bubble_chart Overview

Mucocutaneous lymph node syndrome (MCLS), also known as Kawasaki disease, is an acute febrile eruptive pediatric disease primarily characterized by systemic vasculitis. It was first reported in 1967 by Japanese physician Tomisaku Kawasaki. Due to its potential to cause severe cardiovascular complications, this condition has garnered significant attention, with increasing incidence in recent years. In 1990, Beijing Children's Hospital recorded 67 cases of Kawasaki disease among hospitalized patients with rheumatic diseases, compared to 27 cases of rheumatic fever. Data from 11 hospitals in other provinces showed Kawasaki disease cases were twice as many as rheumatic fever cases. Clearly, Kawasaki disease has replaced rheumatic fever as one of the leading causes of acquired heart disease in Chinese children. Currently, Kawasaki disease is considered an immune-mediated vasculitis and is temporarily classified under connective tissue disorders.

bubble_chart Epidemiology

This disease can affect both infants and children, but 80–85% of patients are under 5 years old, with a peak incidence in infants aged 6–18 months. Boys are more commonly affected, with a male-to-female ratio of 1.3–1.5:1. There is no distinct seasonal pattern, though some suggest a higher incidence in summer. By 1990, Japan had reported approximately 100,000 cases of Kawasaki disease, with three epidemics occurring in 1979, 1982, and 1986. During these outbreaks, the incidence rate among children under 4 years old was 172–194 per 100,000. Although fewer cases have been reported worldwide compared to Japan, the disease has been documented in countries ranging from Sweden, the Netherlands, the United States, Canada, the United Kingdom, and South Korea in the north to Greece, Australia, and Singapore in the south. In China, the first few cases were reported in 1978 in Beijing, Shanghai, Hangzhou, Chengdu, and Taiwan. By 1989, the *Journal of Practical Pediatrics* had compiled 220 cases from across the country. A nationwide survey of major children’s hospitals and affiliated medical colleges from 1983 to 1986 recorded 965 hospitalized cases. A second survey from 1987 to 1991 showed an increase to 1,969 hospitalized cases, with an upward trend each year. Among these cases, 78.1% were under 4 years old, with a male-to-female ratio of 1.6:1. In the United States, cases are more prevalent among individuals of Japanese descent. Reports from Japan indicate a 1–2% incidence among siblings, suggesting a genetic predisposition.

bubble_chart Etiology

The cause of the disease remains unclear. This condition exhibits certain epidemic and geographic characteristics, with clinical manifestations such as fever and rash, suggesting an association with infection. It is generally believed to be potentially caused by multiple pathogens, including Epstein-Barr virus, retroviruses, or infections by streptococcus and propionibacterium. In 1986, it was reported that the supernatant of peripheral blood lymphocyte cultures from patients showed increased reverse transcriptase activity, indicating that the disease might be caused by a retrovirus. However, most studies have not yielded consistent results. Previous hypotheses also proposed mycoplasma, rickettsia, or dust mites as causative agents, but these have not been confirmed. Some also consider environmental pollution or chemical allergies as possible pathogenic factors.

bubble_chart Pathogenesis

Recent studies indicate that during the acute phase of this disease, there is significant immune dysregulation, which plays an important role in the pathogenesis. In the acute phase, an imbalance in peripheral blood T-cell subsets is observed, with an increase in CD4, a decrease in CD8, and an elevated CD4/CD8 ratio. These changes are most pronounced 3–5 weeks after onset and normalize by the 8th week. The increased CD4/CD8 ratio activates the immune system, leading to heightened secretion of lymphokines by CD4 cells. This promotes polyclonal activation, proliferation, and differentiation of B cells into plasma cells, resulting in elevated serum levels of IgM, IgA, IgG, and IgE. Activated T cells also secrete high concentrations of interleukins (IL-1, 4, 5, 6), gamma-interferon (IFN-γ), and tumor necrosis factor (TNF). These lymphokines and cytokines can induce endothelial cells to express and produce new antigens while also stimulating B cells to secrete autoantibodies, leading to endothelial cytotoxicity and vascular injury, thereby causing vasculitis. Elevated levels of IL-11, IL-6, and TNF can further induce hepatocytes to synthesize acute-phase proteins such as C-reactive protein, α1-antitrypsin, and haptoglobin, contributing to the acute febrile response in this disease. Patients with this condition exhibit increased circulating immune complexes (CIC), detectable in 50–70% of cases as early as the first week of illness, peaking at weeks 3–4. The exact mechanism of CIC in this disease remains unclear. However, unlike typical immune complex diseases, no immune complex deposition is found at the lesion sites, and serum C3 levels do not decrease but rather increase. The trigger for this immune dysregulation is unknown. Currently, Kawasaki disease is widely regarded as an immune-mediated systemic vasculitis triggered by multiple infectious agents in genetically susceptible hosts.

