【Overview】.
Mucocutaneous lymph node syndrome (muco-cuta-meous lymph node syndrome, MCLS), also known as Kawasaki disease (Kawasaki diseaes), is an acute febrile exanthematous pediatric disease with systemic vasculitis as the main pathology. was first reported by Dr. Tomisaku Kawasaki in Japan in 1967. Because this disease can occur serious cardiovascular pathology, attracting attention, the incidence of increased in recent years, in 1990 Beijing Children’s Hospital rheumatic diseases inpatient cases, Kawasaki disease 67 cases, rheumatic fever 27 cases; 11 hospitals in foreign provinces and cities the same information, Kawasaki disease for the rheumatic 2 parts. Apparently Kawasaki disease has replaced rheumatic fever as one of the main causes of pediatric acquired heart disease in China. At present, Kawasaki disease is considered to be a kind of immune-mediated vasculitis, temporarily coded within the connective tissue diseases chapter.
[Diagnosis
The Japanese MCLS Research Committee (1984) proposed that the diagnostic criteria for this disease should be determined by meeting at least five of the following six major clinical symptoms.
① Fever of unknown origin lasting 5 days or more;
(ii) Bilateral conjunctival congestion;
③ diffuse congestion of the mucous membrane of the mouth and pharynx, red and dry lips, and a prune tongue;
(④The early onset of hand and foot hard swelling and palmoplantar redness, as well as the recovery of S finger and toe end of membranous peeling;
⑤ erythema multiforme on the trunk without blistering and crusting;
⑥Non-suppurative swelling of the cervical lymph nodes, which are 1.5 cm in diameter or larger. However, if a coronary artery aneurysm or dilatation is detected by two-dimensional echocardiography or coronary angiography, a positive diagnosis is confirmed by four major symptoms.
In recent years, an increase in incomplete or atypical cases has been reported in about 10% to 20% of cases. There are only 2 to 3 major symptoms but typical coronary artery lesions. It occurs mostly in infants. The incidence of coronary aneurysms is similar in typical and atypical cases. Once Kawasaki disease is suspected, echocardiography should be done as soon as possible.
【Treatment measures
Acute phase treatment
Recent studies have confirmed that early treatment with intravenous gammaglobulin plus oral aspirin can reduce the incidence of coronary artery aneurysms in Kawasaki disease. Emphasis must be placed on administering the drug within 10 days of onset. The method is to administer 400mg/kg of gammaglobulin intravenously daily for 2-4 hours for 4 days, and 50-100mg/kg/d of oral aspirin in 3-4 doses for 4 days, and then 5mg/kg/d in intervals.
2.Aspirin Early oral aspirin can control the acute inflammatory process and reduce coronary artery lesions, but there is no controlled study to show that aspirin treatment can reduce the incidence of coronary aneurysm. The dose is 30-100 mg/kg per day, divided into 3-4 doses. Japanese physicians prefer to use small doses, based on the belief that aspirin absorption is reduced and clearance is increased in patients with acute Kawasaki disease, and that the anti-inflammatory effect can be achieved with large doses. After 14 days of use, the fever subsides and is reduced to 3-5mg/kg per day, with a single dose to achieve the anti-platelet aggregation effect.
3, corticosteroids It has always been believed that adrenocorticosteroids have strong anti-inflammatory effects and can relieve symptoms, but later it was found that corticosteroids are prone to thrombosis, and prevent coronary artery lesion repair and promote aneurysm formation, so corticosteroids such as prednisone alone should not be used for treatment. Unless complicated by severe myocarditis or persistent hyperthermia in severe cases, prednisone and aspirin may be used in combination. Corticosteroids alone are generally not used to control the early inflammatory response in Kawasaki disease.
Treatment and follow-up in the recovery period
1.Anticoagulant therapy In recovery cases, aspirin is used 3-5mg/kg daily, once until the blood sedimentation and platelets return to normal, and if there is no coronary artery abnormality, the drug is usually stopped 6-8 weeks after the onset of the disease. Thereafter, echocardiography was repeated at 6 months and 1 year. For patients with chronic phase of residual coronary artery, long-term anticoagulant medication and close follow-up are required. Patients with small solitary coronary artery aneurysms should be given long-term aspirin 3-5 mg/kg・d until the aneurysm subsides. For those who are intolerant to aspirin, use Pansentine 3-6mg/kg/day in 2-3 doses. Annual heart condition. If echocardiography, clinical data or exercise test suggest myocardial ischemia, coronary angiography should be done. Patients with multiple or large coronary aneurysms should have long-term oral angiography.
