The Kawasaki disease
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Published: Mon, 5 Dec 2016
Kawasaki disease is an intense systemic paediatric vasculitis disease that is seen commonly in childhood. Kawasaki disease is one of the most common heart diseases. It is the inflammatory disorder but the aetiology of Kawasasaki disease is unknown. It first appeared in 1967 by report of Tomisaku Kawasaki who was a Japanese paediatrician. He also called Kawasaki disease as mucocutaneous lymph node syndrome. There is no diagnostic test; therefore, doctors are using the clinical criteria that were proposed by Dr. Kawasaki 45 years ago to diagnose the Kawasaki disease. There are many different diagnosis of Kawasaki disease such as viral infections, genetic predisposition or environmental factors. Many research proposed that Kawasaki disease is an infectious disease that may be caused by Epstein-Barr virus, measles, adenovirus, enterovirus. However, there is no confirmed evidence. Usually, KD can found more in Japanese society but it keep spread to western countries and the incidence of KD in western countries are increase dramatically. There are typical symptoms that can be seen in KD such as rash, edema, and mucosal membrane changes. But there are more symptoms that are involved which are not typically found from every KD patients. Therefore, it is hard to diagnosis patients if they have KD or not. The treatment of KD is different depends on if patients are complete or incomplete KD and also, the susceptibility of IVIG will make treatment different along patients. The etiology is not certain but there are several researches shown that KD is caused by infectious agents, genetic factors, or immune system disorder.
Current knowledge on the subject
There are several symptoms that can be found in patients with Kawasaki disease. When patients have more than 5 days of fever for more than 38C and have more than 4 symptoms such as bilateral nonexudative conjunctival injection, polymorphous exanthem, nonvesicular rash, strawberry tongue, edema of hands and feet, bilateral non-suppurative cervical lymphadenopathy, and mucosal membrane changes, patients will diagnosis as KD. Kawasaki disease can be divided into complete Kawasaki disease and incomplete or atypical Kawasaki disease depending on the number of symptom that are present in the patient. When patients have more than four symptoms or have developed coronary artery abnormality, patients will be diagnosed as complete Kawasaki disease. In contrast, patients who have less than four of the diagnostic criteria and still develop coronary artery abnormality is diagnosed as atypical or incomplete KD. Because of the cause of Kawasaki disease is unknown, diagnosis of Kawasaki disease in infants are very challenging. Kawasaki disease can be divided into three phases. First, from one week to two weeks from onset is called acute phase. Typical symptoms are highly febrile, irritable and the fever approaches more than 39 Celsius. Oral changes occurs and also rash can be found in perineal area. Secondly, from two to eight weeks from onset is called subacute phase. In this phase, fever start to decrease slowly and the perineal area, soles, and periungual areas start to peel off. Lastly, from months to years from onset, it is called convalescent phase. In this phase, laboratory value gets normal but there may be severe consequences. For example, patients who had aneurysms may continuously have, for rest of their life, persistent cardiac dysfunction, or myocardial infarction.
Coronary artery aneurysm can be highly found in incomplete Kawasaki disease patients. It is defined as coronary dilatation that the diameter of coronary vessel gets enlarged 1.5 folds. It can be diagnosed by angiographically and it is similar to patients with coronary artery disease. The end-diastolic pressure, end-diastolic volume, and ejection fraction levels are not normal and the left ventricular contraction is not normal. The coronary artery aneurysms are mostly caused by atherosclerosis.
There are several associated symptoms that can be seen in Kawasaki patients. Diarrhea and abdominal pain and patients may develop arthritis. Also, myocardial dysfunction can be found in early phase of Kawasaki disease such as pancarditis which is the inflammation of all three layers of heart. Another symptom is periarteritis nodosa which is disease in connective tissue that is blocked by nodules in arteries thereby causing blood to not circulate properly. When Kawasaki disease shows periarteritis nodosa, other symptoms cannot be found.
