Pediatrics

Kawasaki disease

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Kawasaki Disease? What are the typical findings for this disease?

Kawasaki Disease (KD) is an acute, febrile illness caused by self-limited vasculitis of unknown etiology that can be seen in children of all ages, but is most common in young children (<5 years of age). It is the leading cause of acquired heart disease in the United States.

The illness is characterized by fever, nonexudative conjunctivitis, oral changes (red, cracked or chapped lips, erythema of oral mucosa), cervical lymphadenopathy, extremity changes (edema of hands/feet, palm/sole erythema), and rash. Children do not always have all of the characteristic signs at one point in time and many children never develop all of the characteristic signs. Children who have fever and less than four of the major diagnostic criteria, and who are ultimately diagnosed with KD are said to have “Incomplete Kawasaki Disease (IKD).”

In 20-25% of untreated children with KD, coronary artery aneurysms, dilation, or ectasia develop. Coronary artery abnormalities may lead to serious morbidity such as myocardial infarction or cardiac ischemia in some patients. Since the etiology of KD is unknown, there is no diagnostic test. The diagnosis is based on clinical criteria and the exclusion of other things on the differential diagnosis.

Clinical Diagnosis of Kawasaki Disease (Classic Clinical Criteria):

Adapted from the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, 2004.

Fever for at least 5 days* PLUS presence of at least 4 of the following principal features†:

1. Eye changes: Bilateral bulbar conjunctival injection without exudates

2. Oral Changes: Includes erythema of the oral/pharyngeal mucosa; red, cracked or chapped lips; strawberry tongue

3. Extremity changes: Includes erythema of the palms/soles; edema of the hands/feet; in the subacute phase (week 2 or 3 of illness) peeling of the fingers/toes or palms/soles

4. Skin: Polymorphous rash

5. Nodes: Cervical lymphadenopathy; node >1.5 cm in diameter, usually unilateral

* If fever and ≥4 principal features are present, the diagnosis can be made on day 4. Clinicians with experience in diagnosis of KD may establish the diagnosis before day 4 of illness.

†Patients with ≥5 days of fever, but less than 4 principal features can be diagnosed with KD if coronary artery abnormalities are observed.

Other clinical entities may have similar or overlapping signs and symptoms.

What other disease/condition shares some of these symptoms?

Differential Diagnosis of Kawasaki Disease:

1. Viral infections - fever and rash are common is young children with viral infections (examples - adenovirus, enterovirus, Epstein Barr virus, measles)

2. Scarlet fever

3. Staphylococcal aureus or Group A streptococcus toxin mediated disease or toxic shock

4. Stevens-Johnson Syndrome or Drug Reaction

5. Juvenile Idiopathic Arthritis

6. Acute bacterial cervical lymphadenitis

7. Leptospirosis or Rocky Mountain Spotted Fever

8. Hypersensitivity reaction to mercury (acrodynia) - very rare in the United States

The differential diagnosis of KD includes bacterial disease, viral disease, and autoimmune disease. Developing a more limited differential diagnosis can be accomplished by paying attention to history and physical examination clues and laboratory results which may rule out some things and make other things more likely.

The major clinical criteria for KD may develop over time, so sometimes children ultimately diagnosed with KD have been seen by physicians earlier in the illness and given a diagnosis that reflects recognition of some component of their KD. For example, febrile patients may have a urinalysis done which shows WBCs in the urine. They may then receive a diagnosis of urinary tract infection, although the urine culture then fails to grow. Other common initial diagnoses include acute bacterial cervical adenitis (reflecting the finding of an enlarged cervical node), aseptic meningitis (as the result of an LP done for fever and irritability), or drug reaction (due to rash which developed after patient was given an antibiotic prescribed when the patient was evaluated for fever).

What caused this disease to develop at this time?

Kawasaki Disease is more common in boys (about 1.5 boys:1 girls) and in young children less than 5 years of age. A median age of 18 months-2 years is reported by most studies. Although 75% of cases occur in children less than 5 years of age, KD is seen in older children. Older children with KD (particularly those >8yrs) and very young children (<6 months) have higher risks of coronary artery aneurysms.

