Predominately medium-sized vessel

Kawasaki Disease

  • What is it?
    • Kawasaki Disease (KD), formerly known as mucocutaneous lymph node syndrome, is a form of vasculitis that affects the walls of medium-sized blood vessels of the body. This type of vasculitis can affect a variety of the blood vessels and organs. This disease is initially characterized by fever and symptoms of inflammation for 12 days on average. Though not seen in a majority of patients, the coronary arteries (which supply blood to the heart) have been specifically affected in patients with KD. Common symptoms of this disease include bilateral conjunctivitis (inflammation of the lining of both eyes), reddening of the lips and inside of the mouth, and rashes.
    • Patients can also be found to have Incomplete (atypical) Kawasaki Disease if they do not meet the required classification criteria. However, these patients with Incomplete KD do not appear different from patients with classic Kawasaki disease and are also at risk for heart/blood vessel complications.
  • How does it happen?
    • As in other forms of vasculitis, the narrowing of these medium-sized vessels limits the amount of blood supply to certain organs. This decrease in blood to organs, such as the heart, can lead to complications such as coronary artery aneurysms (enlargement of these vessels due to weak walls), weaker pumping of the heart, heart attacks and heart failure.
  • Though the causes of KD are currently unknown, infection-related causes have been discussed in past studies. This suspicion is supported by how KD displays infection-like symptoms such as fever, rashes, lymph node enlargement in the neck, and redness of the eyes.
  • Other factors have also been discussed in the causes of KD. Factors such as age distribution, seasonal changes, outbreaks in communities, and geographical spread and cycles of the disease suggest a transmissible childhood disease. However, though there have been attempts to find a bacteria or virus that may cause this disease, nothing has been found yet.
  • A genetic factor has been suggested to play a role in KD, since higher incidence rates have been found in siblings and twins. This may point to a genetic feature that works with an agent in the environment to lead to Kawasaki Disease.
  • Kawasaki Disease is a rare, but still one of the most common forms of vasculitis in children. Though this disease can be seen around the world, it is more common in Japan and in children with a Japanese ancestry. A high majority of patients with Kawasaki disease are children, and the peak age occurs before or around 2 years of age. It has been seen in patients that children younger than 3 months and older than 5 years with KD are more common to present with heart complications such as coronary artery aneurysms. Though this disease can be seen year-round, higher rates have been found in later winter and spring.
  • Mainly clinical features are used in the diagnosis of Kawasaki Disease. Some common symptoms include redness of the eyes, skin rashes, bright red and cracked lips, and red tongue (“strawberry tongue”).
  • Click here for more detailed information on classifying and diagnosing GPA.
  • The treatment of Kawasaki Disease largely involves intravenous immune globulin (IVIG) and Aspirin. However, other treatments such as glucocorticoids are being researched and used in specific cases.
    • Click here for more detailed information on suggested treatment protocols

Baker, A. L., Lu, M., Minich, L. L., Atz, A. M., Klein, G. L., Korsin, R., … & Vetter, V. L. (2009). Associated symptoms in the ten days before diagnosis of Kawasaki disease. The Journal of pediatrics, 154(4), 592-595.

Burns, J. C., Mason, W. H., Glode, M. P., Shulman, S. T., Melish, M. E., Meissner, C., … & United States Multicenter Kawasaki Disease Study Group. (1991). Clinical and epidemiologic characteristics of patients referred for evaluation of possible Kawasaki disease. The Journal of pediatrics,118(5), 680-686.

Cai, Z., Zuo, R., & Liu, Y. (2011). Characteristics of Kawasaki disease in older children. Clinical pediatrics, 50(10), 952-956.

Dajani, A. S., Taubert, K. A., Gerber, M. A., Shulman, S. T., Ferrieri, P., Freed, M., … & Wilson, W. (1993). Diagnosis and therapy of Kawasaki disease in children. Circulation, 87(5), 1776-1780.

Morens, D. M., Anderson, L. J., & Hurwitz, E. S. (1980). National surveillance of Kawasaki disease. Pediatrics, 65(1), 21-25.

