KAWASAKI DISEASE ( KD ) - Leeds Congenital Hearts



KAWASAKI DISEASE GUIDELINE

Document Control:

Author: Rebecca Newbigin, Matthew Pye, Mark Wood and …

Date: June 16

Version: 2

Type: Clinical Guidelines

Approved: Approved by Yorkshire and Humber CHD Network June 2017

Status:

Circulation: Trust wide

Review Date: June 2019

Pages:

KAWASAKI DISEASE GUIDELINE

Introduction

This guideline aims to help the early appropriate diagnosis and management of Kawasaki disease in children, which will mainly be led by General Paediatric teams. We also cover the Paediatric Cardiology management of coronary artery aneurysms. Obviously not every eventuality can be covered and ‘clinical acumen’ and ability to recognise the need to ask for advice is crucial. Many aspects of the ideal management do not have a high level research base.

The Leeds Paediatric Rheumatology on-call consultant (available through Leeds Children’s Hospital at LGI switchboard) is available for advice as needed.

Background

Kawasaki disease (KD) is a monophasic systemic vasculitis which affects small and medium sized arteries, presenting as a febrile illness. Pathogenesis not fully understood; thought to be linked to infectious agents and genetic factors. KD is the most common cause of acquired heart disease in children due to coronary arteritis leading to coronary artery aneurysms, usually developing within the first month and therefore prompt recognition of the possibility of KD and treatment is important.

Key facts

|UK incidence |8.1 / 100,000 Asian>African>Caucasian |

| | |

| |25% |

|Incidence of coronary artery aneurysms in untreated KD | |

|Incidence of coronary artery aneurysms in KD treated with IVIG within |2-4% |

|10 days | |

Aims of the management of Kawasaki disease

The main aims are:

1) to reduce the risk of developing coronary artery aneurysms (by early recognition and treatment)

2) to identify coronary artery aneurysms that develop (despite treatment or when untreated) and then reduce the risk of myocardial harm

3) to identify and manage other complications, most of which are rare

4) to support the family, including with information

Coronary artery aneurysms produce a risk of myocardial infarction, which can early in the disease process (e.g. before diagnosis) or much later in life, as a distressing surprise, with a risk of mortality and morbidity.

.

Diagnosis

There are 2 main presentations of KD:

a) children who are referred early, meet the classical diagnostic criteria at assessment and the diagnosis is clear early on, often before 5 days of fever

b) children who have a Pyrexia of Unknown Origin who do not meet the classical diagnostic criteria: often called ‘Incomplete KD’

More detail:

a) ‘Classical’ diagnostic criteria

Initially proposed by Kawasaki:

Fever for at least 5 days with 4 of the 5 clinical features below, with no other reasonable cause for the findings:

1. Bilateral non-purulent conjunctivitis

• Spares the limbus (rim around iris)

2. Oral mucosal changes

• Erythema, strawberry tongue, fissuring of lips

3. Polymorphous rash

• Usually in first few days on trunk

• Very variable: may be macular, maculopapular, urticarial, morbilliform, scarlettina

• Bullous/vesicular lesions should not be present

4. Cervical lymphadenopathy

• Seen in 50%, often includes a single tender enlarged node >1.5cm

5. Peripheral extremities changes

• Erythema and oedema of palms and soles, may be painful

• Desquamation of hands and feet, usually at end of 2nd week and when fever has resolved.

[pic][pic][pic][pic][pic]

The features are usually sequential, i.e. not necessarily all present at the same time, so a detailed history, specifically asking about key features, is important. The clinical presentation varies over time with the clinical course artificially being divided into 3 stages:

Acute/Febrile Stage:

Fever is typically high-spiking, remittent and often unresponsive to antipyretics (& antibiotics). Fever may persist for up to 3 to 4 weeks if untreated, but usually remits within 48 hours of appropriate treatment (see below). Nearly all are irritable.

Mucocutaneous changes and lymphadenopathy are most evident during this phase: erythema and oedema of hands and feet may be last finding to develop.