Kawasaki disease can be diagnosis by physical exam but also it can be diagnose by laboratory exam and imaging technique. First, complete blood count test should be performed to look at the amount of white blood cell in blood. Complete blood count is the calculation of white blood cells, red blood cells, and platelet. The number of white blood cell increased to more than 15,000. Also, the erythrocyte sedimentation rate and C-reactive protein increase. After 2 weeks from onset of disease, the platelets’ level dramatically increases up to 1 to 2*106. There are other abnormalities such as sterile pyuria, increases of hepatic transaminases, hypoalbuminemia. In patients who have KD will have higher level of transaminase than normal person. Also, they will have higher level of ALAT and GGT than other patients who have other febrile diseases. When ALAT level increases, it will lead to coronary artery disease. Research proposed that almost 50% of incomplete KD patients had pyuria in bladder urine. Pyuria can cause different diseases depends on where it is. When pyuria is in bladder, it can cause tubulointerstitial nephritis but when it is in voided urine, it will cause urethral inflammation. Another symptom to diagnosis incomplete KD is to look at acute anterior uveitis after the onset. Patients who have anterior uveitis do not have pain, photophobia, nor visual impairment. By using ophthalmological evaluation, it can detect if patients have different disease which have similar symptoms with anterior uveitis. One of the research in 2006 showed that there were 40% of KD patients had hyponatromia. It is caused by incorrect hormone secretion by cerebral vasculitis, dehydration, or tubular dysfuction. It is hard to diagnosis KD since there is no diagnosis test. To treat incomplete KD, the principle clinical criteria should be renewed in order not to miss out some patients who did not have principle symptoms. By missing out patients will develop severe other diseases and will not be able to give proper treatments.
KD also can be found out by using imaging technique. At acute phase, chest x-ray or echocardiography (ECG) are used to look at heart problem. Patients may develop coronary artery abnormalities in acute phase and this can be showed by ECG. When patients are very severe, heart specialists sometimes use single photon emission computed tomography to look into bloodstream of patients. SPECT will provide an image in 3D by using gamma rays.
Kawasaki disease is new disease that is predominantly found among Asian children1,2,3. It was first found in Japan by Dr.Kawasaki in 1961. In early 1970s, Pathologist Eunice Larson and Benjamin Landing at Los Angeles recognized it as a new disease. Still today, there is no evidence of how Kawasaki disease emerged but some researchers proposed that Kawasaki disease emerged from Japan and spread to Western countries through Hawaii after World War II. Kawasaki disease was nationwide epidemics but now it is more likely a regional outbreak. The mean annual incidence rate is different in variety of countries and districts3. There are 90 to 112 per 100,000 in Japan, 8.0 to 47.7 per 100000 in US, and 3.6 to 3.7 per 100000 in the United Kingdom and Australia for children who are less than 5 years old. Research in China indicates that the incidence rate is 18.2 to 18.6 per 1000003. The statistics shows that Japan predominantly has highest incidence rate among Asian. Kawasaki disease can be found commonly in males than females and the reoccurrence rate is less than 1%3. The incidence of Kawasaki disease has been increasing annually. In 2000, the incidence rate was 73.7 per 100000 but in 2002, the number of occurrence increased to 95.5 per 1000003.
There are relationships between season and occurrence of Kawasaki disease3. But there are variations among different countries. From Japanese reports, there were more patients in winter but in American data shows that patients will develop KD more in the spring and winter. For female the occurrence appeared to be high in March, and highest in July. For boys, the highest occurrence rate was in May and the lowest occurrence rate was in February. As the research indicated, the season and climates have relationship with the susceptibility to Kawasaki disease3.
Patients with Kawasaki disease may develop coronary artery abnormalities (CAAs) if patients are not treated early. Usually patients are treated with high amounts of intravenous gamma-globulin (IVGG) as well as aspirin which are used to reduce the possibility of developing CAAs2. However, 10-20% of Kawasaki patients do not response to induced intravenous gamma-globulin. Coronary artery abnormality will develop more frequently to patients who are not responding well to IVGG than patients who respond well to IVGG. Recent research reported that matrix metalloproteinase-9 (MMP-9) is involved in formation of CAA in acute phase of Kawasaki disease patients2. From research, the level of MMP-9 in serum who have Kawasaki disease have much higher than serum from children who does not have KD and patients who have other kinds of febrile diseases2. Using MMP-9 inhibitors might prevent the formation of CAA. However, MMP-9 inhibitors are not used clinically. MMP-9 is endopeptidase that depends on zinc that has zinc at the active site. MMP-9 have major role in tissue remodelling of extracellular membrane (ECM) 2. It can be seen in cardiac remodelling after myocardial infarction, plaque destabilization of atherosclerotic lesion. The mechanism of angiotensin-converting enzyme (ACE) inhibitors is involve with the bind zinc to the active site and stabilize by hydrogen bonds and hydrophobic interactions in the active site. The ACE inhibitor can inhibit the activity of MMP-9 and MMP-2, which have major role in neointimal formation and angiogenesis. The effect of the ACE inhibitor on MMP-9 can be measure by using captopril to the enzyme2.
