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• A 3-month-old infant with atypical Kawasaki disease
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• Nichkamol Lertamornkitti ,
• Anchalee Wangjirapan
• Department of Pediatrics , Faculty of medicine, Lampang Hospital , Lampang , Thailand
• Correspondence to Dr Anchalee Wangjirapan, cherry_cmu{at}hotmail.com

We report a 3-month-old girl who presented with high-grade fever for 3 days. Her initial physical examination was normal. Investigation showed abnormal white cells in her urine. She was diagnosed with a urinary tract infection and received an antibiotic for 1 day. After that, she developed a generalised maculopapular rash over her body. An adverse drug reaction from the antibiotic was suspected, and the patient was referred to our hospital. On admission, she still had fever and was irritable. She was diagnosed with sepsis and given another broad-spectrum antibiotic for 2 days. However, her fever still persisted. An additional thorough physical examination showed redness of her BCG inoculation scar. Consequently, a diagnosis of Kawasaki disease (KD) was made. After she received intravenous immunoglobulin, her fever diminished straight away. This case highlights an unusual manifestation of KD in an uncommonly young age group.

• paediatrics

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https://doi.org/10.1136/bcr-2017-221456

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The usual incidence of Kawasaki disease (KD) is from 6 months up to 5 years of age. 1 There are only a few reported cases of neonatal KD. 2 An important and distinctive clinical sign that is not included in the classical clinical criteria of KD is a reaction at the BCG inoculation site. BCG redness is found in more than 50% of KD patients aged less than 12 months. 3 The crust formation or redness at the BCG scar should alert the physician to consider KD as a differential diagnosis for any febrile children, even when there are only a few or no classic clinical presentations. 4

Since it is challenging to establish a diagnosis, coronary artery complications occur frequently in infants with KD. 5 To prevent such harmful consequences, paediatricians can treat patients with KD through intravenous immunoglobulin (IVIG) infusion within 10 days of onset of the disease. 6 IVIG can decrease the risk of coronary artery abnormalities from 25% to 5%. 5 Our patient was diagnosed rapidly enough and received IVIG in good time, so she had no residual coronary artery complications.

Persistent fever can be caused by infectious and non-infectious diseases. Infectious diseases may be caused by bacteria, viruses, fungi or parasites. In this case, we gave her broad-spectrum antibiotics, but her symptoms did not improve indicating that bacterial infection was less likely. We therefore also included other micro-organisms and non-infectious diseases such as autoimmune diseases or neoplasm in the differential diagnosis. KD should also be considered as a differential diagnosis in cases of persistent fever especially in children under 5 years. A detailed history and physical examination are required to reveal the cause of persistent fever.

Case presentation

A 3-month-old infant from northern Thailand presented with fever for 3 days. She was a healthy term infant. She received BCG vaccination at birth. Her vaccination was completed according to Thailand’s national immunisation programme. Before she was referred to our hospital, she was admitted to a primary care hospital due to high-grade fever together with poor intake. Investigations for the source of the infection were conducted. Her urine examination showed a concentration of white cells of 20–30 cells/high-power field (hpf). As a result, she was diagnosed with a urinary tract infection. She was given ceftriaxone. After that, she developed a generalised maculopapular rash, so a ceftriaxone allergy was suspected. She was referred to our hospital.

On the first day of admission to our hospital, physical examination revealed high-grade fever (39˚C), a heart rate of 155 beats per minute and a respiratory rate of 32 breaths per minute. She looked irritable. She had erythematous lips and a mildly injected pharynx. She had no erythema of the palms or soles. Other systems were within normal limits. We thought of sepsis, so we gave her meropenem. However, the fever still persisted after 2 days of the antibiotic. We repeated the physical examination and found that she had redness and induration around her BCG scar ( figure 1 ). She had neither conjunctival injection nor cervical lymphadenopathies.

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Redness and induration around her BCG scar.

Investigations

A complete blood count revealed a haemoglobin concentration of 10.7 g/dL, haematocrit of 32.1%, a mean corpuscular volume of 83.1 fL and a white cell count of 23.7 x 10 9 /L  with 66% neutrophils, 22% lymphocytes and 3% monocytes. The platelet count was as high as 450 x 10 9 /L. The erythrocyte sedimentation rate (ESR) was 19 mm/hour. C reactive protein (CRP) was elevated to 130.7 mg/L. The liver function tests revealed a total bilirubin of 0.3 mg/dL, direct bilirubin of 0.1 mg/dL, aspartate aminotransferase of 38 U/L, alanine transaminase of 21 U/L, alkaline phosphatase of 111 U/L, total protein of 5.3 g/dL, albumin of 3.3 gm/dL and globulin of 2 g/dL. Urinary analysis showed a white cell count of 20–30 cells/hpf with 1–2 epithelial cells/hpf. The cerebrospinal fluid profile was normal. All cultures from catheterised urine, blood and cerebrospinal fluid were negative.

Echocardiography showed no anatomical cardiac defect. The coronary arteries were normal sized: the left main coronary artery was 1.7 mm, left anterior descending artery 1.7 mm, left circumflex artery 1.2 mm and the right coronary artery 1.8 mm. There was normal left ventricular function and trivial mitral valve regurgitation without pericardial effusion.

Differential diagnosis

Incomplete KD (two clinical criteria of red lips and polymorphous exanthem). On additional physical examination, erythema induration at BCG inoculation site plus three supplementary laboratory criteria of white cells ≥15 000 cells/mm 3 , urine white cell count ≥10 cells/hpf and platelet count ≥450 000 cells/mm 3 ).

The patient received IVIG 2 g/kg and aspirin 80 mg/kg/day on her seventh day of fever.

Outcome and follow-up

After administration of IVIG and aspirin, the fever dramatically defervesced in the following 24 hours. The infant was discharged 48 hours later. Her vaccination programme was postponed for the next 11 months to avoid live attenuated vaccines. Aspirin was prescribed at an antithrombotic dose for 8 weeks.

A follow-up echocardiography showed normal coronary arteries. The right coronary artery was 1.2 mm, the left main coronary artery was 2 mm and the left anterior descending artery was 1.5 mm. At follow-up examination, she had no periungual peeling of fingers or toes.

Only about 10% of KD occurs in infants who are less than 6 months. 5 Moreover, the incidence of KD in infants less than 3 months in Japan and Korea is only 1.67% and 2.2%, respectively. 7 8 The diagnosis of KD in infants 3 months of age or younger is difficult because very few cases (about 24%) meet 4 out of the 5 classical clinical criteria: changes in lips and oral cavity, polymorphous exanthem, bilateral non-exudative bulbar conjunctivitis, changes in extremities and a cervical lymphadenopathy over 1.5 cm in size. 7 As a consequence, cardiac complications are more common in KD patients less than 6 months of age. 9 IVIG and aspirin remain the mainstay of KD treatment. 10 Prompt diagnosis and administration of IVIG within 10 days, or ideally before day 7 of the disease, is mandated in order to reduce such cardiac complications. 11 Aspirin in the acute inflammatory period is prescribed at either 80–100 mg/kg/day or 30–50 mg/kg/day. Forty-eight to seventy-two hours after cessation of fever, aspirin should be decreased to a low dose (3 to 5 mg/kg/day). Additional therapy may include corticosteroid, infliximab and etanercept. 10

Since diagnosing KD in infants younger than 6 months is difficult, any febrile infants who have fever for 7 days or more without other explanations, even without any clinical clues of KD, should receive a blood analysis of systemic vascular response. If the ESR or CRP is elevated, echocardiography should be performed. 12 However, there are many limitations of echocardiography in the diagnosis of KD. First, it is an operator-dependent imaging. Second, it also requires co-operation from the patient. Third, the growth of children and the increasing body size cause difficulties in visualising the coronary arteries. These could possibly be diagnostic limitations as the sensitivity and specificity of echocardiography to determine coronary artery stenosis are uncertain. 10

There are many studies concentrating on the early diagnostic criteria of infantile KD. 9 13–16 Kang et al reviewed medical records of 64 KD patients from January 2010 to October 2014. Twenty of the analysed KD patients were infants less than 1 year of age. They discovered that infants had higher rates of inflammation at the BCG inoculation site (P<0.001), but lower incidence of changes in the extremities (P=0.029) and cervical lymphadenopathy (P=0.006). They stated that BCGitis is an initial sign that could lead to the diagnosis of incomplete infantile KD. 13 Yoon et al reviewed medical histories of 239 KD patients from January 2013 until June 2015, of which 26 were less than 6 months. They recognised that infants less than 6 months with KD rarely express cervical lymphadenopathy (P=0.005) or non-exudative conjunctival injection (P=0.027) when compared with KD patients aged 6 months or older. 9 Limbach and Lindinger claimed that all infants with KD shared similar characteristics of persistent fever despite administration of antibiotics and a polymorphous skin manifestation. They also revealed that abnormal urinalysis and thrombocytosis were frequently observed in this age group. 16

In our case, the patient was only 3 months. She had BCGitis, polymorphous exanthem, persistent fever even after infusion with several antibiotics, a sterile pyuria and thrombocytosis which provided the clues for a diagnosis. She had neither cervical lymphadenopathy, changes in extremities nor conjunctival injection. Fortunately, IVIG was given within 10 days of the onset of the disease and so she had no coronary artery complications.

Learning points

Kawasaki disease (KD) should be considered in infants less than 6 months even though the incidence is low in this age group.

Careful physical examination is important. If BCGitis is found in febrile children without a source of infection, consideration of KD is warranted.

Early diagnosis of KD and administration of intravenous immunoglobulin could reduce the risk of coronary artery complications.

• Rowley AH ,
• Kagawa J , et al
• Shahmohammadi S
• Igarashi H ,
• Yashiro M , et al
• Park JS , et al
• Chuang CH ,
• Chiu CH , et al
• Hong YM , et al
• McCrindle BW ,
• Newburger JW , et al
• Newburger JW ,
• Seo IA , et al
• Chen SJ , et al
• Choi KM , et al
• Limbach H ,
• Lindinger A

Contributors AW: picked a topic, made an outline and revised the manuscript. NL and AW: researched and wrote the paper.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient consent Gaurdian consent obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

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• Published: 23 October 2018

Kawasaki disease: two case reports from the Aga Khan Hospital, Dar es Salaam-Tanzania

• Mariam Noorani   ORCID: orcid.org/0000-0002-6455-1675 1 &
• Nuruddin Lakhani 1  

BMC Pediatrics volume  18 , Article number:  334 ( 2018 ) Cite this article

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Kawasaki disease is a common childhood vasculitis which may result in cardiovascular morbidity if not adequately treated. Its epidemiology in the African region is not well described. Its features may mimic other childhood infections and hemoglobinopathies and it is rarely diagnosed in the East African region. These are the first reports of this disease from Tanzania.

Case presentation

We present two cases of complete Kawasaki disease seen over a 2 year period and diagnosed as per the criteria defined by the American Heart Association. One child was and infant and the other a 3 year old. Both of them presented with a prolonged fever and mucocutaneous findings. None of the children developed coronary artery aneurysms. One was treated with aspirin alone and the other with both aspirin and intravenous immunoglobulin. Both children had complete recovery and did not have any cardiovascular sequelae.

Kawasaki disease may be more common in the East African region than previously thought. It should be considered as a differential diagnosis in children who present with a prolonged fever of greater than 5 days and mucocutaneous findings. More awareness about this condition, its epidemiology, diagnosis and management are required in order to prevent the cardiovascular morbidity associated with it.

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Kawasaki disease is one of the most common vasculitides in childhood. It occurs predominantly in infants and young children and has long term cardiovascular morbidity due to coronary artery lesions if not adequately treated [ 1 ]. It is the leading cause of acquired heart disease in children in developed countries. The highest incidence is in Asia with almost 1 in a 100 children in Japan having the disease by age 5 [ 2 ]. In Africa, two cases were reported in South Africa in Caucasian children in 1980 but the first case in an African child was reported in Ivory Coast in 1981. Despite of sporadic cases being reported across many countries in Africa, mainly North Africa and the West African region, the epidemiological data for KD is limited for African countries [ 3 , 4 , 5 ].

The etiology of the disease remains unknown and several hypothesis exist in trying to explain the cause. Epidemiologic data suggest that an infectious agent may be causing the disease in genetically susceptible individuals [ 6 ]. The classic presentation of the disease occurs in children below 5 years. This suggests that there is an environmental trigger to which children mount an immune response after which the disease no longer manifests [ 7 ]. Postulated infectious agents include variants of normal flora which are induced by environmental factors such as improved hygiene [ 8 ]. Pathogenetic mechanisms postulated to result in endothelial injury include that of a protein homeostasis system in which immune cells target pathogenic proteins bound to endothelial cells resulting in host cell injury [ 9 ].

The initial symptoms are of a febrile illness lasting longer than 5 days with other mucocutaneous features including a rash, conjuctivitis and adenopathy. Diagnostic criteria exist to make a diagnosis of both complete and incomplete forms of disease [ 10 ]. If left untreated, the symptoms resolve in about 10 days. However, the coronary artery lesions may lead to long term cardiovascular complications including myocardial infarction, heart failure and arrhythmias. Treatment in the acute phase reduces the incidence of coronary artery lesions from 25 to 30% to 3–5% [ 11 ]. Currently, the recommended treatment is intravenous immunoglobulin in addition to acetylsalicylic acid at high doses [ 10 ].

In sub-saharan Africa, children suffer from many tropical and infectious diseases that present with symptoms similar to those of kawasaki disease such as fever, irritability and a rash. Common conditions include malaria, typhoid fever, meningitis and viral exanthems such as measles and roseola infantum. Other conditions that may mimic this disease include sickle cell dactylitis and infection with group A beta hemolytic streptococcus. A high index of suspicion is hence required to identify cases of kawasaki disease and institute early treatment.

We report here 2 cases of kawasaki disease seen at our institution that met diagnostic criteria defined by the American Heart Association. These are the first reports in published literature from the East African region.

Case presentations

A.M was a 3 year old female child of African ethnicity who presented in July 2012 with a 8 day history of high grade fever and a 1 day history of swelling of the hands and feet. (Table  1 – timeline of case 1). She had received oral antibiotics, anti malarials and antihistamines with no improvement in symptoms. Her past medical history had been uneventful and her vaccinations were uptodate.

On examination, she was alert, had dry, red lips and non pitting edema on her hands and feet. She had cervical nodes measuring about 0.5 cm. Her cardiovascular exam was normal. She was admitted for further work up for the cause of her fever.

Her results showed an elevated WBC count of 36,000/μl, Hb of 9.1 g/dl and platelets of 380,000/μl. Her CRP was 173 mg/l. Malaria antigen and slide were both negative. Her urinalysis was normal. She was started empirically on ceftriaxone for presumed bacteremia and blood and urine cultures were sent. A differential diagnosis of sickle cell anaemia with dactylitis was also made and a peripheral smear, reticulocyte count and sickling test were requested. The reticulocyte count was low with a percentage of 0.38. Sickling test was negative and the peripheral smear was normal.

She continued to have fever spikes despite the antibiotics and then developed a maculopapular hyperemic rash on her chest. A diagnosis of incomplete kawasaki disease was now made which met 3 out of the 5 required criteria. An echocardiogram was done which showed normal coronary arteries. High dose aspirin was started at 80 mg/kg/day. IVIG was not available at the institution at that time. A repeat complete blood count showed some improvement in white blood cells (28000/μl) but elevated platelets of 644000/μl. The blood and urine culture were both reported as negative after 48 h.