Newburger, J.W. et al. (2004), 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.

  • According to the 2010 EULAR/PRINTO/PRES criteria for classification of Kawasaki Disease, a patient must present with a fever for at least 5 days, and an additional 4 of the following 5 features:
  1. Bilateral conjunctival injection
  2. Oral mucous membrane changes, including injected or fissured lips, injected pharynx, or strawberry tongue
  3. Perineal and peripheral extremity changes, including erythema of palms or soles, edema of hands or feet (acute phase), and periungual or perineal desquamation (convalescent phase).
  4. Polymorphous exanthema (rash).
  5. Cervical lymphadenopathy (at least one lymph node >1.5 cm in diameter).
    • Though these criteria have not been validated, it is very similar and closest to the criteria provided by the American Heart Association (AHA).
  • In order to more accurately reach a diagnosis, physicians can further consult results from laboratory tests and imaging. For more details view the diagnostic algorithm for Kawasaki Disease.
  • The most common symptoms displayed by Kawasaki Disease patients are discussed below. These symptoms do not present at the same time, and do not have a typical order in which they are seen. This often means that frequent physical examinations and histories are required to make a timely diagnosis of KD in patients who may not meet the diagnostic criteria at first.
  • Patients with KD can experience some or all of the following:
    • Fever
      • Elevated body temperature is the most common and consistent symptom of Kawasaki Disease. The diagnosis of this disease should be considered in all children that have fever for greater than 5 days. However, even without a prolonged fever, KD should still be considered if they have other symptoms that match the KD criteria.
    • Conjunctivitis
      • Conjunctivitis, also known as “pink eye”, is the swelling (inflammation) of the outer layer of the eye and inner surface of the eyelid. In KD, conjunctivitis is seen in both eyes, and is seen in approximately 90% of cases. In many cases, children have also been found to be very sensitive to light (photophobia).
    • Oral mucositis
      • Oral mucositis describes the swelling of skin layers of the mouth. This can be seen as cracked, red lips and a strawberry tongue in Kawasaki Disease. These symptoms become more visible and apparent as the disease progresses.
    • Rash
      • Skin-related symptoms of Kawasaki begin during the first few days of the illness. These are presented as reddening of the skin surface, and peeling of skin around the perineal region.
    • Extremity changes
      • These changes are usually the last symptoms to appear. One symptom includes the reddening of the surface of the palms and soles (erythema). The swelling of the outer portions of the hands and feet (due to too much fluid) also occurs.
    • Lymphadenopathy
      • Swelling of the lymph nodes in the neck region is the least consistent feature seen in Kawasaki Disease, as it is absent in one-half to three-quarters of patients. Usually, it is seen in the front portion of the neck, in the form of one large node. An ultrasound of the neck can also show many smaller grape-like nodes.
    • Cardiovascular findings
      • Though cardiovascular findings are not actually involved in the criteria of KD, they can be used to indicate involvement of the heart. Since heart involvement is uncommon in diseases similar to Kawasaki, these findings can help support a diagnosis of KD.
    • Arthritis
      • Arthritis is also not included in the diagnostic criteria. It has been seen in studies in approximately 7.5 to 25% of patients with Kawasaki Disease.
    • Additional Diagnosis Features
      • Crust/ redness formation where patients were inoculated with the Bacille Calmette-Guerin (BCG) vaccination. In one particular study, it was found that 50% of patients with KD presented this feature.
    • Other Symptoms (uninvolved in the diagnosis of Kawasaki Disease)
      • These symptoms, like arthritis and cardiovascular findings, are not part of the criteria for this disease. However, these symptoms are seen in patients around 10 days before they are diagnosed with Kawasaki Disease.
        • Diarrhea, Vomiting, or abdominal pain (61%)
        • Irritability (50%)
        • Only vomiting (44%)
        • Cough or runny nose (rhinorrhea) (35%)
        • Decreased fluid intake (37%)
        • Joint pain (15%)

Although there are no laboratory studies included in the criteria for Kawasaki, there are certain laboratory features that can help in the diagnosis of KD. These may be more important in the diagnosis of Kawasaki Disease when looking at Incomplete Kawasaki cases.