Involvement of the immune system
From the studies by Satoshi Sato, Kawasaki disease is commonly found from patients who are younger than 5 years old1. The average age of occurrence of this disease is 2 years. Kawasaki disease does not occur frequently from children who is less than 6 months and can hardly find patients who are less than 3 months1. Kawasaki disease usually does not occur for adults who have immunity to common infectious disease. This result explains that children are more susceptible to Kawasaki disease because they might not produced antibodies to common infectious viruses, and bacteria1. Mannose bind lectin (MBL) is an important component of the innate immunity and is a reactant for hepatic origin which can bind to multiple lectin domains1. MBL has very important role in complement activation and opsonization. Complement activation refers to as the biochemical activity that helps to get rid of pathogen from animal and opsonization have similar activity to complement activation that plays role of pathogens to get rid of the organism by ingestion and destruction by phagocyte1. It is usually found in bacterial cells, fungus cells, and viruses. It has repeating pattern of mannose and N-acetylglucosamine sugar. There are three single polymorphisms in chromosome 10 for MBL gene at codon 52 (CGT to TCT), codon 54 (GGC to GAC), and codon 57 (GGA to GAA). This mutation will lead to reduction of the level of MBL concentration but polymorphism of the promoter region of MBL will lead to increase the level of MBL concentration in the serum1. When the base changes from glycine to aspartic acid in codon 54, it will distract the interaction between MBL and MBL-associated serine protease. The interaction between MBL and MBL-associated serine protease defend against infection when patients are young. But when patients become older, the interaction of these two molecules will not have impact on the innate immunity1. Because, the patients will develop the mature lymphocytes and immunoglobulins and they will engulf the invaded pathogen. Therefore, this research proposes the susceptibility of the Kawasaki disease will be influenced by the MBL polymorphism1.
Children who have Kawasaki disease develop endothelial dysfuntion in early phase after onset of disease and this will caused by the production of nitric oxide (NO)5. As described earlier, the primary innate immune system is very important feature for Kawasaki disease. Tumour necrosis factor alpha, IL-1, 6, 8, monocyte, chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) will be activated to produce cytokine storm5. After cytokines are produced, it will release iNOS (inducible nitric oxide synthase) in neutrophils, endothelial cells, and smooth muscle cells. Nitric oxide is produced by two enzymes which are endothelial NOS and iNOS5. Recent research found out that patients who developed Kawasaki disease have higher level of iNOS concentration in neutrophils in acute phase. Also, children have high level of nitric oxide metabolites such as NOx, NO3-, and NO2-. After production of Nitric Oxide, it will react with Reactive Oxygen Species (ROS) to give more biochemical reactions. This will be measured by new device called fluorescent indicators5. There are new devices used to measure the concentration of NO and ROS. First, Hydroxyphenyl fluorescence (HPF) was used to measure the concentration of ROS. Another device is called Diaminofluorescin-Flu Diacetate (DAF-FM DA) which is used to measure the concentration of intracellular Nitric Oxide5.
There are significant evidences that the production of ROS and NO by neutrophils were much higher in Kawasaki disease patients in compare to people who have non-KD febrile children or non-febrile children5. By treating with IVIG, NO level will decrease. But, the production of NO can be beneficial or harmful. Usually, NO is cytotoxic but sometimes, it can protect cells from toxic materials. NO may react with hydroxyl radicals to produce much higher toxicity. To control the influence of NO, the duration, the amount of NO synthesis should be controlled. Therefore, in acute phase of Kawasaki disease, NO and ROS is highly produced and will cause damage to endothelial cells5.
Treatment and future research
When patients are diagnosis as complete or incomplete KD, treatment should be induced right away. Because when patients have more than 10 days of fever will develop CAA. Major treatment that doctors use to treat KD is intravenous immunoglobulin (IVIG). Intravenous immuglobulin induced into bloodstream which contains immunoglobulin antibody G that is brought from other control blood donors. IVIG is still a major recommended treatment but some patients do not response to this treatment. The effects of IVIG last for 2 weeks up to 3 months. The typical amount of IVIG is a dose of 1000mg per kg of patient’s bodyweight. High amount of IVIG with aspirin will reduce the rate of coronary artery abnormalities (CAA) which includes coronary artery dilatation or aneurysms from 20% to 3 to 5%. Also, depends of patients, IVIG can also used with acetylsalicylic acid to treat KD.