Subacute Stage:

Begins when fevers have settled and continues until weeks 4-6. Hallmarks include desquamation of the digits, marked thrombocytosis and development of coronary aneurysms (therefore normal early echocardiography cannot rule out coronary artery artery involvement). Often accompanied by persistent irritability, anorexia, and conjuctival injection.

Convalescent Phase:

Complete resolution of most clinical signs, usually within 3 months of presentation, although deep transverse grooves across the nails (Beau lines) may become apparent 1-2 months after the onset of fever.

Coronary artery aneurysms

Traditional guidance suggests that if coronary artery aneurysms are present, only 3 of the 5 classical criteria plus persistent fever are needed to make a diagnosis. However I practice, new detection of coronary artery aneurysms during / after a monophasic febrile illness with some features of KD, even without 3 classical criteria met, usually is appropriately labelled as KD.

Aneurysms develop in 15-25% of untreated children and are the principle cause of long term morbidity following Kawasaki’s disease, potentially leading to thrombosis formation, ischaemic heart disease and/or sudden death. On average dilatation of coronary arteries starts around 10 days from the onset of fever, and so performing echocardiography early in the disease process does not give reassurance that aneurysms will develop.

Those at higher risk of cardiac sequelae include being male, less than 1 year of age, older than 5 years of age, CRP >100, WC >30, recurrence of disease (~1 in 50 develop a recurrence). However most of this information is from studies in KD in Japanese populations and may not be transferable to the UK population as a whole, presumably due to different prevalence of certain alleles.

It is important to note that young adults, after unrecognized KD as a child and consequently no cardiac follow-up, can develop myocardial infarcts with a risk of sudden death.

Incomplete Kawasaki Disease

This describes the variable presentation of KD (ie the same disease process), when classical criteria are not met. In practice the diagnosis of KD is often subsequently confirmed subsequently by development of coronary artery aneurysms. Incomplete KD is more common in children under 6 months of age. It is an important group as the risk of developing coronary artery aneurysms is probably higher than in classical Kawasaki disease.

Considering the diagnosis of incomplete KD is analogous to assessing a child to decide if they could have appendicitis or septicaemia: the decision to perform a laparotomy or start antibiotics is often made before the diagnosis is secure.

In the same way the decision to start treatment for presumed KD (below) is guided by the following principles:

1. clinical judgement of how likely KD seems

2. clinical judgement of how likely alternative diagnoses seem

3. risks to child of giving IVIG and aspirin

4. risks to child of missing KD that produces cardiac sequelae

Obviously IVIG and aspirin should not be given to every child with an unexplained persistent fever, but serious consideration about the possibility of incomplete KD should be given when a child has an unexplained fever (PUO) that hasn’t responded to antibiotics. Especially if the child is irritable or under 12 months of age.

The American Heart Association (2004, Newburger et al) suggest a diagnosis of incomplete Kawasaki’s Disease can be made if there is fever ≥5 days and 2 or 3 clinical criteria plus ≥ 3 supplemental lab criteria (albumin 450 after 7 days, WBC > 15, and urine >10 WBC/high-power field). If these criteria are met then the AHA guidance recommends commencing treatment. If these criteria are not met and there is still diagnostic uncertainty then an echo may be a useful adjunct with the presence of echocardiographic changes, including ‘bright coronary arteries’ suggesting the diagnosis, but this is very subjective,

Other features which may be due to KD are listed below:

• Extreme misery, usually associated with aseptic meningitis: presenting very differently at different ages e.g. poor sleep and feeding, hard to comfort

• Diarrhoea & vomiting

• Abdominal pain (can be severe, due to bowel ischaemia)

• Cough, coryza, acute otitis media

• Sensorineural hearing loss (temporary and permanent)

• Uveitis (non-granulomatous), retinal arteritis

• Arthritis (typically large joints)

• Meatal inflammation and orchitis in boys or vulvitis in girls

• Urethritis

• Gallbladder hydrops, pancreatitis

• Hepatitis (can produce jaundice)

