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. in addition, children with kawasaki disease, with or without coronary artery complications, may have a more adverse cardiovascular risk profile, such as high blood pressure, obesity, and abnormal serum lipid profile. gastrointestinal complications in kawasaki disease are similar to those observed in henoch–schönlein purpura, such as: intestinal obstruction, 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, amaurosis, and ocular artery obstruction. 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, or even a cerebral infarction with no neurological manifestations. other neurological complications from cranial nerve involvement are reported as ataxia, facial palsy, and sensorineural hearing loss. behavioral changes are thought to be caused by localised cerebral hypoperfusion, can include attention deficits, learning deficits, emotional disorders (emotional lability, fear of night, and night terrors), and internalization problems (anxious, depressive or aggressive behavior). causes the specific cause of kawasaki disease is unknown. a plausible explanation is that it may be caused by an infection that triggers an inappropriate immunologic cascade in a small number of genetically predisposed children. the pathogenesis is complex and incompletely understood. various explanations exist. (see #classification) circumstantial evidence points to an infectious cause. 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. despite intensive search, no single pathogen has been identified. there has been debate as to whether the infectious agent might be a superantigen (i.e. one commonly associated with excessive immune system activation). current consensus favors an excessive immunologic response to a conventional antigen which usually provides future protection. research points to an unidentified ubiquitous virus, 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. winds blowing from central asia correlate with numbers of new cases of kawasaki disease in japan, hawaii, and san diego. 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. genetic factors are also thought to influence development of coronary artery aneurysms and response to treatment. 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. the associated genes and their levels of expression appear to vary among different ethnic groups, both with asian and non-asian backgrounds. snps in fcgr2a, casp3, blk, itpkc, cd40 and orai1 have all been linked to susceptibility, prognosis, and risk of developing coronary artery aneurysms. various other possible susceptibility genes have been proposed, including polymorphisms in the hla region, but their significance is disputed. genetic susceptibility to kawasaki disease appears complex. 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 criteria for diagnosis fever of ≥5 days' duration associated with at least four† of these five changes bilateral nonsuppurative conjunctivitis one or more changes of the mucous membranes of the upper respiratory tract, including throat redness, dry cracked lips, red lips, and "strawberry" tongue one or more changes of the arms and legs, including redness, swelling, skin peeling around the nails, and generalized peeling polymorphous rash, primarily truncal large lymph nodes in the neck (>15 mm in size) disease cannot be explained by some other known disease process †a diagnosis of kawasaki disease can be made if fever and only three changes are present if coronary artery disease is documented by two-dimensional echocardiography or coronary angiography. source: nelson's essentials of pediatrics, review angiography 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. subtypes based on clinical findings, a diagnostic distinction may be made between the 'classic' / 'typical' presentation of kawasaki disease and 'incomplete' / 'atypical' presentation of a "suspected" form of the disease. regarding 'incomplete' / 'atypical' presentation, american heart association guidelines state that kawasaki disease "should be considered in the differential diagnosis of prolonged unexplained fever in childhood associated with any of the principal clinical features of the disease, and the diagnosis can be considered confirmed when coronary artery aneurysms are identified in such patients by echocardiography." a further distinction between 'incomplete' and 'atypical' subtypes may also be made in the presence of non-typical symptoms. 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. infectious and noninfectious conditions requiring consideration include: measles and other viral infections (e.g. adenovirus, enterovirus); staphylococcal and streptococcal toxin-mediated diseases such as scarlet fever and toxic shock syndrome; drug hypersensitivity reactions (including stevens johnson syndrome); systemic onset juvenile idiopathic arthritis; rocky mountain spotted fever or other rickettsial infections; and leptospirosis. infectious conditions that can mimic kawasaki disease include periorbital cellulitis, peritonsillar abscess, retropharyngeal abscess, cervical lymphadenitis, parvovirus b19, mononucleosis, rheumatic fever, meningitis, staphylococcal scalded skin syndrome, toxic epidermal necrolysis, and lyme 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. the world health organization is examining possible links with covid-19. 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. inflammation, or vasculitis, of the arteries and veins occurs throughout the body, usually caused by increased production of the cells of the immune system to a pathogen, or autoimmunity. systemic vasculitides may be classified according to the type of cells involved in the proliferation, as well as the specific type of tissue damage occurring within the vein or arterial walls. under this classification scheme for systemic vasculitis, kawasaki disease is considered to be a necrotizing vasculitis (also called necrotizing angiitis), which may be identified histologically by the occurrence of necrosis (tissue death), fibrosis, and proliferation of cells associated with inflammation in the inner layer of the vascular wall. other diseases involving necrotizing vasculitis include polyarteritis nodosa, granulomatosis with polyangiitis, henoch–schönlein purpura, and eosinophilic granulomatosis with polyangiitis. kawasaki disease may be further classified as a medium-sized vessel vasculitis, affecting medium- and small-sized blood vessels, 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. within this classification of childhood vasculitides, kawasaki disease is, again, a predominantly medium-sized vessel vasculitis. it can also be classed as an autoimmune form of vasculitis. it is not associated with anti-neutrophil cytoplasmic antibodies, unlike other vasculitic disorders associated with them (such as granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis). 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). to prevent damage to coronary arteries, treatment should be started immediately following the diagnosis. intravenous immunoglobulin (ivig) is the standard treatment for kawasaki disease 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. a 2023 systematic review and meta-analysis revealed that no prediction models