follow-up”, limiting the search to documents onhumans and written in English or Italian. Heterogeneityof the available researches and their low number did notallow to perform a meta-analysis of each item. The rec-ommendations of these Guidelines are based on the bestevidences available. Stronger recommendations arebased on high scientific quality data or, alternatively, onthe consensus of experts. In the Evidence Based Medi-cine clinical Guidelines provide evidence levels based on

the study design (Table 1) and reported effectiveness(Table 2).

IntroductionNine years have passed since the first announcement ofthe Italian Guidelines for diagnosis and management ofKawasaki disease (KD) in a national journal, but recentlymany more data have become available in relationshipwith this acute systemic vasculitis occurring in childhood[1]. According to the 2012 “Revised International ChapelHill Consensus Conference Nomenclature of Vasculitides”[2], KD involves small and medium-sized vessels in eachorgan and apparatus. In general terms, we can considerKD as a self-limited heterogeneous disease with unknown,probably multi-factorial, etiology, which primarily affectsinfants and children under 5 years of age [3, 4].The most significant complications in KD are coronary

artery aneurysms (CAA), but their overall incidence hasbeen consistently reduced by prompt recognition of thedisease and treatment with intravenous immunoglobulin(IVIG) within 10 days of fever onset [5–9]. Unfortu-nately, patients who show an insufficient response toIVIG are more prone to develop cardiac sequelae, suchas dilation or stenosis of coronary arteries, myocardialinfarction, and valvular lesions [10]. Diagnosis of KD ismerely clinic, based on the diagnostic clinical criteria(shown in the Part I of these Guidelines). Actually, noclinical findings or tests can be considered specific forKD, and this circumstance makes diagnosis extremelychallenging.Goal of the second part of these Guidelines is to rec-

ommend the best practice tools in the management ofcomplicated KD, based on the most actual scientific evi-dence, and improve the overall prognosis of the disease.These Guidelines have been created for pediatriciansworking in hospital, family pediatricians, and generalpractitioners or nurses managing children affected byKD and for families of KD patients.Complications of KD can be distinguished in:

- Resistant forms of Kawasaki disease;- Cardiovascular complications of Kawasaki disease;- Other systemic complications of Kawasaki disease;- Recurrent forms of Kawasaki disease.

Table 1 Level (class) based on study design, defined as follows

class I meta-analyses or systematic reviews fromrandomized controlled trials

class II single randomized controlled trials

class III nonrandomized controlled trials

class IV retrospective case-control studies

class V number of cases without control group

class VI opinions of committees of experts and authorities

Marchesi et al. Italian Journal of Pediatrics (2018) 44:103 Page 2 of 18

Resistant forms of Kawasaki diseaseA resistant KD is defined by failure in the response toinitial therapy with IVIG [11]. Patients may have a per-sistent or recrudescent fever (> 38 °C, axillary or rectal)after 36 h since the end of IVIG infusion. This event oc-curs in more than 10% of patients with KD [12, 13]. It isbelieved that IVIG non-responsiveness might reflect theseverity of the underlying inflammation, explaining theincreased incidence of CAA in this subset of patients. Itwould seem useful to stratify patients according to therisk to develop IVIG resistance and subsequent risk ofdeveloping CAA to undertake in those at higher risk amore aggressive initial treatment. Initial attempts weremade by Asai and Kusakawa, followed by Iwasa, Haradaand more recently by Kobayashi, Egami and Sano [14].These predictive models have considered multiple fac-tors, such as patient’s age, sex, duration of disease, whiteblood cell count, hematocrit, platelet count, C-reactiveprotein, transaminases, total bilirubin, albumin, sodium,but all models have shown a lower sensitivity in Westernpopulations than in Japanese patients [15]. Unfortu-nately, there is currently no universally accepted scoringsystem to predict IVIG non-responsiveness, and for theCaucasian population there is no validated risk score yet.

Cardiovascular complications of Kawasaki diseaseThe most relevant complications in KD are representedby CAA, and different remodeling phenomena will affecttheir outcome. The coronary artery dilation may start asectasia, slight expansion (less than 5 mm in diameter),moderate dilation (from 5 to less than 8 mm) up to giantaneurysms (more than 8 mm in diameter).As exposed in the Part I of these Guidelines, the con-

cept of z-score was introduced several years ago to com-pare the coronary artery diameter to the body surfacearea and measure the standard deviation from the aver-age in Z units (SD, z-score), using specific nomograms(www.parameterZ.com). This is recommended for theright coronary, left anterior descending, left main coron-ary arteries, and also for other vessels such as the aorticring and ascending aorta. An accurate measurement ofweight and particularly height is important to enable cal-culation of an accurate body surface area. According tothe most updated data in the medical literature relatedto KD, we define the absence of coronary artery

involvement if the z-score is < 2, the presence of coronaryartery dilation if the z-score is between 2 and 2.5, andthe presence of coronary artery aneurysm if the z-scoreis ≥2.5. This standard deviation system should be usedin the initial diagnosis of CAA, when there is a suspicionof KD or when the selection may be more “coarse”, toavoid losing patients who may be at substantial risk in anear future (Table 3). Conversely, size criteria might beused in the follow-up of KD patients, particularly if lo-calized coronary artery injuries have been found [16, 17].The majority of CAA occurs in the proximal segments

and at the branch level. KD patients with normal coron-ary arteries or with mild ectasia at 6 weeks since diseaseonset have an overall good prognosis [6, 18, 19]. On thecontrary, patients with persistent aneurysms are at riskof stenosis and/or thrombosis of the same arteries. Giantcoronary aneurysms do not revert to a normal morph-ology. The repair of affected vessels occurs by wall re-modeling without total “renstitutio ad integrum”, butwith progressive intimal hyperplasia and fibrosis, thatlead to stenotic changes of the coronary artery, with riskof thrombosis, myocardial ischemia, and sometimes evensudden death. Rarely new aneurysms appear later in pa-tients with pre-existing aneurysms and, if this occurs,they represent post-stenotic dilations. In rare cases aneu-rysms can develop in the axillary or celiac arteries. Otherdifferent cardiovascular complications may develop lessfrequently in patients with acute KD, and include myo-carditis, pericarditis or pericardial effusion with myoper-icarditis, valvular insufficiency, and, rarely, cardiacarrhythmias. A specific treatment may be required forthese manifestations as well as for cardiac dysfunctionor heart failure [20, 21].Echocardiography remains the gold-standard to iden-

tify CAA during the acute phase of KD up to the first6 weeks. However, computed tomography (CT) or mag-netic resonance (MR) angiography can be required foran accurate risk stratification via evaluation of the vascu-lar system, especially in growing children (see Part I,Chapter “Long-term” follow-up).