Patients with multiple or large coronary artery aneurysms should take oral aspirin and pentoxifylline for a long time. Patients with giant aneurysms are prone to thrombosis, coronary artery stenosis or occlusion and may be treated with oral Favarine anticoagulants. These patients should limit their activities and not participate in sports. The heart should be checked every 3 to 6 months. If there are signs of myocardial ischemia or a positive exercise test, a coronary angiogram should be performed to understand the progression of the stenotic lesion. Patients with occlusion of one or more major coronary arteries should receive long-term anticoagulation therapy, repeatedly check the heart condition including myocardial scan, exercise test, coronary angiography, etc., and consider surgical treatment.
2.Thrombolytic therapy Patients with heart infarction and thrombosis are given intracoronary drugs by intravenous or catheter percutaneous puncture to promote coronary revascularization and myocardial reperfusion. Urokinase is administered within 1 hour of intravenous thrombolysis at 20,000u/kg, followed by 3000-4000u/kg per hour. Streptokinase can also be used. 10,000 u/kg of streptokinase can be administered within 1 hour of intravenous thrombolysis, followed by another dose half an hour later. The above drugs dissolve fibrin quickly, with good effect and no adverse reaction.
3.Coronary angioplasty In recent years, the application of balloon catheter to dilate coronary artery stenosis cases has been successful.
4.Surgical treatment The indications for coronary artery bypass grafting are
①Highly occluded left main stem;
②High occlusion of multiple branches;
(3) High occlusion of the left anterior descending branch. In cases of severe mitral valve insufficiency, if medical treatment is ineffective, valvuloplasty or valve replacement is feasible. In Japan, 62 patients with Kawasaki disease who underwent coronary artery bypass surgery were reported, and 7 of them underwent mitral valve surgery at the same time. Seventy percent of the patients had angina pectoris, heart failure, or other symptoms before surgery. The postoperative survival rate was 87% at 4 years and 45% at 10 years, and most died of late myocardial infarction or sudden death.
The occurrence of cardiogenic shock, heart failure and arrhythmia should be treated accordingly.
Etiology
The etiology is not yet clear. The disease is somewhat epidemic and localized, with clinical manifestations such as fever and rash, presumably related to infection. In 1986, an increase in reverse transcriptase activity in peripheral blood lymphocyte culture supernatant was reported, suggesting that the disease may be caused by retrovirus. However, most studies have not obtained consistent results. Mycoplasma, rickettsia, and dust mites have also been proposed as the etiologic agent of the disease, but this has not been confirmed. Environmental pollution or chemical allergies have also been considered as possible causes of the disease.
Pathogenesis]
Recent studies have shown that there is a significant immune dysregulation in the acute phase of the disease, which plays an important role in the pathogenesis. In the acute phase, peripheral blood T-cell subsets are imbalanced, with increased CD4, decreased CD8, and increased CD4/CD8 ratio. The increased CD4/CD8 ratio puts the body’s immune system in an activated state and increases the secretion of lymphokines by CD4, which promotes the activation, proliferation and differentiation of B-cell polyclonal water into plasma cells, leading to an increase in serum IgM, IgA, IgG and IgE, and the secretion of high concentrations of interleukins (1L-1, 4, 5, 6), r , 5, 6), r-interferon (IFN-r), and tumor necrosis factor (TNF).
These lymphokines and active interferons can induce endothelial cells to express and produce neoantigens; on the other hand, they promote the secretion of autoantibodies by B cells, which leads to endothelial cell lysis cytotoxic effects and endothelial cell damage so vasculitis occurs. 1L-11L-6 and TNF increase can also induce hepatocytes to synthesize acute reactive proteins, such as C-reactive protein, αr-antitrypsin, bound bead protein, etc. This causes an acute febrile response to the disease. The circulating immune complex (CIC) is increased in 50-70% of cases, and is absent in the first week of the disease, reaching a peak in the third to fourth week.
