OVERVIEW
A specific type of Kawasaki disease in a group of patients whose clinical presentation does not fully meet the diagnostic criteria for Kawasaki disease
Patients usually present with fever typical of Kawasaki disease.
It is not fully recognized, but research suggests that it may be associated with infection by pathogens such as staphylococcus.
Treatment is primarily with oral or injectable medications, such as aspirin, immunoglobulins, and glucocorticoids
Definition
Kawasaki disease, also known as pediatric cutaneous mucocutaneous lymph node syndrome, is an acute febrile rash that occurs in infants and young children and involves the heart and blood vessels throughout the body, making it the leading cause of acquired heart disease in children.
Atypical Kawasaki disease is a condition in which a patient has a prolonged febrile behavior, but only some of the symptoms in the diagnostic criteria for Kawasaki disease are present in other clinical manifestations.
Typical symptoms include bulbar conjunctival congestion, diffuse oral mucosal congestion and strawberry tongue, erythema multiforme, enlarged cervical lymph nodes, and sclerosing edema of the hands and feet, and patients with atypical Kawasaki disease usually meet only two to three of these symptoms [1].
Incidence
Atypical Kawasaki disease is usually disseminated or in small epidemics, mostly in infants and young children under 5 years of age, and can occur in all seasons, with the incidence rate being higher in winter and spring than in other seasons, and the incidence rate being higher in male than in female infants and young children.
At present, there are fewer epidemiological studies on atypical Kawasaki disease in China, and some studies have shown that atypical Kawasaki disease in Shanghai accounted for about 35% of the total number of Kawasaki disease cases in 1998-2017, which is lower than the incidence in South Korea (32.8%-44.9% in 2009-2017) and higher than that in Japan (20.2%-20.2% in 2007-2016), and higher than the incidence in Japan (20.2%-20.2% in 2007-2016). -2016 was 20.2% to 22.2%) [2].
Etiology
Causes of the disease
The cause of Kawasaki disease has not been fully clarified, and some studies have shown that Kawasaki disease is often secondary to infections with various pathogens and is associated with autoimmune abnormalities, which mainly cause damage to the cardiovascular system in the body.
The causes of atypical Kawasaki disease are the same as those of Kawasaki disease. Common pathogens reported to cause Kawasaki disease include herpesvirus (EBV), hemolytic streptococcus, respiratory syncytial virus, Mycobacterium tuberculosis, Staphylococcus aureus, adenoviruses, Mycoplasma pneumoniae, influenza and parainfluenza viruses, cytomegalovirus, and Klebsiella pneumoniae, among others.
High risk factors
Infectious events: Infants and children with infectious diseases caused by the types of pathogens described above are at increased risk of developing Kawasaki disease.
Age: Kawasaki disease occurs most often in the infant and young child population, with a particularly high prevalence in infants and young children under 5 years of age.
Gender: Male infants and young children have a higher number of cases than female infants and young children.
Season and climate: Winter and spring, and climatic conditions with large temperature differences are more likely to make the body susceptible to infections, thus indirectly increasing the risk of atypical Kawasaki disease.
Genetic factors: relevant studies have shown that if parents and siblings have a history of Kawasaki disease, they have a significant genetic susceptibility to Kawasaki disease [3].
Pathogenesis
At present, the pathogenesis of atypical Kawasaki disease has not been completely studied, and some studies have hypothesized that its pathogenesis may be due to the abnormal activation of the body’s immune system by certain special superantigens produced by the pathogen, which leads to the occurrence of inflammatory diseases in small and medium-sized blood vessels throughout the body.
Superantigens are a class of bacterial products without major histocompatibility complexes (MHC) that can stimulate the body’s immune system to produce a strong immune response, such as staphylococcal enterotoxin-like toxins of food poisoning shock syndrome, epidermal exfoliative toxins, and thermogenic ectotoxins of streptococci.
Superantigens can induce the release of immune mediators such as interleukins IL-2, IL-6, tumor necrosis factor α (TNF-α), transforming growth factor β, etc. by binding to specific regions of the T-cell receptor, which further prompts the secretion of autoantibodies by B cells, such as anti-endothelial cell antibodies, anti-neutrophil cytoplasmic antibodies, and anticardiolipin antibodies, and causes the endothelial cells to lyse, leading to the development of systemic vasculitis [4].
Arterial inflammation leads to clinical manifestations of Kawasaki disease, such as fever, conjunctival and mucosal congestion, lymph node enlargement, etc. In severe cases, the lesions may involve the coronary arteries that supply blood to the heart, resulting in complications such as coronary artery aneurysm.