The child was then flown out to Nairobi, Kenya for IVIG treatment which she received uneventfully. She was discharged on low dose aspirin and subsequent echocardiograms remained normal.

W.I was an 8 month old infant of African ethnicity who presented in August 2013 with a 6 day history of a high grade fever with temperatures upto 39 degrees celsius. (Table 2 – Timeline of case 2). This was associated with redness of the eyes, lips and mouth. He had been treated at various health facilities with antimalarials and 2 antibiotics: cefalexin and coamoxiclav. He had also received paracetamol, ibuprofen and diclofenac injections to control the fever. His past medical history was uneventful and his vaccines were uptodate. He had attained milestones appropriately.

On examination, the child was irritable and difficult to console. He was febrile with a temperature of 38.5 0 C and was not pale. He had dry, cracked, hyperemic lips and conjuctival injection bilaterally. Cervical nodes were not palpable. He had a papular rash on the neck and at the site of the BCG scar. The rest of his physical exam was normal.

A presumptive diagnosis of incomplete kawasaki disease was made meeting 3 of the five criteria required in addition to the fever. A complete blood count showed mild anaemia with normal platelet count. (WBC: 9.07 *10 3 /μl, Hb: 9.3 g/dl, platelets:190,000/μl). Malaria antigen and blood slide were both negative. He was started on high dose aspirin at 90 mg/kg/day as IV IG was not available in our institution at that time. An echocardiogram was done which showed normal coronary arteries and normal cardiac function.

His fever resolved after 72 h and he developed swelling of the hands and feet which now confirmed the diagnosis of complete kawasaki disease. The aspirin dose was reduced to 5 mg/kg/day after the fever subsided. The platelet count was repeated and it showed elevated platelets of 742,000/μl. The CRP was also high: 153 mg/l.

On follow up after a week, the limb swelling had reduced and he had skin exfoliation. His CRP had reduced to 60 mg/l and the platelets were 605,000/μl.

A follow up echo done after 1 month was normal and the aspirin was stopped after the hematological parameters had normalised. He has subsequently remained well with no cardiovascular sequelae.

Discussion and conclusions

Both cases described above presented to us after a prolonged duration of fever and failure to respond to antimalarials and antibiotics. This is a common presentation also described in case reports from Ghana [ 3 ].

The first case was 3 year old child while the second was an infant. This is in keeping with epidemiologic studies from Algeria and Japan which have shown that more than 90% of children are less than 5 years of age [ 2 , 5 ].

The children had the classical mucocutaneous features that are key to making the diagnosis. The first child had limb swelling, a skin rash and oral mucosal changes. The limb swelling was initialy thought to be sickling dactylitis which is a common condition seen in our environment and is one of the presenting signs of sickle cell disease [ 12 ].

The second child had non purulent conjuctivitis, swelling of limbs and the skin rash with involvement of the BCG scar which has been described previously [ 13 ]. Hematologic parameters are not diagnostic of kawasaki disease, however they can assist to confirm or support the diagnosis. Both our children were admitted with normal platelet counts which subsequently became elevated. This is a common finding in the second week of illness and is used as an adjunct in making diagnosis of incomplete kawasaki disease [ 10 ]. The first child had an elevated WBC count leading to a diagnosis of bacteremia and initiation of parenteral antibiotics. However, the blood culture eventually ruled out a bacteremia. The CRP was raised for both the cases as expected and eventually reduced after initiation of aspirin.

The first case was treated with both aspirin and IVIG while the second received only aspirin. The role of aspirin remains uncertain in the current era of use of IVIG, however it still remains as part of the standard treatment protocols. The current treatment: IVIG is an expensive drug that is not readily available or affordable to most families in our population. A single vial of 5 g costs as much as 1 million tanzanian shillings which is about 450 US dollars. This hampers effective treatment which is essential to reduce the cardiovascular sequelae.

Other treatment options that could be considered are use of corticosteroids. A cochrane review of 7 trials showed benefits of reducing cardiac complications by using steroids as adjunct therapy to IVIG early in the course of illness [ 14 ]. Use of steroids alone without IVIG has not been studied. However, in low resource settings where IVIG is not available, steroids could be used to reduce the cardiovascular morbidity [ 15 ]. Other agents such as infliximab have shown promise as adjuncts to IVIG but are also not widely available in sub – saharan Africa [ 16 ].

The echocardiograms for both children were normal at baseline and on subsequent follow ups. This was reassuring since the incidence of coronary abnormalities is as high as 25–30% in patients who are not treated with IVIG [ 11 ]. Echo is a vital modality to follow up the cardiac sequelae in chidlren with kawasaki disease. However, it is not widely available in most resource limited settings and requires specialised training to operate. In Tanzania, it is only available at a few referral hospitals in the cities. This is yet another challenge in providing long-term care to children with kawasaki disease.

Kawasaki disease has not commonly been described in sub-saharan Africa. However, these 2 cases were seen over a 2 year period at a single tertiary institution. This raises concern about how many missed cases there may be which are not diagnosed or managed effectively since the fever and mucocutaneous changes eventually resolve within 3 weeks even without specific treatment. The subsequent devastating cardiovascular morbidity of this condition in children with missed diagnosis remains unknown.

The pattern of disease in the setting of tropical infections like malaria also remains unknown. Kawasaki like syndromes have been described in adults with HIV infection especially with severe immunosupression [ 17 ]. Similar illness in children infected with HIV has not been described but may also occur.

We recommend that a diagnosis of kawasaki disease be entertained for any febrile illness lasting longer than 5 days and presenting with mucocutaneous findings. Any child presenting with a prolonged fever should promptly be referred to and evaluated at a tertiary centre. Doctors and other care providers should be made familiar with this condition in order to diagnose, treat and prevent the cardiovascular morbidity and mortality.

Cases that are seen at other institutions should be published in literature so that the spectrum of the disease, its epidemiologic characteristics and its outcomes in sub-saharan Africa can be described. Equally important is that IVIG be made available at a subsidised and more affordable cost in order to benefit patients with kawasaki disease and other autoimmune conditions where it is indicated.

Abbreviations

Complete blood count

• Intravenous immunoglobulin

White blood cells

Burns JC, Glodé MP. Kawasaki syndrome. Lancet. 2004;364:533.

Article   Google Scholar  

Nakamura Y, Yashiro M, Uehara R, et al. Epidemiologic features of Kawasaki disease in Japan: results of the 2007-2008 nationwide survey. J Epidemiol. 2010;20:302.

Badoe EV, Neequaye J, Oliver-Commey JO, et al. Kawasaki disease in Ghana: case reports from Korle Bu teaching hospital. Ghana Med J. 2011;45:38.

Article   CAS   Google Scholar  

Chemli J, Kchaou H, Amri F, Belkadhi A, Essoussi AS, Gueddiche N, Harbi A. Clinical features and course of Kawasaki disease in central Tunisia: a study about 14 cases collected over a period of three years (2000-2002). Tunis Med. 2005;83(8):477–83.

PubMed   Google Scholar  

Boudiaf H, Achir M. The clinical profile of Kawasaki disease in Algerian children: a single institution experience. J Trop Pediatr. 2016;62(2):139–43.

Kim KY, Kim DS. Recent advances in Kawasaki disease. Yonsei Med J. 2016;57(1):15–21.

Burgner D, Harnden A. Kawasaki disease: what is the epidemiology telling us about the etiology? Int J Infect Dis. 2005;9:185–94.

Lee KY, Han JW, Lee JS. Kawasaki disease may be a hyperimmune reaction of genetically susceptible children to variants of normal environmental flora. Med Hypotheses. 2007;69(3):642–51.

Lee KY, Rhim JW, Kang JH. Kawasaki disease: laboratory findings and an immunopathogenesis on the premise of a “protein homeostasis system”. Yonsei Med J. 2012;53(2):262–75.

Newburger JW, Takahashi M, Gerber MA, et al. 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. 2004;110(17):2747–71.

Terai M, Shulman ST. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. J Pediatr. 1997;131(6):888.

Bainbridge R, Higgs DR, Maude GH, Serjeant GR. Clinical presentation of homozygous sickle cell disease. J Pediatr. 1985;106(6):881.

Uehara R, Igarashi H, Yashiro M, Nakamura Y, Yanagawa H. Kawasaki disease patients with redness or crust formation at the Bacille Calmette-Guérin inoculation site. Pediatr Infect Dis J. 2010;29(5):430.

Wardle AJ, Connolly GM, Seager MJ, Tulloh RM. Corticosteroids for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2017;1:CD011188.

Singh S, Newburger JW, Kuijpers T, Burgner D. Management of Kawasaki disease in resource-limited settings. Pediatr Infect Dis J. 2015;34(1):94–6.

Jone PN, Anderson MS, Mulvahill MJ, Heizer H, Glodé MP, Dominguez SR. Infliximab plus intravenous immunoglobulin (IVIG) versus IVIG alone as initial therapy in children with Kawasaki disease presenting with coronary artery lesions: is dual therapy more effective? Pediatr Infect Dis J. 2018;37(10):976–80.

Stankovic K, Miailhes P, Bessis D, Ferry T, Broussolle C, Seve P. Kawasaki-like syndromes in HIV-infected adults. J Inf Secur. 2007;55:488–94.

CAS   Google Scholar  

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Noorani, M., Lakhani, N. Kawasaki disease: two case reports from the Aga Khan Hospital, Dar es Salaam-Tanzania. BMC Pediatr 18 , 334 (2018). https://doi.org/10.1186/s12887-018-1306-5

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Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) are inflammatory conditions that present diagnostic and therapeutic challenges to the physician. Although many of their features overlap, they are two distinct conditions. KD is a febrile illness most commonly affecting children younger than five years. It manifests with prolonged fever and at least four of the following features: bilateral bulbar conjunctivitis, mucositis, diffuse maculopapular rash, extremity changes, and cervical lymphadenopathy of 1.5 cm or more in diameter. Patients with MIS-C may have many of the same manifestations but tend to have higher rates of gastrointestinal and neurocognitive symptoms and signs of shock on presentation. Both conditions are associated with cardiac sequelae, including coronary artery aneurysms, although children with MIS-C are at high risk of developing ventricular dysfunction and depressed cardiac output. Lymphocytopenia, thrombocytopenia, elevated troponin, and elevated B-type natriuretic peptide are key laboratory findings of MIS-C that can help distinguish it from KD. The use of intravenous immune globulin is well established in KD and also appears to have a role in the treatment of MIS-C. Aspirin has been used in KD for an anti-inflammatory effect, and low-dose aspirin is recommended for MIS-C to reduce the risk of thrombosis. In addition to supportive care, patients with MIS-C may benefit from immunomodulatory medications, although data on this topic are evolving.

First described in Japan in 1967, Kawasaki disease (KD) is a vasculitis affecting small- and medium-sized vessels; it is predominantly seen in children younger than five years. 1 This febrile illness is characterized by systemic inflammation and is the most common cause of acquired coronary artery disease in children. 2 With the emergence of multisystem inflammatory syndrome in children (MIS-C), a new inflammatory syndrome associated with COVID-19, KD has received increased attention because features of the diseases overlap.

Epidemiology

Although the underlying cause of KD remains unknown, the epidemiology and pathophysiology suggest that it is an inflammatory response in a genetically susceptible host to an infectious or other exogenous trigger. A number of viruses have been implicated as potential triggers for KD, including coronaviruses (non–COVID-19 strains). 3 , 4 KD is an illness predominantly occurring in toddlers, with a mean age of three years in the United States (76% of cases occur in children younger than five years). 5 There is a predilection for children of Asian and Pacific Islander descent, 5 and boys are affected slightly more often than girls (1.5:1). 6

In contrast, MIS-C affects a wider age range, from one week to 20 years with a median age of seven to nine years. 7 – 11 In the United States, 62% of patients are Hispanic or Latino (32%) or non-Hispanic Black (30%)—the ethnic groups disproportionately affected by COVID-19. 7 Similarly to KD, MIS-C occurs more often in boys (60%) than in girls. 7

The clinical features of classic KD are shown in Table 1 . 2 A diagnosis of classic KD is made in patients with prolonged fever (five or more days) and four or more of the following principal features: oral mucosal inflammation; bilateral bulbar conjunctivitis; a diffuse maculopapular rash; extremity changes, including erythema and edema of the hands and feet; and cervical lymphadenopathy of 1.5 cm or more in diameter. 2 Incomplete KD is a diagnosis made when a patient has fewer than four of the major criteria but has sufficient laboratory features or suggestive changes on echocardiography. The 2017 American Heart Association KD guidelines provide a diagnostic algorithm to assist with this often challenging diagnosis 2 ( Table 2 ) .

When diagnosing KD, physicians must have a strong understanding of the features of each major symptom. The conjunctivitis of KD is bilateral, nonexudative, and affects the bulbar conjunctiva but classically spares the limbus ( Figure 1 ) . The rash of KD is typically diffuse and maculopapular, often accentuated in the perineal region ( Figure 2 ) . The oral mucous membrane changes of KD can manifest as erythema of the oropharyngeal mucosa or lips; dryness, cracking, and/or peeling of the lips ( Figure 3 ) ; or a “strawberry” appearance of the tongue. Anterior cervical lymphadenopathy is typically unilateral and involves at least one node larger than 1.5 cm in diameter. In contrast to bacterial lymphadenitis, the lymphadenopathy of KD is typically not associated with marked erythema of the overlying skin and is not exquisitely painful to palpation. Rarely, painful lymphadenopathy is the presenting feature of KD and may be misdiagnosed as bacterial lymphadenitis. 12 The extremity changes of KD manifest as erythema and edema of the palms and soles and, at times, refusal to walk because of painful induration. Subacute extremity changes include periungual desquamation and deep transverse grooves across the nail lines, termed Beau lines. Outside of the major diagnostic criteria, profound irritability is commonly described. Children may also have arthritis or arthralgia, gastrointestinal complaints such as diarrhea and vomiting, or rhinorrhea and cough. Symptoms, physical examination findings, and laboratory evidence of viral infection should not exclude the diagnosis of KD because studies have reported that 30% to 40% of children who meet the diagnostic criteria of KD are also positive for at least one respiratory virus. 3 , 13

The Centers for Disease Control and Prevention case definition of MIS-C is presented in Table 3 . 7 Similarly to KD, fever is the principal diagnostic finding of MIS-C. A shorter duration of fever (24 hours or longer) is used to diagnose MIS-C, which is a significant distinction from KD. Gastrointestinal symptoms, including vomiting, diarrhea, and abdominal pain, are the second most common set of symptoms reported in MIS-C, present in about 80% of cases. 8 Neurocognitive symptoms have been described in approximately one-fifth of patients and include headache, irritability, lethargy, altered mental status, or features of aseptic meningitis. 8 Respiratory symptoms, including cough, congestion, dyspnea, and sore throat, are less common but have also been reported. 8

Of note, the clinical manifestations of MIS-C may have tremendous overlap with those of KD ( Table 4 2 , 6 , 7 , 11 ) . A recent systematic review reported that 36% of patients with MIS-C had symptoms consistent with KD (6% with classic KD and 30% with incomplete KD). 8 The individual symptoms of KD were present with varying frequency in patients with MIS-C: 58% had rash; 40% had conjunctival injection; 23% had red, cracked lips; 4.5% had a strawberry tongue; and 4% had cervical lymphadenopathy. 8

Exposure to or a history of COVID-19 is often noted among patients with MIS-C; however, because COVID-19 can present asymptomatically, this may not be apparent from the history in these patients. Therefore, testing for evidence of COVID-19 is included in the Centers for Disease Control and Prevention's case definition. Among patients with MIS-C, 94% to 99% have tested positive for SARSCoV-2 by reverse transcriptase polymerase chain reaction or for antibodies against this virus. 7 , 8