Some tests that can assist in making a diagnosis of KD include:

  • Complete blood counts (hemoglobin, white blood cell counts etc.)
  • Aspartate transaminase (AST) and alanine transaminase (ALT)
  • C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
  • Urinalysis
  • Inflammatory markers
    • Systemic Inflammation is a common characteristic
    • Typical features which reflect systemic inflammation include:
      • Elevated erythrocyte sedimentation rate (ESR)
      • Elevated c-reactive protein (CRP)
      • Thrombocytosis
        • Commonly seen after the 7th day of illness
      • Leukocytosis
      • Left-shift in WBC count (increased immature neutrophils)
    • Hemoglobin
      • Patients with Kawasaki Disease are often found to present with anemia (lower hemoglobin levels) during the first 2 weeks.
    • Urinalysis
      • Pyuria, which describes white blood cells (WBCs) present in urine, can be seen through urinary microscopy.
    • Liver Function
      • In one study, 45% of patients with Kawasaki Disease were found to have abnormal liver function tests.
    • Cerebrospinal fluid (CSF)
      • Studies have shown patients with elevated counts of white blood cells (WBCs), or elevated CSF protein levels.
    • Additional tests
      • Serum sodium levels
        • Lower levels of sodium have been noticed in a previous study, and have been thought to be associated with an increased risk of coronary artery aneurysms
      • Serum lipid levels
        • Increased triglyceride levels and low-density lipoproteins were seen, along with a decreased level of high-density lipoproteins

There are no significant imaging techniques that can be used in directly diagnosing Kawasaki Disease. However, imaging results can still help identify certain clinical features, which can contribute to a more accurate diagnosis of Kawasaki Disease.

  • Possible imaging tools used in assessing Kawasaki Disease:
    • Ultrasound
      • Used to identify the clinical feature lymphadenopathy, which describes the disease of the lymph nodes.
      • Seen in images as grape-like nodes in the neck region
    • Echocardiography
      • Used to determine if a coronary artery aneurysm has occured
  • In the early phase of Kawasaki Disease, cardiac (heart) involvement can be seen in the cases of coronary artery (CA) aneurysms. These cases describe the most serious complications of Kawasaki Disease, and can be diagnosed through echocardiography. The development of coronary artery (CA) aneurysms occur in patients who do not receive the initial recommended treatment early enough. This is seen in 1 in 5 patients with Kawasaki Disease.
  • The coronary arteries (CA) are blood vessels that supply the heart muscle with blood. In a CA aneurysm, the walls of the CAs can become weak and lead to an enlargement of the blood vessels. CA aneurysms can lead to a lack of oxygen in the heart muscle tissue (myocardial ischemia), a heart attack, and even sudden death.
  • Aside of CA aneurysms, the heart muscle can become less functional, aneurysms can occur elsewhere, and the valves of the heart can become less effective.

Figure 1: Conjunctivitis in a patient with Kawasaki Disease -Retrieved from:  http://www.uptodate.com/contents/image?imageKey=PEDS/78898&topicKey=ALLRG%2F6417&source=outline_link

Figure 2: Cracked, red lips of patient with Kawasaki Disease -Retrieved from:  http://pubs.rsna.org/doi/full/10.1148/rg.2015140076

Figure 3: Strawberry tongue – Retrieved from   http://www.uptodate.com/contents/image?imageKey=ID/68321&topicKey=ALLRG%2F6417&source=outline_link

Figure 4: Indurated edemia seen on the hands of a patient with Kawasaki Disease – Retrieved from:  http://www.uptodate.com/contents/image?imageKey=ALLRG/72040&topicKey=ALLRG%2F6417&source=outline_link

Figure 5: Periungual desquamation seen on the hands a feet of a patient with Kawasaki Disease – Retrieved from:  http://www.uptodate.com/contents/image?imageKey=ALLRG/53452&topicKey=ALLRG%2F6417&source=outline_link

In this image, you can see the diagnostic algorithm for GPA by following the diagram from the “INDICATIONS FOR TESTING” box (at the top) to the bottom-right box for “Granulomatosis with polyangiitis…”

Retrieved from: https://arupconsult.com/content/takayasu-arteritis/?tab=tab_item-1This is the website for ARUP Consult, whose disclaimer and policies outline that the “content at this website may be freely downloaded and used for non-commercial purposes.” 

