Kawasaki disease (KD) is an acute, self-limiting vasculitis syndrome of unknown etiology. With the increasing understanding of this disease, the diagnosis of incomplete KD has become a hot and difficult clinical concern. Because of its varied clinical manifestations, it is often misdiagnosed or missed, leading to the occurrence of coronary artery aneurysm (CAA). Some cases abroad have reported that children may exhibit no febrile symptoms, so clinicians should pay special attention to the reference items of incomplete KD diagnostic criteria including changes in BCG inoculation sites during the diagnosis process, and Kawasaki disease, especially the presence of incomplete KD, should often be considered during the diagnosis and treatment of pediatric fever of unknown origin. A recent multicenter study in Japan showed that 5% of Kawasaki disease patients with combined coronary artery damage had less than 3 clinical symptoms, and the disease occurred between 6 months and 1 year of age and above 5 years of age, which should be taken seriously and given comprehensive examination and necessary treatment.
1. Definition of incomplete KD
Incomplete KD refers to those who do not have the conditions of KD diagnostic criteria, which can be seen in the following two cases
(1) Those who meet only 4 or less of the 6 diagnostic criteria, but have coronary artery aneurysms confirmed by echocardiography or cardiovascular imaging during the course of the disease (mostly seen in infants <6 months old or older children >8 years old), and are seriously ill.
(2) Only 4 of the diagnostic criteria are met, but the coronary artery wall glow enhancement is visible on echocardiography, and other infectious diseases should be excluded . Since the clinical symptoms do not fully meet the diagnostic criteria of Kawasaki disease, it is named incomplete Kawasaki disease. A large domestic study showed that the incidence of incomplete KD was 19.4%. It is worth noting that incomplete KD occurs in young infants, and its clinical symptoms are more insidious, with a higher rate of coronary artery lesions than in older children. The U.S. diagnostic criteria suggest that 2-DE should be routinely performed in young infants with fever of unknown origin for ≥5 days with one of the clinical manifestations, and the diagnosis can be clarified if coronary artery lesions are present.
KD’s are called suspected Kawasaki disease until the nomenclature of incomplete Kawasaki disease is established. Currently, patients with less than 5 major symptoms are defined as incomplete Kawasaki disease in Japan. In cases where clinical symptoms and changes in the course of the disease are atypical, the diagnosis of atypical Kawasaki disease is not made.
2. Clinical symptoms of incomplete Kawasaki disease
The six main clinical symptoms in incomplete KD are fever and membranous desquamation of the extremities during the recovery period, and swelling of the lymph nodes in the neck is rare. Among them, perianal flushing (or with desquamation) and finger (toe) end desquamation are of characteristic significance for the diagnosis of KD. According to the results of a study conducted by Japanese scholars comparing the frequency of the six major symptoms of incomplete KD in the broad sense and typical KD, the frequency of swollen lymph nodes in the neck is low in cases of incomplete KD (35%), while the frequency of typical KD cases is 65%, and the frequency of other symptoms of incomplete KD are 75% for fever, 50% for rash, 65% for changes in the lips and mouth, 70% for changes in the ends of the limbs, 75% for conjunctival changes, and 75% for tetralogy of Fallot. , conjunctival changes 75%, and limb end changes in mildly ill patients often based on specific desquamation at the junction of mucosa and skin as an important basis for the diagnosis of Kawasaki disease, and there are also delays in diagnosis due to several hospital transfers ignoring the manifestation of specific limb end desquamation.
Japanese scholars did not report several cases of sudden death diagnosed as incomplete KD due to thrombotic embolism within the coronary artery aneurysm and coronary artery aneurysm rupture found at autopsy. There are also cases showing cardiac insufficiency as the main symptom, which can be diagnosed as incomplete KD based on the past history of the child with fever rash, etc. in the medical history.
In cases where incomplete KD has been diagnosed, other manifestations such as facial nerve palsy, acute abdomen, and incomplete paralysis of the lower limbs are often combined. However, these symptoms are not unique to incomplete KD, and a few cases have been reported in which typical KD can also be associated with these comorbidities.
The delayed onset of the main symptoms of Kawasaki disease often occurs and is not limited to incomplete KD. in some cases, coronary artery aneurysms have been detected on the fifth day of fever, while mild redness of the lips, tiny papules and terminal changes in the extremities appear later. In Japan, there is a report of the above-mentioned condition in a child 51 days after life, which should be taken seriously.
