Kawasaki disease

, and is followed by extreme irritability. Recently, it is reported to be present in patients with atypical or incomplete Kawasaki disease; nevertheless, it is not present in 100% of cases. The first day of fever is considered the first day of the illness, It responds partially to antipyretic drugs and does not cease with the introduction of antibiotics. Bilateral conjunctival inflammation has been reported to be the most common symptom after fever. It typically involves the bulbar conjunctivae, is not accompanied by suppuration, and is not painful. This usually begins shortly after the onset of fever during the acute stage of the disease. Iritis can occur, too. Keratic precipitates are another eye manifestation (detectable by a slit lamp, but are usually too small to be seen by the unaided eye). Kawasaki disease also presents with a set of mouth symptoms, the most characteristic of which are a red tongue, swollen lips with vertical cracking, and bleeding. The mucosa of the mouth and throat may be bright red, and the tongue may have a typical "strawberry tongue" appearance (marked redness with prominent gustative papillae). According to the diagnostic criteria, at least one impaired lymph node ≥ 15 mm in diameter should be involved. Around 11% of children affected by the disease may continue skin-peeling for many years. One to two months after the onset of fever, deep transverse grooves across the nails may develop (Beau's lines), and occasionally nails are shed. The rash varies over time and is characteristically located on the trunk; it may further spread to involve the face, extremities, and perineum. It can be polymorphic, not itchy, and normally observed up to the fifth day of fever. However, it is never bullous or vesicular. diarrhea, Other reported nonspecific symptoms include cough, rhinorrhea, sputum, vomiting, headache, and seizure. • The convalescent stage begins when all clinical signs of illness have disappeared, and continues until the sedimentation rate returns to normal, usually at six to eight weeks after the onset of illness. Some children, especially young infants, have atypical presentations without the classic set of symptoms. Cardiac Heart complications are the most important aspect of Kawasaki disease, which is the leading cause of heart disease acquired in childhood in the United States and Japan. It is first detected at a mean of 10 days of illness and the peak frequency of coronary artery dilation or aneurysms occurs within four weeks of onset. Death can occur either due to myocardial infarction secondary to blood clot formation in a coronary artery aneurysm or to rupture of a large coronary artery aneurysm. Death is most common two to 12 weeks after the onset of illness. low hemoglobin concentrations, low albumin concentrations, high white-blood-cell count, high band count, high CRP concentrations, male sex, and age less than one year. Coronary artery lesions resulting from Kawasaki disease change dynamically with time. Narrowing of the coronary artery, which occurs as a result of the healing process of the vessel wall, often leads to significant obstruction of the blood vessel and the heart not receiving enough blood and oxygen. The highest risk of MI occurs in the first year after the onset of the disease. but a very small group of the lesions persist and progress. There is also late-onset aortic or mitral insufficiency caused by thickening or deformation of fibrosed valves, with the timing ranging from several months to years after the onset of Kawasaki disease. Some of these lesions require valve replacement. Other Other Kawasaki disease complications have been described, such as aneurysm of other arteries: aortic aneurysm, with a higher number of reported cases involving the abdominal aorta, axillary artery aneurysm, brachiocephalic artery aneurysm, aneurysm of iliac and femoral arteries, and renal artery aneurysm. Other vascular complications can occur such as increased wall thickness and decreased distensibility of carotid arteries, aorta, and brachioradial artery. This change in the vascular tone is secondary to endothelial dysfunction. colon swelling, intestinal ischemia, intestinal pseudo-obstruction, and acute abdomen. Eye changes associated with the disease have been described since the 1980s, being found as uveitis, iridocyclitis, conjunctival hemorrhage, optic neuritis, It can also be found as necrotizing vasculitis, progressing into peripheral gangrene. The neurological complications per central nervous system lesions are increasingly reported. The neurological complications found are meningoencephalitis, subdural effusion, cerebral hypoperfusion, cerebral ischemia and infarct, cerebellar infarction, manifesting with seizures, chorea, hemiplegia, mental confusion, lethargy and coma, and sensorineural hearing loss. Behavioral changes are thought to be caused by localised cerebral hypoperfusion, == Causes ==