Other systemic complications of Kawasaki diseaseOther systemic KD complications are represented byanemia, hypoalbuminemia, electrolyte imbalance (espe-cially hyponatremia), paralytic ileus, liver dysfunction,

Table 2 Classification (grade) based on effectiveness, defined asfollows

grade A highly recommended

grade B recommended

grade C recommended, but evidence is uncertain

grade D non recommended

grade E contraindicated

Table 3 Classification of coronary artery abnormalities in theacute phase of Kawasaki disease and severity classification

No coronary artery involvement: z-score < 2

Dilation of the coronary artery: z-score > 2 to < 2.5 SD

Small aneurysm of the coronary artery: z-score≥ 2.5 to < 5 SD

Medium aneurysm of the coronary artery: z-score≥ 5 to < 10 SD

Giant aneurysm of the coronary artery: z-score≥ 10 SD


http://www.parameterz.com

cholecystitis, seizures, diarrhea, vomiting, dehydration,and heart failure, even iatrogenic from IVIGinfusion-related overload. Specific treatments are re-quired for these complications. The exact cause of thesevere hypotension in these patients is unknown, thoughprobably due to several factors, i.e. inflammatory capillaryleak, myocardial dysfunction and imbalance of cytokines.The occurrence of macrophage activation syndrome(MAS) has also been reported in KD, heralded bynon-remitting fever, impaired liver function, hypofibrino-genemia, hypertriglyceridemia, hyperferritinemia, pan-cytopenia and frequently hemophagocytosis, that can beobserved in bone marrow fine needle aspiration [22, 23].Some authors have reported the presence of clinical symp-toms and laboratory abnormalities compatible with MASin 1.1% of KD patients if using the Ravelli’s diagnostic cri-teria and in 0.42% if using the 2009 hemophagocytic lym-phohistiocytosis diagnostic criteria [24, 25]. Anothercomplication is KD shock syndrome (KDSS), with similarsymptoms to MAS, but with higher incidence, which wasdescribed by Kanegaye et al. in 2009 [26]: this disorder isassociated with severely increased inflammatory markers,platelet consumption and increased risk of CAA, mitralregurgitation and prolonged myocardial dysfunction. Inaddition, patients with KDSS may be resistant to treat-ment with IVIG and may need additionalanti-inflammatory treatments.

Recurrent forms of Kawasaki diseaseRecurrence of KD ranges from 1.4 to 3% (respectivelyfrom the Chinese and Japanese epidemiologic collec-tion of studies available). Often KD symptoms are thesame as for the first episode. A longlasting fever,IVIG resistance, elevated AST level, and reducedhemoglobin are all risk factors significantly associatedwith KD recurrence [27]. A recurring KD, sometimesincomplete and atypical, may be associated withhigher incidence of CAA. Autoinflammatory syn-dromes should be considered for a comprehensivedifferential diagnosis in children with recurrence ofKD [28, 29].

Treatment of resistant forms of Kawasaki diseaseSeveral second-line treatment options are availablein the resistant KD, represented by additional IVIGinfusions, intravenous methylprednisolone pulses,infliximab, ulinastatin, cyclosporine A, methotrexate,and plasmapheresis. Clinical trials for anakinra orcanakinumab are ongoing. Randomized controlledtrials that evaluated the effectiveness of differentdrugs apart from the second infusion of IVIG arefew.

CorticosteroidsCorticosteroids are usually administered in all vasculitidesdue to their immunosuppressive and anti-inflammatoryeffect, with the aim of blocking the potential risk of CAAin KD. Their use as first and second-line treatment is de-bated, because of the differences regarding the selection ofpatients (all patients versus high-risk patients) and theethnicity (Caucasian versus Eastern populations) reportedin different studies.

MethylprednisoloneRational The intravenous pulses of methylprednisolonehave a quick immunosuppressive effect by blocking theinflammatory cytokines and give a lower risk of imbal-ance in electrolytes.

Indications Intravenous pulses of methylprednisoloneare indicated for patients with resistance to IVIG on thebasis of symptoms and laboratory tests, and for patientsresistant to IVIG after a first-line therapy. Intravenouspulses of methylprednisolone are off-label in KD.

Dosage A single intravenous pulse of methylpredniso-lone at the dose of 30 mg/kg of body weight can be pro-vided in combination with IVIG as a first-line treatmentof high-risk KD patients; pulses can be provided for3 days in the resistant cases.Low-risk KD patients resistant to two previous infu-

sions of IVIG can receive pulses of methylprednisolone(30 mg/kg/day) for 3 days.

Effectiveness There is no evidence that a first-line treat-ment with IVIG combined with an intravenous pulse ofmethylprednisolone prevent CAA in all patients withKD, but only in those suspected to be resistant to IVIG.For IVIG-resistant KD patients the second-line treat-ment with intravenous methylprednisolone reduces theduration of fever, but the overall incidence of CAA re-mains similar [30–34].

Side effects Intravenous methylprednisolone side effectsare bradycardia, hypertension, hyperglycemia, andhypothermia. A close monitoring of vital signs, ECG,and blood pressure is required during pulse [35].

PrednisoneRational The main purpose of therapy with prednisoneis to exert its anti-inflammatory effect, solving the vascu-litis and blocking the potential risk of CAA: it has amore powerful action in comparison with cortisol, in-hibits transcription of different inflammatory cytokinegenes, and promotes transcription of anti-inflammatorycytokines and proteins.


Indications Suspected IVIG-resistant patients on thebasis of symptoms and laboratory tests or patients resist-ant to IVIG given as first-line therapy.

Dosage If used in combination with IVIG in thefirst-line treatment the dose of prednisone is 2 mg/kg/day given intravenously in three doses; after fever andimprovement of inflammatory markers prednisone canbe administered orally. When CRP is normalized, pred-nisone can be continued for 5 days, then is reduced to1 mg/kg/day in 2 doses for further 5 days, then at0.5 mg/kg/day for further 5 days.

Effectiveness The efficacy should be acceptable forhigh-risk patients, but different studies have showncontradictory results [36–38].(Initial treatment with IVIG and prednisone for sus-

pected IVIG-resistant KD: level of evidence class I, gradeB; second-line treatment with prednisone forIVIG-resistant KD: level of evidence class III, grade B).

Side effects Shock, infection, Legg-Calvé-Perthes dis-ease, gastrointestinal perforation or bleeding, diabetes,cataracts, glaucoma, chorioretinopathy, pancreatitis,congestive heart failure, liver failure, arrhythmia, adreno-cortical insufficiency, osteoporosis, myopathy, throm-bosis, increased intracranial pressure, and seizures. Itsuse is contraindicated in patients with infections, heartor kidney failure, and history of previous heart attack.

Biological drugsBiologic agents are highly effective drugs targeting thepresumed key-steps in the immune system, namelytumor necrosis factor (TNF)-α and interleukin (IL)-1,that are the triggering molecules in the KD-related vas-culitis. Because of the paucity of safety and efficacy data,many considerations are derived from the experiencewith anti-TNF or anti-IL-1 drugs on short series ofpatients.

InfliximabRational The serum concentration of TNF-α is elevatedin patients with KD and many studies have reported acorrelation between KD severity and CAA [39]. Inflixi-mab (IFX), a chimeric monoclonal antibody againstTNF-α, suppresses inflammation by blocking the actionof TNF-α only, reducing the levels of interleukin-6, CRP,and TNF-α soluble receptor, reducing the severity ofvasculitis, as demonstrated in animal models [40–42].IFX may cause the production of antibodies in patientsundergoing repeated doses, and lead to allergic reactionsor loss of efficacy.