bubble_chart Pathological Changes

According to the summary of 217 fatal cases by the Japanese MCLS Research Committee in 1990, the pathological morphology of this disease's vasculitis can be divided into four stages:

**Stage I**: Approximately 1–2 weeks, characterized by:

1. Inflammation of small arteries, small veins, microvessels, and their surrounding tissues;
2. Inflammation of medium and large arteries and their surrounding tissues;
3. Infiltration of lymphocytes and other white blood cells, along with localized edema.

**Stage II**: Approximately 2–4 weeks, characterized by:

1. Reduced inflammation in small blood vessels;
2. Predominance of inflammation in medium arteries, often with coronary artery aneurysms and thrombosis;
3. Rare vascular inflammation in large arteries;
4. Prominent mononuclear cell infiltration or necrotic changes.

**Stage III**: Approximately 4–7 weeks, characterized by:

1. Subsidence of small vessel and microvascular inflammation;
2. Formation of granulomas in medium arteries.

**Stage IV**: Approximately 7 weeks or longer, where acute vascular inflammation mostly disappears, replaced by thrombosis, obstruction, intimal thickening leading to aneurysms, and scar formation in medium arteries. Regarding the distribution of arterial lesions, they can be divided into:

1. Extrinsic medium or large arteries, often involving coronary, axillary, iliac arteries, and other arteries in the neck, chest, and abdomen;
2. Intrinsic arteries, affecting organs such as the heart, kidneys, lungs, gastrointestinal tract, skin, liver, spleen, gonads, salivary glands, and brain.

Beyond vasculitis, the pathology also involves multiple organs, with interstitial myocarditis, pericarditis, and endocarditis being the most prominent, potentially affecting the conduction system and often leading to death during Stage I. In Stages II and IV, ischemic heart disease is common, and myocardial infarction can be fatal. Additionally, aneurysm rupture and myocarditis are significant causes of death in Stages II and III.

The vascular pathology of MCLS closely resembles that of infantile polyarteritis nodosa. Apart from coronary or pulmonary artery aneurysms and thrombosis, changes are also observed in the intima of the aorta, ileal arteries, or pulmonary arteries. Fluorescent antibody tests reveal immunoglobulin IgG deposits in the arterial walls of the heart, spleen, and lymph nodes. Vasculitis may occur in cervical lymph nodes and skin, accompanied by small vessel fibrinoid necrosis. Other findings include severe thymic atrophy, increased heart weight, hypertrophic dilation of the ventricles, grade I fatty liver degeneration, lymph node congestion, and follicular hyperplasia. However, the glomeruli show no significant lesions.

The differences between this disease and classic polyarteritis nodosa (Kussmaul-Maier type) are as follows:

1. The latter exhibits marked fibrinoid necrosis in vasculitis, whereas MCLS rarely shows such necrotic changes or only mild ones;
2. Classic polyarteritis nodosa rarely involves pulmonary arteries.

bubble_chart Clinical Manifestations

Main symptoms

Common persistent fever lasting 5–11 days or longer (2 weeks to 1 month), with body temperature often reaching above 39°C, unresponsive to antibiotic treatment. Bilateral conjunctival congestion is common, along with reddened lips, rhagades or bleeding, and a strawberry-like tongue. Hard edema appears in the hands, with early erythema on the palms and soles, followed by characteristic large-scale peeling of the fingertips after 10 days, occurring at the junction of the nail bed and skin. Acute non-suppurative transient cervical lymphadenopathy is also present, most prominent in the anterior neck, with a diameter of about 1.5 cm or more, mostly unilateral, slightly tender, occurring within 3 days of fever, and resolving spontaneously after a few days. Shortly after the onset of fever (approximately 1–4 days), maculopapular or polymorphous erythema-like rashes appear, occasionally miliaria-like rashes, mostly on the trunk, without vesicles or crusts, and typically resolve within about a week.

