Kawasaki Disease
by Kenneth Lyen
INTRODUCTION
The diagnosis of Kawasaki Disease can be challenging, especially in the early stages of the illness. When patients come to see you during the first few days of fever, there may be hardly any other signs or symptoms. Their illness can be palmed off as a “viral fever” and the patient sent off with some paracetamol and advice to drink more and to rest at home. Many would not come back to see you, or they may ask you for telephone advice if the fever persists.
The cause of Kawasaki Disease is unknown, and it remains a mystery to this day. There are no tests that definitively diagnose the condition, at least not in the early stages. Therefore, to make a diagnosis largely depends upon our clinical judgement or our intuition. Not everyone gets it right every time.
Recently Kawasaki Disease has come to the fore because some children with Covid-19 condition developed features that made some doctors wonder if they are dealing with a Kawasaki-like illness or something similar. The World Health Organisation has named this condition the "Multisystem Inflammatory Syndrome in Children (MIS-C)".
For this reason, it may be a good time to re-look at the criteria for the diagnosis and management of Kawasaki Disease.
KAWASAKI DISEASE
Classically Kawasaki Disease mainly affects children under 5 years of age. It is more common in Asians, Africans, and African-Americans, with an incidence of 1 in 150, compared to Caucasians, with an incidence of 1 in 1,000. Boys are affected more often than girls.
DIAGNOSIS OF KAWASAKI DISEASE
To make a diagnosis, there is fever lasting more than 5 days. The fever is usually quite high, hovering around 39C, and this is the commonest presenting symptom. It can persist for 1-2 weeks. The fever does not respond very well to paracetamol, but falls readily with intravenous immunoglobulin and aspirin treatment.
To make a diagnosis of Kawasaki Disease we need to find four of the following five symptoms and signs:
1. Conjunctivitis: red eyes. This comes on shortly after the onset of fever, and is the second most common symptom. It is neither itchy nor painful, and there is no discharge. Note that the redness tends not to go all the way up the the pupil, leaving a ring around the pupil which is relatively whiter.
2. Lymphadenopathy: swollen lymph nodes. Enlargement of the neck lymph nodes occur in 50-75% of patients. They are usually not painful, or only minimally painful.
3. Skin Rash: there is quite a widespread maculopapular skin rash without any vesicles or crusts, and it is not itchy, but the rash can be mistaken for measles.
4. Red lips and mouth: the lips can be red or cracked, and the tongue can be strawberry red. The red or cracked lips, and the strawberry tongue are often the signs that draw the clinician’s attention to the diagnosis of Kawasaki Disease.
5. Hands and feet: the palms and soles of the feet can be red, the fingers and toes can be swollen. The palms and soles are occasionally painful.
During the convalescent stage around 2-3 weeks after the onset of fever, there is peeling of the skin from the fingers and toes. The peeling usually start from the tips of the fingers and toes. Peeling can also be seen in other body areas, including the groin, abdomen and neck.
6. Coronary Artery Aneurysms: One of the cardinal features of Kawasaki Disease Is the dangerous complication of aneuryms of the coronary artery which can cause arrhythmias or a heart attack.
It is estimated that between 15-25% of patients with Kawasaki who have not received any treatment, may develop coronary artery aneurysms. If there are coronary artery aneurysms, then you need fewer than 4 out of the 5 diagnostic criteria (see table below) to diagnose Kawasaki Disease. Coronary artery aneurysms are the most serious complication of Kawasaki Disease because it can lead to myocardial infarction, and is the main cause of death.
In addition to the clinical features listed above, some children may have further symptoms, like abdominal pain, diarrhoea, cough and runny nose, headaches, and joint pains, which complicates matters, and makes the diagnosis even more difficult than it already is.
THE COURSE OF KAWASAKI DISEASE
The course of Kawasaki Disease can be divided into three phases.
1. Acute Phase (1-2 weeks)
This is the initial phase when the patient presents with prolonged fever, red eyes, enlarged lymph nodes, a skin rash, red lips and tongue, swollen fingers and toes. The heart may already start becoming involved with myocarditis.
2. Subacute Phase (2-7 weeks)
During this phase, the acute phase symptoms settle, and peeling of the skin appears around 2-3 weeks after the onset of fever.
3. Convalescent Phase (6-9 weeks)
All the symptoms resolve, and the erythrocytes sedimentation rate returns to normal. Lines may show up on the fingernails (Beau Lines), suggesting transient stopping of fingernail growth during the few months of Kawasaki Disease.
INVESTIGATIONS
Blood tests show a raised C-reactive protein and erythrocytes sedimentation rate. These normally go up during an inflammatory immune response. Coronary artery aneurysms and myocardial infarction are the most serious complications of Kawasaki Disease; therefore one should measure the cardiac enzymes, including troponin and the creatine kinase myocardial band (CK-MB). The liver enzymes may also be elevated.
An electrocardiogram (ECG) is also carried out to look for signs of myocarditis which can show up as ventricular dysfunction or arrhythmias.
The gold standard for diagnosing coronary artery aneurysm is coronary angiography, and it may be done using low radiation dose computer tomography (CT scan) or by cardiac catheterization.
TREATMENT OF KAWASAKI DISEASE
Medicines currently used for the treatment of Kawasaki Disease are:
1. Intravenous Immunoglobulin
It prevents the coronary aneurysm complication of Kawasaki Disease, reduces fever, and shortens the duration of hospital stay. This is the treatment of choice.