Indications KD patients resistant to IVIG. IFX use isoff-label for KD.

Dosage Single intravenous dose of 5 mg/kg of bodyweight in 200–500 ml of saline solution for at least 2 h.IFX has a half-life of about 9.5 days, and it has not

been established a lower age limit for use. No absolutesafety studies are available for infants and newborns.

Effectiveness Many studies confirm IFX short-term effi-cacy in both IVIG-resistant and corticosteroid-resistantKD patients, and also its safety, in about 80% of cases[43–52]. In particular, the incidence of CAA might bereduced if infliximab is used within the 10th day ofdisease.(Level of evidence for patients resistant to IVIG: class

II, grade C).

Side effects There are few data available for pediatricpatients. Infusion-associated reactions, such as anaphyl-axis, skin rashes, pruritus, headache, bronchospasm, andangioedema can appear; symptoms of hypersensitivitymay occur even after 3 days, and include myalgia, fa-tigue, arthralgia, face and hand edema, dysphagia, urti-caria, and headache. Exacerbation of heart failure andinfectious diseases might be disclosed. Any ongoing in-fectious disease, and especially tuberculosis is an abso-lute contraindication to the use of IFX. Therefore, ascreening strategy with family history, interferon-gammarelease assays, and also chest X-ray might be useful torule out tuberculosis. IFX should also be avoided in car-riers of hepatitis B or C virus patients because of a riskof activation and acute exacerbation of chronic hepatitis.In addition, IFX should be postponed in case of MMRvaccination in the previous 2 months and V vaccinationin the past month. There are no data about the develop-ment of malignant tumors.

AnakinraRational Anakinra is a recombinant IL-1 receptor an-tagonist blocking the natural biological activity of IL-1,by competitively inhibiting binding of IL-1 and its recep-tor, and down-regulating many IL-1-mediated inflamma-tory reactions [53]. Based on a hypothetical model ofKD as an autoinflammatory disease, it was assumed thatanakinra might exert an antinflammatory effect on sys-temic and coronary artery inflammation in these patients[54].

Indications KD patients resistant to IVIG. Anakinra useis off-label for KD.


Dosage The suggested daily dose is 4–8 mg/kg of bodyweight for subcutaneously injections given for an overallperiod of 15 days since KD onset.

Effectiveness There are only anecdotal reports aboutusing anakinra in children with KD.(Levels of evidence for patients resistant to IVIG: class

V, grade C).

Side effects They might involve the gastrointestinaltract (nausea, diarrhea, abdominal pain, hypertransa-minasemia), respiratory system (upper respiratory in-fections, sinusitis, influenza-like illness, rarelypneumonia), or skin (bruising, urticarial-like lesions,local infections). Pain, erythema, and inflammationmight often appear in the injection sites, usuallyduring the first 4 weeks of therapy, then reversiblewithin 1 or 2 weeks. Rare are allergic reactions,including anaphylaxis. Frequent is the report ofneutropenia, moderate eosinophilia, or moderatethrombocytopenia.

CanakinumabRational Canakinumab is a high-affinity human mono-clonal antibody targeted at IL-1β, with no cross-reactivitywith other members of the IL-1 family, including IL-1α,which has been authorized for the treatment of systemicjuvenile idiopathic arthritis and different hereditary auto-inflammatory syndromes [55, 56].

Indications KD patients resistant to IVIG. Canakinumabuse is off-label for KD.

Dosage Single subcutaneous injection of 4 mg/kg for abody weight less than or equal to 40 kg.

Effectiveness Clinical trials are currently in phase I totest canakinumab as a potential treatment for differentdisorders, such as chronic obstructive pulmonary dis-ease, gout, and coronary heart disease.(Level of evidence for KD patients resistant to IVIG:

Class V, grade C).

Side effects They can be of minor relevance: rhinitis,nasopharyngitis, nausea, vomiting, diarrhea, dizziness,headache, or a mild redness with swelling, warmth, oritching at the injection site. Sometimes they can be se-vere: allergic reactions (rash, hives, difficulty in breathingor swallowing, asthma, oral allergy syndrome),hemoptysis, and infections.Other drugs which have been used in the

drug-resistant forms of KD are ulinastatin, cyclospor-ine, and methotrexate. Table 4 summarizes mechan-ism of action, indication, dosage, side effects, and thelevels of evidence for these drugs. However, the useof ulinastatin, cyclosporine, and methotrexate isoff-label in KD.In 2008 Onouchi et al. reported a gene responsible

for susceptibility to KD, inositol 1,4,5-triphosphate3-kinase C (ITPKC), which suppresses the activity ofT cells and leads to oversecretion of multiple

Table 4 Other drugs used in the drug-resistant Kawasaki disease

Ulinastatin [93, 94] Cyclosporine A [95–97] Methotrexate [98]

Mechanism of action Inhibitor of human trypsin Inhibition of calcineurin andincreased activity of T cells

Folic acid antagonist, suppressionof lymphoproliferation

Indications Patients resistant to IVIG(also as initial treatmentcombined with IVIG and ASA inhigh-risk patients)

Patients resistant to IVIG(there are no studies in patients< 4 months of life)

Patients resistant to IVIG

Dosage Optimal dosing in not yetdetermined in children, though inmany studiesThe dosage is 5000 U/kg for 3–6times per day (maximum dose:50000 U); it should be given in asecond vein or temporarilysuspending IVIG infusion (as itbecomes turbid in contact withother drugs)

4 mg/kg/day in 2 doses per os; incase of persistence of fever thedosage can be increased to5–8 mg/kg/day; administereduntil CRP normalization or for10–14 days

10 mg/m2/week per os,administered until feverdisappears

Side effects Anaphylactic shock, liverdysfunction, leukopenia, rash,itching, diarrhea, pain at theinjection site

Hypercalcemia, hypomagnesemia,hirsutism, hypertension

Gastrointestinal signs, alopecia,risk of myelosuppression,anaphylaxis, infections, liverdysfunction, acute kidney failure

Level of evidence Class III, grade C(First-line treatment with IVIG +ASA: class II, grade B)

Class V, grade C Class V, grade C


cytokines, if dysfunctional, suggesting that it maymake KD patients more prone to IVIG resistance anddevelopment of CAA [57].

PlasmapheresisRational Plasmapheresis removes cytokines and chemo-kines activated in KD directly from the bloodstream.

Indication KD patients resistant to IVIG.

Dosage The circulating plasma is replaced with albu-min at 5%; the volume to replace corresponds to ap-proximately 1–1.5 times the volume of circulatingplasma, calculated according to the formula: [weight(kg)/13 × (1-Ht/100) × 1000] (Ht, hematocrit [in %]).A larger vein (femoral, subclavian, or jugular) shouldbe used for albumin administration with a doublelumen catheter; simultaneously heparin is adminis-tered at an intravenous bolus of 15–30 U/kg, then at15–30 U/kg/hour.

Effectiveness There are no prospective randomizedstudies to evaluate the efficacy of plasmapheresis in KD,but few retrospective ones comparing plasmapheresis toIVIG [58].(Level of evidence: class V, grade C).