The specific cause of Kawasaki disease is unknown. The pathogenesis is complex and incompletely understood. Various explanations exist. Since recurrences are unusual in Kawasaki disease, it is thought that the trigger is more likely to be represented by a single pathogen, rather than a range of viral or bacterial agents. Various candidates have been implicated, including upper respiratory tract infection by some novel RNA virus. Current consensus favors an excessive immunologic response to a conventional antigen which usually provides future protection. possibly one that enters through the respiratory tract. Seasonal trends in the appearance of new cases of Kawasaki disease have been linked to tropospheric wind patterns, which suggests wind-borne transport of something capable of triggering an immunologic cascade when inhaled by genetically susceptible children. These associations are themselves modulated by seasonal and interannual events in the El Niño–Southern Oscillation in winds and sea surface temperatures over the tropical eastern Pacific Ocean. Efforts have been made to identify a possible pathogen in air-filters flown at altitude above Japan. One source has been suggested in northeastern China. Genetics Genetic susceptibility is suggested by increased incidence among children of Japanese descent around the world, and also among close and extended family members of affected people. The exact genetic contribution remains unknown. Genome-wide association studies and studies of individual candidate genes have together helped identify specific single nucleotide polymorphisms (SNPs), mostly found in genes with immune regulatory functions. SNPs in FCGR2A, CASP3, BLK, ITPKC, CD40 and ORAI1 have all been linked to susceptibility, prognosis, and risk of developing coronary artery aneurysms. Gene–gene interactions also seem to affect susceptibility and prognosis. At an epigenetic level, altered DNA methylation has been proposed as an early mechanistic factor during the acute phase of the disease. == Diagnosis ==

showing ectatic LAD, with largest aneurysm = 6.5 mm in diameter Since no specific laboratory test exists for Kawasaki disease, diagnosis must be based on clinical signs and symptoms, together with laboratory findings. Timely diagnosis requires careful history-taking and thorough physical examination. Establishing the diagnosis is difficult, especially early in the course of the illness, and frequently children are not diagnosed until they have seen several health-care providers. Many other serious illnesses can cause similar symptoms, and must be considered in the differential diagnosis, including scarlet fever, toxic shock syndrome, juvenile idiopathic arthritis, and childhood mercury poisoning (infantile acrodynia). Classically, five days of fever plus four of five diagnostic criteria must be met to establish the diagnosis. The criteria are: • erythema of the lips or oral cavity or cracking of the lips • rash on the trunk • swelling or erythema of the hands or feet • red eyes (conjunctival injection) • swollen lymph node in the neck of at least 15 mm Many children, especially infants, eventually diagnosed with Kawasaki disease, do not exhibit all of the above criteria. In fact, many experts now recommend treating for Kawasaki disease even if only three days of fever have passed and at least three diagnostic criteria are present, especially if other tests reveal abnormalities consistent with Kawasaki disease. In addition, the diagnosis can be made purely by the detection of coronary artery aneurysms in the proper clinical setting. Investigations A physical examination will demonstrate many of the features listed above. Blood tests • Complete blood count may reveal normocytic anemia and eventually thrombocytosis. • Erythrocyte sedimentation rate will be elevated. • C-reactive protein will be elevated. • Liver function tests may show evidence of hepatic inflammation and low serum albumin levels. Other optional tests include: • Electrocardiogram may show evidence of ventricular dysfunction or, occasionally, arrhythmia due to myocarditis. • Echocardiogram may show subtle coronary artery changes or, later, true aneurysms. • Ultrasound or computerized tomography may show hydrops (enlargement) of the gallbladder. • Urinalysis may show white blood cells and protein in the urine (pyuria and proteinuria) without evidence of bacterial growth. • Lumbar puncture may show evidence of aseptic meningitis. • Angiography was historically used to detect coronary artery aneurysms, and remains the gold standard for their detection, but is rarely used today unless coronary artery aneurysms have already been detected by echocardiography. Biopsy is rarely performed, as it is not necessary for diagnosis. Case definition For study purposes, including vaccine safety monitoring, an international case definition has been proposed to categorize 'definite' (i.e. complete/incomplete), 'probable' and 'possible' cases of Kawasaki disease. Differential diagnosis The broadness of the differential diagnosis is a challenge to timely diagnosis of Kawasaki disease. Kawasaki-like disease temporally associated with COVID-19 In 2020, reports of a Kawasaki-like disease following exposure to SARS-CoV-2, the virus responsible for COVID-19, emerged in the US and Europe. This emerging condition was named "paediatric multisystem inflammatory syndrome" by the Royal College of Paediatrics and Child Health, and "multisystem inflammatory syndrome in children" by the Centers for Disease Control and Prevention. Guidance for diagnosis and reporting of cases has been issued by these organizations. Classification Debate has occurred about whether Kawasaki disease should be viewed as a characteristic immune response to some infectious pathogen, as an autoimmune process, or as an autoinflammatory disease (i.e. involving innate rather than adaptive immune pathways). Overall, immunological research suggests that Kawasaki disease is associated with a response to a conventional antigen (rather than a superantigen) that involves both activation of the innate immune system and also features of an adaptive immune response. Identification of the exact nature of the immune process involved in Kawasaki disease could help guide research aimed at improving clinical management. Other diseases involving necrotizing vasculitis include polyarteritis nodosa, granulomatosis with polyangiitis, Henoch–Schönlein purpura, and eosinophilic granulomatosis with polyangiitis. such as the smaller cutaneous vasculature (veins and arteries in the skin) that range from 50 to 100 μm in diameter. Kawasaki disease is also considered to be a primary childhood vasculitis, a disorder associated with vasculitis that mainly affects children under the age of 18. A recent, consensus-based evaluation of vasculitides occurring primarily in children resulted in a classification scheme for these disorders, to distinguish them and suggest a more concrete set of diagnostic criteria for each. This form of categorization is relevant for appropriate treatment. == Treatment ==