Cardiac Manifestations

Coronary artery dilation and aneurysm formation are well-known complications of KD. If untreated, 15% to 25% of patients with KD will develop coronary artery abnormalities; the percentage drops to around 5% with prompt treatment. 14 Therefore, echocardiography is important for patients suspected of having KD but should not delay treatment. 2 , 7 For risk stratification, coronary artery lumen diameter is compared with the child's body surface area and normalized as a z score. Scores of at least 2.5 in the left anterior descending branch and proximal right coronary artery are highly specific for KD. 2 Some patients with mild dilation will experience spontaneous resolution, whereas others will develop giant aneurysms ( z score of 10 or more) and can experience significant morbidity, including arterial stenosis, clot formation, and cardiac ischemia or infarction, sometimes requiring cardiac bypass surgery or transplant. 2

Coronary artery changes in KD are not typically symptomatic in the acute phase, and physicians should remain cognizant that the myocardium and endocardium may become inflamed, which could manifest as tachycardia, a hyperdynamic precordium, a gallop rhythm, and accentuation of flow murmurs. 2 Valvular dysfunction has been reported in about 25% of patients with KD (with the mitral valve being the most commonly affected), whereas aortic root dilation has been reported in about 10% of cases. 15 In about 5% of children with KD in the continental United States, intracardiac inflammation can lead to severe tachycardia, hypotension, and cardiovascular collapse, also known as KD shock syndrome. 2

Similarly to KD, MIS-C can have profound cardiac manifestations, the principal of which is shock, which can lead to death. 8 Although shock is rare in KD, most patients with reported MIS-C develop hypotension, likely because of a combination of cardiac dysfunction and systemic vasodilation, 16 and require admission to an intensive care unit. 17 Echocardiography is used to visualize the coronary arteries and to establish the degree of cardiac dysfunction, which has been noted in about 30% of patients with MIS-C in the United States. 16 , 17 Reports have cited a range of rates of coronary artery dilation or aneurysms in MIS-C; one large cohort of 1,733 patients in the United States reported that 16.5% of those with MIS-C developed coronary artery changes, similar to the rate in untreated KD. 17 In addition to echocardiography, electrocardiography has an important diagnostic role in MIS-C because electrocardiographic changes and cardiac arrhythmias, including ST segment changes, premature beats, QTc prolongation, atrioventricular block, and sustained life-threatening arrhythmias, have been well described. 16 , 18

Laboratory Findings

The laboratory findings of KD and MIS-C indicate systemic inflammation; however, some key differences exist. Table 4 provides a comparison of the laboratory values found in an early cohort of patients with MIS-C in England and a large cohort of patients with KD in San Diego, Calif. 2 , 6 , 7 , 11 Diagnostic workup for children with suspected MIS-C should include complete blood count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, and SARS-CoV-2 polymerase chain reaction and/or serologies. Additional workup includes B-type natriuretic peptide, troponin, ferritin, prothrombin time, partial thromboplastin time, d dimer, fibrinogen, lactate dehydrogenase, cytokine panel, electrocardiography, and chest radiography. 19 In KD, inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, ferritin, and d dimer, are most often mildly to moderately elevated. Patients with MIS-C tend to have very high markers of inflammation, especially C-reactive protein values. 11

In complete blood count values, patients with KD typically demonstrate elevated white blood cell counts. 2 Patients with MIS-C present with a low absolute lymphocyte count and frank lymphocytopenia. Both illnesses manifest with mild to moderate anemia, although it tends to be more profound in MIS-C. 11 The platelet count is another area of divergence: Patients with KD classically develop thrombocytosis, with platelet counts of more than 450,000 per μL (450 × 10 9 per L) after seven days of illness, whereas patients with MIS-C tend to develop mild to severe thrombocytopenia. 11

Elevated transaminase and decreased albumin levels can occur in patients with both illnesses. 11 The hypoalbuminemia in KD tends to be mild, but it can be severe in patients with MIS-C and lead to complications, such as pulmonary edema, especially in the setting of aggressive fluid resuscitation.

Finally, the elevation of troponin and B-type natriuretic peptide is a notable difference between patients with MIS-C and those with KD. Troponin and B-type natriuretic peptide levels are not routinely evaluated in KD, but in children with KD whose levels were measured, elevations were minimal. 11

The fundamental goal of treatment for patients with KD and MIS-C is to rapidly reduce systemic inflammation. Intravenous immune globulin (IVIG), 2 g per kg in a single dose, has been a long-established therapy for KD and is an effective way to reduce vascular inflammation, improve symptoms, and reduce risk of coronary artery abnormalities. 2 , 20 – 24 High-dose aspirin (80 to 100 mg per kg per day) has been used for decades for anti-inflammatory effect; however, no evidence supports a reduction in coronary artery abnormalities. 25 , 26 Many clinicians have begun to use medium-dose aspirin (30 to 50 mg per kg per day) or low-dose aspirin (3 to 5 mg per kg per day) during the acute phase to avoid the potential toxicity of high-dose aspirin. 27 Low-dose aspirin provides an antiplatelet effect, given the risk of clotting in patients who develop aneurysms. 2 Systemic corticosteroids for the treatment of KD have been a subject of controversy, but a landmark randomized controlled trial published in 2012 (RAISE study) demonstrated a clear benefit in Japanese children who were at high risk. 28 A subsequent meta-analysis of 16 trials supported the role of corticosteroids as well, especially in early, severe KD. 29 Most of the trials were conducted in Japan, where validated scoring tools are available to identify high-risk patients; thus, results may not be generalizable to other populations, and large practice variation exists. Some centers and KD experts have advocated for the addition of corticosteroids in the treatment of North American patients at high risk of IVIG resistance, including those with coronary artery aneurysms at diagnosis, those younger than 12 months, those with KD shock syndrome, and those who have KD presenting with macrophage activation syndrome. 30 , 31 There is no universally accepted dosing regimen, but corticosteroid courses similar to those used in the RAISE study have been proposed (methylprednisolone or prednisone in a dosage of 2 mg per kg per day for five days, followed by a two-week taper). 31

Treatment for MIS-C is a topic of ongoing research and is based largely on expert opinion and therapies used in KD and other childhood inflammatory conditions. Given the severity of disease, patients with suspected MIS-C in the clinic setting should be quickly referred to the hospital, where a multidisciplinary and multispecialty team can assist with treatment recommendations. 19 Supportive measures, including respiratory support and judicious fluid resuscitation, are critical to prevent patient morbidity and mortality. Many patients also require inotropic support. 8 As in patients with KD, IVIG given at 2 g per kg has been a consensus first-line therapy for those with MIS-C. 19 , 32 Low-dose aspirin is recommended to reduce the risk of thrombosis associated with coronary artery aneurysms. 19 Corticosteroid use to improve outcomes in MIS-C is a topic of ongoing research. Early observational data have suggested that adjunctive systemic corticosteroids can reduce the course of fever in patients with MIS-C. 33 Additional observational studies published in July 2021 had seemingly conflicting results, however, indicating a need for prospective trials using a standardized treatment approach. 34 – 36 Immunomodulators such as anakinra (Kineret), an interleukin-1 receptor antagonist, have been recommended in severe cases, although no robust published data are available on their use. 19

This article updates a previous article on this topic by Saguil, et al. 37

Data Sources: Our review of the literature was conducted by searching PubMed Clinical Queries using the following key terms: pediatric multisystem inflammatory syndrome, SARSCoV-2 related, multisystem inflammatory syndrome in children, Kawasaki disease, mucocutaneous lymph node syndrome. The PubMed MeSH database was also used to search related terms. The search included meta-analyses, randomized controlled trials, clinical trials, reviews, letters to the editor, and case reports. Government disease-tracking websites, such as the Centers for Disease for Control and Prevention website on multisystem inflammatory syndrome in children, were also important sources of information and references. Search dates: January 19 and July 19, 2021.

The authors thank Dr. Lindsay Strowd and the Wake Forest School of Medicine Graham Archives Library for contributing the images included in this work.

Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children [in Japanese]. Arerugi. 1967;16(3):178-222.

McCrindle BW, Rowley AH, Newburger JW, et al.; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Epidemiology and Prevention. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association [published correction appears in Circulation . 2019;140(5):e181–e184]. Circulation. 2017;135(17):e927-e999.

Turnier JL, Anderson MS, Heizer HR, et al. Concurrent respiratory viruses and Kawasaki disease. Pediatrics. 2015;136(3):e609-e614.

Esper F, Shapiro ED, Weibel C, et al. Association between a novel human coronavirus and Kawasaki disease. J Infect Dis. 2005;191(4):499-502.

Holman RC, Belay ED, Christensen KY, et al. Hospitalizations for Kawasaki syndrome among children in the United States, 1997–2007. Pediatr Infect Dis J. 2010;29(6):483-488.

Holman RC, Curns AT, Belay ED, et al. Kawasaki syndrome hospitalizations in the United States, 1997 and 2000. Pediatrics. 2003;112(3 pt 1):495-501.

Centers for Disease Control and Prevention. Multisystem inflammatory syndrome (MIS). Updated June 25, 2021. Accessed July 14, 2021. https://www.cdc.gov/mis/hcp/index.html

Kaushik A, Gupta S, Sood M, et al. A systematic review of multisystem inflammatory syndrome in children associated with SARS-CoV-2 infection. Pediatr Infect Dis J. 2020;39(11):e340-e346.

Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771-1778.

Cheung EW, Zachariah P, Gorelik M, et al. Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City. JAMA. 2020;324(3):294-296.

Whittaker E, Bamford A, Kenny J, et al.; PIMS-TS Study Group and EUCLIDS and PERFORM Consortia. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020;324(3):259-269.

Kanegaye JT, Van Cott E, Tremoulet AH, et al. Lymph-node-first presentation of Kawasaki disease compared with bacterial cervical adenitis and typical Kawasaki disease. J Pediatr. 2013;162(6):1259-1263.

Kim JH, Yu JJ, Lee J, et al. Detection rate and clinical impact of respiratory viruses in children with Kawasaki disease. Korean J Pediatr. 2012;55(12):470-473.

Freeman AF, Shulman ST. Kawasaki disease: summary of the American Heart Association guidelines. Am Fam Physician. 2006;74(7):1141-1148. Accessed July 5, 2021. https://www.aafp.org/afp/2006/1001/p1141.html

Printz BF, Sleeper LA, Newburger JW, et al.; Pediatric Heart Network Investigators. Noncoronary cardiac abnormalities are associated with coronary artery dilation and with laboratory inflammatory markers in acute Kawasaki disease. J Am Coll Cardiol. 2011;57(1):86-92.

Sperotto F, Friedman KG, Son MBF, et al. Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach. Eur J Pediatr. 2021;180(2):307-322.

Belay ED, Abrams J, Oster ME, et al. Trends in geographic and temporal distribution of US children with multisystem inflammatory syndrome during the COVID-19 pandemic. JAMA Pediatr. 2021;175(8):837-845.

Choi NH, Fremed M, Starc T, et al. MIS-C and cardiac conduction abnormalities. Pediatrics. 2020;146(6):e2020009738.

Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARS-CoV-2 and hyperinflammation in pediatric COVID-19: version 2. Arthritis Rheumatol. 2021;73(4):e13-e29.

Furusho K, Kamiya T, Nakano H, et al. High-dose intravenous gamma-globulin for Kawasaki disease. Lancet. 1984;2(8411):1055-1058.

Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986;315(6):341-347.

Terai M, Shulman ST. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. J Pediatr. 1997;131(6):888-893.

Mori M, Miyamae T, Imagawa T, et al. Meta-analysis of the results of intravenous gamma globulin treatment of coronary artery lesions in Kawasaki disease. Mod Rheumatol. 2004;14(5):361-366.

Oates-Whitehead RM, Baumer JH, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2003(4):CD004000.

Baumer JH, Love SJL, Gupta A, et al. Salicylate for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2006(4):CD004175.

Dallaire F, Fortier-Morissette Z, Blais S, et al. Aspirin dose and prevention of coronary abnormalities in Kawasaki disease. Pediatrics. 2017;139(6):e20170098.

Son MBF, Newburger JW. Kawasaki disease. Pediatr Rev. 2018;39(2):78-90.

Kobayashi T, Saji T, Otani T, et al.; RAISE study group investigators. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet. 2012;379(9826):1613-1620.

Chen S, Dong Y, Kiuchi MG, et al. Coronary artery complication in Kawasaki disease and the importance of early intervention: a systematic review and meta-analysis. JAMA Pediatr. 2016;170(12):1156-1163.

Friedman KG, Gauvreau K, Baker A, et al. Primary adjunctive corticosteroid therapy is associated with improved outcomes for patients with Kawasaki disease with coronary artery aneurysms at diagnosis. Arch Dis Child. 2021;106(3):247-252.

Sundel R. Kawasaki disease: initial treatment and prognosis. UpToDate. Accessed May 1, 2021. https://www.uptodate.com/contents/kawasaki-disease-initial-treatment-and-prognosis

Harwood R, Allin B, Jones CE, et al.; PIMS-TS National Consensus Management Study Group. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process [published correction appears in Lancet Child Adolesc Health . 2021;5(2):e5]. Lancet Child Adolesc Health. 2021;5(2):133-141.

Ouldali N, Toubiana J, Antona D, et al.; French Covid-19 Paediatric Inflammation Consortium. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children [published correction appears in JAMA . 2021;326(1):90]. JAMA. 2021;325(9):855-864.

DeBiasi RL. Immunotherapy for MIS-C—IVIG, glucocorticoids, and biologics [editorial]. N Engl J Med. 2021;385(1):74-75.

McArdle AJ, Vito O, Patel H, et al.; BATS Consortium. Treatment of multisystem inflammatory syndrome in children. N Engl J Med. 2021;385(1):11-22.

Son MBF, Murray N, Friedman K, et al.; Overcoming COVID-19 Investigators. Multisystem inflammatory syndrome in children—initial therapy and outcomes. N Engl J Med. 2021;385(1):23-34.

Saguil A, Fargo M, Grogan S. Diagnosis and management of Kawasaki disease. Am Fam Physician. 2015;91(6):365-371. Accessed June 28, 2021. https://www.aafp.org/afp/2015/0315/p365.html

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Kawasaki Disease

A case report in extreme of pediatrics.

Kara, Ates; Tezer, Hasan MD; Devrim, İlker MD; Korkmaz, Esra Klç MD ıı ; Karagöz, Tevfik MD; Özer, Sema MD; Cengiz, A. Bülent MD; Seçmeer, Gülten MD

Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Address correspondence and reprint requests to Ates Kara, MD, Department of Pediatrics, Pediatric Infectious Disease Unit, Hacettepe University Faculty of Medicine, Hacettepe 06100 Ankara, Turkey. E-mail: [email protected] .

Kawasaki disease (KD) is a systemic vasculitis and the leading cause of acquired heart disease in the developed world. Kawasaki disease mainly occurs in infants and young children. The illness is rare in infants younger than 3 months. There is no specific diagnostic test or pathognomonic clinical features; clinical criteria have been established to assist physicians in diagnosing KD. So clinician should be aware of the possibility of KD. In this report, we present a case of KD in an infant where the disease manifestation appeared as early as 40 days after birth-perhaps the youngest ever reported from Turkey. Our experience highlights the need to consider KD even in a newborn with a case of prolonged fever.