Symptoms
Major Symptoms
There are six main clinical symptoms of Kawasaki disease, which are typical of Kawasaki disease when they are fully compatible and atypical of Kawasaki disease when they are not.
Fever: Temperature can reach 39～40℃, which usually lasts for more than 5 days, and in severe cases, it can last for 7～14 days or longer. Fever is in the form of indolent or flaccid fever, which usually cannot be reduced with antibiotic treatment.
Bilateral conjunctival non-suppurative congestion: it appears on the 3rd to 4th day of illness, with congestion at the conjunctiva bilaterally, but without purulent secretion, and the conjunctival congestion naturally dissipates after the fever subsides.
Symptoms of oral mucosal congestion in the mouth and lip area: the skin around the mouth and lip area is dry and red, the lips are congested and cracked, the mucous membranes of the oral cavity and pharynx are diffusely congested, and the papillae of the tongue are protruding, congested, and presenting a strawberry tongue-like change (also known as prune tongue change) [5].
Symptoms of extremities: at the early stage of the disease, hard edema of hands and feet and erythema of palms and metatarsals can be seen; in the recovery period, membranous desquamation occurs at the junction between the nail and skin at the end of fingers (toes), and there can be transverse grooves on the finger (toenails), and the finger (toenails) may also be detached in the severe cases.
Polymorphic rash: the onset of the disease is most common in the trunk, manifesting as polymorphic erythema and scarlet fever-like rash, which often appears in the first week.
Cervical lymph node enlargement: unilateral or bilateral lymph nodes in the neck are enlarged non-purulent, not red, and may be tender on pressure.
Patients with atypical Kawasaki disease usually have fever, while only 2-3 or less of the other 5 items are fulfilled, so the rate of missed diagnosis and misdiagnosis in clinical diagnosis is high.
Other symptoms
Gastrointestinal symptoms: some children with the disease may have gastrointestinal symptoms such as abdominal pain, vomiting, diarrhea, paralytic intestinal obstruction, hepatomegaly, and jaundice at the onset of the disease.
Erythema at the BCG vaccination scar: If the child has received BCG vaccine before the onset of the disease, the erythema at the vaccination scar can be reproduced at the onset of the disease, which is important in the diagnosis of atypical Kawasaki disease.
Symptoms of infection: Some children develop with secondary symptoms of infection, such as interstitial pneumonia, aseptic meningitis, urethritis, otitis media, and so on.
Other symptoms: children are often irritable at the onset of the disease, occasionally with lethargy, some children may also have arthralgia, arthritis and other symptoms.
Complications
Complications of atypical Kawasaki disease mostly involve the heart, and common complications mainly include coronary artery lesions, heart valve disease and other cardiac complications.
Coronary artery lesions (CAL): the most common complication of atypical Kawasaki disease, which is the manifestation of vascular inflammatory injury involving coronary arteries, mainly including coronary artery dilatation and coronary artery aneurysm, often appearing 1-4 weeks after the onset of the disease, and in severe cases, it may cause heart failure or myocardial infarction [6, 7].
Heart valve disease: a condition in which the heart valves are narrowed or not closed properly due to inflammation or infection.
Other cardiac complications: Inflammatory diseases of the heart, such as myocarditis, pericarditis, endocarditis, etc., most often caused by inflammatory diseases of the blood vessels.
Consultation
Department of Medicine
You can choose cardiovascular medicine or pediatrics.
When a child develops shock or other critical symptoms, immediately call 120 to send the child to the emergency room for resuscitation.
Preparation
Consultation: Registration, Preparation of documents, Frequently Asked Questions
Tips for seeking medical treatment
When a child has a high fever that lasts for several days (more than three days) and antibiotic treatment is ineffective, consideration should be given to hospitalization to investigate the cause of the fever.
Early diagnosis and treatment of children with atypical Kawasaki disease is recommended to minimize the chance of serious complications such as coronary artery damage caused by vascular inflammation.
Preparation Checklist
Symptom checklist
Pay particular attention to the time of onset of symptoms and specific manifestations.
When did the fever start? What is the highest temperature?
Does the child have symptoms such as congestion of the skin and mucous membranes, skin erythema, rash, etc.?
Is the child irritable, lethargic, or otherwise abnormal?
Did the child have any other symptoms or discomfort before or after the fever?
Medical History Checklist
Has the child had any recent or previous infectious diseases?
Does the child have a history of cardiovascular disease or other immune system disorders?
Has the child had any recent vaccinations or medications?
Does the child have any previous allergies?
Does the child have a family history of Kawasaki disease?
Has the child been seen and treated for similar symptoms before? What treatments have been taken?