Children with Kawasaki disease should be hospitalized and cared for by a physician who has experience with this disease. In an academic medical center, care is often shared between pediatric cardiology, pediatric rheumatology, and pediatric infectious disease specialists (although no specific infectious agent has yet been identified). and is administered in high doses with marked improvement usually noted within 24 hours. If the fever does not respond, an additional dose may be considered. In rare cases, a third dose may be given. IVIG is most useful within the first seven days of fever onset, to prevent coronary artery aneurysm. IVIG given within the first 10 days of the disease reduces the risk of damage to the coronary arteries in children, without serious adverse effects. The largest clinical study to date on treatment of resistant Kawasaki disease has shown that infliximab is more effective and safer than a second dose of IVIG in treating children with IVIG-resistant Kawasaki Disease, offering faster fever resolution and reduced hospitalization times without significant adverse events. Salicylate therapy, particularly aspirin, remains an important part of the treatment (though questioned by some) but salicylates alone are not as effective as IVIG. There is limited evidence to indicate whether children should continue to receive salicylate as part of their treatment. Aspirin therapy is started at high doses until the fever subsides, and then is continued at a low dose when the patient returns home, usually for two months to prevent blood clots from forming. Except for Kawasaki disease and a few other indications, aspirin is otherwise normally not recommended for children due to its association with Reye syndrome. Because children with Kawasaki disease will be taking aspirin for up to several months, vaccination against varicella and influenza is required, as these infections are most likely to cause Reye syndrome. High-dose aspirin is associated with anemia and does not confer benefit to disease outcomes. About 15-20% of children following the initial IVIG infusion show persistent or recurrent fever and are classified as IVIG-resistant. While the use of TNF alpha blockers (TNF-α) may reduce treatment resistance and the infusion reaction after treatment initiation, further research is needed. Due to the potential involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the development of the disease, a 2019 study found that the combination of ciclosporin and IVIG infusion can suppress coronary artery abnormalities. Further research is needed to determine which patients would respond best to this treatment. Corticosteroids have also been used, especially when other treatments fail or symptoms recur, but in a randomized controlled trial, the addition of corticosteroid to immune globulin and aspirin did not improve outcome. Additionally, corticosteroid use in the setting of Kawasaki disease is associated with increased risk of coronary artery aneurysm, so its use is generally contraindicated in this setting. In cases of Kawasaki disease refractory to IVIG, cyclophosphamide and plasma exchange have been investigated as possible treatments, with variable outcomes. However, a Cochrane review published in 2017 (updated in 2022) found that, in children, the use of corticosteroids in the acute phase of KD was associated with improved coronary artery abnormalities, shorter hospital stays, a decreased duration of clinical symptoms, and reduced inflammatory marker levels. Patient populations based in Asia, people with higher risk scores, and those receiving longer steroid treatment may have greater benefit from steroid use. == Prognosis ==