• Myocarditis +/- pericardial effusion, myocardial infarction

• Aseptic meningitis (CSF lymphocytosis)

• Facial palsy

• Petechial rash

• KD shock syndrome

• Febrile convulsions

• Encephalopathy or ataxia

• Leukaemia (can cause meningitis, rashes, uveitis, arthritis, irritability and variable FBC picture)

• Hyponatraemia, due to SIADH

• Erythema and induration around a pre-existing BCG vaccination scar is described and may be pathognomonic (hypothetically ascribed to cross-reactivity between mycobacterial heat shock protein (HSP) 65 and a human homologue HSP 63)

• Peripheral gangrene due to medium artery aneurysms e.g. axillary artery

• Renal involvement (pyuria, proteinuria, tubular disturbances, tubulo-interstitial

nephritis and renal failure)

• Macrophage activation syndrome (secondary haemophagocytic lymphohistiocytosis): features include persistent fever, cytopenia and hyperferritinaemia

Differential diagnosis

(see appendix for key points of these illnesses)

• Streptococcal infection (including scarlet fever)

• Staphylococcal infection (toxic shock syndrome, scalded skin syndrome)

• Measles, rubella, roseola infantum

• EBV, Influenza A, adenovirus infection

• Leptospirosis

• Rickettsial spotted fevers

• Mycoplasma infection

• Infective endocarditis

• Steven-Johnson syndrome

• Systemic juvenile idiopathic arthritis (sJIA), especially with macrophage activation syndrome (= secondary HLH)

• Drug reaction including Anticonvulsant Hypersensitivity Syndrome

• Cogan’s syndrome

Please note

• Kawasaki disease has been described alongside group A streptococcal and staphylococcal infections.

• Raised ASOT and positive throat swab results do not confirm recent / current group A streptococcal infection.

• Extremely common symptoms in children with viral infections (including cough, coryza, otitis media, diarrhoea and vomiting)

Investigations to consider to help assess likelihood of Kawasaki disease

Investigations should be guided by clinical picture. This is not a list of investigations needed for all children with a PUO.

• FBC + film

o Neutrophilia, changing to lymphocytosis at end of 1st week.

o Thrombocytosis in peaking 2nd or 3rd week.

o Progressive mild normocytic, normochromic anaemia.

• HMDS flow cytometry of WBCs and Bone Marrow Aspirate (refer to Paediatric Haematology): if any concern about the possibility of leukaemia or lymphoma, lower threshold if systemic corticosteroids to be used (as they can mask / partially treat)

• ESR + CRP (raised) – normal values in acute phase virtually rules out KD

• Blood cultures when pyrexial

• Lumbar puncture, if concerned of possibility of infective meningitis

• U&E, LFT, clotting screen

o Low sodium, elevated transaminases, hypoalbuminaemia

• Urine microscopy

o Sterile pyuria and proteinuria

• ASO titre, antiDNAse B

• Throat swab: bacterial culture and PCR respiratory virus screen

• Nasopharangeal secretions: viral screen

• Stool viral studies and culture if diarrhoea

• Viral titres (enterovirus, adenovirus, EBV, CMV) or PCRs (D/W Sean / microbiology)

• Mycoplasma IgM

• Abdominal ultrasound (to look for hydrops of gall bladder, lymph nodes)

• Ophthalmology assessment

NB after receiving IVIG antibody serology results can be altered for upto 3 months afterwards

Other Investigations:

• ECG:

o Perform baseline ECG in all cases of suspected Kawasaki’s disease and on alternate days whilst in hospital

▪ Other than tachycardia, may see changes associated with myocarditis/pericarditis (common in acute phase) or ischaemia such as pronged PR interval, ST-T wave changes or Q waves, decrease R wave voltages, flattened T-waves, or prolonged QT intervals.

▪ Arrhythmias including heart block can occur.