Other symptoms

Cardiac involvement often occurs, manifesting as symptoms of myocarditis, pericarditis, and endocarditis. The patient's pulse accelerates, and auscultation may reveal tachycardia, gallop rhythm, and muffled heart sounds. Systolic murmurs are also relatively common. Valvular insufficiency and heart failure may develop. Echocardiography and coronary angiography can detect coronary artery aneurysms, pericardial effusion, left ventricular enlargement, and mitral regurgitation in most patients. Chest X-rays may show cardiomegaly. Occasionally, joint pain or swelling, cough, runny nose, abdominal pain, grade I jaundice, or manifestations of aseptic meningoencephalitis may occur. In the acute phase, about 20% of cases exhibit perineal and perianal skin erythema and desquamation, with reappearance of erythema or crusting at the site of previous BCG vaccination 1–3 years prior. During the convalescent stage, transverse grooves of varying lengths may appear on the nails.

The initial stage [first stage] of the disease course is the acute febrile phase, generally lasting 1–11 days, during which the main symptoms appear sequentially after fever onset, and severe myocarditis may occur. The intermediate stage [second stage] is the subacute phase, typically spanning days 11–21 of the illness, where most patients experience a decline in fever and symptom relief, with membranous desquamation of the fingertips. Severe cases may still have persistent fever. Coronary artery aneurysms may develop, leading to myocardial infarction or aneurysm rupture. Most patients enter the late stage [third stage], or convalescent stage, by the 4th week, generally lasting from days 21–60, during which clinical symptoms subside. If no significant coronary artery lesions are present, gradual recovery occurs; however, if coronary artery aneurysms exist, they may continue to progress, potentially resulting in myocardial infarction or ischemic heart disease. A small number of patients with severe coronary artery aneurysms enter a chronic phase, which may persist for years, leaving behind coronary artery stenosis, cardiac colic, cardiac insufficiency, or ischemic heart disease, and may be life-threatening due to myocardial infarction.

bubble_chart Treatment Measures

Acute phase treatment

1. Gamma globulin: Recent studies have confirmed that early intravenous administration of gamma globulin combined with oral aspirin can reduce the incidence of coronary artery aneurysms in Kawasaki disease. It is crucial to administer the treatment within 10 days of onset. The regimen involves intravenous infusion of gamma globulin at 400 mg/kg per day, administered over 2–4 hours for four consecutive days, along with oral aspirin at 50–100 mg/kg per day, divided into 3–4 doses, for four days. Afterward, the aspirin dose is reduced to 5 mg/kg per day, administered at draught.
2. Aspirin: Early oral aspirin can control the acute inflammatory process and mitigate coronary artery lesions, but no controlled studies have demonstrated that aspirin reduces the incidence of coronary artery aneurysms. The dosage is 30–100 mg/kg per day, divided into 3–4 doses. Japanese physicians tend to use lower doses, based on the observation that patients in the acute phase of Kawasaki disease exhibit reduced absorption and increased clearance of aspirin, necessitating higher doses to achieve anti-inflammatory effects. After 14 days, once fever subsides, the dose is reduced to 3–5 mg/kg per day, administered once at draught, to exert an antiplatelet aggregation effect.
3. Corticosteroids: Adrenal corticosteroids have long been recognized for their potent anti-inflammatory effects and symptom relief. However, subsequent findings indicate that corticosteroids increase the risk of thrombosis, impede the repair of coronary artery lesions, and promote aneurysm formation. Therefore, corticosteroids like prednisone should not be used alone. They may be combined with aspirin in severe cases complicated by myocarditis or persistent high fever, but corticosteroids are generally not recommended as monotherapy for controlling early inflammatory responses in Kawasaki disease.