With early treatment, rapid recovery from the acute symptoms can be expected, and the risk of coronary artery aneurysms is greatly reduced. Untreated, the acute symptoms of Kawasaki disease are self-limited (i.e., the patient will recover eventually), but the risk of coronary artery involvement is much greater, even many years later. Many cases of myocardial infarction in young adults have now been attributed to Kawasaki disease that went undiagnosed during childhood. The likelihood that an aneurysm will resolve appears to be determined in large measure by its initial size, in which the smaller aneurysms have a greater likelihood of regression. Other factors are positively associated with the regression of aneurysms, including being younger than a year old at the onset of Kawasaki disease, fusiform rather than saccular aneurysm morphology, and an aneurysm location in a distal coronary segment. This severe outcome may require further treatment such as percutaneous transluminal angioplasty, coronary artery stenting, bypass grafting, and even cardiac transplantation. A relapse of symptoms may occur soon after initial treatment with IVIG. This usually requires rehospitalization and retreatment. Treatment with IVIG can cause allergic and nonallergic acute reactions, aseptic meningitis, fluid overload, and rarely, other serious reactions. Overall, life-threatening complications resulting from therapy for Kawasaki disease are exceedingly rare, especially compared with the risk of nontreatment. Evidence indicates Kawasaki disease produces altered lipid metabolism that persists beyond the clinical resolution of the disease. Rarely, recurrence can occur in Kawasaki disease with or without treatment. == Epidemiology ==

Kawasaki disease affects boys more than girls, with people of Asian ethnicity, particularly Japanese people. The higher incidence in Asian populations is thought to be linked to genetic susceptibility. Incidence rates vary between countries. Currently, Kawasaki disease is the most commonly diagnosed pediatric vasculitis in the world. By far, the highest incidence of Kawasaki disease occurs in Japan, with the most recent study placing the attack rate at 218.6 per 100,000 children less than five years of age (about one in 450 children). At this present attack rate, more than one in 150 children in Japan will develop Kawasaki disease during their lifetimes. However, its incidence in the United States is increasing. Kawasaki disease is predominantly a disease of young children, with 80% of patients younger than five years of age. About 2,000–4,000 cases are identified in the U.S. each year (9 to 19 per 100,000 children younger than five years of age). In the continental United States, Kawasaki disease is more common during the winter and early spring, boys with the disease outnumber girls by ≈1.5–1.7:1, and 76% of affected children are less than 5 years of age. In the United Kingdom, before 2000, it was diagnosed in fewer than one in every 25,000 people per year. Incidence of the disease doubled from 1991 to 2000, however, with four cases per 100,000 children in 1991 compared with a rise of eight cases per 100,000 in 2000. By 2017, this figure had risen to 12 in 100,000 people with 419 diagnosed cases of Kawasaki disease in the United Kingdom. In Japan, the rate is 240 in every 100,000 people. Coronary artery aneurysms due to Kawasaki disease are believed to account for 5% of acute coronary syndrome cases in adults under 40 years of age. == History ==

The disease was first reported by Tomisaku Kawasaki in a four-year-old child with a rash and fever at the Red Cross Hospital in Tokyo in January 1961, and he later published a report on 50 similar cases. In 1974, the first description of this disorder was published in the English-language literature. In 1976, Melish et al. described the same illness in 16 children in Hawaii. Melish and Kawasaki had independently developed the same diagnostic criteria for the disorder, which are still used today to make the diagnosis of classic Kawasaki disease. A question was raised whether the disease only started during the period between 1960 and 1970, but later a preserved heart of a seven-year-old boy who died in 1870 was examined and showed three aneurysms of the coronary arteries with clots, as well as pathologic changes consistent with Kawasaki disease. Kawasaki disease is now recognized worldwide. Why cases began to emerge across all continents around the 1960s and 1970s is unclear. Possible explanations could include confusion with other diseases such as scarlet fever, and easier recognition stemming from modern healthcare factors such as the widespread use of antibiotics. == References ==