Side effects Hypotension, hypovolemic shock, urticaria,anaphylactic reactions, hypocalcemia, nausea, vomiting,or bleeding disorders.As already explained in the Part I of these Guidelines,

we define KD high-risk patients those who are youngerthan 12 months, show elevated CRP, elevated serumaminotransferase, hypoalbuminemia, severe anemia atdisease onset and those who might display early devel-opment of CAA, signs of macrophage activation syn-drome or shock.Recommendation 1.Treatment of non-responder low-risk KD patients is a

second bolus of IVIG. Pulses of methylprednisolone(30 mg/kg/day) for 3 consecutive days are suggested inthe case of no response.(III - B)Recommendation 2.Treatment of non-responder high-risk KD patients

is a second bolus of IVIG + 3 pulses of methylpred-nisolone (30 mg/kg/day for 3 consecutive days,followed by prednisolone: 2 mg/kg/day), followinggradual reduction of prednisolone dose and its sus-pension after the resolution of symptoms andnormalization of CRP.(I - B)Recommendation 3.

Biological drugs may be used in IVIG-refractory KDpatients.(II - C)Finally, we have summarized the therapeutic recom-

mendations for patients with KD, both low-risk andhigh-risk ones (Figs. 1 and 2).

Treatment of the cardiovascular complications ofKawasaki diseaseRegression of CAA depends on the initial size of thevascular dilation: about half of CAA resolves within afew years. In particular, a pseudo-normalization of lu-minal dimensions is observed within 1–2 years whenaneurysms are small-sized and within 5 years in 80%of cases if medium-sized. Rarely giant aneurysmsshow a tendency to regress. Because of the repairprocess, however, a stenosis can occur in the incom-ing or outgoing aneurysmal area, secondary to intimalhyperplasia or thrombotic occlusion, with risk ofmyocardial ischemia, heart attack, and unexpecteddeath [59]. Long-term therapy in KD patients withCAA aims at prevention of cardiovascular sequelae,reduction of both frequency and severity of heart at-tacks, and improvement of patient’s quality of life[60–62]. Such therapy depends on the severity andextension of coronary artery involvement. In the ab-sence of “evidence-based” studies, recommendationshave been drafted by pediatric retrospective studies,case reports, and extrapolation from experiences inadults.Platelet activation is critical in all KD phases, there-

fore, in case of persistent CAA, a chronic use of anti-platelet low-dose ASA (3–5 mg/kg/day) must beprovided, optionally associated with other antiplateletand/or anticoagulant and/or anti-angina drugs, ac-cording to the size of aneurysms, flow characteristics,and presence or absence of myocardial ischemicchanges.

Other anti-platelet drugsClopidogrelMechanism of action of clopidogrel is based on theinhibition of platelet aggregation induced by ADP,and antiplatelet action is usually achieved with lowdoses of clopidogrel (0.2 mg/kg/day) in children aged< 24 months. Unfortunately there are no data relatedto children aged ≥25 months and the dose suggested is1 mg/kg/day (the maximum adult dose is 75 mg/day). Incase of ASA allergy or varicella (either wild disease or vac-cination against varicella) clopidogrel might be an al-ternative to ASA [63]. Side effects of clopidogrelinclude malaise, myalgia, headache, dizziness, gastro-intestinal symptoms, rash, itching, thrombotic


thrombocytopenic purpura, and bleeding tendency.Clopidogrel is off-label in KD.

AnticoagulantsIn KD patients anticoagulants are indicated in case ofmedium and giant aneurysms and in cases complicated bythrombosis. Warfarin is the most widely used drug. Both

in urgency and at the beginning of anticoagulant therapywarfarin should be associated with intravenous continuousinfusion of heparin, administered at a full anticoagulantdose (monitoring the PTT, targeted between 60 and 85″and 1,5–2,5 times the normal) for at least 48 h and in anycase until reaching a steady INR between 2 and 2.5 toavoid the paradoxical thrombosis caused by the depletion

Fig. 2 Treatment of high-risk KD patients

Fig. 1 Treatment of low-risk KD patients


of protein C and S, induced by early therapy with warfarin;then heparin should be suspended. It is recommended topay attention to the bleeding tendency induced by thesedrugs. Although no large-scale studies exist, related to theuse of heparin and low molecular weight heparin(LMWH) in KD, their use can be considered both in in-fants, for whom INR examination is not easy, and in caseof reintroduction of warfarin after eventual suspension(due to eventual surgery). However, subcutaneous injec-tions are required twice a day. Particularly, enoxaparin is aLMWH with demonstrated safety and efficacy, frequentlyused in the pediatric age [64]. Fondaparinux, a newLMWH with a longer half-life, might be used in selectedcases (Table 5).

New oral anticoagulantsThe new oral anticoagulants (e.g. dabigatran, rivaroxa-ban, apixaban) show the advantage of having a predict-able clinical effect without requiring routine laboratorycheck, though they are off-label in the pediatric age anddo not currently have a clear indication in KD.Recommendation 4.Anti-platelet prophylaxis must be based on low-dose

ASA (3–5 mg/kg/day) associated with clopidogrel(0.2 mg/kg/day in patients aged < 24 months or 1 mg/kg/day if age ≥ 25 months, max 75 mg/day) in a singledose for KD patients with medium-sized aneurysms(≥5 mm and ≤ 7 mm or if z-score ≥ 7 and < 10) or inthose with multiple and complex aneurysms.

(VI - C)Recommendation 5.It is reasonable to treat KD patients with giant aneurysms

(≥8 mm), with or without stenosis, with low-dose ASA as-sociated with warfarin (keeping INR targeted at 2.0–3.0).(II-III - B)Recommendation 6.In infants or older children in whom warfarin is diffi-

cult to adjust, it is reasonable to treat giant aneurysmswith ASA and LMWH.(VI - B)Recommendation 7.In KD patients with relevant and/or extraordinary risk

of thrombosis, e.g. those with giant aneurysms or a recentcoronary artery thrombosis, triple therapy with ASA, clo-pidogrel, and warfarin or LMWH should be considered.(VI - C)

Anti-angina drugs and coronary artery vasodilatorsIn KD patients younger than 2 years, symptoms of an-gina are rare. The main purpose of the anti-angina ther-apy is reducing heart rate and cardiac workload,reducing pre- and afterload, and increasing the coronaryartery flow. Drugs of this group are beta-blockers, cal-cium channel blockers and nitro-vasodilators (seeTable 6). Beta-blockers are the first-choice drugs forstable exercise-induced angina, and in KD they may beadministered when a history of previous heart attack ispresent both to prevent the reinfarction, and reducelong-term mortality. The selective β-1 blockers are

Table 5 Anticoagulant drugs used in Kawasaki disease

Warfarin Non-fractionated heparin Low molecular weight heparin(LMWH)

Mechanism of action Block of synthesis of vitaminK-dependent coagulationfactors (II, VII, IX and X)

Bond with AT-III and inhibition ofII, VII, IX, X, XI, XII coagulationfactors

Bond with AT-III and inhibition ofII, VII, IX, X, XI, XII coagulationfactors

Therapeutic indications Medium to giant aneurysms, historyof heart attack, history of intra-aneurysm thrombosis