April, M. M., Burns, J. C., Newburger, J. W., & Healy, G. B. (1989). Kawasaki disease and cervical adenopathy. Archives of Otolaryngology–Head & Neck Surgery, 115(4), 512-514.

Ayusawa, M., Sonobe, T., Uemura, S., Ogawa, S., Nakamura, Y., Kiyosawa, N., … & Harada, K. (2005). Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatrics International, 47(2), 232-234.
Burns, J. C., & Glodé, M. P. (2004). Kawasaki syndrome. The Lancet,364(9433), 533-544.

Gong, G. W., McCrindle, B. W., Ching, J. C., & Yeung, R. S. (2006). Arthritis presenting during the acute phase of Kawasaki disease. The Journal of pediatrics, 148(6), 800-805.

Kishimoto, S., Muneuchi, J., Takahashi, Y., Izu, K., Nakano, R., & Joo, K. (2010). Psoriasiform skin lesion and supprative acrodermatitis associated with Kawasaki disease followed by the treatment with infliximab: a case report. Acta Paediatrica, 99(7), 1102-1104.

Nofech-Mozes, Y., & Garty, B. Z. (2003). Thrombocytopenia in Kawasaki disease: a risk factor for the development of coronary artery aneurysms.Pediatric hematology and oncology, 20(8), 597-601.

Recommended Initial Therapy

  • The American Heart Association (AHA) and the American Academy of Paediatrics (AAP) have set guidelines for treating patients with Kawasaki Disease that meet the diagnostic criteria. The generally accepted therapy includes both intravenous immune globulin (IVIG) and Aspirin, which are discussed below. Other therapies that are far less commonly used are discussed below in “Other Treatments”.
    • Intravenous immune globulin (IVIG)
      • IVIG and Aspirin help reduce risks of CA aneurysms in patients
      • IVIG acts as an anti-inflammatory, which helps reduce fever and laboratory features such as C-reactive protein (CRP) and fibrinogen levels.
        • However, values for ESR might actually increase after IVIG treatment
      • In general, IVIG treatment is a very cost-effective medical therapy that yields great short-term and long-term results.
      • Mechanism by which IVIG has these beneficial effects is still unknown.
      • It should be noted that patients who require live-virus vaccinations (such as measles, varicella etc.), should postpone their vaccinations for another 11 months.
    • Aspirin
      • Aspirin is known to have anti-inflammatory effects (ex. reduce swelling, reduce duration of a fever) and anti-platelet effects (prevent the aggregation of blood-clot cells).
      • Aspirin is combined with IVIG treatment in almost all treatments of Kawasaki Disease.
      • However, the specific benefits of Aspirin in this type of treatment have not been specifically found yet. Very few, limited studies have actually found that Aspirin may have little benefit compared to IVIG therapy.
      • Though Aspirin treatment can lead to complications in specific cases, it is generally found to have low risks. The use of Aspirin in the treatment of Kawasaki Disease is meant to keep the beneficial effects of Aspirin, while minimizing the risk of producing toxic levels in the body.

Other Treatments

                The treatments discussed below are usually referred to as adjuvant therapies, which are used in combination with the initial therapy discussed above.