2. Aspirin
This reduces fever, and is usually given for 6-8 weeks. If there is coronary artery aneurysm, low-dose aspirin is given for life to prevent myocardial infarction, due to blood clotting inside the aneurysm.
3. Corticosteroids
A corticosteroid like methylprednisolone is given if intravenous immunoglobulins and aspirin are not effective. It is also used in severe Kawasaki Disease.
4. Infliximab
Infliximab is a chimeric monoclonal antibody which blocks the proinflammatory cytokine, tumour necrosis factor alpha. Originally it was developed for the treatment of autoimmune disease like Crohn's Disease and rheumatoid arthritis, and has now been added to intravenous immunoglobulin in the treatment of severe Kawasaki Disease. The results are promising and it reduces the formation of coronary artery aneurysms.
5. Anakinra
Another drug that is also proving promising, is anakinra, which blocks a cytokine (immune messenger) called interleukin 1 (IL-1). Anakinra is used for severe Kawasaki Disease where the patient goes into shock. The early trials of anakinra also show that it may help prevent the dilatation and the development of coronary artery aneurysms.
PROGNOSIS
Early treatment with intravenous immunoglobulins reduces the formation of coronary artery aneurysms, settles the fever, and helps resolve the other symptoms. Rarely there may be a relapse of Kawasaki Disease.
COVID-19 AND MULTISYSTEM INFLAMMATORY SYNDROME OF CHILDREN (MIS-C)
Although Covid-19 is relatively rare in children, there have been a few cases where the presentation is with fever and a skin rash resembling Kawasaki Disease, or some other inflammatory condition, such as the toxic shock syndrome. It is named Multisystem Inflammatory Syndrome of Children (MIS-C).
One of the first children to be diagnosed with a Kawasaki-like illness is a 6-month old girl from Stanford, California, who developed fever, skin rash, and hardly any respiratory symptoms. She tested positive for Covid-19. Her eyes showed mild conjunctivitis. Pictures of this girl have already been published (see below):
Her fingers were reddish and slightly swollen and her legs showed a maculopapular skin rash.
The USA and Europe have currently seen a total of over 100 children with a positive diagnosis of Covid-19 presenting with a multisystem inflammatory syndrome in children (MIS-C) suggestive of Kawasaki Disease. Below are some photographs of Covid-19 positive children with these clinical features, published in the news.
The age range of the Covid-19 children presenting with Kawasaki-like manifestations range from 2 to 17 years, which is a bit older than that seen in classical Kawasaki Disease. All had fever and the other symptoms (conjunctivitis, skin rash) started 2-4 days after the onset of fever, which is earlier than the 4-7 days for classical Kawasaki Disease. More than half the Covid-19 patients had skin rash, and more than half had abdominal pain, vomiting, diarrhoea and respiratory symptoms. These symptoms are also more frequent compared to classical Kawasaki Disease. The C-reactive protein, the erythrocyte sedimentation rate, and ferritin levels, are all raised. Some of the Covid-19 children suddenly collapsed due to systolic dysfunction of the left ventricle, and their troponin levels were elevated.
An 8-year old boy whose mother was tested positive Covid-19, was admitted to a London hospital. He had a fast heart an breathing rate. Initially he tested negative for SARS-CoV-2 but later, the antibody test became positive. Ultrasound of the heart showed a coronary aneurysm (see below), which suggests a diagnosis of Kawasaki Disease:
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TREATMENT
Multisystem Inflammatory Syndrome of Children (MIS-C) is a serious condition and hospital admission is recommended. Some children may need intensive care. Dexamethasone appears to be an effective treatment, but more research is needed.
QUESTIONS RAISED
Many questions are raised by the finding of Kawasaki-like symptoms in Covid-19 positive children. Is it really Kawasaki Disease or some other inflammatory disorder? What is the causal link? Why is this complication only found in children? To this day, we are unable to discover the aetiology of Kawasaki Disease; can this link throw new light onto an age-old mystery?
Because there are no definitive tests to confirm the diagnosis of Kawasaki Disease, it is possible that many cases have been missed or misdiagnosed. Is this also going to happen with Covid-19 cases?
Written by Kenneth Lyen
20 May 2020, revised 25 June 2020
REFERENCES
Kawasaki Disease Medscape: https://emedicine.medscape.com/article/965367-overview#showall
Kawasaki Disease Wikipedia: https://en.wikipedia.org/wiki/Kawasaki_disease
Royal College of Paediatrics and Child Health Guidelines on the management of Kawasaki Disease https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease (Cardiac manifestations):
https://www.ahajournals.org/doi/10.1161/01.cir.0000145143.19711.78
Kawasaki Disease from Covid-19 (Stanford, California):
https://www.medpagetoday.com/infectiousdisease/covid19/86393
Aude Lecrubier: COVID-19: How to Recognize and Manage Kawasaki-like Syndrome (France)
https://www.medscape.com/viewarticle/930203
Veena G Jones, Marcos Mills, MD; Dominique Suarez et al. Kawasaki and Covid-19 Disease (Palo Alto, California)
https://hosppeds.aappublications.org/content/early/2020/04/06/hpeds.2020-0123
Shlley Riphagen, et al: Hyperinflammatory shock in children during COVID-19 pandemic
https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31094-1.pdf
Lyen KR, Brook CGD. The mucocutaneous lymph node syndrome (Kawasaki Disease) in two siblings. British Medical Journal 1978; 1: 1187. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1604252/pdf/brmedj00124-0029a.pdf
Lyen Ken. Covid Storm (talk)