Kawasaki Disease

Kawasaki disease is an autoimmune disease. It usually affects young children, but can sometimes affect adults as well.^[1] It typically causes high fever, rash, red eyes, swelling of the hands and feet, enlarged lymph nodes, and heart abnormalities. The heart abnormalities, which include dilation of the arteries to the heart and even heart attacks, are the most worrisome complications. In developed countries, Kawasaki disease is the most common cause of acquired heart abnormalities in children.^[2]

Other Names

• Mucocutaneous lymph node syndrome

Types

Kawasaki disease is a type of autoimmune vasculitis—a disease that causes the body to attack its own blood vessels all over the body. Because of this widespread attack of blood vessels, a wide range of organs in the body may be affected, including meninges (outer covering of the brain), heart,^[3]gallbladder,^[4] joints,^[5] and skin.^[6] Rarely, severe liver^[7] and kidney^[8] complications may develop. Kawasaki disease is much more prevalent in Japan, but occurs regularly in the United States as well. Currently, Kawasaki disease is the leading cause of acquired heart disease in Japan and in the United States, surpassing acute rheumatic fever.

Kawasaki disease may affect the coronary arteries, which carry oxygen-rich blood to the heart. As a result, a small number of children who have Kawasaki disease may develop serious heart problems, including heart attacks.^[9]

Signs and Symptoms

Symptoms of Kawasaki disease include:

• Red eyes: Both eyes are red, not just one. This resembles conjunctivitis or "pinkeye," except that there is no discharge. If there is discharge (watery or whitish liquid) coming from the eyes, then it is likely that the symptoms are due to something else, such as conjunctivitis or measles.

Conjunctivitis. Source: Wikimedia Commons

• Changes in the mouth, including a bright red throat, resembling strep throat; bright red lips; dry or cracked lips; and strawberry tongue. The latter can also be seen in scarlet fever and toxic shock syndrome).

Strawberry tongue. Source: Wikimedia Commons, CCASA 2.5 License

• Changes in the hands and feet, including swelling; redness of the palms, soles, or fingers; and peeling (desquamation) of the skin around the fingernails. Peeling generally begins about 14 days into the illness, so should not be relied upon for diagnosis.
• Rash, which can be pink to red and can vary, although vesicles (tiny blisters with clear fluid) are not present. The rash can resemble the rashes of scarlet fever or of measles, which can make the diagnosis confusing.
• Enlarged lymph nodes in the neck: Usually one lymph node is very enlarged on one side of the neck, although there may be other lymph nodes somewhat enlarged as well. The node feels like a large round mass in the neck that moves and is not painful. The largest lymph node must measure at least 1.5 centimeters in diameter, as children often have small round lymph nodes that are not a sign of serious disease.
• Fever: In order to make the diagnosis, a patient must have a fever of greater than 100.4° Fahrenheit for at least five days. The fever tends to persist even if the patient is given medications like acetominophen (Tylenol), ibuprofen (Motrin), or antibiotics. Although the criterion for diagnosis calls for five days of persistent fever, an experienced specialist may make the diagnosis sooner and start treatment earlier than five days if there are other obvious features of Kawasaki disease.

Other signs and symptoms

In addition to the above symptoms, the following complications of Kawasaki may occur, which may be present early or late in the illness.

• Arthritis, or joint pain with signs of inflammation, such as redness, swelling, loss of function
• Arthralgia, or joint pain. Typically, the joint pain occurs as the disease progresses past the early acute phase.
• Diarrhea
• Aseptic meningitis, or inflammation of the meninges, the outer covering of the brain. Unlike bacterial or viral meningitis, aseptic meningitis is not caused by any infection but is caused by the autoimmune process itself. The cells of the body's own immune system attack the cells of the meninges. Aseptic meningitis is diagnosed by a lumbar puncture (spinal tap), which will show a mild elevation of white blood cells in the cerebrospinal fluid without any bacteria or viruses. It isn't necessary to perform a lumbar puncture if the diagnosis of Kawasaki disease is already clear from other symptoms.
• Sterile pyuria, or infection-fighting cells in the urine without any bacteria to cause an infection. This is caused by the autoimmune process attacking the cells of the urethra. A urine test will show a mild elevation in white blood cells, but the urine culture will not show any significant bacteria present.
• Thrombocytosis, or high levels of platelets (red blood cells that help with clotting). This begins to develop after at least a week into the illness.
• Pancreatitis, or inflammation of the pancreas. Pancreatitis may cause abdominal pain in the child with Kawasaki disease.^[10] A blood test for amylase and lipase can help establish the diagnosis.
• Hydrops of the gallbladder: The gallbladder, a storage bag for bile under the liver, can become enlarged and painful in Kawasaki's disease. This complication is rare, but a mass in the upper right side of the abdomen in a child with Kawasaki disease is likely to indicate hydrops of the gall bladder.^[4] This condition can be treated supportively and generally does not require surgery.
• Irritability: Extreme irritability is seen in children during the acute phase of the illness, which generally resolves after treatment.