Aneurysms with high thromboticrisk, before starting therapy withwarfarin

Same as non-fractioned heparin

Dosage Initial dose of 0.05–0.12 mg/kg/day,progressively increased over 4–5 days to obtain an INR between 2.0and 2.5

Initial intravenous dose: 50 U/kgin 10 min or more, followed by20–25 U/kg/hour to maintainaPTT between 60 and 85″

Side effects Bleeding (epistaxis, gum bleeding,intracranial and intra-abdominalhemorrhage), embryopathies(dysostosis, dyschondroplasia,microcephaly)

Hemorrhage, thrombocytopenia,hepatic dysfunction, rash,diarrhea, hair loss, osteoporosis

Same as non-fractionated heparin,but less osteoporosis

Interactions Reduced efficacy with chlorophyllcontained in green and yellowvegetables (with high contents ofvitamin K), vitamin K-enriched milk,phenobarbital, carbamazepine,rifampicin; increased efficacy ifbreastfeeding, use of erythromycin,fluconazole, corticosteroids,amiodarone

None None


recommended to avoid side effects in other organs.Calcium channel blockers are the first-choice drugsfor angina, but their intravenous administration iscontraindicated in newborns and infants [17]. The useof all the above-mentioned drugs is off-label in KD.

StatinsHydroxymethylglutaryl coenzyme-A reductase inhibitors(statins) are a cornerstone of therapy for the primaryand secondary prevention of atherosclerotic cardiovascu-lar events in adults. They reduce low-density lipoproteincholesterol and have potentially beneficial pleiotropic ef-fects on inflammation, endothelial function, oxidativestress, platelet aggregation, coagulation, and fibrinolysis[1]. Although controversy continues concerning whetherthe vascular pathology of KD may lead to early athero-sclerosis, statins could have a role in the long-term man-agement of KD and an empirical low-dose treatmentmay be considered for patients with past or current an-eurysms, regardless of age or sex [1].

Treatment of coronary artery thrombosisPatients with medium and giant aneurysms of coron-ary arteries and those in whom the aneurysm sizesrapidly increase over time are at greater risk of devel-oping thrombosis and acute coronary syndrome. Themajority of acute heart attacks caused by a thrombusin KD occurs within 2 years since disease onset. Cor-onary thrombosis may occur more frequently withinthe first 3 months of illness in these patients, with apeak incidence between 15 and 45 days after onset. Itis therefore recommended to check frequently echo-cardiography during this period. A heart attack inchildhood and in young children may be clinically si-lent or it may be associated with sneaky and nonspe-cific symptoms, such as unusual restlessness,vomiting, or shock. A sudden deterioration of cardiacfunction or a change in ECG findings should promptthe suspicion of coronary thrombosis.

Actually, more and more patients with KD-related cor-onary aneurysms reach adulthood, and this increases therisk of heart attacks caused by thrombosis of theaneurysm or progressive arterial stenosis caused by vas-cular remodeling. The goal of treatment in KD patientswith coronary thrombosis is to restore the patency ofthe flow, “preserve” the myocardial tissue, and increasepatient’s survival [65]. In the absence of randomizedcontrolled trials recommendations about therapy of cor-onary thrombosis are derived from evidences in adultpopulation-related studies, despite the etiology of sten-osis is different, and from small series of pediatric cases.Recommendation 8.Coronary artery thrombosis with actual or imminent oc-

clusion of the lumen should be treated with thrombolytictherapy or with interventional cardiac catheterization.(I - C)

Thrombolytic drugsThe most commonly administered thrombolytic therapyis intravenous tissue plasminogen activator (tPA, alte-plase) [66–68].

Tissue plasminogen activator

Mechanism of action Plasminogen activators are en-zymes activating the conversion of plasminogen intoplasmin, which can promote clot lysis.

Therapeutic indications KD patients with acute heartattack or intra-aneurysmal thrombi, and KD patientswith sudden extension of a thrombus in the coronary ar-tery. Their use in KD patients is off-label.

Dosage For alteplase: 29.0–43.5 × 104 U/kg (administer-ing 10% of the total dose over 1–2 min intravenouslyand infusing the remainder over 60 min).

Effectiveness There are no data about the clinical effi-cacy and safety of thrombolytic agents in children,though we know that reperfusion following thrombolytictherapy is usually reached by approximately 70–80% ofadult patients.Recommendation 9.Thrombolytic drugs have to be associated with

low-dose ASA and low-dose heparin with careful moni-toring for the bleeding risk.(I - C)Recommendation 10.In children tPA (alteplase) is the first-choice thrombo-

lytic drug, requiring to be associated with oral low-doseASA and intravenous heparin (10 U/kg/hour).(VI - A)

Table 6 Long-term therapy for patients with coronary arteryaneurysms related to Kawasaki disease and anginal symptoms

Patients without anginal symptoms:

- patients without demonstrated ischemia: antiplatelet drugs- patients with demonstrated ischemia: antiplatelet drugs + calciumchannel blockers. Evaluate revascularization, according to the pediatriccardiologist’s opinion

Patients with anginal symptoms:

In addition to antiplatelet drugs:

- patients with exercise-induced angina: nitro-vasodilators and/orcalcium channel blockers- patients with angina at rest or during sleep: calcium channelblockers- patients with angina in the night: calcium channel blockers +nitro-vasodilators


Other anti-platelet drugsLess frequently, in the case of limited venous access,subcutaneously injected LMWH might be used.Considering the high risk of bleeding, unfractio-nated heparin should be a second-choice drug.Blood clotting test must be monitored daily, whilefibrinogen level should be maintained > 100 mg/dL,and platelet count > 100.000/mm3 to minimize thebleeding risk during treatment with unfractionatedheparin. In the case of significant thrombosis withhigh risk of occlusion, a combination of low-dosethrombolytic therapy may be also associated with aplatelet aggregation inhibitor, i.e. abciximab (glycopro-tein IIb/IIIa inhibitor) infused intravenously as a bolusof 0.25 mg/kg in 30 min, then followed by a continu-ous infusion of 0.125 mg/kg/minute (max 10 μg/min)for 12 h [69–71].Recommendation 11.Intravenous abciximab may be used as a bolus,

followed by a continuous infusion for 12 h, in case ofsignificant thrombosis with high risk of occlusion.(VI - B)Recommendation 12.A small intracoronary mural thrombus “without im-

mediate threat of occlusion”, detected by echocardiog-raphy in an early KD phase, may be treated withintravenous abciximab (10 U/kg/hour).(VI - B)

Non-pharmacological treatment of coronaryartery thrombosisInvasive cardiologic proceduresInterventional catheterization procedures are limitedby the large delivery systems for small patients, highrisk of complications, and low efficacy, followed byhigh risk of reintervention. Coronary artery reperfu-sion both by invasive cardiologic interventional pro-cedures and cardiac surgery can be considered afteran initial unsuccessful pharmacological thrombolysis.Cardiologic procedures include percutaneousthrombolysis, percutaneous angioplasty, and rota-tional ablation [72–74]. CAA in KD are in generalterms more difficult to treat than those in adults,and they often require that inflation pressure of theball is greater, with higher risk of causing new aneu-rysms related to balloon dilation; the inflation pres-sure recommended is ≤10 atm. The application of astent (“stenting”) is indicated in older children(≥13 years of age) in whom the calcification of CAAis relatively modest. The risk of development of newaneurysms after balloon dilation is lower in patientstreated with the balloon dilation and stent comparedto those treated with only balloon dilation, but theinsufflation pressure of the ball should not be

greater than 14 atm. A rotablator may be requiredto modify the shape of the lesion. Considering thatsurgery is performed in patients between 13 and18 years of age, it is imperative that pediatric cardi-ologists share the clinical information with col-leagues who will manage them into adulthood, for amore efficient transition. In order to determine themost appropriate interventional procedure it is desir-able that physicians consider patient’s body size, cor-onary angiography findings, and the use ofintravascular ultrasound (IVUS) [75].