Kawasaki Disease is most commonly seen in the winter/spring in temperate climates. Outbreaks sometimes occur over a few weeks in a geographical area. Outbreaks in Japan have sometimes been associated with movement of the outbreak across the country. There is no strong evidence for person to person transmission. However, many experts believe this disease is caused by a common viral or bacterial pathogen or an abnormal immune response in an individual to the pathogen. There is some evidence that there may be a respiratory portal of entry. Recent studies by one group of investigators have focused on a possible etiologic agent transmitted by the wind. There is some evidence that winds originating over an agricultural area in China may transmit some yet unknown toxin or agent that causes KD. More research is needed to to establish the cause of KD.

There is evidence of a genetic predisposition to KD. Although KD is seen in all ethnicities, persons of Japanese, Korean and Pacific Islander heritage have the highest incidence rates. Disease rates in these populations are the same even if children of those heritages are born and live in countries with lower attack rates.

Although KD seldom occurs in siblings at the same time, family members of an index case do appear to be at higher risk to contract KD. Higher rates of KD have been reported in the siblings of index cases, twins, and of children of a parent with a history of KD. These observations suggest that genetic predisposition may be important.

A number of authors have reported genetic variants or single nucleotide polymorphisms in a variety of genes which may convey increased risk of KD or of coronary artery lesions in patients with KD in certain populations. Examples include pro-inflammatory genes (TNF-alpha, IL-4), genes involved in angiogenesis (VEGF), matrix metalloproteinases, and genes involved in apoptosis (caspace3).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory studies are not part of the clinical diagnostic criteria for classic KD, but can be helpful in considering the likelihood of KD or in establishing another etiology for the patient’s signs/symptoms.

Laboratory studies are utilized in the American Heart Association algorithm for patients with possible IKD: the algorithm is further described later in this article and is utilized in patients who do not meet the classic clinical criteria for diagnosis but have fever for ≥5 days and 2 or 3 of the principal features described in the classic clinical criteria.

In evaluating patients with suspected KD, the following studies are helpful:

1) CBC with differential

2) ESR

3) CRP

4) Liver function tests (to include total bilirubin, AST, ALT, GGT, albumin)

5) Urinalysis with microscopic analysis

6) Blood culture

7) Echocardiogram – An echocardiogram should be done in all patients in whom you believe have KD and will initiate therapy, and may be helpful in those who the diagnosis is being seriously considered in. A normal echocardiogram does not rule out KD as most patients with KD never develop coronary artery abnormalities. However, in patients with a compatible clinical presentation for KD (even without all required standard criteria), the presence of coronary artery dilation or aneurysm formation establishes the diagnosis.

Other laboratory studies should be considered on a situational basis to help rule out other diagnoses. For example, in an unimmunized child who has recently travelled to Africa, measles might be important to exclude. A lumbar puncture may be appropriate in some patients with irritability to exclude meningitis.

For a discussion of laboratory test use in patients with suspected IKD, please see the description of the American Heart Association algorithm in next section.

CBC - Typically, an elevated white blood cell count, with a left shift is seen. A normochromic, normocytic anemia for age is commonly seen. In the second or third week of illness, the platelet count may be elevated. Thrombocytosis typically peaks in the third week of illness, often with platelet counts of 700,000-1 million/mm3. Thrombocytopenia is seen occasionally on presentation, and has been associated with admission to the intensive care unit and development of coronary artery aneurysms.

ESR/CRP - Inflammatory markers, such as ESR and CRP are typically elevated at presentation. However, a substantial number of patients with KD may have a discrepancy in the amount of elevation in the ESR and CRP (i.e. high ESR and low-to-mildly elevated CRP or high CRP and low to mildly elevated ESR). Patients who present very late in the illness may have mild or no elevation in inflammatory markers.

Liver Panel - About 45% of KD patients have at least mild abnormalities of bilirubin, AST, ALT, and/or GGT. Most patients have low albumin. Occasionally patients present with jaundice and the diagnosis of KD is delayed by focusing on the liver as the primary problem. Therefore, it is important to consider KD in the differential diagnosis of febrile children with jaundice or hepatitis if they have other clinical manifestations of KD (for example, red eyes, mucosal changes, adenopathy, extremity changes, or rash).