Kawasaki disease (KD) is an acute, self-limited vasculitis of unknown etiology that was first described in the Japanese literature in 1967 and has since been recognized as both endemic in the Americas and Europe and community-wide epidemic in Asia. 1 Kawasaki disease has now become the leading cause of acquired heart disease in children in North America and Japan and is increasingly recognized as a worldwide problem. 1 It occurs in young children, with a yearly incidence of 80 to 90 per 100,000 children younger than 5 years in Japan and 10 per 100,000 children younger than 5 years in the United States. 2

Kawasaki disease is diagnosed using clinical criteria that include fever for 5 days or longer and at least 4 of the following: (1) nonexudative conjunctival injection; (2) oral involvement, including any of strawberry tongue, mucosal hyperemia, and cracked or erythematous lips; (3) changes in the peripheral extremities, including edema or desquamation in convalescence; (4) polymorphous rash; and (5) acute cervical adenopathy greater than 1.5 cm in diameter. 3

There is no specific diagnostic test or pathognomonic clinical features; those previously mentioned clinical criteria have been established to assist physicians in diagnosing KD. So clinician should be aware of the possibility of KD. In this report, we would like to present a case of KD in an infant where the disease manifestation appeared as early as 40 days after birth. Our experience highlights the need to consider KD even in a newborn with a case of prolonged fever.

CASE REPORT

A 30-day-old female infant who was previously healthy developed a high-grade fever, which was followed 2 days later by maculopapular rash on her trunk and extremities. She also had reddish discoloration of her lips and conjunctival infection. She was admitted to another hospital with those complaints and hospitalized with a diagnosis of sepsis, and she was given intravenous antibiotic for 12 days but did not recover from any of the symptoms and her fever. Levels of serum acute phase reactants including erythrocyte sedimentation rate (80 mm/h) and C-reactive protein (5 mg/dL) were remarkably high; no bacterial growth was detected in any of her culture.

She was referred to us for the evaluation of prolonged fever. Upon examination, she had desquamation of the skin at her fingers starting from the fingertips and the anal region. The child was hospitalized with the diagnosis of KD based on her medical history and physical examination findings. Her peripheral leukocyte and thrombocyte counts were 10,200/mL and 680,000/mL, respectively. Her echocardiography revealed minimal aneurysmal dilatation of coronary arteries ( Fig. 1 ). Intravenous immunoglobulin (2 g/kg) for 12 hours and high-dosage (100 mg/kg per day divided into 4 dose/d) acetylsalicylic acid treatment were applied. Her fever disappeared after the dose of intravenous immunoglobulin therapy, and acute phase reactants including erythrocyte sedimentation rate and C-reactive protein decreased at the end of the first week. The patient was discharged from the hospital with low-dosage (3 mg/kg per day) acetylsalicylic acid. The aneurysmal dilatation was persisting on her second month follow-up echocardiography.

Kawasaki disease occurs primarily in young children, with 80% of patients are under the age of 4 years and with the peak incidence occurring at 9 to 11 months of age. 2 In the United States, median age was 2 years. 1 The illness is extremely rare in infants under the age of 3 months. 2 In one Japanese series, only 1.7% of patients were younger than 3 months. 4 The youngest reported patient in the literature is a 2-week-old neonate 5 In infants, the atypical presentations (longer duration of illness before diagnosis, lower incidence of conjunctivitis, lower incidence of rash, lower incidence of extremity change, and lower C-reactive protein) are common, and this may result in a delay in diagnosis and effective treatment. 1,5 The illness is rare under the age of 3 months, but coronary artery involvement-more rapid and severe coronary artery disease-is also more common in them. 2,5-7 Delayed diagnosis in KD was a significant risk factor for the development of coronary artery abnormalities. 8 In addition, there may be as yet unknown physiological differences among KD patients at extremes of pediatrics that make them more vulnerable to coronary complication.

Kawasaki disease is rare in Turkey, with this patient being perhaps the youngest ever reported from Turkey. 9 The presence of clinical manifestation and elevated acute phase reactants in association with typical echocardiographic coronary artery dilatation established the diagnosis. The diagnosis was not suspected at an earlier date possibly because of lack of awareness of neonatal occurrence of KD. Pannaraj et al 10 reported that 71 of 124 general pediatricians in San Diego County did not consider the diagnosis of KD in children younger than 6 months; similarly, 86 of 324 pediatric infectious disease subspecialists did not consider KD in their differential diagnosis of children younger than 6 months.

In this study, we would like to call pediatricians' and neonatologists' attention to consider KD even in neonates and to follow a rapid and severe course.

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Article Contents

Introduction, summary figure, lead author biography, supplementary material, data availability.

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Adult Kawasaki disease: a rare and challenging diagnosis—a case report

Conflict of interest: None declared.

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Timothy O’ Connor, Cora McNally, Mark W Kennedy, Adult Kawasaki disease: a rare and challenging diagnosis—a case report, European Heart Journal - Case Reports , Volume 7, Issue 9, September 2023, ytad397, https://doi.org/10.1093/ehjcr/ytad397

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Kawasaki disease (KD) is an acute systemic vasculitis which predominantly occurs in childhood but rarely in adulthood. Diagnosis relies on the presence of typical clinical features; however, patients may present atypically, increasing the challenge of timely diagnosis for physicians.

We report a case of a 40-year-old male presenting with persistent fever, rash, and unilateral neck swelling. Initial investigations were suggestive of necrotizing lymphadenitis, with a presumed infective aetiology. However, extensive microbiology and immunological investigations remained negative. Cardiac injury was evident with elevated troponin T and NT-proBNP; however, left ventricular systolic function was normal. After 4 days, clinical features consistent with KD were noted and the results of a lymph node biopsy supported this diagnosis. Despite timely treatment with intravenous immunoglobulins (IVIG) and high-dose aspirin, follow-up computed tomography (CT) coronary angiography demonstrated two sequential aneurysms (max 6 mm) in the right coronary artery, plus one small subtle aneurysm in the proximal left anterior descending artery (4 mm).

Diagnosis of adult KD remains challenging, as symptoms often present sequentially over time rather than simultaneously and many of the clinical features necessary for diagnosis share commonality with other infectious disease processes.

Adult Kawasaki disease is a rare diagnosis which is classically diagnosed clinically based on the presence of key clinical findings. However, patients can present atypically and clinical findings can present sequentially, making diagnosis challenging.

Delayed or misdiagnosis is associated with an increased incidence of coronary artery aneurysm formation and can have devastating long-term impacts due to myocardial ischaemia from coronary artery thrombosis and stenosis.

Risk stratification and long-term follow-up is advised in those with persistent and regressed coronary aneurysms.

Kawasaki disease (KD) is an acute self-limiting febrile illness and systemic vasculitis of unknown aetiology, predominantly affecting children and rarely adults. 1 This systemic arteritis of medium-sized vessels is the leading cause of acquired heart disease in children due to coronary artery aneurysm formation, occurring in up to 30% of untreated patients. 2 The classical diagnosis of KD is based on the presence of fever for 5 days and at least 4/5 principal clinical findings: bilateral non-exudative conjunctivitis, lip/oral mucosal changes, maculopapular or erythema multiforme–like rash, changes in peripheral extremities with subsequent periungual desquamation in the sub-acute phase, and cervical lymphadenopathy. 3 However, diagnosis remains challenging, particularly in adults, as symptoms often present sequentially rather than simultaneously and the clinical findings necessary for a diagnosis of KD share commonality with other infectious diseases. 2 Delayed or misdiagnosis is associated with an increased incidence of coronary artery aneurysm formation and can have devastating long-term impacts due to myocardial ischaemia from coronary artery thrombosis and stenosis. 3 We present a case of a 40-year-old male with KD who presented atypically and critically unwell.

Case presentation

A 40-year-old male presented with a 4-day history of fever, nausea/vomiting, and an enlarging non-tender left neck swelling. The patient was hypotensive, febrile, and confused. Clinical examination demonstrated a unilateral anterior cervical triangle swelling and an erythematous rash on the left side of his neck and anterior chest wall. Electrocardiogram (ECG) demonstrated sinus rhythm with left anterior fascicular block. Treatment was initially with intravenous fluid resuscitation and broad-spectrum antibiotics. Laboratory findings indicated elevated inflammatory markers [C-reactive protein (CRP) 205 mg/L], and a computed tomography (CT) neck and thorax demonstrated an acute inflammatory process of the left submandibular space, unilateral enlarged lymph nodes (largest 4 cm × 2 cm), and evidence of necrotizing lymphadenopathy.

Rapidly, the patient clinically deteriorated, requiring admission to the intensive care unit (ICU) for septic shock. Laboratory findings showed normal haemoglobin (Hb) and neutrophils (Hb 11.1 g/dL; 6.20 10 9 /L) with elevated inflammatory markers [CRP 205 mg/L; erythrocyte sedimentation rate (ESR) 91 mm/h], lymphopoenia (0.21 10 9 /L), thrombocytopoenia (59 10 9 /L), hyponatraemia (127 mmol/L), hepatitis [alanine aminotransferase (ALT) 275 IU/L; aspartate aminotransferase (AST) 51 U/L; bilirubin 23 umol/L], hypoalbuminaemia (27 g/L), coagulopathy [international normalized ratio (INR) 1.8], and myocarditis (troponin T 1104 ng/L; NT-proBNP 48 412 pg/mL). Viral and bacterial investigations were performed but remained negative throughout hospitalization. Additionally, a vasculitis screen returned negative. Transthoracic echocardiogram demonstrated normal left ventricular function and moderate central mitral regurgitation.

Despite ongoing broad-spectrum antibiotics, the patient remained critically unwell and febrile with no definitive aetiology. An ultrasound-guided biopsy of a left anterior cervical lymph node on Day 3 demonstrated features suggestive of suppurative necrotizing lymphadenitis ( Figure 1 ). On Day 4, clinical assessment noted new erythema of the oral mucosa, fissured lips, strawberry tongue, and bilateral conjunctival injection. Coupled with persistent fever, laboratory findings, and lymph node histology, a possible diagnosis of classic KD was made. Treatment with intravenous immunoglobulins (IVIG) and high-dose aspirin (300 mg) commenced, with dramatic clinical improvement noted within 2 days. On Day 10, acute transient left upper limb weakness occurred. This was investigated by CT angiogram and magnetic resonance imaging (MRI) which excluded vertebral artery dissection or stroke.

Histopathology of lymph node core biopsy. Evidence of areas of necrosis (arrow) which are associated with abundant neutrophils and debris. Occasional fibrin thrombi are noted in small vessels. Features are of suppurative necrotizing lymphadenitis with a wide differential diagnosis including Kawasaki disease.

Given the likely diagnosis of KD, with elevated cardiac enzymes on admission, a computed tomography coronary angiography (CTCA) and cardiac magnetic resonance imaging (CMRI) was undertaken as an outpatient ( Figures 2 and 3 ). A CTCA at 3 months demonstrated two sequential aneurysms (max 6 mm) in the right coronary artery (RCA), with one smaller subtle aneurysm in the proximal left anterior descending (LAD) artery (4 mm). No associated thrombus, mural thickening, coronary plaque, or perivascular fatty changes were noted. Cardiac MRI showed normal left ventricular volumes with preserved function but focal regions of mid-wall fibrosis consistent with previous myocarditis. A follow-up CTCA at 12 months showed resolution of the LAD aneurysm and improvement of the two focal aneurysms in the RCA (3 mm).

Coronary computed tomography angiography shows aneurysms (marked with asterisk) in the right coronary artery and left anterior descending artery 3 months post discharge ( A – C ). Interval improvement in size of aneurysms noted on follow-up imaging at 12 months post discharge ( D – F ) Ao, aorta; RCA, right coronary artery; LAD, left anterior descending artery.

Cardiac magnetic resonance imaging with post contrast (gadolinium) imaging showing a confluent stripe of mid-wall fibrosis in the inferolateral/lateral wall at the basal level ( A ) as well as some patchy inferolateral mid-wall fibrosis at the mid-ventricular level ( B ).

Kawasaki disease is a systemic vasculitis, typically affecting young children, and is the leading cause of acquired heart disease in children in developed countries. Aetiology of the disease remains unknown, but current consensus suggests an infectious trigger initiating an abnormal immune response in genetically predisposed persons. 4 Treatment focuses on prevention of coronary artery aneurysm formation, which occurs in up to 30% of untreated cases and predisposes to stenosis/thrombosis. 2 It is estimated that 5% of acute coronary syndromes (ACS) in adults < 40 years of age results from coronary artery aneurysms from KD. 3 Whilst coronary artery aneurysms receive the majority of attention with regard to cardiovascular complications of Kawasaki disease, myocarditis is more common from a histological perspective and, in a small subset of patients, may result in diffuse myocarditis and fibrosis formation. 2

Adult-onset Kawasaki disease is rare and often misdiagnosed or diagnosed late due to the natural history of the disease, the lack of a specific diagnostic test, and clinical similarities to other more common infectious diseases. 5 According to current guidelines, diagnosis of classic Kawasaki disease requires the presence of fever for 5 days and at least four principal clinical findings. 3 However, in patients whose clinical features do not meet the epidemiological case definition, a diagnosis of atypical Kawasaki disease can be made aided by supporting laboratory findings and imaging studies. As in the current case, Kawasaki disease can rarely manifest with fever and cervical adenopathy before the onset of other clinical signs or may even present with adenopathy dominating the presentation. 6 , 7 Such presentations may be misdiagnosed as bacterial cervical lymphadenitis which may delay a definitive diagnosis of KD and lead to serious cardiac sequale. 6 Indeed, node-first or node-predominant presentations have represented 9–23% of acute KD admissions in some series. 8 , 9

Based on current guidelines, echocardiography is the primary imaging modality for cardiac assessment of Kawasaki disease, but the diagnostic yield is reduced in adults due to inadequate visualization of the coronary arteries. 3 In an adult population, the incidence of abnormal findings on initial echocardiography is low at 44%. 5 Thus, other imaging modalities such as CTCA and CMRI may play a vital role in the diagnosis of adult Kawasaki disease and identify patients at risk of future cardiac adverse sequela. Furthermore, due to the long-term damaging effects to coronary artery function, it is recommended that stress CMRI perfusion be carried out during follow-up of persistent and now regressed coronary aneurysms. 3 , 4

Clinical experience demonstrates that long-term follow-up requires risk stratification to identify those at risk of myocardial ischaemia. This stratification, based on the presence, size, and persistence of aneurysms, allows for individualized long-term management to guide the frequency of clinical follow-up, diagnostic testing, and medical therapy. 3 Whilst therapy with aspirin is well established, statins may play a key role in lowering low-density lipoprotein cholesterol in addition to potential pleiotropic effects on inflammation, endothelial function, platelet aggregation, and fibrinolysis. 3

Kawasaki disease is a rare presentation in adulthood and may have serious long-term cardiac consequences if misdiagnosed. Diagnosis remains challenging; however, an understanding of the typical clinical features and potential atypical presentations may reduce delays in diagnosis and appropriate treatment.

Supplementary material is available at European Heart Journal – Case Reports online.

Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been received from the patient in line with the Committee on Publication Ethics (COPE) guidelines.

Funding: None declared.

The data underlying this article are available in the article and in its online Supplementary material .

Harnden   A , Takahashi   M , Burgner   D . Kawasaki disease . BMJ   2009 ; 338 : b1514 .

Google Scholar

Soni   PR , Rivas   MN , Arditi   M . A comprehensive update on Kawasaki disease vasculitis and myocarditis . Curr Rheumatol Rep   2020 ; 22 : 6 .

McCrindle   BW , Rowley   AH , Newburger   JW , Burns   JC , Bolger   AF , Gewitz   M , et al.    Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association . Circulation   2017 ; 135 : e927 – e999 .