Indications- Patients with ischemic symptoms caused bysignificant coronary artery stenosis (≥75% of theluminal diameter).- Patients in whom stenosis is significant (≥75% of theluminal diameter) in the absence of ischemicsymptoms, but with instrumentally demonstratedischemia (stress ECG, stress perfusion imaging,perfusion imaging stress).

Contraindications- Patients with coronary ostial lesions.- Patients with multi-vessel disease.- Patients with significant coronary artery stenosis(≥75% of the luminal diameter) or occlusion of thecontralateral coronary artery.

Recommendation 13.First-choice cardiologic interventional treatment in pa-

tients with KD should be chosen on the experience ofthe center and its technical feasibility in the shortestpossible time.(V - C)

Cardiac surgeryPercutaneous coronary angioplasty is associated withthe risk of restenosis or occlusion in patients withKD, requiring often the use of coronary stents or al-ternative procedures, such as coronary artery bypassgrafting (CABG) or rotational ablation. For childrenwith persistent or progressive CAA who develop is-chemic heart disease in early childhood a reliable op-tion is represented by CABG using grafts from theinternal mammary artery [76, 77].

Indications- Patients with severe occlusive lesions of the leftcoronary artery.- Patients with severe occlusive lesions in more [2 or 3]vessels.- Patients with severe occlusive lesions in the proximalportion of the left anterior descending coronary artery.


- Patients with a compromised collateral circulation.- Patients with previous history of a heart attack (toensure secondary prevention of heart attacks).

In Japan the average age of children undergoingCABG is between 5 and 12 years, though it can beperformed safely in younger children. The more fre-quent used surgical CABG technique is graft of theright or left thoracic mammary internal artery, whichensures good long-term patency (equal to 87% in gen-eral until 20 years). Other cardiac surgery associatedwith CABG may be required for the reduction ofgiant aneurysms in order to improve the coronary ar-tery flow pattern and prevent the formation ofthrombi caused by the increase of the “shear stress”on vessel walls [78, 79].

Heart transplantationA dozen of KD cases has been reported worldwidefor heart transplantation, with an average age of8.5 years, but also in subjects aged less than4 months who experienced ventricular tachycardia orfibrillation [80].

Indications- Patients with a significant left ventricular dysfunction.- Patients with potentially lethal arrhythmias.- Patients with significant lesions in the peripheralsegments of the coronary arteries.

Follow-up of patients with Kawasaki diseaseShort-term follow-upPatients with KD must undergo a careful clinical moni-toring of blood and instrumental exams in thelong-term, but cardiological evaluations with ECG andechocardiography are crucial also in the short-termfollow-up.Recommendation 14.Cardiologic evaluation with ECG and echocardiog-

raphy should be performed at diagnosis of KD, tohighlight eventual early CAA, then should be re-peated at 2, 4 and 8 weeks after disease onset in pa-tients who do not have developed aneurysms. Inpatients with CAA it is recommended to performechocardiography 2 times a week during the periodof rapid expansion of the dilation of coronary arter-ies, and at least once a week in patients with giantcoronary aneurysms in the first 45 days after diseaseonset.(VI - B)Cardiological evaluation performed on the second

month since disease onset allows to subdivide KD pa-tients according to the cardiovascular impairment in dif-ferent risk classes to establish a personalized follow-up.

It is important an accurate measurement of coronary ar-tery diameters by the evaluation of the relative z-scores.

Long-term follow-upFollow-up of KD patients must continue over time, espe-cially for those who have presented CAA, consideringthat it is not possible to exclude remote complicationseven in the non-complicated cases. The aneurysmal le-sions tend to regress (50–95%, according to case stud-ies), mostly medium-sized and small-sized aneurysms.Such regression may be due to myointimal proliferationor thrombus organization and recanalization. Therefore,it is extremely important a careful long-term follow-upin KD patients with both persistent and regressed aneu-rysms with different timing and mode.The class stratification risk, related to the risk of

myocardial ischemia, established by the AmericanHeart Association (AHA), is a useful tool for a stan-dardized management of KD patients with regard totiming of controls, diagnostic tests, and therapeuticindications [6, 8].It should be noted that risk classes of each patient

with coronary artery impairment may vary over timebecause of morphological changes in the coronary ar-teries’ wall. The occurrence of thrombosis or stenosisassociated with CAA, in fact, increases the risk ofmyocardial ischemia. Furthermore, the optimalfollow-up of patients with regressed aneurysms re-mains still controversial since, even with thenormalization of vessel diameter, morphological andfunctional alterations might persist. Indeed, the nor-mal ultrasound coronary artery framework does notnecessarily coincide with the normal endothelial func-tion. This justifies continuing seriated controls, al-though less frequent, to trace the natural history ofthe disease, also regarding the possible risk of athero-sclerosis. It is reasonable to use echocardiographiccoronary artery luminal dimensions converted to bodysurface area-adjusted z scores to determine risk strati-fication of patients [81, 82]. Risk categories accordingto the AHA are shown in Table 7. Different therapiesand follow-up modalities are recommended for eachcardiovascular risk class.Recommendation 15.CLASS I

▪ Treatment with ASA for the first 8 weeks and in anycase until a documented normalization of both plateletcount and inflammatory markers.▪ Cardiologic evaluations (ECG, echocardiogram,monitoring of blood pressure) and any blood chemistrytests with evaluation of lipid profile at 12 months sincedisease onset.


▪ No restriction of physical activity after the first8 weeks.

CLASS II

▪ Treatment with ASA until normalization of bothplatelet count and inflammatory markers anddisappearance of coronary artery lesions (alsotortuosity/stiffness of the vessel walls), documented bytwo subsequent controls.▪ Cardiologic evaluations (ECG, echocardiogram,monitoring of blood pressure) and blood chemistrytests with evaluation of lipid profile at 6 and 12 monthsafter disease onset.▪ Clinical reassessment of the eventual cardiovascularrisk with physical activity counseling at 1 year sincedisease onset.▪ No restriction of the physical activity after the first8 weeks.