Urinalysis with Microscopic - Patients with KD commonly have sterile pyuria, so a urinalysis with microscopic is helpful.

Blood Culture - A blood culture, if positive, may establish an alternative diagnosis that would require antibiotics. The most common bacterial etiologies that could be confused with KD are Staphylococcal or Streptococcal toxin-mediated disease or toxic shock. Both Staphylococcus aureus and Group A Streptococcus can cause focal or systemic infections (abscess, sinusitis, osteomyelitis, bacteremia, septic arthritis, etc), and in some cases, toxic shock syndrome. The signs and symptoms of toxin-mediated disease or toxic shock are similar to many of the features of KD (conjunctival injection, red, cracked lips, rash, swollen hands and feet).

Other laboratory studies sometimes done in the evaluation of patients ultimately diagnosed with KD include:

  1. Lumbar Puncture - In children with KD who have undergone a lumbar puncture, approximately 30-50% have evidence of aseptic meningitis, usually with lymphocyte/monocyte predominance, normal glucose and protein, and a negative gram stain and culture. A mild increase in CSF protein and low CSF glucose is observed in some patients rarely.

  2. Nasal Wash - A nasal wash with viral direct fluorescent antibody or PCR may be helpful to establish an alternate diagnosis if the virus isolated is compatible with the clinical syndrome AND other laboratory studies support a viral etiology (as opposed to KD). However, KD incidence is highest in the winter/spring, when there is a high incidence of many respiratory viral infections. It is not uncommon for KD patients to test positive for a virus. Therefore, the exclusion of KD, based on documentation of a virus present in the nasal wash sample, must be considered carefully. Expert opinion may be helpful in determining the correct diagnosis in these patients.

Would imaging studies be helpful? If so, which ones?

An echocardiogram, including evaluation of the coronary arteries is indicated in all patients diagnosed with KD.

Dilation, ectasia, or aneurysms of the coronary arteries may be observed. Coronary artery measurements are adjusted based on body surface area and reported as Z scores. Z scores ≥2.5 are usually considered abnormal. Aneurysm diameter is measured in millimeters; giant aneurysms are those with a diameter of >8 mm. A normal echocardiogram does not rule out KD; in fact, most patients have normal echocardiograms. Please see the next section for a description of the use of echocardiogram in the evaluation of patients with suspected IKD.

Confirming the diagnosis

The diagnosis of classic KD is established clinically by the patient's history and physical examination findings fulfilling the Classic Clinical Criteria. Some KD patients may present without all of the manifestations to satisfy the Classic Clinical Criteria , yet they may still have KD and be at risk for developing coronary artery abnormalities. This has been termed “Incomplete” KD. Children of any age, may have IKD. Infants younger than 6 months of age are more likely to present with subtle clinical criteria or to present with IKD.

In 2004, the American Heart Association Committee on Rheumatic Fever, Endocarditis, and KD, published an algorithm to provide guidance on evaluation and treatment of those children in whom IKD is suspected. This algorithm can be used for children presenting with ≥5 days of fever AND 2-3 clinical diagnostic criteria. This algorithm does not constitute an evidence based algorithm, but rather is a consensus opinion of national experts. Consult an expert on KD for assistance in evaluation of suspected cases whenever needed.

Summary of Algorithm for Evaluation of Patients with Suspected Kawasaki Disease Who Do Not Meet the Classic Clinical Criteria for Diagnosis of Kawasaki Disease*

*Due to the complexity of this algorithm (and footnotes that are not reproduced here), it is recommended that the full algorithm be viewed at http://aappolicy.aappublications.org/cgi/reprint/pediatrics;114/6/1708.pdf (Newburger JW, Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics, 114(6):1708-1733, 2004).