The mechanism of CIC in this disease is still unclear, but the absence of immune complex deposition at the lesion site and the increase in serum C3 instead of decrease are not consistent with general immune complex disease. The trigger cause of the above immune dysregulation is unknown. Nowadays, it is believed that Kawasaki disease is an immune-mediated systemic vasculitis triggered by a variety of infectious agents in a certain susceptible host.
[Pathological changes
According to the summary of 217 fatal cases by the MCLS Research Committee in Japan in 1990, pathomorphologically, the inflammatory vascular changes of the disease can be divided into four stages.
Stage I: about 1 to 2 weeks, which is characterized by.
① inflammation in and around small arteries, small veins and microvessels ;
② inflammation of medium and large arteries and their surroundings;
(iii) infiltration of lymphocytes and other leukocytes and local edema.
Phase II: Approximately 2 to 4 weeks, characterized by.
(i) reduced inflammation of small vessels ;
(2) Inflammation of medium-sized arteries is predominant, with coronary artery aneurysms and thrombosis;
③Vascular inflammation in large arteries is rare;
④ Mononuclear cell infiltration or necrotic changes are more prominent.
Stage III: about 4-7 weeks, characterized by.
① small vessels and microangiitis subsides;
② granulomas occur in medium-sized arteries.
Stage IV: About 7 weeks or longer, most of the acute inflammatory changes in the vessels disappear and are replaced by thrombosis, obstruction, intimal thickening with aneurysm and scar formation in the medium-sized arteries. Regarding the distribution of arterial lesions, they can be divided into.
(i) extra-organ medium or large arteries, mostly involving coronary, axillary, iliac arteries and other arteries of the neck, chest and abdomen;
② intra-organic arteries, which involve the heart, kidneys, lungs, gastrointestinal, skin, liver, spleen, gonads, salivary glands and brain and other organs of the body.
In addition to vascular inflammation, the pathology also involves various organs, especially interstitial myocarditis, pericarditis and endocarditis, which can affect the conduction system and often lead to death in stage I lesions. In stages II and IV, ischemic heart disease is common, and myocardial infarction can lead to death. Ruptured aneurysms and myocarditis are also important causes of death in stages II and III.
The vascular pathology of MCLS is very similar to that of infantile polyarteritis nodosa. In addition to coronary or pulmonary aneurysms and thrombosis, there are intimal changes in the aorta, ileal artery or pulmonary artery. Fluorescent antibody examination reveals immunoglobulin IgG deposits in the arterial walls of the myocardium, spleen, and lymph nodes. Vasculitis with fibrous necrosis of small vessels may be seen in the cervical lymph nodes and skin homogenization. There is also a high degree of thymic atrophy, increased heart weight, hypertrophic dilatation of the ventricles, mild steatosis of the liver, and congestion and follicular enlargement of the lymph nodes. However, there are no significant glomerular lesions.
This disease is distinguished from typical periarteritis nodosa (Kussmaul-Maier type) by the following.
(1) In the latter, the vasculitis shows marked fibrinoid necrosis (fibrinoid necrosis), whereas in MCLS, such necrotic changes are rare or only slight;
The typical periarteritis nodosa rarely involves the pulmonary arteries.
Epidemiology
This disease can be disease in infants and children, but 80-85% of patients are within 5 years of age, preferably in infants aged 6 to 18 months. There is no obvious seasonality, or more in summer. In Japan, there were about 100,000 cases of Kawasaki disease by 1990. There were three epidemics in 1979, 1982 and 1986, with an incidence rate of 172 to 194/100,000 children within 4 years of age during the epidemic. Although the number of reported cases is not as many as in Japan, the disease has been reported 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, a few cases were first reported in 1978 in Beijing, Shanghai, Hangzhou, Rong, and Taiwan, etc. In 1989, the Journal of Practical Pediatrics synthesized 220 cases from all over the country. 965 cases were hospitalized in the correspondence survey of major children’s hospitals and hospitals affiliated with medical schools from 1983 to 1986. The number of patients within 4 years of age was 78.1%, male: female 1.6:1. The number of cases seen in the United States was more of Japanese descent, and Japan reported that 1 to 2% of siblings had the disease, suggesting a genetic predisposition.