Checklist
Test results from the last 6 months, which can be brought to the doctor’s office
Recent blood test results
Electrocardiogram
Serum immunology results
X-ray chest radiograph or CT chest examination results
Other laboratory results: C-reactive protein, rheumatoid factor, antinuclear antibodies, etc.
Medication List
Medications used in the last 3 months, if available in boxes or packages, bring with you to the doctor’s office
Antibiotic drugs: penicillins, cephalosporins, etc.
Antiviral drugs: ribavirin, oseltamivir, etc.
Vaccine products: chickenpox vaccine, measles vaccine and other live virus vaccines, etc.
Anti-inflammatory drugs: aspirin, acetaminophen, ibuprofen, etc.
Other medications: any other types of medications recently used by the child, such as Western medications, Chinese medications, vitamins, supplements, etc., that are needed to treat other conditions.
Diagnosis
Diagnosis is based on
Medical history
The possibility of atypical Kawasaki disease should be considered in a child with prolonged hyperthermia and a history of infectious disease.
Clinical manifestations
The clinical criteria in the diagnosis of atypical Kawasaki disease are not obvious, the child meets the two to three clinical criteria described above, and other diseases that may cause similar symptoms are excluded, and the diagnosis of atypical Kawasaki disease can be confirmed by combining with coronary artery injury [8].
Routine physical examination
Mainly through observation, palpation, auscultation and other means to initially determine whether the symptomatic manifestations of the child are consistent with the characteristics of atypical Kawasaki disease, such as observing whether the skin and mucous membranes are congested, whether there is a rash or erythema, and other inspection methods.
Blood tests
Routine blood tests: Routine blood tests with elevated white blood cell counts may indicate inflammation. Mild anemia and thrombocytosis are also associated with Kawasaki disease, and the presence of such results should be considered as a possible cause of atypical Kawasaki disease.
Immunological serum examination: if the child has Kawasaki disease, the serum IgG, IgM, IgA, IgE and circulating immune complexes will be significantly elevated; TH2 cytokines, such as IL-6, will be significantly elevated, and total complement and C3 will be normal or elevated.
Other blood tests: Erythrocyte sedimentation rate, platelets, and C-reactive protein are elevated risk factors for coronary artery disease in young children, and further tests should be considered to clarify the cause when the test results are abnormal.
Other laboratory tests
Mainly used to exclude other diseases that may cause similar symptoms, such as antinuclear antibodies, rheumatoid factor, etc. If the results are negative, other diseases can be excluded and further diagnosis of atypical Kawasaki disease can be considered [9].
Imaging
Echocardiography: it is a diagnostic imaging technique that utilizes the physical properties of ultrasound to observe the morphology and structure of the heart and great vessels, their functional status and hemodynamics, and it is also the most important auxiliary examination for atypical Kawasaki disease. It can directly observe the damage and degree of lesions of coronary arteries in atypical Kawasaki disease, which is important for confirming the diagnosis and guiding the follow-up treatment of atypical Kawasaki disease [10-11].
Other imaging examinations: supplementary examinations for specific situations, such as coronary angiography to guide the treatment of patients with multiple coronary aneurysms, and multilayer spiral CT to further detect lesions in patients with coronary artery stenosis.
Electrocardiogram
Electrocardiogram (ECG) is mainly used to determine the disease process and complications. Patients with atypical Kawasaki disease may have non-specific ST-T changes in the early stage of ECG.
If there is pericarditis, the electrocardiogram may show extensive ST-segment elevation and low voltage.
When there is myocardial infarction, there are ST-segment elevation, T-wave inversion and abnormal Q-wave.
Differential diagnosis
Since there is no gold standard for the diagnosis of atypical Kawasaki disease, it is necessary to exclude a variety of diseases that can cause similar symptoms in order to confirm the diagnosis of atypical Kawasaki disease, and the following is a list of several diseases with similar symptoms.
Erythema multiforme
An acute inflammatory skin disease characterized by target-shaped or iridescent erythema, often with mucosal lesions.
The mucosal lesions of the disease may involve the eyes, mouth, and external genitalia; there may be purulent discharge formation from the eyes and lips, purulent conjunctivitis, and a rash with oozing herpes and ulcers, whereas atypical Kawasaki disease has none of these features.
Scarlet fever
Scarlet fever is an acute infectious disease caused by hemolytic streptococcus type B. Patients may also present with fever, rash, and prune tongue, but its onset is at an older age, and there is often a history of contact with the disease. There is no conjunctival congestion and no end-of-limbs manifestations typical of patients with Kawasaki disease, and the combination of a positive culture of throat swabs for group A streptococci can be used for differential diagnosis.