The algorithm begins with those patients with possible IKD who have >5 days of fever and only 2 or 3 of the principal features (conjunctival injection, oral changes, extremity changes, rash, and enlarged cervical node >1.5 cm in diameter):

A) Assess CRP and ESR

1. If CRP <3.0 mg/dL AND ESR<40 mm/hr, follow the patient daily to see if fever resolves over the next 2 days:

a. If fever resolves in the next 2 days and there is no peeling during convalescence, no further follow-up is recommended

b. If fever resolves in the next 2 days, but typical peeling (beginning under the nailbeds of the fingers and toes; may involve palms and soles) is observed, an echocardiogram is recommended. If the echocardiogram shows coronary artery abnormalities, the patient should be treated for KD.

c. If fever continues for 2 more days, patient characteristics (principal features) should be reassessed to ensure following this algorithm is still appropriate. If the patient now fulfills classic KD criteria, the patient should be treated appropriately (with IVIG and aspirin - see section on treatment). If the patient’s illness is still consistent with KD but does not meet full classic criteria (and patient possesses 2-3 of the principal features) then the algorithm directs you to reassess CRP and ESR (go back to point "A" in the algorithm summary) and continue through the algorithm again.

2. If CRP ≥3.0 mg/dL OR ESR ≥40 mm/hr supplementary laboratory criteria are evaluated for abnormalities. Supplemental lab criteria abnormalities include albumin <3.0 g/dL, anemia for age, elevation of alanine aminotransferase, platelets after illness day seven ≥450,000/mm3, white blood cell count ≥15,000/mm3, and urine ≥10 white blood cells/high-power field.

a. If there are ≥ 3 supplementary laboratory criteria with abnormalities as described above, the child should have an echocardiogram and be treated (regardless of whether the echocardiogram is abnormal) for KD.

b. If there are LESS than 3 supplementary laboratory criteria with the abnormalities described above then an echocardiogram is recommended.

i. If the echocardiogram shows coronary artery abnormalities, (aneurysms or coronary arteries with z score ≥2.5) OR has ≥3 other described echocardiographic abnormalities associated with KD (perivascular brightness, lack of tapering of the vessels, decreased left ventricular function, mitral regurgitation, pericardial effusion, right coronary artery, or left anterior descending coronary artery z scores of 2-2.5), the child should be treated for KD. Note the interpretation of the echocardiogram findings is complex. Complete review of the full algorithm and footnotes is recommended, as is consultation with a KD expert.

ii. If the echocardiogram is normal, follow the patient, to see if fever abates in the next 2 days. For those children whose fever resolves, KD is unlikely and no further testing or follow-up is recommended. For children with fever that persists, a repeat echocardiogram is recommended and it is recommended that an expert in KD be consulted for further advice.

Young infants are treated as a special case in IKD evaluation, since they are more likely to have subtle clinical criteria and are at higher risk for coronary artery abnormalities if they have KD. Infants < 6 months of age who have >7 days of fever without identified explanation should undergo laboratory testing looking for evidence of systemic inflammation even if the infant meets no clinical criteria for KD. If there is evidence of inflammation (elevated CRP or ESR), an echocardiogram should be done, and the child treated for KD if coronary artery abnormalities are present.

If you are able to confirm that the patient has Kawasaki Disease, what treatment should be initiated?

Patients diagnosed with acute KD (or IKD) should receive intravenous immune globulin (IVIG) and aspirin therapy. IVIG is given as a single 2 gram/kg intravenous infusion over 10-12 hours. Aspirin is initiated at 80-100 mg/kg/day orally in 4 divided doses.

A randomized, placebo-controlled, multi-center trial established that in KD patients presenting within the first 10 days of illness, IVIG plus aspirin significantly reduced the risk of developing coronary artery abnormalities. Although studies have not been done in children presenting after 10 days of illness, clinical experience and national guidelines (American Heart Association) recommend treatment of all children diagnosed with KD (possible exceptions being those children diagnosed later than 10 days who have a normal echocardiogram and no evidence of ongoing inflammation). However, referral to an expert on the evaluation and management of children with KD is advised before deciding to withhold treatment from any child diagnosed with KD.