3. Diagnosis and differential diagnosis of incomplete KD
Incomplete KD is often diagnosed during the treatment of children initially suspected of having other diseases, and most cases are diagnosed by the presence of specific membranous peeling at the ends of the fingers (toes). In some cases, the diagnosis of rheumatoid arthritis is misdiagnosed in the course of treatment, but the diagnosis of incomplete KD is confirmed only after the appearance of finger and toe end desquamation and the presence of coronary artery aneurysm is confirmed by ultrasound, so when other diseases are diagnosed and there is no strong evidence, it is necessary to differentiate from Kawasaki disease to avoid missing the diagnosis and misdiagnosis.
4. Fever and coronary artery aneurysm
A study by Japanese scholars Asai and Kusakawa showed a positive correlation between fever duration and the frequency and severity of coronary artery damage (diameter of coronary artery aneurysm), but there are also reported cases of incomplete KD in which the fever duration is short but a coronary artery aneurysm of moderate degree or more has developed. Two special cases are described below.
Case 1 (no fever combined with a giant aneurysm) Male 5 months old, complaining of cough and runny nose without fever. At the beginning of the illness, there were symptoms of flushing of the lips and conjunctival congestion. Fourteen days after the onset of flushing, he was found to have bilateral coronary aneurysms of 5-6 mm by echocardiography due to suspected Kawasaki disease, and three days later, he developed extremity desquamation, blood WBC 21000*109/L, hematocrit 21 mm/h, and cardiovascular angiography confirmed that the left coronary aneurysm was 8 mm and the right 6.5 mm.
Case 2 (one day fever with bilateral moderate coronary artery aneurysm) Male, 8 months, the first day of illness, temperature 37.8 degrees, mild conjunctival congestion, red lips, poppy tongue, mild redness at BCG inoculation, suspected Kawasaki disease fever subsided on the next day. WBC: 8800*109/L, PLT: 640*109/L, CRP 1.1, ESR 93mm/h. Echocardiography revealed a left coronary artery aneurysm of 6mm and a right coronary artery aneurysm of 7mm. 11 years of follow-up, no retraction of coronary artery aneurysm.
5. Diagnostic steps of incomplete KD
According to the main symptoms of Kawasaki disease as a clue, it is very important to take a detailed medical history to determine the presence or absence of related symptoms. Subsequently, according to the diagnostic criteria of Kawasaki disease, it is especially important to judge the reference symptoms for the diagnosis of incomplete KD, especially the changes in the BCG vaccination site has a high value, and the corresponding changes often appear in cases within 3 months to 3 years after vaccination. During the outpatient physical examination, it is necessary to observe the BCG vaccination site and swollen lymph nodes in the neck and other manifestations comprehensively, and if changes in the BCG vaccination site occur, it is considered as one of the main symptoms, especially when fever is accompanied by one to three other main symptoms and changes in the BCG vaccination site, Kawasaki disease should be considered highly likely. Kawasaki disease is often considered in the differential diagnosis of patients with unexplained fever, especially incomplete KD.
Incomplete KD has the same pathophysiological changes as typical KD, and the clinical examination items are basically the same, for the purpose of early diagnosis and judgment of severity. The corresponding laboratory tests can be given basically relying on the content of the Harada score. The application of gammaglobulin preparations can also be selected with reference to the results of the Harada score. However, most incomplete KD cases with less than 2-3 major symptoms often have mildly altered laboratory findings compared to typical KD cases. The presence of coronary artery aneurysms, especially distal coronary artery aneurysms, should be especially noted. Other highly specific laboratory tests include a decrease in HDL (to be compared with the recovery period), and in recent years, changes in BNP (Brain Natriuretic Peptide) have also been noted, which may show a significant increase in BNP at the beginning of the disease. In addition to aseptic pyuria, recent abnormalities in urine LDH (increased activity in the acute phase) have been reported in specific cases.
In addition to blood and urine tests and ultrasonography of the heart and gallbladder, the diagnosis of iridocyclitis can also be used as a basis for determining Kawasaki disease. Confirmation of the diagnosis is given on the basis of comprehensive analysis excluding diseases similar to Kawasaki disease such as hemolytic streptococcal infection.