Sepsis
Sepsis is a life-threatening organ dysfunction caused by dysregulation of the body’s response to infection, characterized by fever, rash, increased total number of peripheral blood leukocytes with neutrophils predominating, etc. It is the same as that of atypical Kawasaki disease, but patients with sepsis do not have the typical symptoms of Kawasaki disease at the ends of the limbs, and there is no damage to the coronary arteries in imaging examinations, and the treatment of antibiotics is effective, which can be used for differentiation and differential diagnosis.
Juvenile rheumatoid arthritis
Patients younger than 16 years of age present with arthritis that lasts more than 6 weeks and is localized to one or more joints. The disease also presents with persistent fever, rash, and symptoms of enlarged superficial lymph nodes, accompanied by an elevated peripheral blood leukocyte count and ineffective antibiotics.
However, the disease has a relatively long course, there are no signs of Kawasaki disease such as conjunctival congestion, chapped lips, strawberry tongue, and no coronary artery damage on echocardiography, and immunologic tests may be positive for serum rheumatoid factor, but overall it is more difficult to differentiate from atypical Kawasaki disease.
Treatment
Aims of treatment: temperature control, pharmacologic anti-inflammation, thromboprophylaxis, prevention of cardiovascular damage, especially coronary artery damage.
Treatment principles: Early treatment to reduce the burden and damage to the cardiovascular system caused by prolonged morbidity and to reduce the risk of cardiac complications.
Drug therapy
Immunoglobulin
One of the main treatment modalities for patients with atypical Kawasaki disease, once the diagnosis is confirmed, intravenous high-dose immunoglobulin should be used as soon as possible to reduce vascular inflammation and achieve the goal of reducing fever as soon as possible, reducing the risk of coronary artery damage.
Aspirin
Aspirin is one of the main therapeutic options for patients with atypical Kawasaki disease. It is used to relieve pain, reduce fever, and treat inflammation, and should be continued for a period of time after the symptoms have subsided in order to achieve an antithrombotic effect. It should be noted that aspirin in children may lead to Reye’s syndrome, should be strictly under the guidance of a medical professional to take medication, not to change the medication program on their own.
Glucocorticoids
Glucocorticosteroids are indicated for children who are not responding to immunoglobulin therapy or who are at risk of immunoglobulin resistance, usually in combination with aspirin and dipyridamole. Glucocorticosteroids must be used in strict compliance with medical advice because they promote thrombosis and increase the risk of coronary artery disease and coronary artery aneurysms.
Other treatments
Symptomatic treatment
Symptomatic and supportive therapies, such as fluid supplementation, control of heart failure, and correction of arrhythmias, should be given according to the course of the disease and specific symptoms in the clinic, and should be carried out in a timely manner when myocardial infarction is present in the child.
Surgery
Coronary artery bypass grafting can be used as a therapeutic measure for children with severe coronary artery disease that affects the blood supply to the heart.
Prognosis
Cure
Kawasaki disease is a self-limiting disease with a favorable prognosis. The recurrence rate is about 1% to 2%. Children without coronary artery disease are usually cured at 1, 3, 6 months, and 1 to 2 years after discharge from the hospital, and no recurrence is recognized.
Atypical Kawasaki disease, due to the high rate of misdiagnosis and underdiagnosis, usually starts treatment later, has a relatively high risk of developing coronary artery lesions, and functional abnormalities, such as wall thickening and reduced elasticity, are often left behind after recovery from coronary artery lesions. Children should be followed closely for a long period of time after discharge from the hospital, every 6 to 12 months to prevent complications in advance.
Prognostic factors
Timing of consultation: Early treatment can minimize the damage of inflammation to the blood vessels and better protect the cardiovascular system of the child, and the earlier the treatment, the better the prognosis.
Coronary artery damage: Children without coronary artery disease usually have a better prognosis, while children with coronary artery involvement usually have a worse prognosis.
Daily
Daily Management
Dietary management
Maintain a light diet during treatment, and try to choose easy-to-digest liquid or semi-liquid food.
Avoid spicy and meaty diets during medication, and avoid contraindicated diets in strict accordance with the doctor’s prescription and medication instructions.
Life management
Children should avoid strenuous exercise and maintain sufficient sleep during treatment.
If there are skin injuries such as rashes, erythema, etc., choose clean and soft clothes to reduce the pain caused by skin friction.
Children should live in a clean and hygienic environment, and open windows regularly for ventilation.
Prevention
Pay attention to nutritional intake and physical exercise to strengthen immunity, and actively prevent the increased risk of atypical Kawasaki disease caused by various pathogens.
Regular follow-ups and regular medication should be taken to prevent recurrence of atypical Kawasaki disease [12].