Once the patient is significantly clinically improved and has been afebrile for at least 48-72 hours, the aspirin dose is decreased to 3-5 mg/kg/day given orally once a day. This dose should be continued until the cardiologist determines that it can be discontinued. Usually, patients are seen by cardiology at 1-2 weeks and 6-8 weeks after discharge for repeat echocardiograms. Low dose aspirin is typically discontinued if no coronary artery abnormalities have been detected between onset of illness and the 6-8 week follow-up.

Children found to have giant coronary artery aneurysms (>8mm) are usually anti-coagulated with low molecular weight heparin or warfarin (under the direction of a cardiologist or hematologist) to prevent thrombosis.

Patients who develop influenza or varicella while on aspirin may be at risk for Reye syndrome. Parents of children taking aspirin should be instructed to contact their physician if the patient develops symptoms of either disease to determine if therapy should be interrupted or if further evaluation is needed. Discussion with the patient’s cardiologist about an alternative agent (or interruption of therapy) is needed if the patient is suspected to have influenza or varicella.

Prevention of influenza is important. The patient and all household contacts should receive seasonal influenza vaccine unless otherwise contraindicated (prior to discharge if possible). Patients with KD (or who have recovered from KD) and who are taking aspirin should receive the injectable (killed) influenza vaccine. The live intranasal vaccine is contraindicated in patients taking aspirin due to theoretical concerns that, because it is a live vaccine, it could increase risk of Reye syndrome.

Rarely, patients have a history of aspirin allergy. Those patients should be discussed with a cardiologist for recommendations for an alternative agent.

Receipt of routine measles and varicella vaccines should be deferred for 11 months after receiving IVIG for KD, since IVIG may interfere with the development of an appropriate serologic response to these vaccines. If a patient is at risk for exposure to measles or varicella (i.e. impending international travel to a country where exposure may occur), measles and/or varicella vaccines can be given earlier, with reimmunization at >11 months after receipt of IVIG (and at least 4 weeks after the previous immunization).

The manufacturer of the varicella vaccine recommends avoiding aspirin use in patients for 6 weeks after the varicella vaccine (due to the association of aspirin use and Reye Syndrome after naturally-acquired varicella). This presents a problem for the occasional KD patient still on aspirin at the time the varicella vaccine is indicated.

The most recent guidance from the Advisory Committee on Immunization Practices' regarding varicella vaccination states that no adverse events have been reported that are associated with varicella vaccine in children taking salicylates. They state that vaccination with subsequent close monitoring should be considered for children on aspirin, and that the risk of serious complications associated with aspirin is likely higher in those children who acquire varicella naturally than in those that receive the vaccine. (See full recommendations at MMWR 2007, http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5604a1.htm).

If there is family or physician concern about varicella vaccination with ongoing aspirin use, the patient's cardiologist could provide an opinion on whether an alternative agent could be temporarily used in the place of aspirin.

The administration schedule for inactivated vaccines is not affected by IVIG.

What are the adverse effects associated with each treatment option?

Intravenous immune globulin and aspirin is the only first line therapy that has been studied and shown effective in decreasing risk of coronary artery abnormalities. IVIG has been used for treatment of KD for many years. Most patients defervesce and have clinical improvement within 24-36 hours of the end of the infusion. IVIG is a blood product made from several thousand donors. The product is screened for known infectious agents, as are other blood products. Special processes in the manufacturing of IVIG occur to inactivate known viruses. However, since the product is a blood product there is a very small risk that it could contain a known or unknown infectious agent. HIV has never been reported to be transmitted via IVIG.

The most common side effects of IVIG are fever, and/or shaking chills that occur in some patients at the beginning of the infusion. Most can be treated by temporarily stopping the infusion and restarting it a slower rate. Many physicians pretreat the patient with acetaminophen and diphenhydramine prior to starting the IVIG infusion to reduce the frequency of high fevers and chills. Aseptic meningitis has been described in about 10% of IVIG recipients and usually presents as headache. However, aseptic meningitis is also seen in some KD patients (prior to treatment with IVIG). Uncommon or rare risks of IVIG include renal insufficiency or failure (usually reversible), anaphylaxis (described in patients with IgA deficiency), and hemolytic anemia (rare).

What are the possible outcomes of Kawasaki Disease?