Clinical manifestations
Main symptoms Common persistent fever, 5-11 days or more (2 weeks to 1 month), temperature often reaches 39 ℃ or more, antibiotic treatment is ineffective. It is common to see bilateral conjunctival congestion, flushed lips with chapped or bleeding, and a prune-like tongue. There is hard edema in the hands, early flushing of the palms and soles, and after 10 days, characteristic large flaky peeling of the ends of the toes, which appears at the skin junction of the nail bed.
There is also acute nonsuppurative transient cervical lymph node swelling, most prominent in the anterior neck, about 1.5 cm or more in diameter, mostly appearing unilaterally, with slight tenderness, occurring within 3 days after the onset of fever and resolving spontaneously after a few days. A maculopapular or erythematous rash, or occasionally a prickly rash, mostly on the trunk, without herpes or crusts, appears soon after the onset of fever (about 1 to 4 days) and resolves in about a week.
Other symptoms Heart damage is often present, with symptoms of myocarditis, pericarditis and endocarditis. The patient’s pulse is accelerated and tachycardia, gallop rhythm, and low heart sounds can be heard on auscultation. Systolic murmurs are also more frequently present. Valvular insufficiency and heart failure may occur. Echocardiography and coronary angiography may reveal coronary aneurysms, pericardial effusion, left ventricular enlargement, and mitral valve insufficiency in most patients.
An enlarged heart shadow may be seen on X-ray chest radiographs. Occasionally, joint pain or swelling, cough, runny nose, abdominal pain, mild jaundice, or signs of aseptic encephalomyelitis are seen. In the acute phase, about 20% of cases show flushing and desquamation of the perineal and perianal skin and reappear as erythema or crusting at the original site of BCG vaccination 1 to 3 years ago. In the recovery phase, transverse grooves are spun on the nails.
The length varies. The first phase of the disease is the acute febrile phase, generally lasting 1 to 11 days, with the main symptoms appearing one after another after the fever, and severe myocarditis may occur. The second phase is the subacute phase, generally lasting 11 to 21 days, with most of the body temperature dropping, symptoms relieved, and membranous peeling of the finger and toe ends. Severe cases may still have persistent fever. Coronary aneurysms occur, which can lead to myocardial infarction and aneurysm rupture.
Most patients enter the third stage, recovery, in the fourth week, usually for 21-60 days, when clinical symptoms subside and gradually recover if there is no obvious coronary artery lesion; with coronary aneurysm it can still continue to develop and myocardial infarction or ischemic heart disease can occur. A few patients with severe coronary artery aneurysm enter the chronic stage, which can be prolonged for several years, leaving coronary artery stenosis, angina pectoris, cardiac insufficiency and ischemic heart disease, which can be life-threatening due to myocardial infarction.
[Complications].
Since cardiovascular lesions are both symptoms of the disease itself and complications that can cause death, their passage will be detailed in this section for early detection and timely and appropriate treatment.
1, coronary artery lesions According to the observation of 1009 cases of Kawasaki disease in Japan, it is suggested that transient coronary artery dilatation accounts for 46% and coronary artery aneurysm accounts for 21%. The application of two-dimensional echocardiography revealed that coronary artery dilatation could appear on the third day of disease onset, and most of them subsided within three to six months. Coronary artery aneurysms can be detected on day 6 of disease onset, with the highest detection rate in weeks 2 to 3 and few new lesions after week 4. The incidence of coronary artery aneurysms is 15-30%, and the presence of clinical myocarditis does not predict coronary artery involvement.
Some risk factors that are clearly associated with coronary aneurysms include age at onset less than 1 year, boys, persistent fever for more than 14 days, anemia, total leukocyte count above 30×109/L, hematocrit above 100 mm/h, markedly elevated C-reactive protein, reduced plasma albumin, and those who develop somatic aneurysms. Most coronary aneurysms are self-limiting, and most of them resolve on their own within 1 to 2 years.
Coronary artery lesions in this disease involve the proximal part of the main trunk, with the left anterior descending branch being the most common, followed by the left circumflex branch being the least common. Isolated distal aneurysms are rare. The severity of coronary artery lesions is generally classified into four degrees.