Treatment during the convalescent stage and follow-up

1. Anticoagulation therapy: During the convalescent stage, aspirin is administered at 3–5 mg/kg per day in a single dose until erythrocyte sedimentation rate and platelet counts normalize. If no coronary artery abnormalities are detected, treatment is usually discontinued 6–8 weeks after onset. Follow-up echocardiography is recommended at 6 months and 1 year. Patients with chronic coronary artery lesions require long-term anticoagulation and close monitoring. Those with small, solitary coronary artery aneurysms should continue aspirin at 3–5 mg/kg per day until the aneurysm resolves. For patients intolerant to aspirin, dipyridamole may be used at 3–6 mg/kg per day, divided into 2–3 doses. Annual cardiac evaluations, including echocardiography, clinical data, or exercise testing, are advised. If myocardial ischemia is suspected, coronary angiography should be performed. Patients with multiple or large coronary aneurysms should receive long-term aspirin and dipyridamole. Those with giant aneurysms are at high risk for thrombosis, stenosis, or occlusion and may require oral warfarin. These patients should avoid strenuous activities and undergo cardiac evaluations every 3–6 months. If ischemia or positive exercise tests are observed, coronary angiography is warranted to assess disease progression. Patients with occlusion of one or more major coronary arteries require long-term anticoagulation, regular cardiac evaluations (including myocardial scans, exercise tests, and angiography), and consideration of surgical intervention.
2. Thrombolytic therapy: For patients with myocardial infarction or thrombosis, intravenous or catheter-based intracoronary thrombolysis is performed to restore coronary patency and myocardial perfusion. Intravenous thrombolysis involves administering urokinase at 20,000 U/kg over 1 hour, followed by 3,000–4,000 U/kg per hour. Intracoronary administration involves 1,000 U/kg of urokinase over 1 hour. Streptokinase may also be used, with an initial intravenous dose of 10,000 U/kg over 1 hour, repeatable after 30 minutes. These agents rapidly dissolve fibrin with good efficacy and minimal adverse effects.
3. Coronary angioplasty: In recent years, balloon catheter dilation for coronary artery stenosis has been successfully applied.
4. Surgical treatment: The indications for coronary artery bypass grafting are:
   1. Severe occlusion of the left main trunk;
   2. Multiple branches with severe occlusion;
   3. Severe occlusion of the proximal left anterior descending artery. For cases of severe mitral regurgitation where medical treatment is ineffective, mitral valve repair or mitral valve replacement can be performed. A Japanese study reported 62 Kawasaki disease patients who underwent coronary artery bypass grafting, among whom 7 also underwent mitral valve surgery. Preoperatively, 70% of patients experienced angina, heart failure, or other symptoms. The 4-year survival rate post-surgery was 87%, and the 10-year survival rate was 45%, with most deaths attributed to late-stage [third-stage] myocardial infarction or sudden death.

In cases of cardiogenic shock, heart failure, or arrhythmia, appropriate treatment should be administered.

bubble_chart Complications

Due to the pathological changes in the heart blood vessels, which are both symptoms of the disease itself and potentially fatal complications, this section will detail their progression to facilitate early detection and timely appropriate treatment.

1. Coronary artery lesions: According to observations of 1,009 cases of Kawasaki disease in Japan, transient coronary artery dilation accounted for 46%, and coronary artery aneurysms accounted for 21%. Two-dimensional echocardiography revealed that coronary artery dilation could appear as early as the third day of illness, with most cases resolving within 3 to 6 months. Coronary artery aneurysms could be detected by the sixth day of illness, with the highest detection rate occurring in the second to third weeks. New lesions rarely appeared after the fourth week. The incidence of coronary artery aneurysms was 15–30%, and the presence of clinical myocarditis did not predict coronary artery involvement. Some well-established risk factors associated with coronary artery aneurysms included age under 1 year, male gender, persistent fever exceeding 14 days, anemia, total white blood cell count above 30×10⁹/L, erythrocyte sedimentation rate over 100 mm/h, significantly elevated C-reactive protein, reduced plasma albumin, and the presence of systemic artery aneurysms. Most coronary artery aneurysms followed a self-limiting course, with the majority resolving spontaneously within 1 to 2 years.
   The coronary artery lesions in this disease most commonly affected the proximal main trunk and the left anterior descending branch, followed by the left circumflex branch. Isolated distal artery aneurysms were rare. The severity of coronary artery lesions is generally classified into four grades:
   1. Normal (Grade 0): No dilation of the coronary artery.
   2. Grade I: Localized aneurysmal dilation with an internal diameter <4 mm.
   3. Grade II: Single, multiple, or extensive aneurysms with an internal diameter of 4–7 mm.
   4. Grade III: Giant aneurysms with an internal diameter ≥8 mm, often extensive and involving more than one branch. The incidence was approximately 5%, with a poor prognosis.
   Therefore, patients with coronary artery lesions should undergo close follow-up and regular echocardiographic examinations. Typically, examinations should be performed weekly within the first 4 weeks of illness, then at 2 months and 6 months, followed by at least annual examinations based on the severity of the lesions. Symptomatic patients and those with severe coronary artery involvement should undergo coronary angiography. Angiography can accurately assess the degree of coronary artery stenosis, occlusion, and distal lesions. Transient myocardial ischemia, ventricular fibrillation, and other severe complications may occur due to distal vessel occlusion. Indications for coronary angiography include:
   1. Symptoms of myocardial ischemia.
   2. Persistent cardiac valve lesions.
   3. X-ray showing coronary artery calcification.
   4. Echocardiography revealing persistent coronary artery aneurysms.
2. Gallbladder hydrops: Most commonly occurs during the subacute phase and may present with severe abdominal pain, abdominal distension and fullness, and jaundice. A mass may be palpable in the right upper abdomen, and abdominal ultrasound can confirm the diagnosis. Most cases resolve spontaneously, though paralytic ileus or intestinal bleeding may rarely occur.
3. Arthritis or arthralgia: Occurs during the acute or subacute phase, affecting joints of any size, seen in approximately 20% of cases, and resolves as the condition improves.
4. Changes in the nervous system: The acute phase includes aseptic meningoencephalitis, facial nerve palsy, hearing loss, acute encephalopathy, and febrile seizures, among others, caused by vasculitis. These are clinically common, recover quickly, and have a good prognosis. Among them, aseptic meningoencephalitis is the most frequent, with an incidence of about 25%. It mostly occurs within the first 2 weeks of illness. Some children experience increased intracranial pressure, manifesting as bulging fontanelles. A few children exhibit neck stiffness and may have drowsiness, fixed gaze, unconsciousness, or other consciousness disturbances. Cerebrospinal fluid shows grade I lymphocytosis, with normal glucose and chloride levels, and protein levels are mostly normal. Clinical symptoms usually disappear within a few days. Facial nerve palsy is more common in severe cases, often presenting as peripheral palsy, possibly due to vasculitis affecting the facial nerve or adjacent vascular lesions, such as aneurysm formation or arterial dilation, leading to transient compression of the facial nerve. During the convalescence stage, limb paralysis caused by stenosis or occlusion of the middle cerebral artery may result in sequelae, though this is relatively rare.
5. Other complications: Pulmonary vasculitis may show increased lung markings or patchy shadows on chest X-rays, with occasional pulmonary infarction. During the acute phase, urethritis may occur, and urine sediment may reveal increased white blood cells and grade I proteinuria. Iridocyclitis is relatively rare. Approximately 2% of patients develop aneurysms, most commonly in the axillary and iliac arteries. Digital gangrene is occasionally observed.