Adverse outcomes of KD are related to underlying coronary abnormalities: myocardial infarction, sudden death, or ischemic heart disease. In general, the more severe the coronary artery abnormalities, the higher the risk of adverse events. The most serious adverse outcome associated with KD is thrombosis of a coronary artery leading to myocardial infarction or death. The highest risk period for this is between the 15-45th day of the acute illness when both vasculitis and thrombocytosis are peaking. This is a rare event with the overall mortality rate estimated at 0.17% in hospitalized KD patients in the United States. However, sudden death from MI can occur years later in patients who developed coronary aneurysms and stenosis as a result of acute KD.

Most patients respond very quickly to treatment with IVIG and aspirin, in terms of general appearance, resolution of fever, and improvement of rash and other clinical findings. Only 15% of patients have persistent fever (fever lasting beyond 36 hours after the end of the IVIG infusion) or have recrudescent fever. Patients with persistent or recrudescent fever need additional therapy. These patients should be promptly referred to a physician with expertise in KD for further evaluation and treatment.

Many (but not all) patients that have coronary artery abnormalities as a result of KD have an abnormal echocardiogram at diagnosis. Even if the initial echocardiogram is normal, follow-up echocardiograms will be done after discharge to ensure that coronary artery abnormalities have not developed.

Parents often ask about long term sequelae from KD. Answers to these questions depend upon whether there are abnormalities noted in the coronary arteries and may need to be individualized based on discussion with the patient’s cardiologist. For patients with normal echocardiograms (at diagnosis and through 6-8 weeks of follow-up), the prognosis is excellent and most children resume normal activities with no restrictions once they have convalesced. However, some studies have suggested that even in children with normal echocardiograms, abnormalities in endothelial function may persist. Whether this will ultimately increase risk of atherosclerosis later in life is unknown at this time.

Advice regarding maintenance of a heart healthy lifestyle throughout life is prudent including avoidance of a high-fat diet, avoidance of smoking, and maintaining good blood pressure and lipid panel control.

Prognosis in patients with coronary artery abnormalities should be discussed with the cardiologist. In general, mild dilation of the coronary arteries often resolves in the first 2-3 months of follow-up. In patients with small aneurysms, approximately 50% will have normal appearing echocardiograms in 1 year, due to arterial remodeling. More extensive dilation, large aneurysms, or giant aneurysms (those >8mm in diameter) are indicative of more severe involvement and are associated with a higher risk of cardiac morbidity (stenosis, infarction). These patients will be closely monitored by a cardiologist.

What causes this disease and how frequent is it?

The etiology of KD is unknown. The highest incidence of KD is seen in Japan, where the incidence rate is 130 of 100,000 children <5 years age-per year. In the United States, the incidence rate varies in ethnic populations, but in general is about 20 cases per 100,000 children <5 years age-per year. In the United States, the incidence is highest in Asian or Pacific Islanders, intermediate in African Americans and Hispanics, and lowest in Caucasians. In Hawaii, the incidence is much higher than the continental United States (45 cases per 100,000 children < 5 years age- per year), likely due to a large proportion of the Hawaiian population being of Japanese or Pacific Islander descent.

How do these pathogens/genes/exposures cause the disease?

The cause of KD is currently unknown. Some studies have found environmental exposures to freshly shampooed carpets, residing near a body of water, and humidifier use to increase risk of KD, but these findings have not been confirmed in other studies.

Please see the section on "What Caused this Disease to Develop" for further information on other associations with KD.

Other clinical manifestations that might help with diagnosis and management

Irritability is often seen in patients with KD, but absence of irritability does not rule out the diagnosis. Tachycardia out of proportion to the fever may be an indicator of myocarditis, which occurs to some extent in many patients with KD. Although not a diagnostic criteria, accentuation of rash in the groin or perineal area is common. Peeling in the groin/perineal area may also be seen.

Rarely, KD patients develop hypotension, necessitating admission to the intensive care unit for blood pressure support. KD patients admitted to the intensive care unit are more likely to be female, have thrombocytopenia, have a higher percent band count (on CBC differential), and have higher CRP values. They are also more likely to have persistent or recrudescent fever after treatment with IVIG (IVIG resistance) requiring additional therapy. One study found KD patients admitted to the intensive care unit were more likely to have coronary artery abnormalities. It is important to consider KD in the differential diagnosis of febrile patients in shock to avoid diagnostic delays.