Dietz   SM , Van Stijn   D , Burgner   D , Levin   M , Kuipers   IM , Hutten   BA , et al.    Dissecting Kawasaki disease: a state-of-the-art review . Eur J Pediatr   2017 ; 176 : 995 – 1009 .

Fraison   JB , Seve   P , Dauphin   C , Mahr   A , Gomard-Mennesson   E , Varron   L , et al.    Kawasaki disease in adults: observations in France and literature review . Autoimmun Rev   2016 ; 15 : 242 – 249 .

Kanegaye   JT , Van Cott   E , Tremoulet   AH , Salgado   A , Shimizu   C , Kruk   P , et al.    Lymph-node-first presentation of Kawasaki disease compared with bacterial cervical adenitis and typical Kawasaki disease . J Pediatr   2013 ; 162 : 1259 – 1263 , 1263 e1251 – 2

Stamos   JK , Corydon   K , Donaldson   J , Shulman   ST . Lymphadenitis as the dominant manifestation of Kawasaki disease . Pediatrics   1994 ; 93 : 525 – 528 .

Kubota   M , Usami   I , Yamakawa   M , Tomita   Y , Haruta   T . Kawasaki disease with lymphadenopathy and fever as sole initial manifestations . J Paediatr Child Health   2008 ; 44 : 359 – 362 .

Nomura   Y , Arata   M , Koriyama   C , Masuda   K , Mlrita   Y , Hazeki   D , et al.    A severe form of Kawasaki disease presenting with only fever and cervical lymphadenopathy at admission . J Pediatr   2010 ; 156 : 786 – 791 .

Author notes

• coronary aneurysm
• signs and symptoms
• kawasaki's disease
• persistence

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• Case Report
• Open access
• Published: 29 January 2024

Kawasaki disease in neonates: a case report and literature review

• Mingjun Shen 1 , 2   na1 ,
• Die Liu 2   na1 ,
• Fang Ye 2 ,
• Jing Zhang   ORCID: orcid.org/0009-0005-3370-6784 2 &
• Jun Wang 1 , 2  

Pediatric Rheumatology volume  22 , Article number:  23 ( 2024 ) Cite this article

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Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that affects infants and young children but is extremely rare in neonates, especially afebrile KD. We present a case of KD without fever in a neonate and review the literature on KD in neonates.

Case presentation

A newborn female was hospitalized because her peripheral blood leukocytes increased for half a day. The admission diagnosis was considered neonatal sepsis and bacterial meningitis. She had no fever since the admission, but a rash appeared on her face by the 7th day. On day 11 after admission, there was a desquamation on the distal extremities. On day 15 after admission, ultrasound showed non-suppurative cervical lymphadenopathy. Echocardiogram revealed coronary artery aneurysms in both sides. Finally, the patient was diagnosed with incomplete KD (IKD). The follow-up echocardiogram showed that the internal diameter of both coronary arteries returned to normal three months after birth.

Conclusions

Fever, rash, and distal extremity desquamation during the recovery phase are the most common symptoms of IKD. When newborns present with clinical manifestations such as rash, distal extremity desquamation and cervical lymph adenitis and with an increased peripheral blood leukocyte count and progressive increase in platelets simultaneously, the medical staff should be highly alert to the possibility of KD even without fever. The echocardiogram needs to be performed promptly. The incidence of coronary artery lesions is significantly higher if neonatal KD patients miss timely diagnosis and treatment.

Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that affects infants and young children [ 1 ], but is extremely rare in neonates, especially afebrile KD. Data on 130,323 patients from the Japanese nationwide surveys of KD (2001–2012) identified 23 neonatal KD cases, representing 0.02% of KD in patients of all ages [ 2 ]. In this study, we present a neonatal case of incomplete KD (IKD) without fever and review the literature on KD in neonates. This report aims to increase awareness of afebrile KD in neonates to reduce the risk of cardiac complications.

A 19-hour-old female patient was transferred to the pediatric ward of China-Japan Friendship Hospital because her peripheral blood leukocytes increased for half a day. She was G1P1, at a gestational age of 40 weeks + 2days, and delivered by cesarean section due to acute intrauterine distress with III-degree contaminated amniotic fluid and slowed fetal heart rate. The Apgar score was 10-point at 1, 5, and 10 min after birth, respectively. The birth weight was 3386 g. The child had no fever, no irritability with a high-pitched cry, no convulsions, and no groans or vomiting after admission. Her temperature was 36.5 ℃, pulse 140/minute, respiration 40/minute, BP 80/55 mmHg, capillary refill less than two seconds. The face and trunk were light yellow. The bregma was bulged and the pressure was slightly higher. The neck resistance was suspiciously positive. The muscular tension in the limbs was normal, and the primitive reflexes were derived.

Laboratory investigations on the day of birth showed white blood cell (WBC) was 41.33 × 10 9 /L (neutrophils 75.3%, lymphocytes 15.4%, monocytes 7.8%), red blood cell (RBC) was 4.65 × 10 12 /L, hemoglobin was 167 g/L, platelet (PLT) was 266 × 10 9 /L, and C-reactive protein (CRP) was 6.86 mg/L. Total bilirubin was 124.11 µmol/L and direct bilirubin was 10.4 µmol/L. The cerebrospinal fluid contained total cells was 15 × 10 6 /L, WBC was 13 × 10 6 /L (multinuclear 85%, mononuclear 15%), protein 0.603 g/L, glucose 4.48 mmol/L (peripheral blood glucose: 5.1 mmol/L), and LDH 96 IU/L. Hepatitis B virus, hepatitis C virus, human immunodeficiency virus, treponema pallidum antibody and TORCH were all negative. Rheumatoid factor was normal. Chest X-ray, cranial ultrasound and abdominal ultrasound were unremarkable. Amplitude integration EEG showed no abnormal discharges. The patient was suspiciously diagnosed with neonatal sepsis and bacterial meningitis upon admission. Meropenem and vancomycin were given to control the infection. Mannitol was used to lower the intracranial pressure, and dexamethasone was used to prevent adhesions. On day 2 of hospitalization, intravenous immunoglobulin (IVIG) was used for three days (total dose 2 g/kg) as supportive therapy.

On day 4, cerebrospinal fluid was rechecked and contained total cells 6 × 10 6 /L, WBC 5 × 10 6 /L, protein 0.758 g/L, glucose 2.21 mmol/L (peripheral blood glucose 4.9 mmol/L), and LDH 76 IU/L. She had transient hyponatremia (127 mmol/L). Bacterial cultures from blood and cerebrospinal fluid were sterile.

The patient had no fever since admission, but a rash appeared on her face by the 7th day and lasted for five days. The PLT reached from 603 × 10 9 /L on day 7 to 1345 × 10 9 /L on day 12 (Table  1 ). Distal extremity desquamation began on day 11 and continued for ten days (Fig.  1 ). However, other manifestations including conjunctivitis, erythematous dry lips, red raspberry tongue and swollen extremities did not appeared. Low molecular dextran was given to reduce blood viscosity, enoxaparin sodium was given for anticoagulation, and dipyridamole and low-dose aspirin (5 mg/kg) were administered for anti-platelet aggregation. On the 15th day of the illness, ultrasound showed non-suppurative cervical lymphadenopathy. Echocardiogram showed that the internal diameter of the proximal segment of the left main coronary artery (LMCA) was 5.9 mm (Z = 11.40), the internal diameter of the left anterior descending coronary artery (LAD) was 2.4 mm (Z = 5.19) and the internal diameter of the right coronary artery (RCA) was 3.1 mm (Z = 8.07) (Fig.  2 ). Electrocardiogram was normal. Moreover, no abnormal blood flow was found in the arteries of the upper and lower extremities. No thrombus was found in the deep veins. Finally, the patient was diagnosed with IKD. Low-dose aspirin and dipyridamole were given to prevent platelet aggregation continuously.

Sheet-like desquamation of extremities emerged on day 11. ( A ) Skin on toes peeling. ( B ) Skin on fingers peeling

Echocardiography on 15th day after birth revealed coronary artery aneurysms in the left coronary artery

On 21 days after admission, the blood analyses showed WBC was 10.17 × 10 9 /L (neutrophils was 17.2%, lymphocytes was 61.2%, monocytes was 12.1%), RBC was 2.69 × 10 12 /L, hemoglobin was 90 g/L, PLT was 499 × 10 9 /L, and CRP was < 2.5 mg/L. Echocardiogram revealed LMCA of 2.6 mm (Z = 4.29), LAD of 2.1 mm (Z = 4.13), and RCA of 2.3 mm (Z = 4.95).

The patient was discharged with low-dose aspirin and dipyridamole after 21 days in the hospital. Regular follow-up was carried out every 2–4 weeks after discharge. Echocardiogram revealed LMCA of 2.0 mm (Z = 1.69) and RCA of 1.7 mm (Z = 1.78) three months after birth (Table  2 ).

KD is an acute febrile condition seen in children. The diagnostic criteria for KD are fever, bilateral bulbar conjunctival injection, changes in the lips and oral cavity, rash, changes in the peripheral extremities, and non-suppurative cervical lymphadenopathy. Fever is no longer necessary for the diagnosis of KD, according to the sixth revised edition of the Japanese diagnostic criteria [ 3 ]. Statistically, neonates with KD have a higher risk of incomplete presentation than older children [ 2 ].

The number of IKD cases increased yearly from 10% to the current level, which is greater than 20% of all KD patients [ 3 ]. Fever, redness, and swelling of the extremities are the most common symptoms of IKD [ 4 ]. We searched case reports of neonatal KD published in English from January 1, 2000 to February 18, 2023 with the search formula: ((“Mucocutaneous Lymph Node Syndrome“[Mesh]) OR (((Kawasaki Syndrome[Title/Abstract]) OR (Lymph Node Syndrome, Mucocutaneous [Title/Abstract])) OR (Kawasaki Disease [Title/Abstract]))) AND ((“Infant, Newborn“[Mesh]) OR (((((((((Infants, Newborn) OR (Newborn Infant)) OR (Newborns)) OR (Newborn)) OR (Neonate)) OR (Neonates)). The inclusion criteria were cases of KD in newborns and the diagnosis met the Revision of diagnostic guidelines for Kawasaki disease (6th revised edition) [ 3 ]. The exclusion criteria were duplication or literature with incomplete case information (no clinical features, no laboratory findings and outcomes). Nineteen cases in 15 papers were analyzed [ 2 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] (Table  3 ). IKD accounted for 68.4% (13/19). The clinical manifestations included rash in 94.7% (18/19), changes in the terminal extremities in 78.9% (15/19), fever in 78.9% (15/19), erythematous changes in the lips and oral mucosa in 68.4% (13/19), bilateral non-purulent conjunctivitis in 42.1% (8/19), cervical lymph adenitis in 10.5% (2/19), and coronary artery lesions (CALs) in 89.5% (17/19). Laboratory tests showed that elevated CRP accounted for 63.2% (12/19) and PLT > 300 × 10 9 /L accounted for 57.9% (11/19) (Table  4 ).

There were four patients with no fever among the 19 neonatal KD cases in our literature review. Only one afebrile patient was diagnosed as IKD purely based on CALs [ 11 ]. The other three afebrile patients [ 9 – 10 ], including the present case, had the same clinical manifestations, such as rash and periungual desquamation. In addition to the above-mentioned manifestations, conjunctival congestion, changes in the lips, and extremity edema were also observed in cases 6 and 7 [ 9 – 10 ] (Table  3 ).

The immune system of newborns is in a special developmental stage, which might lead to heterogeneity in neonatal KD and explain the higher incidence of IKD in neonates than older children. In this case, the patient did not have fever and other clinical manifestations, such as bilateral bulbar conjunctival injection, changes in the lips and oral cavity, probably associated with the early stage of neonate and the impact of early use of IVIG and dexamethasone.

To date, the etiology of KD is not clear. Previous studies suggested that KD is triggered by an infectious agent based on its occurrence in epidemiological clusters, seasonal variation, and a very low risk of recurrence [ 19 ]. Other research suggested that neonatal KD could be associated with sepsis and pneumonia [ 20 , 21 ]. Although the patient’s blood culture and cerebrospinal fluid were all sterile, the infection could not be excluded since abnormally elevated WBC and III-degree contaminated amniotic fluid at birth. We could not distinguish exactly whether this case was a KD secondary to systemic infection or just a KD case from the beginning.

CALs are the primary serious complication affecting the prognosis of KD. Several studies suggested that infants under the age of 6 months not only present more commonly with IKD, but are also at higher risk for coronary artery abnormalities and death [ 8 ]. In the 19 cases of neonatal KD mentioned above, CALs occurred in 89.5% in 19 neonates and 75% in the four cases of afebrile neonatal KD. 61.1% (11/18) of the patients with CALs had a favorable prognosis after using IVIG. Although this patient initially presented with medium to large coronary aneurysms, the internal diameter of the coronary arteries returned to normal after three months by IVIG treatment on 2nd day after birth. The 24th Nationwide Surveillance in Japan reported that approximately 9%, 25%, and 35% of KD patients received the first IVIG treatment on the 3rd, 4th, and 5th days of illness, respectively, and the prevalence of CALs were lower than before [ 3 ]. Consistent with this finding, our case suggests that early use of IVIG might be beneficial for long-term prognosis in KD.

This case report and review of the literature suggest a relatively higher incidence of IKD in neonates. Therefore, when newborns present with rash, terminal changes in the extremities or cervical lymph adenitis, increased peripheral blood leukocyte count and CRP, or progressive increase in platelets, the medical staff should be highly alert to the possibility of KD even without fever. Echocardiogram needs to be performed promptly. The incidence of CALs in neonatal KD is significantly higher. Timely diagnosis and treatment are essential for neonatal KD to improve the prognosis.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Coronary artery aneurysms

Coronary artery lesions

C-reactive protein

Erythrocyte sedimentation rate

Incomplete Kawasaki disease

Intravenous immunoglobulin

• Kawasaki disease

Left anterior descending

Left coronary artery

Procalcitonin

Red blood cell

Right coronary artery

White blood cell

Burns JC, Glode MP. Kawasaki syndrome. Lancet. 2004;364(9433):533–44.

Article   PubMed   Google Scholar  

Hangai M, Kubota Y, Kagawa J, Yashiro M, Uehara R, Nakamura Y, et al. Neonatal Kawasaki disease: case report and data from nationwide survey in Japan. Eur J Pediatr. 2014;173(11):1533–6.

Kobayashi T, Ayusawa M, Suzuki H, Abe J, Ito S, Kato T et al. Revision of diagnostic guidelines for Kawasaki disease (6th revised edition). Pediatr Int. 2020; 62(10):1135-8.

McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135(17):e927–99.

Li C, Du Y, Wang H, Wu G, Zhu X. Neonatal Kawasaki disease: case report and literature review. Med (Baltim). 2021;100(7):e24624.

Article   Google Scholar  

Tomiko T, Shigetoyo K, Kunihiko T, Futoshi K. Successful infliximab treatment for refractory Kawasaki disease in a neonate: a case report and literature review. Prog Pediatr Cardiology. 2020; 101255.

Zhao QM, Liang XC, Wu L, Liu F. Neonatal Kawasaki disease with multiple arterial aneurysms: a case report. Pediatr Rheumatol Online J. 2020;18(1):50–4.

Article   PubMed   PubMed Central   Google Scholar  

Altammar F, Lang B. Kawasaki disease in the neonate: case report and literature review. Pediatr Rheumatol Online J. 2018;16(1):43–9.