Causes

The cause of Kawasaki disease is uncertain, but it is suspected that an infection by an unknown virus triggers the autoimmune response in certain genetically-predisposed children.

Autoimmune

Kawasaki disease is an autoimmune disease, meaning that the body is induced to attack its own cells. antibodies, the immune system's attack proteins, are supposed to attack germ invaders like bacteria and viruses, but can sometimes turn on the body itself. Antibodies seem to do the majority of the damage in Kawasaki disease. High levels of autoantibodies, or antibodies against the body, are present in Kawasaki patients, and some treatments are designed to block these autoantibodies.

Virus

A virus may trigger the autoimmune process. Evidence for a virus includes the fact that the disease tends to be self-limited, occurs in clusters in certain geographical locations, tends to affect young children, produces a fever and a rash, and is characterized by periodic epidemics of that tend to move geographically in a wavelike distribution. This is just how viruses behave. But it is not yet known what virus may cause Kawasaki disease.

Genetic

Even though a virus may trigger this disease, only certain children develop it. Such children may have a genetic predisposition that makes them vulnerable when infected by the virus that causes it. Another clue that genes might be contributing is that Kawasaki disease disproportionately affects children of Asian descent. Children with Japanese heritage are particularly affected. Males are more affected than females, and most cases occur in children younger than five years old.

A recent study identified a single genetic defect in inositol 1,4,5-triphosphate 3-kinase, a substance that is involved in the regulation of T-cell activation (a white blood cell that functions in the immune response). This defect is associated with an increased risk of Kawasaki disease in Japan and in the United States. This genetic defect also seems to increase the risk of coronary artery problems in Kawasaki patients.^[11]

Vaccine-associated

Vaccines have been implicated in Kawasaki disease. Most recently the FDA and others reported an increased risk for Kawasaki disease from the RotaTeq vaccine recently licensed for the prevention of rotavirus in children.^[12][13] The Bacille Calmette-Guérin vaccine, used in some parts of the world to prevent tuberculosis, has been noted to help in the diagnosis of Kawasaki disease in cases when the vaccine scar became red and irritated.^[14][15][16] It is not clear that there is any causal relationship, though.

Diagnosis

Specific criteria exist for the diagnosis of Kawasaki disease. The child must have fever lasting for at least five days. In addition, at least four of the five above mentioned symptoms must be present.

Tests

In addition to the above criteria, the following tests may be useful in diagnosing Kawasaki disease.

• Complete blood count: The white blood cell count may be elevated. The hemoglobin level may also be low, indicating that the child has a mild anemia. More importantly, platelet levels are often very high, sometimes exceeding 1,000,000 (a normal range is 200,000 to 500,000). Platelet levels are often not elevated until after a week of having the illness.

• High ESR level: The ESR, or erythrocyte sedimentation rate, is an indirect way of measuring inflammation. But the ESR can be elevated in many type of inflammation, so it is not a very specific test. A very high ESR level can support, but not prove, the diagnosis.

• Elevated CRP level: The CRP, or C-reactive protein, is another measure of inflammation. This test basically provides the same information as the ESR level. Some physicians prefer the CRP level instead of the ESR level because it is a more specific test.

• Echocardiogram: In cases that are uncertain or do not meet all the criteria of Kawasaki disease, an echocardiogram to detect heart abnormalities may be done as a precautionary measure. An echo can also help diagnose the disease.