CLASS III

▪ Treatment with ASA until complete regression of theaneurysms documented by two subsequent negative controls.▪ Cardiologic evaluations (ECG, echocardiogram,monitoring of blood pressure) and blood chemistrytests every 4–6 months, depending on the severity oflesions. If there is a complete regression of aneurysmsdocumented by two subsequent negative controls,cardiologic examinations (ECG, echocardiogram,monitoring of blood pressure) annually in the first3 years, then every 3–5 years (up to 18 years).▪ Evaluation of myocardial perfusion every 2 yearsabove the age of 10 (stress-ECG and/or stress ECO)with evaluation of the lipid profile.▪ Coronary angiography or CT angiography if anymyocardial ischemia is highlighted.▪ After the first 8 weeks physical activity withoutrestrictions (excluding athletic activities), guided bymyocardial perfusion assessment tests in patients over10 years.

CLASS IV

▪ Antiplatelet treatment (ASA + possible associationwith clopidogrel in selected patients) and anyanticoagulant (warfarin in the giant aneurysms orLMWH in selected cases).▪ Cardiologic evaluations (ECG, echocardiogram,monitoring of blood pressure) and blood chemistrytests every 4 months until a stable reduction ofaneurysms is documented by two successive negativecontrols. Then, cardiology checks and blood testsannually with annual assessment of myocardialperfusion (stress ECG and/or stress echo or any stressMRI with contrast).▪ Coronary angiography or coronary CT angiography inthe first 6–12 months and thereafter when clinicallyindicated.▪ Physical activity based on annual myocardialperfusion check; forbidden physical contact or collisionsports/games.▪ Counseling for pregnancy in female patients onanticoagulant treatment.

CLASS V

▪ Antiplatelet treatment (ASA + possible associationwith clopidogrel in selected patients) andanticoagulation with warfarin (or LMWH in selectedcases).▪ Cardiologic evaluations every 3 months with ECGand echocardiogram + possible Holter-ECG; annual as-sessment of myocardial perfusion (stress ECG and/orstress echo, stress MRI with contrast).▪ Coronary angiography or coronary CT angiographyto guide treatment options and, in case of myocardialischemia, total body angio-CT.▪ Coronary angiography or coronary CT angiography inthe first 6–12 months, and thereafter when clinicallyindicated or suggested by non-invasive tests.▪ Physical activity based on annual myocardialperfusion evaluation; forbidden physical contact orcollision sports/games; avoid a sedentary lifestyle.▪ Counseling for pregnancy in female patients onanticoagulant treatment.

(VI - C)

Recommendations for a correct lifestyle and preventionof cardiovascular risksCardiovascular sequelae caused by KD differ substan-tially from the classic atherosclerosis from a pathologicalpoint of view. The endothelial dysfunction and chronicinflammatory reactions may occur even late in KD pa-tients with giant or medium aneurysms, including those

Table 7 Cardiovascular risk classes in patients with Kawasakidisease

Class I No abnormality of coronary arteries in the variousphases of the disease

Class II Transient coronary artery ectasia that disappearswithin 8 weeks

Class III Single aneurysm of small-medium caliber between+ 3 and + 7 SD in one or more arteries

Class IV One or more aneurysms ≥7 SD, including multipleand complex giant aneurysms without anyobstruction

Class V Coronary artery obstruction at the angiography


which have regressed, causing intimal hyperplasia andcalcification if there is a localized stenosis. Althoughendothelial dysfunction is a precursor of atherosclerosisand autopsy studies seem to suggest that KD patientsmay have more severe atherosclerotic lesions, it is stillunclear whether all KD patients have a higher risk for aclear progression to atherosclerosis [83–85]. It is reason-able to consider KD patients worthy of close monitoringfor cardiovascular risks, evaluating blood pressure, bodymass index, cholesterol, LDL, HDL, triglycerides, and pro-moting correct lifestyles (for instance, avoid smoking) anda regular physical activity with healthy eating [86, 87]. Theuse of statins is still debated and their role in KD is yet toclarify [88].Recommendation 16.Monitoring cardiovascular risk factors in KD patient

requires body mass index evaluation, blood pressurecontrol, and evaluation of the lipid profile (total choles-terol, LDL, HDL, triglycerides).(VI - B)

Fitness certification for patients with a previous KawasakidiseaseReference personnel for patients with a previous KDwho want to perform agonistic sports (competitivesports or high-intensity activities) includes doctorsspecialized in sports medicine who work in thehealth systems or in authorized private structures;certification for non-agonistic sports can be providedby the family pediatrician and practitioner In KD pa-tients the evaluation for fitness certification is compli-cated by several reasons:

- there are non-subjective functional limitations (pa-tients do not feel sick);- cardiovascular risks depending on the coronary arterydamage is difficult to quantify, and patients affected bygiant aneurysms may show normal stress test whenmyocardial perfusion is evaluated;- few data are available to define exactly risks caused bysport activity;- it is difficult to correlate size of aneurysms to anycertification for fitness, though giant or multipleaneurysms should be very carefully evaluated.

For the reasons above, specialized centres must certifyphysical fitness through multi-disciplinary evaluations.Activity restrictions depend on ongoing therapy (anti-platelet or anticoagulant drugs). Pediatricians can assistfamilies in choosing which is the most appropriate sport.Table 8 reports a classification of contact and collision

sports, showing limited contact or non-contact sports,subdivided in high, mild, and less strenuous. Each pa-tient on antiplatelet treatment must avoid contact and

collision sports, while patients on anticoagulant therapymust also avoid limited contact sports [89].Malattia di Kawasaki: Linee Guida italiane.The following steps should be performed to certificate

fitness: family and personal history, clinical examinationand blood pressure control, resting 12-lead ECG, mono-and 2D-colour Doppler echocardiogram, tapis roulantstress test to determine stress tolerance, rhythm andheart frequency, and possible myocardial ischemia. Inthe presence of heart arrhythmias a dynamic 24 h-ECGmust be performed. If all these examinations are normal,annual fitness certification can be produced fornon-agonistic activities [90–92].

Indications for physical activity in patients with a previousKawasaki diseaseThere are different indications for physical activity inchildren who have presented KD, which can be stratifiedaccording to various risk levels.Recommendation 17.Physical activity is recommended according to the fol-

lowing indications:

- risk level I e II: no restriction of physical activity(non-agonistic) if clinical assessment and instrumentaltests are normal after 6–8 weeks.

Table 8 Sport classification according to the American Academyof Pediatrics

Contact/collision Boxing, field hockey, ice hockey

American football

Motorcycle racing

Martial arts, rodeo, soccer, wrestling

Limited contact Baseball, basketball, bicycling, diving

Field events (high jump, pole vault)

Gymnastics, horse-back riding

Ice roller skating

Canoeing, fencing

Running, swimming, tennis

Race walking, weight lifting

Non-contact Highly strenuous Skiing (cross-country, downhill, water)

Softball

Squash, team handball

Volleyball

Non-contact Mildly strenuous Badminton

Curling

Table tennis

Non-contact Non strenuous Archery

Golf

Rifle range


- risk level III: no restriction of physical activity (non-agonistic) for children younger than 10–11 years after6–8 weeks, then based on stress test each time a newcertification is required. In selected cases the evaluationof myocardial perfusion might be indicated.- risk level IV: physical activity is established on annualstress test and evaluation of myocardial perfusion.Contact/collision sports are not permitted because ofthe risk of bleeding. A coronarography must beperformed if there is evidence of myocardial ischemia.- risk level V: physical activity is established via six-monthly stress test with at least annual evaluation ofthe myocardial perfusion. Contact/collision sports arenot permitted because of the risk of bleeding. Agonisticsports are not permitted, though a sedentary lifestyleshould be avoided.