Vomiting, diarrhea, and/or abdominal pain are reported in about 1/3 of KD patients. Uncommonly, KD patients present with abdominal symptoms being the chief complaint. Mildly elevated transaminases are often seen in KD patients. Rarely, patients will present with clinical jaundice (in addition to fever, rash and other symptoms of KD). Gallbladder hydrops is reported in about 15% of patients.

Patients who have previously had Bacille Calmette-Guérin (BCG) vaccination, may experience erythema and/or induration at the site of immunization.

What complications might you expect from the disease or treatment of the disease?

Cardiac complications are the most serious problems and include myocardial ischemia, myocardial infarction and sudden death. Other cardiovascular complications include valvulitis (usually mitral regurgitation), pericardial effusion, and aneurysms in other systemic arteries.Some specialized centers evaluate KD patients with severe coronary artery abnormalities with cardiac MRI/MRA or ultra-fast computed tomography (CT) scan. These tests are not widely available and are currently used only by some experts in KD management.

Are additional laboratory studies available; even some that are not widely available?

How can Kawasaki Disease be prevented?

The etiology of KD is unknown and there are no known preventative measures.

What is the evidence?

Newburger, JW, Takahaski, M, Gerber, M. "Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association.". Pediatrics,. vol. 114. 2004. pp. 1708-1733,.

(This is a detailed and practical reference geared to diagnosis, treatment and management of patients with Kawasaki Disease. It incorporates use of an algorithm for evaluating patients with suspected Incomplete Kawasaki Disease. It is a useful reference for primary care physicians as well as cardiologists and pediatric infectious disease physicians. Evidence levels are cited. Some recommendations in this article are the consensus of a national expert committee.)

Newburger, JW, Takahashi, M, Burns, JC. "The treatment of Kawasaki Syndrome with Intravenous Gamma Globulin.". NEJM. vol. 315. 1986. pp. 341-347.

(Classic article describing a multicenter, randomized trial of treatment with IVIG plus aspirin versus aspirin alone. A significant reduction in coronary artery abnormalities was seen in the IVIG plus aspirin group.)

Burns, JC, Glodée, MP. "Kawasaki syndrome.". The Lancet. vol. 364. 2004. pp. 533.

(Good general review article with a detailed table on differential diagnosis and clues to narrowing the differential.)

Rowley, AH, Baker, SC, Shulman, ST. " Garcia FL et al. RNA-containing cytoplasmic inclusion bodies in ciliated bronchial epithelium months to years after acute Kawasaki disease.". PLoS One. vol. 3. 2008. pp. e1582.

(Article describes research suggesting a respiratory route of acquisition and possible viral etiology).

Rodó, X, Curcoll, R, Robinson, M. "Tropospheric winds from northeastern China carry the etiologic agent of Kawasaki disease from its source to Japan.". Proceedings of the National Academy of Sciences of the United States of America. vol. 111. 2014. pp. 7952-7.

Ongoing controversies regarding etiology, diagnosis, treatment

Despite over 40 years of research on KD, the etiology is still unknown. Many believe that KD is an infection or the body’s abnormal immune response to an infectious agent. Supporting this is the similar clinical appearance to known Staphylococcus aureus and Group A Streptococcus toxin-mediated disease, an increased incidence in the winter/spring seasons, and clusters of cases that occur in communities over a short period of time.

Many researchers have described genetic polymorphisms that seem to increase risk of KD. KD is predominately a disease of young children, suggesting the agent could be some common agent that most children are exposed to, but only a subset develops a recognizable clinical disease. There is some evidence that the pathogen may enter via the respiratory route and that it may be viral in origin. It is possible that the common agent may incite an enhanced immunologic response in genetically susceptible hosts.

A series of recent investigations have focused on wind patterns and the possible transmission of an etiologic agent o toxin via the wind. Further research is needed to determine the etiology of KD and to develop a diagnostic test.

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