Delayed diagnosis

In a recent study involving eight major hospitals in the United States, it was found that 16% of children with Kawasaki disease were diagnosed after the first ten days of their illness. This is a highly significant finding since the effectiveness of treatment with IVIG (see below) has only been proven if given within the first ten days. The rate of heart complications go up significantly if treatment is delayed.

The children who were most likely to have a delayed diagnosis were:

• Under six months of age
• Those who did not have all the criteria of Kawasaki disease (atypical Kawasaki disease)
• Those who lived further away from a major hospital (tertiary center)
• Those who went to specific clinics that had low referral rates

The last factor implies that some hospitals are better than others in diagnosing Kawasaki disease.

Variants

Atypical Kawasaki disease refers to children who do not have at least four of the five criteria of Kawasaki disease yet have developed coronary artery aneurysms. As no other disease has been known to cause coronary artery aneurysms, a child with such aneurysms is assumed to have some form of Kawasaki disease, even if not all the criteria have been met. If the child has fewer than four signs but there is nonetheless a strong suspicion that the child has Kawasaki disease, the child can be considered to have atypical Kawasaki disease and then treated the same way as a child with Kawasaki disease. If the child promptly recovers with IVIG, that can confirm the diagnosis of atypical Kawasaki disease.

Treatment

Treatment for Kawasaki disease includes aspirin and IVIG.

Aspirin

Aspirin has two roles in the treatment of Kawasaki disease: an anti-inflammatory role and an anti-thrombotic role. Aspirin also reduces the fever.

• Anti-inflammatory role: Aspirin reduces inflammation, which is primarily caused by the body's own immune system attacking cells within the body. Thus, aspirin helps reduce the effects of the illness, including the heart complications.
• Anti-thrombotic role: Aspirin decreases the function of platelets, which decreases the risk of blood clots that are likely when platelets levels run high. This is important in a disease that leads to coronary artery aneurysms (outpouchings in the arteries), as aneurysms are good places for clots to form.

Aspirin in high doses is used mainly for its anti-inflammatory role in the early phase of Kawasaki treatment. Later the dose is decreased, though still high enough to play its anti-thrombotic role. Dose reduction is done on the fourteenth day of the illness, or until the child is free of fever for three to four days, whichever occurs later.

If a child develops coronary artery aneurysm, aspirin is usually continued indefinitely.

IVIG

Immunoglobulins, or antibodies, are proteins that the body makes to fight against disease, but immunoglobulins can also attack a person's own cells. Immunoglobulins that have been taken from other people's blood can be given through the IV (intravenous) line in certain diseases. This treatment is called IVIG. It is unknown how IVIG works to treat Kawasaki disease, but it works well.^[17] Most children recover rapidly after the treatment, usually within 24 hours. IVIG also reduces the rate of coronary disease from 20% to 2%.

A one-time treatment (2 g/kg) is given through the IV over ten to twelve hours, usually overnight. If the child does not improve within 24 hours, a second dose can be given the next night.

IVIG consists of antibodies taken from another person (a donor), so it contains antibodies for various illnesses, including chickenpox and measles. Live-virus vaccines, such as the chickenpox (varicella) vaccine and the measles-mumps-rubella (MMR vaccine) , will not work if given too soon after IVIG is given, since these viruses will be taken up by the IVIG before the child can make his or her own antibodies against the virus. A waiting period of eleven months is required before the measles-mumps-rubella (MMR) vaccine or the chickenpox (varicella) vaccine are given.^[17]

Specialists

In addition to a pediatrician, other specialists involved during the course of treating a child with Kawasaki disease include the following:

• Pediatric infectious disease specialist: Although Kawasaki disease is not in itself an infectious disease, the infectious disease specialist may be initially consulted if the diagnosis is not known and the child has a high fever and a rash. The child is said to have a fever of unknown origin if he or she continues to have a high fever with no known diagnosis for longer than seven days in spite of extensive evaluation in the hospital. This term may be used even before seven days have elapsed. The infectious disease specialist may be called even if the diagnosis of Kawasaki disease is known, since infectious disease specialists are well-versed in diagnosing and beginning treatment for this condition.

• Pediatric cardiologist: These specialists must be involved in every case of Kawasaki disease. He or she will perform echocardiograms and help care for the patient in the hospital as well as check up on the patient afterwards during clinic visits.