①Normal (degree 0): no dilatation of coronary arteries.
② Mild (degree I): marked and limited aneurysmal dilatation with an internal diameter of <4 mm.
③Moderate (degree II): It can be single, multiple or extensive, with an internal diameter of 4-7mm.
④Severe (degree III): giant tumor with an inner diameter ≥8mm, mostly extensive, involving more than 1 branch. The incidence is about 5% and the prognosis is poor. Therefore, those with coronary artery lesions should be closely followed up with regular review of echocardiography. Usually, echocardiography is performed once a week within 4 weeks of the onset of the disease, then once every 2 months or 6 months, and then at least once a year depending on the extent of the lesion. Coronary angiography should be performed in symptomatic patients and in those with severe coronary artery involvement. Coronary angiography can accurately assess the degree of coronary artery stenosis and occlusion and distal lesions. Serious complications such as transient myocardial ischemia and ventricular fibrillation can occur due to blockage of the lumen at the leading end. Indications for coronary angiography are.
① Symptoms of myocardial ischemia.
② Persistent heart valve lesions.
③X-ray plain film shows coronary artery calcification.
④Echocardiography shows persistent coronary aneurysm.
2. Gallbladder effusion Most often appears in the subacute stage, and severe abdominal pain, abdominal distention and jaundice may occur. A mass can be felt in the right upper abdomen, which can be confirmed by abdominal ultrasonography. Most of them heal naturally, but occasionally they may be complicated by paralytic intestinal obstruction or intestinal bleeding.
Arthritis or arthralgia occurs in the acute or subacute phase and can involve both large and small joints, and is seen in about 20% of cases and resolves with improvement.
4. Neurological changes The acute phase includes aseptic encephalomyelitis, facial nerve palsy, hearing loss, acute encephalopathy and hyperthermia, which are caused by vasculitis and are clinically common, with rapid recovery and good prognosis. Among them, aseptic encephalomyelitis is the most common, with an incidence of about 25%. It occurs mostly within the first 2 weeks of the disease. Some children have increased cranial pressure and exhibit anterior chimney augmentation. A few children have cervical tonicity and may have drowsiness, double vision, coma, and other disturbances of consciousness. Cerebrospinal fluid lymphocytes are mildly increased, sugar and chloride are normal, and protein accountants are overwhelmingly normal. Clinical symptoms mostly disappear within a few days. Facial nerve palsy is mostly seen in severe patients and is often peripheral. It may be due to a vascular inflammatory reaction that spreads to the facial nerve, or a vascular lesion in an adjacent area, such as aneurysm formation or arterial dilation, which transiently compresses the facial nerve. In the recovery period, limb paralysis caused by narrowing or occlusion of the middle cerebral artery is likely to leave sequelae, which is less common.
5, other complications Pulmonary vasculitis in the X-ray chest film shows an increase in pulmonary striae or lamellar shadows, and occasionally pulmonary infarction occurs. In the acute phase, there may be urethritis, and the urine sediment may show leukocytosis and mild proteinuria. Iridocyclitis is less common. Body aneurysms occur in approximately 2% of patients, with axillary and iliac arteries being the most common. Occasionally, gangrene of the fingers and toes is seen.
Ancillary tests
In the acute phase, the total white blood cell count and granulocyte percentage increase, and the nucleus shifts to the left. Mild anemia is seen in more than half of the patients. Blood sedimentation is significantly increased, up to 100mm or more in the first hour. The serum protein fluorophoresis shows an increase in globulin, especially alpha 2 globulin. IgG, IgA and IgA are increased. Platelets start to increase in the second week. The blood is hypercoagulable. Anti-streptococcal hemolysin O titers were normal. Rheumatoid factor and antinuclear body are negative.
C-reactive protein is elevated. Serum complement is normal or slightly elevated. Urine sedimentation may show leukocytosis and/or proteinuria. The electrocardiogram may show a variety of changes, with ST-segment and T-wave abnormalities being the most common, and may also show prolonged P-R and Q-R intervals, abnormal Q waves and rhythm disturbances. 2D echocardiography is suitable for cardiac examination and long-term follow-up in half of the cases to detect various cardiovascular pathologies such as pericardial effusion, left ventricular enlargement, mitral valve insufficiency and coronary artery dilatation or aneurysm formation.