▪ Findings are nearly always reversible

• Echocardiography:

o Any patient who reaches the diagnostic criteria for Kawasaki’s disease should be referred for a cardiology opinion and routinely have an echocardiogram performed at:

• 10-14 days

• 6-8 weeks

• 1 year

o Echo may show evidence of sequelae of KD e.g. myocarditis, pericardial effusion, valvular regurgitation, and impaired ventricular function as well as coronary abnormalities. Infective endocarditis can be suggested by vegetations, but blood cultures are a more sensitive investigation which should also be performed if suspicion.

o Do not need to perform echocardiography before 10 – 14 days (after onset fever) unless results will aid diagnosis or if concerns with heart e.g. on ECG or with cardiovascular observations / function

MEDICAL MANAGEMENT OF PROVEN OR SUSPECTED KAWASAKI DISEASE

Overview

Once diagnosis established or thought likely:

1. Counsel family and discuss / seek written consent for treatment (with information leaflets)

2. Start IVIG 2g/kg

3. Start anti-inflammatory dose of aspirin 7.5 – 12.5mg/kg 4 times per day

4. If risk factors for coronary artery aneurysms add IV methylprednisolone 0.8 mg/kg twice daily until CRP normalises

5. Arrange ECG (and repeat every 2 days whilst an inpatient)

6. Consider urgent Paediatric Cardiology review (if concerns with ECG / cardiovascular status or if late diagnosis)

7. Observe response, especially temperature profile and CRP at 48 hours

8. If good response and when apyrexial for 48 hours with normal CRP:

a. discharge

b. advise on open access to return it fever returns / other concerns

c. request routine hearing test as an outpatient

d. arrange cardiology follow-up (if normal: 10-14 days, 6-8 weeks and 12 months)

If fever does not defervesce after above treatment, or returns within a few days:

1. Review diagnosis, but be aware that approximately 20% of children with KD do not fully respond to a single dose of IVIG and aspirin

2. Consider discussion with Paediatric Rheumatology consultant on-call at Leeds Children’s Hospital (at Leeds General Infirmary) or transfer to their care

3. Consider discussion with Leeds Children’s Hospital Paediatric Haematology consultant on-call if concern re possibility of leukaemia and considering high dose corticosteroids

4. Give a second dose of 2g/kg IVIG or IV methylprednisolone 10 - 30mg/kg daily for 3 days. If no response 12 hours after either, give the other.

5. If no response strongly recommend involvement of the Leeds Paediatric Rheumatology service (and Paediatric Cardiology service) with the child transferred to Leeds Children’s Hospital. Infliximab may be considered.

Intravenous Immunoglobulin (IVIG)

IVIG for Kawasaki disease is classed as a RED indication by the Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee. This means there is sufficient evidence to allow this to be automatically authorised.

Mode of action

IVIG has an anti-inflammatory effect, and significantly reduces the incidence of coronary artery aneurysms.

Dosing regime

Give IVIG 2 g/kg as a single infusion over 12 hours (Human normal immunoglobulin).

• Within 10 days of illness.

• Can give after 10 days if still febrile or aneurysm present, with raised ESR/CRP.

• Can repeat 2 g/kg dose if fever persists 36 hours after 1st dose IVIG.

Cautions

• Anaphylaxis.

• Can de-activate live vaccines (defer BCG, MMR, varicella for 3 months).

• IVIG causes ESR to be raised.

Aspirin

Mode of action

High dose used initially for anti-inflammatory action. It has an additive effect with IVIG of reducing aneurysm development, and leads to faster resolution of fever. Lower dose then used for its anti-platelet effect.

Dosing regime

Neonate

• High dose

o 8 mg/kg PO QDS for 2 weeks or until afebrile for >48 hours.

• Then low dose

o 5 mg/kg PO OD for 6-8 weeks.

Children >1month – 12 years

• High dose

o 7.5-12.5 mg/kg PO QDS for 2 weeks or until afebrile for >48 hours. (Calculate practical dose using dispersible tablets).

• Then low dose

o 2-5 mg/kg PO OD for 6-8 weeks.

Patient should remain in patient on ward to monitor temperature until documented apyrexial for at least 48 hours and can then be discharged on low dose aspirin.