bubble_chart Differentiation

It should be differentiated from various eruptive pestilence diseases, viral infections, acute lymphadenitis, Bi disease, and other connective tissue diseases, viral myocarditis, and wind-dampness inflammatory carditis.

The differences between this condition and scarlet fever are:

1. The rash begins on the third day after the onset of the disease;
2. The rash morphology resembles measles and erythema multiforme;
3. The susceptible age is infancy and early childhood;
4. Penicillin is ineffective.

The differences between this condition and juvenile Bi disease are:

1. The fever period is shorter, and the rash is more transient;
2. Hard swelling of the hands and feet, often showing metatarsal flushing;
3. Rheumatoid factor is negative.

The differences from exudative erythema multiforme are:

1. No purulent secretions or pseudomembrane formation in the eyes and lips;
2. The rash does not include blisters or crusts.

The differences from systemic lupus erythematosus are:

1. The rash is not prominent on the face;
2. Total white blood cell count and platelets are generally elevated;
3. Antinuclear antibodies are negative.
4. The susceptible age is infancy, and it is more common in boys.

There are many similarities with infantile nodular polyarteritis-like symptoms, but MCLS has a higher incidence, shorter course, and better prognosis. The relationship between these two diseases remains to be studied.

The differences from eruptive sexually transmitted viral infections are:

1. Lip flushing, cracking, bleeding, and Chinese wax myrtle bark tongue;
2. Hard swelling of the hands and feet, often metatarsal flushing, and late-stage [third stage] membranous desquamation of the fingertips and toes;
3. No edema or secretions in the conjunctiva;
4. Total white blood cell count and granulocyte percentage are both elevated, with a left shift;
5. Both ESR and C-reactive protein are significantly elevated.

The differences from acute lymphadenitis are:

1. Cervical lymph node swelling and tenderness are milder, with no local skin or subcutaneous tissue redness or swelling;
2. No suppurative lesions.

The differences from viral myocarditis are:

1. Prominent coronary artery lesions;
2. Characteristic changes in the hands and feet;
3. Persistent high fever.

The differences from wind-dampness carditis are:

1. Prominent coronary artery lesions;
2. No significant heart murmurs;
3. The primary affected age group is infants and young children.