6. Evaluation of suspected children with incomplete KD (KD)
In 2004, the American College of Cardiology included those with fever for more than 5 days and less than 5 major symptoms as suspected cases of incomplete KD, and specified the corresponding diagnostic steps and evaluation.
Evaluation of children with suspected incomplete Kawasaki disease (KD) (Table) Incomplete KD is not the same as mild Kawasaki disease, and its clinical diagnosis is more difficult. Echocardiography and related hematological examinations are required for those who meet the other 4 major symptoms except fever, and those who meet less than 3 major symptoms should be considered as having incomplete KD. Special attention should be paid during the examination to correct the diagnosis in a timely manner when the reference conditions, including changes in the BCG inoculation site, are met.
7. Predictors of IVIG non-response and hormone therapy
Kawasaki disease is a vasculitis syndrome of unknown cause that occurs in pediatric age, and the high incidence of coronary artery lesions in untreated individuals has been confirmed, but the pathogenesis is not yet clear. High-dose gammaglobulin therapy plays an important role in improving clinical symptoms and inhibiting the development of coronary artery lesions. Standardized therapy has been widely used, but in 10-20% of cases it is ineffective, the temperature does not subside, and most cases are combined with coronary artery lesions. Therefore, it is important to predict and control the development of coronary artery lesions for those who are ineffective with gammaglobulin.
(1) Background of the application of corticosteroids in the treatment of Kawasaki disease Corticosteroids have been widely used in various vascular inflammatory syndromes because of their highly effective anti-inflammatory effects. In the 1970s, corticosteroids were commonly used in the acute treatment of Kawasaki disease in foreign countries, but there are reports that corticosteroids promote coronary artery dilation and hypercoagulability leading to thrombosis, which increases the risk of myocardial infarction. Therefore, the application of hormone conventional therapy is almost not advocated. In recent years, with the additional treatment of those who have failed propecia treatment and the application of hormone in the initial treatment, some scholars now believe that hormone has the ability to shorten the heat course, inhibit the occurrence of coronary lesions, control the inflammatory factor response early, and evaluate the hormone treatment of Kawasaki disease in a prospective study.
(2) High-risk factors for predicting non-response to IVIG and concurrent coronary artery damage Japanese scholar Kobayashi applied statistical multiple regression analysis and initially established high-risk scores for predicting non-response to IVIG and concurrent coronary artery damage by.
1) Na < 133 mmol/L (2 points)
2) AST〉100IU/L (2 points)
3) IVIG initial treatment time < 4 days (2 points)
4) blood neutrophil classification〉80% (2 points)
5) CRP〉100mg/L (1 point)
6) Age < 1 year (1 point)
7) Platelet count ≤300×109/L (1 point)
A total score of 11 points and an assessment score greater than 7 points or more are judged to be at high risk for IVIG non-response and KD complicated by coronary artery damage. The results of a recent multicenter study at Gunma University in Japan showed that the sensitivity of the above scoring method was 86% and the specificity was 67%, and the higher the total score value, the higher the incidence of IVIG non-response and KD concurrent coronary artery damage.
(3) Additional hormonal therapy for IVIG non-responders
If the fever does not subside (temperature >38 degrees) 36 hours after IVIG is given after the diagnosis of Kawasaki disease is clear, or if the fever reappears 2-7 d after the fever has subsided and is accompanied by at least one of the main clinical manifestations of KD, it is judged as IVIG non-response. Japanese scholars suggest that if the fever does not subside after reapplication of IVIG treatment with 1g/Kg, methylprednisolone 2mg/Kg/d can be administered intravenously in three doses until the fever subsides and the CRP and blood picture return to normal and then be replaced by prednisolone 2mg/Kg/d*5d, 1mg/Kg/d*5d, 0.5mg/Kg/d*5d and then discontinued.
Hormone therapy can aggravate the hypercoagulable state of blood, and aspirin is given in combination if necessary. For children with combined coronary artery aneurysms, low-dose intravenous or oral treatment with prednisolone is recommended. Since IVIG non-responders are at high risk for combined coronary artery aneurysms, they should be treated as severe cases of Kawasaki disease, and the evolution of their disease course and follow-up should be given high priority.