If no evidence of coronary artery aneurysms at 6-8 weeks aspirin can be discontinued (to be reviewed at cardiology out-patient appointment). Continue aspirin indefinitely if persistent coronary artery abnormality.

Cautions alongside taking aspirin, especially when used long-term

• Avoid ibuprofen as it antagonises the platelet inhibition of aspirin

• Asthma can very rarely be exacerbated by aspirin

• Peptic ulceration very rare, but if concern add a proton pump inhibitor or stop and consider alternative anti-platelet therapy

• Renal and hepatic impairment

• Increased risk of Reye’s disease especially following influenza or varicella infection.

[pic]

From Eleftheriou et al. Management of Kawasaki disease. Arch Dis Child. doi:10.1136/archdischild-2012-302841

If fever does not resolve, or returns having previously resolved seek expert advice.

• Give 2nd dose 2 g/kg IVIG if not already done so.

• Consider IV methylprednisolone

o 30mg/kg IV infusion over 2-3 hours OD for 1-3 days.

Vaccinations after receiving treatment for KD

1. If IVIG was given, avoid all vaccinations for 3 months, as immunoglobulins from the IVIG may impair effectiveness

2. Consider varicella vaccination if long-term aspirin indicated, to reduce worry about developing Reye’s syndrome

Long Term Implications:

With appropriate treatment about 5% of cases will develop coronary artery aneurysms and in only about 1% of cases do these aneurysms become “giant” (>8mm diameter) which carry a poor prognosis; they can heal with stenosis and cause distal myocardial ischaemia, or more rarely they may rupture.

Parents should be warned that it is not uncommon for children to complain of tiredness for a number of months and occasionally years after an episode of Kawasaki’s disease and that this can sometimes be associated with mood and/or behaviour changes. Peripheral tingling and vasomotor changes have been reported and repeeling of the skin of the tips of fingers and toes is common.

There is also some evidence that even in patients with normal imaging there is residual abnormal endothelial dysfunction and abnormal lipid profiles, even if no coronary artery changes seen. The risk of future cardiac events is uncertain, but it would be reasonable to highlight the additional importance of reducing risk factors for atherosclerotic cardiovascular disease. An alert in early 2016 highlighted this nationally to acute medicine professionals who care for adults and children.

Management of coronary artery aneurysms

[pic]

From Eleftheriou et al. Management of Kawasaki disease. Arch Dis Child. doi:10.1136/archdischild-2012-302841

Sensorineural hearing loss

A 2014 review of data from over 240 children with KD who were assessed in trials showed 36% had some degree of sensorineural hearing loss and 14% had persistent sensorineural hearing loss at latest follow-up (.

The long-term severity of this is not well described. Since KD usually presents in pre-school and early school age and that hearing concerns at this age are often not noticed for some time and that hearing is critical to language development at this age it seems reasonable to arrange a routine hearing test, in the same way as is done routinely after meningococcal disease.

Patient Information Leaflets

NHS Choices:



Vasculitis UK:



References and acknowledgements

Original description

Kawasaki et al. Acute febrile mucocutaneous lymph node syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Jpn J Allergy 1967;16:178-222.

American Heart Association recommendations on identifying Incomplete KD

Newburger et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease. Circulation. 2004; 110: 2747-2771.

Excellent summary of latest understanding, evidence and proposed UK treatment algorithm (used significantly to guide management strategies above)

Eleftheriou et al. Management of Kawasaki disease. Arch Dis Child. doi:10.1136/archdischild-2012-302841

Summary of evidence regarding sensori-neural hearing loss after KD

Smith and Yunker. Kawasaki disease is associated with sensorineural hearing loss: A systematic review. International Journal of Pediatric Otorhinolaryngology. Volume 78, Issue 8, August 2014, Pages 1216–1220.

Other

Kato H, Sugiman RE, Akagi T, et al. Long-term consequences of Kawasaki disease: a 10 to 21 year follow –up study of 594 patients. Circulation 1996;94(6):1379-1385

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