• Pediatric gastrointestinal specialist: Occasionally, the GI specialist may be involved if there are gastrointestinal complications, such as hydrops of the gallbladder or pancreatitis.

• Pediatric rheumatologist: Although Kawasaki disease is an autoimmune disease, a pediatric rheumatologist is rarely involved, unless the disease presented as a fever of unknown origin or with joint pain.

Related Problems

Heart complications

The most concerning and most dangerous aspect of Kawasaki disease is its effect on the heart, specifically its tendency to cause aneurysms. These aneurysms can lead to blood clots, heart attacks, or even death. For this reason, an echocardiogram, or ultrasound of the heart, is performed as soon as the diagnosis is made and again after two to three weeks into the illness. Aneurysms may be prevented if the disease is diagnosed and treated early, especially within the first ten days of illness. Some cardiologists may recommend another echocardiogram a year later, to ensure that a heart complication was not missed.There is little evidence to suggest that any heart complications arise after the illness has resolved; however current guidelines recommend a cardiac evaluation every 3-5 years during childhood, as a precaution

The following are complications of Kawasaki disease that affect the heart.

• Coronary artery aneurysms: The most feared complication of Kawasaki disease is the development of coronary artery aneurysms. These are enlarged outpouchings of the coronary arteries, the small arteries that supply oxygen to the heart. About 15%–25% of children with Kawasaki disease develop coronary artery abnormalities if no treatment is given.^[17]
• Heart attacks: When coronary artery aneurysms get too large, they can burst, causing heart attacks or sudden death. Heart attacks can also occur later because of blood clots that can form in the aneurysms.
• Coronary artery thrombosis (blood clots within the coronary arteries)

Coronary artery aneurysms can develop blood clots, which can result in heart attacks later in life. For this reason, children with coronary artery aneurysms are prescribed anticoagulants (blood thinners), which decrease the tendency of blood to clot.

• Sudden death: This can occur because of a large heart attack or because of a ruptures coronary artery.
• Myocarditis: This inflammation can lead to loss of muscle tissue in the heart. Lost muscle weakens the heart.
• Pericarditis: Inflammation of the outer covering of the heart.

Expected Outcome

The prognosis of a child with Kawasaki disease who is treated within the first ten days is very good. With IVIG therapy, coronary abnormalities develop in 2-4% of cases, as opposed to as many as 25% of untreated cases.^[17] Even if coronary artery aneurysms develop, they usually go away on their own over the next 1 to 2 years in 50% of the cases.^[17] The disease recurs in one to 3% of cases.

In Japan, where the disease is studied more extensively, fatality rates from Kawasaki disease is now less than 0.1%.

A child who has had coronary aneurysms that have then resolved still may have some residual effect, and it is unknown at this point whether these children may be at a higher risk of developing atherosclerosis, coronary heart disease, or heart attacks in adulthood.

Duration

The course of the illness, if left untreated, can be divided into the acute phase, the subacute phase, and the convalescent phase.

Acute phase

The acute phase lasts about ten days, during which time the typical symptoms and signs are present.

Subacute phase

The subacute phase begins as the fever subsides. Arthritis occurs in many children during this time, and affects girls somewhat more often than boys. Peeling of the skin occurs during this time period, beginning on about day fourteen of the illness. The peeling usually begins where the fingernail meets the fingertip.

Convalescent phase

The convalescent phase begins on about day 21 of the illness. During this phase, the child appears to be getting better, but it is during this phase that coronary artery aneurysms might develop. Platelets may still be high during this phase of the illness.

Epidemiology

Kawasaki disease is far more prevalent in Japan than elsewhere, although the disease occurs worldwide. The incidence of Kawasaki disease in Japan is 175 cases per 100,000 people, enough to warrant yearly medical seminars focusing on this disease alone in Japan. The disease is more prevalent in East Asian countries in general. However, the incidence of this disease in the United States is increasing, and Kawasaki disease has surpassed rheumatic fever as the leading cause of acquired heart disease.

Within the United States, the incidence of Kawasaki disease is higher in children of East Asian descent, particularly those of Japanese descent.

Kawasaki disease is a disease of early childhood, particularly affecting children under the age of five. Eighty percent of children with Kawasaki disease are under the age of five. The disease only rarely affects teenagers and young adults. It also occurs infrequently in children under the age of four months.