Preferably, weekly examinations during the acute and subacute phases of the disease are the most reliable non-invasive method of monitoring coronary aneurysms. In cases presenting with aseptic meningitis, lymphocytes in the cerebrospinal fluid may be as high as 50 to 70/mm3. In some cases, slightly high serum bilirubin or ghrelin may be seen. Bacterial culture and viral isolation are negative results.
Differential diagnosis
It should be differentiated from various rash infections, viral infections, acute lymphadenitis, rheumatoid diseases, other connective tissue diseases, viral myocarditis, and rheumatoid cardiitis.
The differences between this disease and scarlet fever are.
(1) The rash begins on the third day after the onset of the disease;
(2) The rash pattern is similar to that of measles and erythema multiforme;
(3) The age of onset is infancy and younger children;
④ Penicillin is not effective.
The differences between this disease and juvenile rheumatoid disease are.
(i) the fever period is shorter and the rash is more transient;
(2) Stiffness and swelling of the hands and feet, showing frequent plantar flushing;
(iii) negative rheumatoid factor.
The differences from exudative erythema multiforme are.
(i) eyes, lips, no purulent discharge and pseudomembrane formation;
②The rash does not include blisters and crusts.
The differences from systemic lupus erythematosus are
①The rash is not significant on the face;
②Total white blood cell count and platelets are generally elevated;
③Negative antinuclear antibody.
The age of predilection is infants and boys.
There are many similarities with the symptoms of infantile nodular polyarteries, but MCLS has a higher incidence, a shorter course, and a better prognosis. The interrelationship between the two diseases has yet to be studied.
The differences from rash virus infection are.
(1) flushed, dry, cracked and bleeding lips, with a prune tongue;
(2) Sclerosis of the hands and feet, often with flushing of the plantar surface and late appearance of membranous peeling of the finger and toe tips;
③ Conjunctiva without edema or secretion;
④Total white blood cell count and granulocyte percentage are increased with left shift of nucleus; ⑥Blood sedimentation and C-reactive protein are significantly increased.
The differences from acute lymphadenitis are.
(1) The cervical lymph nodes are less swollen and less painful, and the local skin and subcutaneous tissue are not red or swollen;
②No purulent lesions.
The differences from viral myocarditis are.
(i) prominent coronary artery lesions;
②Characteristic hand and foot changes;
(3) persistent high fever.
The differences from rheumatic heart disease are.
(1) prominent coronary artery lesions;
②No meaningful heart murmur;
③The age of onset is mainly infants and children.
Prognosis
The majority of children have a good prognosis with a self-limiting course and can gradually recover with appropriate treatment. This differs greatly from infantile periarteritis nodosa. However, coronary artery aneurysms can occur in 15-30% of patients with Kawasaki disease. Death due to coronary aneurysm, thrombo-occlusion or myocarditis occurs in 1 to 2% of all cases, and sudden death can occur even during the recovery period. The number of sequelae of ischemic heart disease is very small. Recurrence occurs in about 2% of cases. The death rate has been reduced to 0.5% to 1.0% in recent years. In Japan, 104 cases of Kawasaki disease cause of death analysis, myocardial infarction 57%, heart failure 12%, myocardial infarction with heart failure 6.7%, coronary artery aneurysm rupture 5%, arrhythmia 1%, other complications such as infection.
In Beijing Children’s Hospital, two-dimensional echocardiography was used to examine 188 cases of Kawasaki disease since 1986, and 60 cases of coronary artery lesions were detected, including 44 cases of dilatation and 16 cases of aneurysm formation. After follow-up from 3 months to 5 years, the average was 22.6 months. Normalization occurred in 40 cases of the former and 6 cases of the latter. The time to normalization was 4.4±2.9 months and 15.7±17.2 months, respectively. Two cases died, one with multiple moderate coronary aneurysms (7 mm internal diameter) due to acute anterior wall myocardial infarction and the other with multiple giant aneurysms that ruptured the right coronary artery on day 28 of the disease course.