(VI - A)

DiscussionNot applicable.

ConclusionThis second part of practical Guidelines related toKawasaki disease (KD) has the goal of contributing tothe most appropriate treatment of resistant forms andKD-related cardiovascular/systemic complications,follow-up, lifestyle and prevention of long-term risksthrough a set of 17 recommendations.These are based on the most actual scientific evidence,

and their aim is improving the overall prognosis of thedisease. We have refined the definition of resistantforms, recurrent forms, cardiovascular and systemiccomplications of KD. Concerning therapies, we have up-dated treatment of resistant forms (especially with corti-costeroids and biological drugs), of cardiovascularcomplications (with anti-platelet and/or anticoagulantsdrugs), and of coronary artery thrombosis (with bothpharmacological and non-pharmacological approaches).Concerning follow-up of KD patients, we have analyzedshort- and long-term suggestions for the follow-up,evaluating timing and type of different instrumentaltechniques, according to each cardiovascular risk class,introducing other advanced cardiovascular imagingtechniques (i.e. computed tomography or magneticresonance angiography). Although every clinicaldecision-making should be individualized to the spe-cific patient with KD, herein we have pointed up rec-ommendations for a correct lifestyle and overallprevention of cardiovascular risks, and finally we havereassessed indications for physical activity in patientswith a previous KD.

AbbreviationsASA: Acetylsalicylic acid; AST: Aspartate aminotransferase; ATIII: AntitrombinIII; CAA: Coronary artery aneurysms; CABG: Coronary artery bypass grafting;CRP: C-reactive protein; CT: Computed tomography; ECG: Electrocardiogram;IFX: Infliximab; IL: Interleukin; INR: International normalized ratio;IVIG: Intravenous immunoglobulin; KD: Kawasaki disease; KDSS: Kawasakidisease shock syndrome; LMWH: Low molecular weight heparin;MAS: Macrophage activation syndrome; MR: Magnetic resonance; PTT: Partialthromboplastin time; TNF: Tumor necrosis factor; tPA: Tissue plasminogen activator

AcknowledgementsWe would like to thank prof. Alessio Maria (Università degli Studi di Napoli FedericoII, Naples), dr. Granato Carmen (Università degli Studi di Napoli Federico II, Naples)and dr. Marotta Rosaria (Università degli Studi di Napoli Federico II, Naples).

FundingNo person who participated in the drafting of these guidelines has beensponsored.

Availability of data and materialsNo datasets were generated or analyzed during the current study.

Authors’ contributionsAM, ITDJ, DR, AR, GC, and AV: conception and design of the guidelines, collectionof in-depth analyses performed by each coauthor, critical revision, manuscriptwriting and final approval of the manuscript. GB6 participated in writing thechapter about high risk patients’ therapy. SB1 analyzed data related todyslipidemia and risk of atherogenesis. FC7 produced the chapter aboutepidemiology. EC8 participated in writing the chapter about presentationand clinical course. FD1 participated in writing the chapter about high-riskpatients’ therapy. AD1 studied application and limits of the echocardiographyin KD. MD9 participated in writing the chapter about immunoglobulin therapy.DDP10 analyzed and synthetized the possible etiopathogenic pathways.RMD11 worked about the non-cardiovascular complications and follow-up.LD12 participated in writing the chapter about presentation and clinical course.MEH1 participated in writing the chapter about presentation and clinical course.SE13 processed the vaccinations’ recommendations. FF14 participated in writingthe chapter about presentation and clinical course. UG1 processed the sportactivity recommendation. MCM5 participated in writing the chapter about highrisk patients’ therapy. SM6 participated in the chapter about echocardiography.GLM 6 participated in the chapter about presentation and clinicalcourse. SM15 participated in writing the chapter about presentation andclinical course, especially about recurrent forms. GM1 co- produced the chapter aboutepidemiology. RM16 and CP16 helped us in making the document accessible to KDfamilies. DP4 analyzed and synthetized proinflammatory conditions and procoagulantactivity in KD. MCP11 worked about patients’ follow-up. PS11 worked about patients’follow-up. AS1 produced the chapter about instrumental investigations in KD. ES4analyzed and synthetized proinflammatory conditions and procoagulant activity in KD.All authors read and approved the final version of this manuscript.

Ethics approval and consent to participateNot applicable.

Consent for publicationNot applicable.

Competing interestsThe authors declare that they have no competing interests.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Author details1Bambino Gesù Children’s Hospital, Piazza S. Onofrio n. 4, 00165 Rome, Italy.2Università Cattolica Sacro Cuore, Fondazione Policlinico A. Gemelli IRCCS,Rome, Italy. 3Giannina Gaslini Institute, Genoa, Italy. 4Istituto Superiore diSanità, Rome, Italy. 5Università degli Studi di Palermo, Palermo, Italy.6Università degli Studi di Pavia, Pavia, Italy. 7Policlinico Giovanni XXIII, Bari,Italy. 8Ospedale S. Eugenio, Rome, Italy. 9Università degli Studi Sapienza,Rome, Italy. 10Università degli Studi Tor Vergata, Rome, Italy. 11Ospedale


Maggiore Policlinico, Milan, Italy. 12Ospedale di Battipaglia, Salerno, Italy.13Università degli Studi di Perugia, Perugia, Italy. 14University of Florence,Florence, Italy. 15Università degli Studi di Torino, Turin, Italy. 16AssociazioneRari ma Speciali, Rome, Italy.

Received: 4 January 2018 Accepted: 29 July 2018

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AbstractBackgroundScopeUsersNote for usersSponsorshipsDisseminationUpdatesMethods

IntroductionResistant forms of Kawasaki diseaseCardiovascular complications of Kawasaki diseaseOther systemic complications of Kawasaki diseaseRecurrent forms of Kawasaki diseaseTreatment of resistant forms of Kawasaki diseaseCorticosteroidsMethylprednisolonePrednisone

Biological drugsInfliximabAnakinraCanakinumabPlasmapheresis

Treatment of the cardiovascular complications of Kawasaki diseaseOther anti-platelet drugsClopidogrel

AnticoagulantsNew oral anticoagulantsAnti-angina drugs and coronary artery vasodilatorsStatins

Treatment of coronary artery thrombosisThrombolytic drugsTissue plasminogen activatorOther anti-platelet drugs

Non-pharmacological treatment of coronary artery thrombosisInvasive cardiologic proceduresIndicationsContraindications

Cardiac surgeryIndications

Heart transplantationIndications

Follow-up of patients with Kawasaki diseaseShort-term follow-upLong-term follow-upRecommendations for a correct lifestyle and prevention of cardiovascular risksFitness certification for patients with a previous Kawasaki diseaseIndications for physical activity in patients with a previous Kawasaki disease

DiscussionConclusionAbbreviationsAcknowledgementsFundingAvailability of data and materialsAuthors’ contributionsEthics approval and consent to participateConsent for publicationCompeting interestsPublisher’s NoteAuthor detailsReferences

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