Cristina MRDM, Riccardo P, Lenora G, Rosa HU, Claudia BP. Onset of Kawasaki disease immediately after birth. Case Rep Perinat Med. 2018; 7(2).

Okazaki K, Matsui K, Takahashi N, Miura M, Kondo M. Kawasaki disease in a preterm neonate: case report and cytokine profile. Pediatr Int. 2018;60(11):1037–9.

Parashar R, Lysecki PJ, Mondal T. Diffuse coronary artery dilatation in a neonate: a case report. J Neonatal Perinatal Med. 2013;6(3):263–6.

Article   PubMed   CAS   Google Scholar  

Nasir A, Al Tatari H, Hamdan MA. Very high serum ferritin levels in three newborns with Kawasaki-like illness. Paediatr Child Health. 2012;17(4):201–4.

Mitchell S, Francis J, Burgner D. Kawasaki Disease in the neonate period. J Pediat Inf Dis-ger. 2011;6(4):265–7.

Karia VR, Hescock GC, Gedalia A, Ross-Ascuitto N. Successful emergent coronary thrombolysis in a neonate with Kawasaki’s disease. Pediatr Cardiol. 2010;31(8):1239–42.

Nakagawa N, Yoshida M, Narahara K, Kunitomi T. Kawasaki disease in an 8-day-old neonate. Pediatr Cardiol. 2009;30(4):527–9.

Thapa R, Pramanik S, Dhar S, Kundu R. Neonatal Kawasaki disease with multiple coronary aneurysms and thrombocytopenia. Pediatr Dermatol. 2007;24(6):662–3.

Bhatt M, Anil SR, Sivakumar K, Kumar K. Neonatal Kawasaki disease. Indian J Pediatr. 2004;71(4):353–4.

Stanley TV, Grimwood K. Classical Kawasaki disease in a neonate. Arch Dis Child Fetal and Neonatal Ed. 2002;86(2):F135–6.

Article   CAS   Google Scholar  

Kumrah R, Vignesh P, Rawat A, Singh S. Immunogenetics of Kawasaki disease. Clin Rev Allergy Immunol. 2020;59(1):122–39.

Takeuchi A, Sugino N, Namba T, Tamai K, Nakamura K, Nakamura M, et al. Neonatal sepsis and Kawasaki disease. Eur J Pediatr. 2022;181(8):2927–33.

Kawamura Y, Miura H, Saito K, Kanno T, Yokoyama T, Aizawa Y, et al. An atypical case of Kawasaki disease with severe pneumonia in a neonate. BMC Pediatr. 2022;22(1):132–7.

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Department of Clinical Medicine, Beijing University of Chinese Medicine, Beisanhuan East Road, Chaoyang District, 100029, Beijing, China

Mingjun Shen & Jun Wang

Department of Pediatrics, China-Japan Friendship Hospital, 2 Yinghuayuan East Street, Chaoyang District, 100029, Beijing, China

Mingjun Shen, Die Liu, Fang Ye, Jing Zhang & Jun Wang

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Mingjun Shen, Die Liu and Jing Zhang conceptualized and designed the work, drafted the initial manuscript, and reviewed and revised the manuscript. Fang Ye acquired, analyzed and interpreted patient’s data for diagnosis of KD. Jun Wang reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Correspondence to Jing Zhang or Jun Wang .

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Shen, M., Liu, D., Ye, F. et al. Kawasaki disease in neonates: a case report and literature review. Pediatr Rheumatol 22 , 23 (2024). https://doi.org/10.1186/s12969-024-00959-3

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Kawasaki disease as a case study

‘Quality diagnostic reasoning’ curbs medical diagnostic errors.

With my previous focus on the urgency of preventing medical diagnostic errors in Contemporary Pediatrics commentaries (July 2018; August 2018), the article in the October 2018 issue authored by Anne Rowley, MD, professor of  Pediatrics (Infectious Diseases)  and  Microbiology-Immunology at Northwestern University Feinberg School of Medicine, titled “Kawasaki disease: AHA statement and recommendations ” provides valuable insights for the care of children with a suspicion of Kawasaki disease (KD) which, when applied to clinical practice, may prevent medical diagnostics errors.

Thus, for many reasons, Dr. Rowley’s article is a must read for all pediatric healthcare providers. Failure of a timely and accurate diagnosis of KD may result in adverse outcomes for children, including coronary artery abnormalities, dilatation, and aneurysms. Dr. Rowley provides an overview of KD based on the latest 2017 American Heart Association’s (AHA) statement and recommendations for diagnosis and treatment of children who present with prolonged, unexplained fever. Throughout the article, Tables and Figures highlight critical information for the diagnosis and treatment of KD and represent the current best-available evidence. Further studies, both prospective and retrospective, are needed to further clarify diagnostic criteria and treatment options for children of different nationalities because the prevalence and severity of the disease vary based on ethnicity-in particular, for Asian/Japanese children who are aged younger than 5 years.

AHA on incomplete Kawasaki disease

The 2017 AHA statement provides an algorithm for the diagnosis of Incomplete KD (previously termed atypical KD) for any infant aged younger than 1 year with an unexplained fever for 7 days, or in infants with a fever for 5 days and presenting with only 2 or 3 of the principle clinical features of KD. In addition, there are recommendations for laboratory testing to aide in the diagnosis, which may help avoid a medical diagnostic error.

The essential history

The value of a comprehensive history cannot be overemphasized. Parents should be asked specific details related to fever onset, use of antipyretic medications, dosage, and the effect on the infant or child’s fever. Some parents may be hesitant to report how long the infant was at home with a fever, while other parents may not have a means of measuring the temperature of an infant at home and merely “take a guess” concerning the height of the fever.

Dr. Hallas’ Practice Pearls

Parents also should be asked whether the infant or child displayed any of the 5 principle clinical criteria of KD that may have spontaneously resolved. These factors must be considered when making a diagnostic decision about an infant or child presenting with an unexplained fever and fewer than the 5 principle clinical criteria of KD.

Recovery and immunization administration

Another consideration for care of the infant and child after recovery from KD is the administration of immunizations. For an infant aged younger than 12 months who has had a diagnosis of KD or Incomplete KD and received intravenous immunoglobulin (IVIG), the live vaccines, such as measles and varicella-containing vaccines, should not be administered until 11 months after receiving IVIG. 1

Likewise, a child who received the first set of measles and varicella vaccines at 12 months of age and has not received the 4- or 5-year-old doses should not receive the vaccines until 11 months after receipt of the IVIG. The rationale for delaying the vaccines for 11 months postreceipt of IVIG for all children who need the live vaccines is attributed to a possible interference with the development of adequate immune response by the child (AAP). However, readers are referred to the Red Book: 2018 Report of the Committee on Infectious Diseases (AAP) 1 for further details for administration of vaccines to children who are at risk for exposure to measles or varicella and for those children on prolonged aspirin therapy. Infants and children recovering from KD may continue to receive inactivated vaccines per the Centers for Disease Control and Prevention (CDC) 2 and Advisory Committee on Immunization Practices (ACIP) vaccine schedules. 3

Quality diagnostic reasoning

Nurse practitioners and all healthcare providers must remain acutely aware of the diagnostic criteria for KD and Incomplete KD and vigilant when an infant or child presents with a prolonged unexplained fever. Let’s remove the diagnosis of KD from the list of diseases that have an increased likelihood of a medical diagnostic error by applying the scientific evidence throughout the diagnostic and treatment processes. 

References:

1. American Academy of Pediatrics. Section 3: Summary of infectious diseases. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Elk Grove Village, IL: American Academy of Pediatrics; 2018:494-500.

2. Centers for Disease Control and Prevention. Immunization schedules. Available at: https://www.cdc.gov/vaccines/schedules/ . Updated February 6, 2018. Accessed October 20, 2018.

3. Advisory Committee on Immunization Practices. Immunization schedules. Available at: https://www.cdc.gov/vaccines/acip/index.html . Updated October 11, 2018. Accessed October 20, 2018.

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Patient Presentation

Differential diagnosis, examination, investigations, final outcome.

• Case Evaluation - Questions & answers

A previously well 17 month old boy presents with a three day history of fever and a skin rash. No accompanying cough or diarrhoea.

Acknowledgements:

Dr Christiaan Scott and Dr Kate Weakley Webb, Paediatric Rheumatology, Red Cross War Memorial Children’s Hospital, University of Cape Town, South Africa.

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The patient and his family recently moved to South Africa from Burundi (Eastern Africa). His mother reports that prior to this presentation the child has been well. She is unaware of him having any contact with TB or other infectious illnesses.

According to his Road to Health Card he was born full term from a normal vaginal delivery with no complications noted.

He was breast fed for the first 10 months.

He is noted to be HIV unexposed, but no PCR had been done to confirm this.

All growth parameters have been consistent and above the 50 th centile for height and weight.

Past Medical History

• Nothing reported

Past Surgical History

Vaccination History

• BCG given at birth
• No other vaccination history available

Family History

• Lives with both parents and three older siblings aged 3, 5 and 8 in a 1 bedroom apartment with all amenities.

Travel History

• Recent road travel from Burundi to South Africa

Differential diagnosis of an otherwise well child with a rash and fever:

Infections:

• Parainfluenza
• Scarlet fever
• Meningococcus
• Lyme disease
• Post streptococcal
• Kawasaki disease
• Henloch-Schonlein Purpura

In Admission:

• Ill looking child, alert and awake
• Well nourished
• Temperature: 40 o C
• Heart rate: 105
• Respiratory rate: 25
• Normal weight
• No dehydration
• Warm peripheries
• Cervical and axillary lymphadenopathy
• Mild pharyngitis
• Chest clear

Cardiovascular

• Mild tachycardia
• Not distended
• Soft, no generalised tenderness
• No organomegally
• Bowel sounds present

Neurological

• Normal level of consciousness
• Alert and co-operative

Dermatological

• Generalised maculo popular rash

Child was admitted (see investigations), and discharged after 2 days on Amoxil, tobe followed up at out patient clinic in 48 hours to have Mantoux test read

Nine days after initial presentation the patient again presents to hospital

Five days earlier, the patient was started on TB treatment following a positive Mantoux test and a suspicious looking chest X-ray. He now presents again with a fever and 7-day swelling of the face.

On Examination

• Ill looking child
• Temperature 39 o C
• Generalized lymphadenopathy
• Lips swollen, drooling, red tongue and throat.
• Perioral peeling
• Periorbital dryness anderythema
• Warm swollen hands and feet, with painless palpable effusions over the ankles
• Swollen, red BCG vaccination site and red mantoux mark
• Peeling rash on trunk, neck and axillae

Patient was re-admitted, an echocardiogram was performed which was normal and he was treated with 2g polygam, paracetomol and 50mg aspirin daily (see investigations).

He improved and was discharged

10 days later the patient returned to hospital

Although he no longer had a fever his mother was concerned about the persistent rash all over his body and a recurrent swelling of his hands and feet, which had become painful, preventing the child from walking.

• Ill looking child with marked irritability
• Swollen hands, feet and ankles,  with +dactylitis.
• Generalized erythematous macular rash

Patient was readmitted

No repeat polygam given as patient had responded to the first dose

Patient was kept on 20mg daily aspirin , Ibuprofen for pain and sucralfate

TB treatment was continued

(see investigations)

He was discharged home on Aspirin, pain medication and a temperature chart

One month later, patient was seen as an outpatient for a check up

The home temperature chart revealed no fever.

• Lymphadenopathy had resolved
• Hands and feet were still swelling occasionally, but he was able to walk. Some residual desquamation was noted on the hands
• No joint involvement
• BCG and Mantoux sites were normal
• Pain medication was stopped
• TB medication was continued for the full course

Patient was booked for a 3-month repeat Echo

On Presentation

• Chest X-Ray- Widened mediastinum and hilar lymphadenopathy
• Mantoux performed based on CXR finding. Area of induration at 48 hours was >15mm and considered positive.

9 days later

• HIV negative
• ASOT negative
• antiDNAse negative
• TB gastric washings, repeated on three occasions- all negative
• Echocardiogram-normal

2 weeks later

• Repeat echocardiogram- normal
• ESR 75, CRP 15
• ANA negative
• Sickle test negative

This case focuses on an acutely ill 17-month-old baby boy who presented to a paediatric hospital in South Africa having recently moved from Burundi in eastern Africa. His initial presentation was of a rash, fever and pharyngitis, for which he was treated with oral antibiotics. A routine TB work up was done.  Based on the hilar  lymphadenopathy on chest X-ray, and a positive Mantouxtest, he was started on TB treatment, despite not having a definitive microbiological diagnosis. As the paediatric hospital lies in an area with high TB prevalence, treatment is standard protocol. However within a few short days his signs and symptoms worsened.

A diagnosis of Kawasaki Disease (KD) was made and the following discussion will focus on this acute multisystem vasculiticsyndrome of unknown etiology. KD is seen predominantly in infants andchildren younger than 5 years of age and the disease occurs globally, having been first diagnosed in Japan in the 1960s.

KD is characterized by prolonged fever, conjunctivitis, diffuse mucosal inflammation, polymorphous skin rashes, indurative oedema of the hands and feet with an associated peeling of finger tips and non-suppurative lymphadenopathy.The most severe complication in KD is that of acute coronary syndrome, including myocardial infarction and coronary artery aneurysms,which ispathognomonic when identified in the setting of a compatible febrile illness.To date, there are no specific diagnostic tests for KD,instead the diagnosis is made clinically by the presence of fever for five days and 4 out of 5 of the following criteria:

• Non-purulentbilateral conjunctivitis
• Cervical lymphadenopathy of nodes >1.5 cm
• Polymorphous skin rashes
• Strawberry tongue, fissured lips and/or diffuse erythema of the oropharynx
• Oedema of the palms and soles and desquamation of the fingertips.

It has also been noted that in countries where newborn babies receive Bacillus Calmette-Guerin (BCG) vaccination, KD canbe associated with erythematousinduration or even ulceration of BCG scars in one-third of cases. The patient in this case study had received BCG at birth and during the course of his illness presented with BCG scar reactivation and a positive Mantoux test with a reading of >15mm.

Although the aetiology of KD is not well understood, with the aid of our case study and graphics we will explore the ways in which immune-mediated destruction of the vascular system occurs following the introduction of a yet to be identified immunogenic agent. We will also discuss the role that genetics has to play in this disease by looking specifically at two of the genes that have been implicated. We will also explain how this vasculitic syndrome may be connected to BCG scar reactivation and a positive Mantoux test in the absence of TB infection.

To better understand Kawasaki disease, let’s first look at the precipitating inflammatory response

It is thought that KD may develop in genetically susceptible individuals following an initial inflammatory response to a potentially inhaled immunogenic agent. Although no specific agent has been identified, prior infection by one of a number of viruses and bacterial species has been associated with the development of KD. These include EBV, HIV, measles , Staph. aureus, Strep. pyogenes and Mycoplasmapneumoniae, to name a few. A primary immune response to the agent occurs in the mucosal lymphoid tissues by activation of T and B cells, which is then thought to be followed by a translocation of the agent or possibly transport of the agent via trafficking phagocytic cells into the systemic circulation. A systemic immune response is then initiated and in genetically susceptible hosts this may lead to the uncontrolled systemic inflammation and immune-mediated damage of blood vessels or vasculitis.

What are the signs of this developing vasculitis in Kawasaki Disease?