  • Glucocorticoids
    • Glucocorticoids (ex. Intravenous methylprednisone) have been used in combination with IVIG therapy in the initial treatment of Kawasaki Disease.
    • In a particular study, this was found to have affected the risk of coronary artery aneurysms. However, the results across most studies are still inconclusive.
  • Disease Stratification
    • This type of therapy refers to evaluating the risks that patients with Kawasaki Disease may have, and whether they are at higher risks of coronary artery aneurysms.
    • These children that may not respond as optimally to IVIG therapy, may benefit from using adjuvant therapies like the addition of glucocorticoids.
    • However, future studies must develop actual criteria which helps identify these high-risk patients.
  • Biological Therapy
    • This type of therapy uses drugs such as Infliximab, which cause an effect through tumor necrosis factor inhibition.
    • Increased levels of tumor necrosis factor-alpha (TNF-alpha) have been noticed in some patients with Kawasaki Disease. In one study, Infliximab was found to help treatment of both fever and laboratory abnormalities.
    • However, studies do not show that TNF inhibitors contribute clear benefits for Kawasaki Disease, and therefore their use is not recommended.
  • Urinary trypsin inhibitor
    • Ulinastatin, for example, has been thought to prevent tissue and organ damage.
    • It has been shown to provide some benefits when used with initial therapy of IVIG and Aspirin.
    • However, further studies are required to identify the usefulness of this treatment.

Refractory Kawasaki Disease

  • Refractory Kawasaki Disease describes cases in which patients do not respond optimally to the initial treatment of IVIG and Aspirin.
  • Fever has been found to either persist or return in 10-15% of Kawasaki Disease patients, though this range can vary as high as 38% in some cases. Any degree of fever that remains can be seen as indicating ongoing vasculitis.
  • Even small increases in the temperature of KD patients should not be ignored. Persistent fevers are actually the strongest risk factors for the development of coronary artery aneurysms.
  • In a study in Japan involving over 15,000 patients, 20% were found to not respond to the initial IVIG treatment. These patients that do not respond to IVIG therapy are found to have a much higher risk for coronary artery aneurysms

Recurrence

  • Kawasaki Disease has been found to have a low rate of recurrence of the disease. In a study following patients after 3 years of follow-up, only 2% of patients were found to have a recurrence of Kawasaki Disease. This recurrence usually occurs within the year of the first episode of Kawasaki Disease.
  • Fever
    • After initial therapy, patients with Kawasaki Disease should be constantly monitored for any recurring fevers. This involves checking the temperature every 6 hours for the next 2 days after the last fever.
  • Cardiac Involvement
    • At baseline, an echocardiogram is done to evaluate the involvement of the coronary arteries of the heart. An echocardiogram should be repeated 2-6 weeks after baseline as well. Often, children who respond well to both IVIG therapy and have a normal echocardiogram, do not develop newly found abnormalities.

Below you can find downloadable PDF files of suggested treatment protocols for patients with Kawasaki Disease. These suggested treatment protocols vary depending on the phase of the treatment (induction, maintenance, flare) and on which conditions are presented in patients.

Suggested Treatment Protocols:

  1. (These numbers depend on the types of treatment protocols provided for Kawasaki Disease)
  2. (These numbers depend on the types of treatment protocols provided for Kawasaki Disease)
  3. (These numbers depend on the types of treatment protocols provided for Kawasaki Disease)

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Kanai, T., Ishiwata, T., Kobayashi, T., Sato, H., Takizawa, M., Kawamura, Y., … & Hatai, Y. (2011). Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with kawasaki disease a retrospective study.Circulation, 124(25), 2822-2828.

Kobayashi, T., Saji, T., Otani, T., Takeuchi, K., Nakamura, T., Arakawa, H., … & Miura, M. (2012). Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. The Lancet, 379(9826), 1613-1620.
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Newburger, J. W., Takahashi, M., Gerber, M. A., Gewitz, M. H., Tani, L. Y., Burns, J. C., … & Wilson, W. R. (2004). 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. Circulation, 110(17), 2747-2771.

Pickering, L. K. (2003). Red book®: 2003 report of the committee on infectious diseases (No. Ed. 26). American Academy of Pediatrics.

Terai, M., & Shulman, S. T. (1997). Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. The Journal of pediatrics, 131(6), 888-893.