Kawasaki disease appears to affect boys slightly more than girls.

History

Kawasaki disease was first described by Tomisaku Kawasaki in Japan in 1967. Because many of the features of Kawasaki disease are similar to measles, the disease may have been confused and misdiagnosed as measles prior to its discovery. The development of the measles vaccine in 1963, caused the incidence of measles to drop dramatically, thus allowing for the discovery of this disease.

Prior to the 1960s, there were children thought to have a rare subtype of infantile polyarteritis nodosa, which usually only affects adults. It is likely that these cases were simply cases of Kawasaki disease.

Kawasaki disease was initially called mucocutaneous lymph node syndrome.

References

1. ↑ Wolff AE, Hansen KE, Zakowski L. Acute Kawasaki disease: not just for kids. J Gen Intern Med. 2007 May;22(5):681-4. Abstract | Full Text
2. ↑ Burgner D, Harnden A. Kawasaki disease: what is the epidemiology telling us about the etiology? Int J Infect Dis. 2005 Jul;9(4):185-94. Abstract
3. ↑ Novelli VM, Galbraith A, Robinson PJ, Smallhorn JF, Marshall WC. Cardiovascular abnormalities in Kawasaki disease. Arch Dis Child. 1984 May;59(5):405-9. Abstract | Full Text | PDF
4. ↑ ^{4.0 4.1} Choi YS, Sharma B. Gallbladder hydrops in mucocutaneous lymph node syndrome. South Med J. 1989 Mar;82(3):397-8. Abstract
5. ↑ Jen M, Brucia LA, Pollock AN, Burnham JM. Cervical spine and temporomandibular joint arthritis in a child with Kawasaki disease. Pediatrics. 2006 Nov;118(5):e1569-71. Abstract | Full Text | PDF
6. ↑ Newburger JW, Fulton DR. Kawasaki disease. Curr Opin Pediatr. 2004 Oct;16(5):508-14. Abstract
7. ↑ Elizabeth KE, Ahamed MZ, Praveen KS. Atypical relapsing course of Kawasaki disease with hemorrhagic serous effusions and hepatic dysfunction. Indian Pediatr. 2007 Oct;44(10):785-7. Abstract | PDF
8. ↑ Bonany PJ, Bilkis MD, Gallo G, Lago N, Dennehy MV, Sosa del Valle JM et al. Acute renal failure in typical Kawasaki disease. Pediatr Nephrol. 2002 May;17(5):329-31. Abstract
9. ↑ Freeman AF, Shulman ST. Kawasaki disease: summary of the American Heart Association guidelines. Am Fam Physician. 2006 Oct 1;74(7):1141-8. Abstract | Full Text | PDF | Summary for Patients
10. ↑ Stoler J, Biller JA, Grand RJ. Pancreatitis in Kawasaki disease. Am J Dis Child. 1987 Mar;141(3):306-8. Abstract
11. ↑ Onouchi Y, Gunji T, Burns JC et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet. 2008 Jan;40(1):35-42. Abstract
12. ↑ Food and Drug Administration: Information Pertaining to Labeling Revision for RotaTeq
13. ↑ Geier DA, King PG, Sykes LK, Geier MR. RotaTeq vaccine adverse events and policy considerations. Med Sci Monit. 2008 Mar;14(3):PH9-16. Abstract
14. ↑ Antony D, Jessy PL. Involvement of BCG scar in Kawasaki disease. Indian Pediatr. 2005 Jan;42(1):83-4. Full Text
15. ↑ Weinstein M. Inflammation at a previous inoculation site: an unusual presentation of Kawasaki disease. CMAJ. 2006 Feb 14;174(4):459-60. Abstract | Full Text
16. ↑ Sinha R, Balakumar T. BCG reactivation: a useful diagnostic tool even for incomplete Kawasaki disease. Arch Dis Child. 2005 Sep;90(9):891.Reference
17. ↑ ^{17.0 17.1 17.2 17.3 17.4} Newburger JW, Takahashi M, Gerber MA et al; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. 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. 2004 Dec;114(6):1708-33. Erratum in: Pediatrics. 2005 Apr;115(4):1118. Abstract | Full Text | PDF

External Links

Kawasaki Disease Foundation