The ensuing vasculitisis thought to be mediated by uncontrolled activation of CD4 + T cells and antigen-presenting cells and subsequent cytokine-mediated activation of medium vessel endothelial cells. The increased levels of cytokines such as IL-1 ,TNF-alpha and IL-6   cause the prolonged fever as seen in this patient. Along with IFN-g, these pro-inflammatory cytokines promote endothelial cells to up-regulate cell-adhesion molecules and secrete cytokines that recruit additional immune cells. Extravasation of immune cells into the subendothelium leads to immune-mediated damage to the elastic lamina and smooth muscle cells.  This weakens the blood vessel wall that in time can progress to aneurysm formation and scarring. When coronary arteries are involved it can result in ischaemic heart complications (not present in this patient). Excessive inflammatory responses to antigens in the skin also occur because there is increased trafficking of immune cells from cutaneous blood vessels into the dermis.  This can result in a persistent generalized rash and BCG scar activation, as seen during the course of illness in our patient.

As we know KD is a multisystem vasculitic syndrome. In the acute stage, numerous immunologic factors including CD4+ T cell activation, cytokine production and enhanced adhesion molecule expression by endothelial cells mediatesthe vasculitis. These various processes are further discussed here.

Lets look more closely at the activation of medium vessel endothelial cells

The activated CD4+ T cells secrete IFN-g that enhances the activity of phagocytic cells such as macrophages. Activated macrophages secrete TNF-a and IL-1 that together with IFN-g activates vascular endothelial cells. Endothelial cells also express CD40 receptors, which engage with CD40L (CD154) present on the surface of activated CD4+ T cells.

The resulting tethered CD4+ cells to the vascular endothelium secrete cytokines, which further activates the endothelial cells and induces them to express further cell adhesion molecules (ICAM-1, VCAM-1 and E-selectin) and secreteIL-1, TNF-a and IFN-g. Genetic susceptibility is thought to play a role in the development of Kawasaki disease. In particular, polymorphisms in two genes encoding the T cell regulatory protein ITPKC and Caspase-3. We will uncover these specific events towards the end of our discussion.

Activated endothelial cells also secrete IL-6 in sufficient amounts to promote fever by acting on the hypothalamus and to induce the liver to synthesize acute phase proteins (such as CRP). MCP-1 is a chemo-attractant for monocytes and VEGF promotes vascular permeability and enhances extravasation of immune cells into the sub-endothelium.

Recruitment of monocytes and neutrophils to the endothelium

Activated monocytes, recruited to the sub-endothelium by interacting with the adhesion molecules (ICAM-1 and VCAM-1) on endothelial cells, mature into macrophages and secrete pro-inflammatory cytokines such as IL- 1, IL-6 and TNF-a.

The recruitment of CD4+ T cells to the endothelium occurs in a similar way

Additional CD4+ T cells in the circulation that express cell adhesion molecules LFA-1 and VLA-4 bind to ICAM-1 and VCAM-1 that are expressed on activated endothelial cells. This CD4+ T cell interactionfacilitates extravasation into the subendotheliumwhere they further secrete IFN-g, which in turn, enhances the maturation of monocytes into macrophages with increased phagocytic and antigen presenting abilities.

Recruitment of IgA-secreting B cells to the endothelium

Immune-mediated damage leading to aneurysm and scarring

The result of this mass movement of activated cells and the effects of cytokines is damage and dissolution of the subendothelium tissues. The elastic lamina is degraded by the action of elastases and matrix metalloproteases and these enzymes also digest extracellular matrix proteins that disrupt the smooth muscle architecture resulting in necrosis of smooth muscle cells. Disrupted endothelial cell barriers allow the influx of erythrocytes into the subendothelium causing aneurysm and the development of thrombosis.

The exposed collagen activates platelets, which express CD40L(CD154). The engagement of CD40L with CD40 expressed by endothelial cells results in platelets secreting IL-1 and soluble CD40L.The release of both these solutes causes further activation of endothelial cells and severe inflammation. At the same time activated fibroblasts secrete extracellular matrix proteins, such as collagen, that promotes scarring which results in vessel stiffness. When this occurs in coronary arteries, the damage may contribute to heart disease.

What leads to skin inflammation?

Alongside the well-documented vasculitis, skin inflammation is also often observed in patients with KD. This is seen predominantly as a polymorphous skin rash and is one of the diagnostic criteria for the disease. It is likely that the generalized skin involvement is a consequence of increased infiltration of immune cells through activated endothelium of cutaneous blood vessels into the dermis where an immune response to skin antigens can be mounted. This inflammatory response is excessive due the dysregulation of CD4+ T cells, probably leading to a predominance of Th17 cells, and the high activation state of antigen-presenting cells.  It has been noted that in regions where BCG vaccination is in use, up to a third of patients who succumb to KDalso have a reactivation of their BCG scar, along with the usual skin rash.

What is the association between Kawasaki disease and BCG scar reactivation?

Since BCG vaccination is usually given at birth and susceptible children show clinical evidence of KD months to years later, it seems likely that the immune response is directed towards antigens present in the vaccine that have persisted in the skin over time. Due to cytokine stimulation, increased numbers of T cells and antigen presenting cells infiltrate the skin (via cutaneous blood vessels) and memory BCG-specific CD4+ T cells become re-activated and clonally expand in numbers. In KD, genetic susceptibility genes that affect negative-regulation of activated CD4+ T cells may promote an excessive immune response by increased pro-inflammatory cytokine production.

In our case study, the patient had both a reactivation of his BCG scar and a (presumed) false positive Mantoux test. While it is well recognized that children who have received BCG vaccination can sometimes have a false-positive Mantoux test due to cross-reactive immune responses to Mycobacterium tuberculosis antigens, there are also some reports of a false-positive Mantoux test in children with KD who were never BCG vaccinated. The Mantoux test involves intradermal administration of Mycobacterium tuberculosis protein antigens.   It is likely that a combination of underlying genetic defects that affect negative regulation of CD4+ T cells, an increased infiltration of CD4+ T cells into the skin and the high activation state of antigen presenting cells all lead to an excessive localized immune response in patients with KD. A true-positive Mantoux test relies on activation of memory Mycobacterium tuberculosis -specific T cells, but in this case, a small pool of naïve CD4+ T cells responding to enhanced antigen presentation may be sufficient to promote an inflammatory response causing an induration to develop. In severe cases of KD, macrophage activation syndrome may even be present, due to the highly-activated state of macrophages.

Along with the immune mediated causes for Kawasaki Disease, as discussed, we will also discuss how a genetic predisposition in the patient together with immune dysregulation plays an important role in susceptibility to KD. We explain this using our graphics below.

A detailed look at CD4+ T cell NFAT activation pathway

As discussed above, KD is associated with uncontrolled activation of CD4+ T cells and over-stimulation of antigen presenting cells. Following T cell receptor (TCR) stimulation after engagement with the MHC class II-peptide complex on the surface of macrophages, one of the intracellular signaling pathways that is activated results in the translocation to the nucleus of NFAT transcription factors that mediate gene transcription. This pathway depends on phospholipase C gamma-2 production of IP3 that opens calcium ion channels in the cell membrane or in the endoplasmic reticulum. Calcium ions bind to calmodulin-calcineurin complexes. Calcineurin dephosphorylates cytoplasmic NFAT, which enters the nucleus and activates gene transcription, such as cytokines and membrane proteins. NFAT is later re-phosphorylated and recycled back to the cytoplasm. There are two mechanisms of negative regulation of NFAT activation that may play a role in Kawasaki disease.

1) Negative regulators of T cell activation: ITPKC

NFAT activation is negatively regulated by ITPKC proteins in the cytoplasm of T cells. IP3 produced by phospholipase C gamma-2 following TCR signal transduction is a substrate of ITPKC and is converted to IP4, which inactivates it. This limits the binding of IP3 to calcium channels to increase intracellular calcium ions needed to activate NFAT via calmodulin-calcineurin complexes. In Kawasaki Disease, gene variants of ITPKC that lead to lower protein levels have been associated with risk of disease development. It is thought that lower levels of ITPKC leads to longer persistence of IP3 following TCR signaling and prolonged activation of NFAT.  This results in prolonged and uncontrolled CD4+ T cell activation resulting in release of higher levels of pro-inflammatory cytokines and over-excitation of antigen-presenting cells. Excessive activation of endothelial cells leads to immune-mediated damage to blood vessels that have been described.

2) Negative regulators of T cell activation: Caspase-3

The NFAT activation pathway is also regulated by caspase-3 found in the cytoplasm of activated T cells. TCR signaling induces transcription of the caspase-3 gene. One of the functions of caspase-3 is to proteolytically degrade cytoplasmic NFAT proteins.

This reduces the amount of NFAT that can be activated by the calmodulin-calcineurin complex. In Kawasaki Disease, gene variants of caspase-3 have been associated with lower transcription levels. Lower levels of cytoplasmic caspase-3 activity leads to increased levels of cytoplasmic NFAT and prolonged CD4+ T cell activation, higher levels of pro-inflammatory cytokines and increased activation of antigen presenting cells. Systemic inflammation can then develop following an antigenic stimulus.

Although the aetiology of Kawasaki Disease remains largely undetermined, understanding the immunology and genetics behind the mechanisms leading to this condition have been identified and provides insights into our patient’s presentation. Thus, in light of our better understanding of this disease it is most likely that this patient was in fact TB negative at presentation. However due to the high incidence of TB in this geographic location, along with his suspicious clinical and laboratory findings and positive Mantoux test, it remained prudent to provide standard TB medication to this patient.

Download images for this case

Kawasaki disease.

Patient was treated for 6 months on standard TB treatment

Five days after starting TB treatment, the patient received the standard Kawasaki Disease regimen – 2g polygam, paracetamol and 50mg aspirin daily.

Polygam was not repeated.

Aspirin was continued at a lower dose, 20mg daily, and ibuprofen was given for pain until all symptoms resolved.

Skin rash and joint involvement resolved

At 3 months, echocardiogram was repeated and was normal

Cassidy, Petty et al. (2011) Textbook of Pediatric Rheumatology. (Sixth edition). Elsevier Inc ISBN: 978-1-4160-6581-4

Link to article

Rodó X, Ballester J, Cayan D (2011). Association of Kawasaki disease with tropospheric wind patterns. Science Reports . Nov 10; 1:152. Epub

Lee KY, Rhim JW, Kang JH (2012). Kawasaki disease: laboratory findings and an immunopathogenesis on the premise of a “protein homeostasis system”. Yonsei Med J. Mar;53(2):262-75.

Link to abstract

Jia S, Li C, Wang G, Yang J, Zu Y (2010). The T helper type 17/regulatory T cell imbalance in patients with acute Kawasaki disease. Clin Exp Immunol. Oct;162(1):131-7. doi: 10.1111/j.1365-2249.2010.04236.x.

Onouchi Y, Ozaki K, Burns JC et al.(2010). A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat Genet. Mar 25;44(5):517-21.

Lee YC, Kuo HC, Chang JS et al. (2012). Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. Nat Genet . Mar 25;44(5):522-5.

Scuccimarri R.(2012). Kawasaki disease., PediatrClin North Am . Apr;59(2):425-45.

Takahashi K, Oharaseki T, Yokouchi Y (2011) Pathogenesis of Kawasaki disease. Clin Exp Immunol .  May;164Suppl 1:20-2.

Alexoudi I, Kanakis M, Kapsimali V, Vaiopoulos G (2011). Kawasaki disease: current aspects on aetiopathogenesis and therapeutic management. Autoimmun Rev .  Jul;10(9):544-7.

Evaluation – Questions & answers

What was the final diagnosis?

What is the primary cause of long term morbidity and mortality in Kawasaki Disease?

Which cytokines are known to cause the prolonged fever present in Kawasaki disease?

What are thought to be the precipitating events of the medium vessel vasculitis seen in Kawasaki disease?

Which genetic variants are thought to play a role in susceptibility to Kawasaki Disease?

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Long-term follow-up of a patient with Kawasaki disease and coronary aneurysm associated with asymptomatic thrombosis: a case report

Affiliation.

• 1 Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Yokohama City Seibu Hospital, Yasashi-cho 1197-1, Asahi-ku, Yokohama 241-0811. [email protected]
• PMID: 16218429

A 20-year-old male was first diagnosed with Kawasaki disease at age 2 years 9 months. Coronary angiography in the acute phase revealed coronary aneurysms, so chronic antiplatelet therapy was initiated with aspirin and ticlopidine. The patient was asymptomatic and was followed up. Stress myocardial imaging showed asymptomatic myocardial ischemia at age 20 years. Coronary angiography was performed, and revealed 99% occlusion of the right coronary artery and collateral circulation from the left coronary artery. Occlusion was attributed to coronary aneurysm thrombosis. Much remains unknown about the long-term prognosis in patients with coronary aneurysm associated with Kawasaki disease. Asymptomatic children who are followed up sometimes develop ischemic heart disease as young adults. This case highlights the need for long-term follow-up in patients with Kawasaki disease and coronary aneurysms.

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Medical Reports & Case Studies

Case Report - (2021) Volume 0, Issue 0

A Typical Kawasaki Disease in an Early Infant a Diagnostic Challenge: Case Report

Author info »

A 4.5-month-old girl presented to us with fever for a total of 10 days, loose stools for 2 days .she took short courses of multiple oral antibiotics during this period but was not relieved. A thorough physical examination was unremarkable her initial investigations were suggestive of urinary tract infection for which broad spectrum antibiotics were started. However, fever still persisted even after 72 hrs of antibiotics. Blood counts showed persistently high TLC and increasing platelet count, along with high CRP. Consequently a diagnosis of Kawasaki Disease (KD) was suspected, which was supported by echocardiographic findings. After she received intravenous immunoglobulins, her fever subsided and lab parameters showed significant improvement. This case highlights an unusual presentation of KD in an uncommonly young age group without much clinical pointers except for persistent fever.

Kawasaki disease • Multiple oral antibiotics • Diagnosis

Introduction

Kawasaki Disease (KD) is an acute inflammatory vasculitis of small- and medium-sized arteries that can cause coronary artery weakening and aneurysm development in approximately 25% of untreated cases, with increased risks of cardiovascular complications and mortality [ 1 ]. Burns, et al. [ 2 - 4 ]. Noted that children of KD in India were older with almost half of them being over the age of five years possibly because it is being missed in infants and young children in whom the condition is being confused with viral exanthemata. Although one or multiple infectious triggers are most likely, the precise etiology is still unknown. Kawasaki disease is primarily a clinical diagnosis but Atypical or incomplete forms of KD are common (15%–20% of all patients) especially in children younger than 6 months [ 5 ]. Who also have the highest likelihood of development of coronary artery aneurysm, long term consequences and resistance to therapy [ 6 , 7 ]. In such patients laboratory and echocardiographic data can assist in diagnosis. For this reason it is recommended that any infant <6 months with fever ≥ 7 days without explanation should undergo echocardiography to assess the coronary arteries. Here we report the case of a 4.5-month-old child with an atypical form of KD, without much clinical clues, who developed aneurysm of the coronary arteries.

Case Presentation

A full term delivered, previously healthy, 4.5-month-old girl presented at our Emergency Department with fever for a total duration of 10 days, loose stools for 2 days. Fever used to occur 3-4 times a day with a peak of 102-103 0 F (axillary). Child was apparently well and playful during afebrile period. Her oral intake was normal. She took incomplete course of treatment with drugs like oral amoxicillin+ clavulanic acid, cefixime, cefuroxime during this period. On physical examination, she presented in good general condition, body temperature was 101.4°F, no signs of dehydration (capillary refill time <2 s), mild perianal rash was noted. Rest of the general and systemic examination was normal.