There is one example about the incorrect treatment will cause severe disease. When IVIG was induced, patients could not cure coronary artery lesion. When patients induced with corticosteroid, they developed more coronary artery lesion3.
There are two therapies which are antiinflammatory and antithrombotic therapy which are to treat Kawasaki disease instead of using IVIG. In antiinflammatory therapy, methylprenisolone, prednisone, prednisolone, and infliximab are used to treat Kawasaki disease. For antithrombotic therapy, Aspirin, heparin, warfarin, exoxaparin, tissue plasminogen activator, clopidogrel, and abciximab are used. Recently, infliximab proved by US Food and Drug administration to cure not only Crohn disease but also used to treat Kawasaki disease patients. It was not used at all in 2001 but today, the administration of infliximab usage increased up to 2.3% of total number of therapies used. It became favourable because of two reasons. First, it only administer to patients only one time. Secondly, by not using infliximab more than once, it reduce the complication as seen in other therapies which are used more than once. Infliximab is an antibody to tumour necrosis factor alpha, and cytokine in inflammatory response. It binds to tumour necrosis factor alpha and blocks the T-cell receptors to block the biochemical cascade. It will decrease the coronary artery abnormalities in patients who developed Kawasaki disease in early acute phase.
To treat KD much better way, there should be more research. First, there should be more laboratory and echocardiographic data. Second, more development of clinical criteria and symptoms should be proposed. Even today, there is no perfect evidence that can explain the cause of KD; therefore, there should be more research on genetic factors by looking at KD patients’ family. Lastly, after treatment of KD in childhood, complication may be developed after several decades and there is not much information about complication. Therefore, by monitoring and keep in touch with KD patients are good way to find out more about complication after initial treatment.
- Sato, S., H. Kawashima, Y. Kashiwagi, T. Fujioka, K Takekuma, and A. Hoshika. 2009. Association of mannose-binding lectin gene polymorphisms with Kawasaki disease in the Japanese. I. Jour. R. Dis. 12:307-310.
- Inoue, N., S. Takai, D. Jin, K. Okumura, N. Okamura, M. Kajiura, S. Yoshikawa, N. Kawamura, H. Tamai, M. Miyazaki. 2010. Effect of angiotensin-converting enzyme inhibitor on matrix metalloproteinase-9 activity in patients with Kawasaki disease. Clinica Chimica Acta. 411:267-269.
- Huang, G.Y., Ma, X.J., Huang, M., Chen, S.B., Huang, M.R., Gui, Y.H., Ning, S.B., Zhang, T.H., Du, Z.D., Yanagawa H., and Kawasaki T. 2006. Epidemiologic Pictures of Kawasaki disease in Shanghai from 1998 through 2002. Journal of Epidemiology. 16:No. 1.
- Yeo, Y.K., Kim, T.Y., Ha, K.S., Jang, G.Y., Lee, J.H., Lee, K.C., Son, C.S., and Lee, J.W. 2009. Incomplete Kawasaki disease in patients younger than 1 year of age: a possible inherent risk factor. Eur J Pediatr. 168:157-162.
- Yoshimura, K., Tatsumi, K., Iharada, A., Tsuji, S., Tateiwa, A., Teraguchi, T., Ogino, H., Kaneko, K. 2009. Increased nitric oxide production by neutrophils in early stage of Kawasaki disease. Eur J Pediatr. 168:1037-1041
- Perrin, L., Letierce, A., Guitton, C., Tran, T.A., Lambert, V., Kone-Paut, I. 2009. Comparative study of complete versus incomplete Kawasaki disease in 59 pediatric patients. Joint Bone Spine. 76:481-485.
- Son, M.B.F., Gauvreau, K., Ma, L., Baker, A.L., Sundel, R.P., Fulton, D.R., Newburger, J.W. 2009. Treatment of Kawasaki Disease: Anlaysis of 27 US Pediatric Hospitals From 2001 to 2006. Pediatrics. 124:1-8.
- Ugi, J., Lepper, P.M., Witschi, M., Maier, V., Geiser, T., Ott, S.R. Nonresolving pneumonia and rash in an adult: pulmonary involvements in Kwasaki’s disease. EUROPEAN RESPIRATORY JOURNAL. 35:452-454.
- Climaz, R., Sundel R. 2009. Atypical and incomplete Kawasaki disease. Best Practice & Research Clinical Rheumatology. 23 (5):689-697.
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