Investigations

Before admission (outside): Showed a very high value of C - reactive protein C-RP: 113.7 mg/L; hemoglobin (Hb) 9.4 g/dL, White Blood Cell (WBC) count 23,670/ mm 3 with 56.5% neutrophils, and Platelet (PLT) count 588,000/mm 3 .Blood culture report was awaited. Malarial antigen report was negative.

On day 1 of admission: Blood tests which had a gap of 2 days showed a similar picture with persistent high value of C-RP 47.5 mg/L, hemoglobin (Hb) 9.3 g/dL, White Blood Cell (WBC) count 24,800/mm 3 with 60% neutrophils, and platelet (PLT) count 784,000/mm 3 . The urine analysis showed plenty of pus cells (35-40/ HPF), transaminases were marginally raised and renal functions were normal. Our patient being a female child of less than 6 months of age with suggestive urine tests we kept high possibility of a urinary tract infection and started with inj. Ceftriaxone and inj amikacin.

On day 3 of admission: Although the fever persisted with minimal variability, the C-RP showed a falling trend 38.3 mg/L, with hemoglobin (Hb) 9.2 g/dL, White Blood Cell (WBC) count 28,400/mm 3 with 60% neutrophils, and Plate Let (PLT) count 7,43,000/mm 3 . The urine analysis showed decrease in pus cells (16-18/ HPF).

On day 4 of admission: Antibiotics were upgraded in view of partial response (decreased CRP and decrease in pus cell in urine)

On day 5 of admission: The fever decreased in intensity but remained well above the base line. The C-RP again increased to 55.0 mg/L, complete blood count showed a similar picture, the only significant change being significant increase in platelet count to 8,03,000/mm 3 . Transaminases values were also increased SGOT-106.5 U/L, SGPT-151.9 U/L. Initial blood culture and urine culture showed no growth. Repeated detailed clinical examinations were not helpful and child showed no clinical signs suggestive of Kawasaki disease. Hence, in view of persistent fever and lab parameters (Raised C-RP, WBC >15000, elevated ALT levels, platelet counts >4.5 lakhs, urine >10 WBC/hpf), an echocardiogram was performed ( Figures 1-3 ).

Figure 1: Transthoracic Echocardiography. Parasternal short axis view showing aorta in cross section and dilated, non-tapering right coronary artery. RCA- Right Coronary Artery.

Figure 2: Transthoracic Echocardiography. Parasternal short axis view showing aorta in cross section with dilated left main coronary artery, left anterior descending coronary and left circumflex coronary artery. LMCA- Left Main Coronary Artery, LAD- Left Anterior Descending Coronary Artery, LCX- Left Circumflex Coronary Artery.

Figure 3: Transthoracic Echocardiography. Apical four chamber view showing dilated right coronary artery in interventricular groove. RCA- Right Coronary Artery, RA- Right Atrium, LA- Left Atrium, LV- Left Ventricle, RV- Right Ventricle.

Interpretation summary

Trace tricuspid regurgitation, trace pulmonic regurgitation, and trace pericardial effusion, dilated coronary arteries as mentioned in above Figures.

Left main coronary artery=4.1 mm (Z score +6.9)

Left anterior descending coronary – 2.4 mm (Z score +4.2)

Left circumflex coronary artery-1.8 mm (Z score +2.5)

Right coronary artery-3.4 mm (Z score +7.7).

With the above findings the diagnosis of KD with medium sized coronary artery aneurysm was made according to the American Heart Association (AHA) criteria [ 6 ]. She received intravenous immunoglobulin (IVIG infusion of 2 g/kg) and highdose oral acetylsalicylic acid (100 mg/kg/day).

Outcome and follow-up

After administration of IVIG and aspirin, the fever dramatically defervesced in the following 24 hours. The TLC dropped down to 15000/mm3 and C-RP was reduced to 18mg/L after 48 hours of afebrile period the dose of aspirin was changed to 5mg/kg and the child was discharged.

KD is an acquired heart disease most common in infants aged 6 months to 2 years. It is challenging to make a diagnosis of incomplete KD, particularly in infants younger than 6 months with fewer clinical manifestations [ 8 - 10 ]. Ram Krishna, et al. [ 11 ]. studfied the predfictors of coronary artery aneurysm. They suggested that anemia; low albumin, elevated ESR, elevated CRP, and pyuria are the risk factors of coronary artery abnormalities. The most common complications of KD include coronary artery dilatation caused by coronary artery vasculitis and aneurysm [ 12 ]. Other complications include decreased coronary arterial compliance, my pericarditis, arrhythmias, ischemic heart disease, pericardial effusion, valvular regurgitation, myocardial infarction, and sudden cardiac death. Prompt diagnosis and administration of IVIG within 10 days, or ideally before day 7 of the disease, is mandated in order to reduce such cardiac complications [ 13 ]. Since diagnosing KD in infants younger than 6 months is difficult, any febrile infant who has fever for 7 days or more without other explanations, even without any clinical clues of KD, should receive a blood analysis of systemic vascular response. If the ESR or CRP is elevated, echocardiography should be performed [ 14 ]. Unfortunately in our case the patient presented on 10th day of fever without any supportive clinical findings of KD and the preliminary tests pointed towards UTI. The fall of C-RP initially, decrease in pus cells in urine and relative decrease in fever spikes after the start of IV antibiotics led to further delay in clinching the diagnosis. Persistent increase in platelet count was one marker that helped us strongly suspect of Kawasaki disease. Apart from medium sized aneurysm in coronary arteries, there were no other complications.

Kawasaki Disease (KD) should be considered in infants less than 6 months even though the incidence is low in this age group. In Such children ,a significant proportion would not fulfil the diagnostic criteria as many would have ‘incomplete’ and ‘atypical’ forms of disease and unfortunately this age group is most vulnerable to development of coronary artery aneurysm. Hence it is recommended that any infant of age <6 months with fever for ≥ 7 days without explanation should undergo echocardiography to assess the coronary arteries.

This case report, including the cost to publish in open access, is self-financed by the first author.

Conflict of Interest

The authors declare no conflict of interest.

• McCrindle, BW., et al. “Diagnosis, treatment, and long-term management of kawasaki disease: A scientific statement for health professionals from the american heart association”. Circulation. 135.17(2017):927-999.
• Kushner, HI., et al. “Impressions of Kawasaki syndrome in India”. Indian Pediatr. 43.11(2006):939-942.
• Kushner, HI., et al. “Kawasaki disease in India: Increasing awareness or increased incidence?” Perspect Biol Med. 52.1(2009):17-29.
• Burns, JC. “Kawasaki disease update”. Indian J Pediatr. 76.1(2009):71-76.
• Singh, S., et al. “Kawasaki disease in infants below 6 months: A clinical conundrum?” Int J Rheum Dis. 19.9(2016):924-928.
• Newburger, JW., et al. “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(2004):2747-2771.
• Yeom, JS., et al. “Kawasaki disease in infants”. Korean J Pediatr. 56.9(2013):377-382.
• Park, YW., et al. “Epidemiologic study of Kawasaki disease in 6 months old and younger infants”. Korean J Pediatr. 51.12(2008):1320-1323.
• Uysal, F., et al. “Outcomes of Kawasaki disease: A single-center experience”. Clin Pediatr (Phila). 54.6(2015):579-584.
• Ram Krishna, M., et al. “Predictors of coronary artery aneurysms in Kawasaki disease”. Clin Pediatr (Phila). 53.6(2014):561-565.
• Ruan, Y., et al. “Clinical characteristics of Kawasaki syndrome and the risk factors for coronary artery lesions in China”. Pediatr Infect Dis J. 32.10(2013):397-402.
• Callinan, LS., et al. “Kawasaki syndrome and factors associated with coronary artery abnormalities in California”. Pediatr Infect Dis J. 31.9(2012):894-898.
• Mbf, S., et al. “Nelson textbook of pediatrics”. 20th edn. (2016)1209-1214.

Author Info

Citation: Siddiqui K. A Typical Kawasaki Disease in an Early Infant a Diagnostic Challenge: Case Report. Med Rep Case Stud, 2021, 06(S4), 014-015

Received: 22-Sep-2021 Published: 13-Oct-2021, DOI: 10.35248/2572-5130.21.s4.014-015

Copyright: © 2021 Siddiqui K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Sources of funding : NO

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Kawasaki Disease: an Update

Eileen rife.

1 Louisiana State University, New Orleans, LA USA

Abraham Gedalia

2 Division of Pediatric Rheumatology, Children’s Hospital and LSU Health Sciences Center, 2000 Henry Clay Avenue, New Orleans, LA 70118 USA

Purpose of Review

Provide the most recent updates on the epidemiology, pathogenesis, and treatment advances in Kawasaki disease.

Recent Findings

Treatment advances in complex, IVIG-refractory cases of Kawasaki disease. Multisystem inflammatory syndrome, a newly reported inflammatory condition with Kawasaki-like features and an association with the 2019 Coronavirus (COVID-19).

Kawasaki disease (KD) is a rare systemic inflammatory disease that predominately affects children less than 5 years of age. Pathogenesis of KD remains unknown; the leading theory is that an unknown stimulus triggers an immune-mediated inflammatory cascade in a genetically susceptible child. Classic KD is a clinical diagnosis based on set criteria and excluding other similar clinical entities. Patients who do not fulfill complete diagnostic criteria for KD are often referred to as atypical (or incomplete) KD. The most feared complication of KD is coronary artery abnormality development, and patients with atypical KD are also at risk. Administration of intravenous immunoglobulin (IVIG) and aspirin has greatly reduced the incidence of coronary lesions in affected children. Several other immune-modulating therapies have recently been utilized in complex or refractory cases.

Introduction

Kawasaki disease (KD) was first described in a 1967 report by Japanese pediatrician Tomisaku Kawasaki. The cardiac sequelae were later documented in 1970, following investigation of 10 autopsy cases of sudden cardiac death following diagnosis of KD. The first reported cases outside Japan were in Hawaii in the early 1970s; KD cases have since been reported in more than 60 countries worldwide.

Epidemiology

The epidemiology of KD varies greatly by geographic location and seasonality. The highest incidence rates (per 100,000) are in children of Japanese ancestry. Recently published data from the Japanese KD nationwide survey reported an increased rate over time from 218.6 per 100,000 in 2008 to 243.1 and 330.2 in 2011 and 2015 respectively [ 1 •, 2 ]. In the United States, the incidence appears to have remained relatively stable. In 2012, the KD-associated hospitalization rate for children < 5 years of age was 18.1 per 100,000. In 2003, the rate was 19.7 per 100,000 children, [ 3 ] which amounts to roughly 4000 to 5500 new cases in the United States each year. The highest rates are seen among children < 5 years of age, with a male predominance (21.0 per 100,000 versus 15 per 100,000 in females). There is considerable ethnic variation, the highest rates seen among Asian/Pacific Islanders at 29.8 per 100,000 children < 5 years, and the lowest recorded rate among white children 13.7 per 100,000 [ 3 , 4 ]. It should be pointed out that analysis of Black and Hispanic race/ethnic groups could not be carried out in the Holman study as there were too few reported cases [ 4 ].

Pathogenesis

Although poorly understood, the predilection for children of East Asian and Pacific Islander descent, even with transmigration, supports the likely role genetics plays in pathogenesis of KD [ 5 , 6 ]. Several additional findings support a genetic component to KD susceptibility, including: concordance risk in identical twins at ~ 13%, increased incidence of KD in children whose parents have a history of KD, and higher occurrence of KD in siblings of affected patients [ 7 – 12 ].

KD does not appear to follow Mendelian pattern of inheritance. However, familial aggregation is well recognized, as are prediction models for severity based on genetic differences. Several single-nucleotide polymorphisms (SNPs) in different genes and gene regions have been implicated in family linkage and genome association studies: caspase 3 (CASP3), inositol 1,4,5-trisphosphate kinase-C (ITPKC), CD40, FCGR2a, and B- cell lymphoid kinase (BLK) [ 13 – 15 ]. Interestingly, many of the SNPs associated with KD have been identified in other inflammatory diseases such as rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, and systemic sclerosis. These findings may indicate a common pathway in the inflammatory immune response [ 16 ].

Vaccine Exposure Theory

Several studies have evaluated the role vaccination may play in triggering KD via robust stimulation of the innate and adaptive arms of the immune system. However, there is currently no evidence to suggest that vaccine administration is associated with development of KD [ 17 – 20 ].

Infectious Theory/Seasonality

The leading theory for the pathogenesis of KD is that an unknown infectious agent leads to activation of the immune system in a genetically susceptible child. Several epidemiologic phenomena support this theory. The first is the apparent seasonality of KD. There is a consistent peak in the number of cases reported in the month of January, with another gradual increase in spring to summer (March–June) [ 1 •, 21 ]. We often see this kind of consistent seasonal fluctuation in relation to infectious agents, especially viral infections. Several temporal clusters of epidemics have been reported in Japan, Canada, the United States, and Finland further supporting an infectious trigger [ 22 ].

The next supporting feature is related to tropospheric wind patterns whose presence in different locations may coincide with the incidence of KD. Studies suggest that winds arising from certain regions may carry either environmental toxins or an infectious agent to another region, thus triggering development of KD [ 23 – 25 ]. Another supporting feature is the significant overlap of clinical features between KD and other infectious agents, most notably scarlet fever, the newly described multisystem inflammatory syndrome (described in detail below), and adenovirus. In one study, it was found that 10% of patients diagnosed with KD also had positive low titer adenovirus infection [ 26 ].

There is a mono-modal age distribution in the occurrence of KD with peak incidence in late infancy (9–11 months), and then a gradual decrease in incidence with advancing age [ 1 •]. This suggests the possible existence of protective trans-placental antibodies to infection, which wanes after the first few months of life [ 27 ]. Finally, there are case reports/series showing higher occurrence of KD cases among siblings. The risk of KD in a child is increased roughly 10 times if a sibling has also been affected. This temporally occurs either on the same day or within 10 days of the initial presentation [ 7 ].

Immune Factors/Dysregulation

To date, no infectious causes have been identified as potential underlying etiologies, despite many investigations into bacterial toxins, super-antigens, fungal organisms, and viral pathogens. The theory remains, however, that an unknown stimulus triggers an inflammatory cascade with activation of both the innate and adaptive arms of the immune system. The innate immune system may be activated via detection of either pathogen-associated molecular patterns (PAMPs), or damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome recognizes these abnormal molecular patterns in the body and activates a signaling cascade, which ultimately results in downstream release of several pro-inflammatory cytokines. Some of the most well studied of these cytokines in KD include IL-1, IL-18, IL-6, TNF-a, IFN-gamma, and IL-8. Several studies have either implicated this pathway of innate activation, or have successfully induced coronary arteritis (resembling KD) in murine models via these innate mechanisms [ 28 – 30 ]. Interleukin-1 has direct inflammatory effects on coronary artery endothelial cells.

In addition to the innate immune response in activating inflammatory mechanisms in KD, there is also significant activation of the adaptive (antigen-specific) immune response. There appears to be increased numbers of circulating pro-inflammatory and regulatory T cells in the acute phase of KD [ 31 ]. Studies have noted an increased number of IgA-producing plasma cells in tissues and coronary artery vascular walls in affected patients with KD [ 32 , 33 ]. Several auto-antibodies directed against myocardial, endothelial, and extracellular matrix proteins have also been described in the literature, although their clinical significance is poorly understood [ 34 ]. Following administration of IVIG, we see an expansion of regulatory T cell populations and normalization of B cell-activating factor. This is associated with subsequent clinical improvement during the acute phase of KD [ 35 , 36 ]. All of the aforementioned findings support the significant role adaptive immune system plays in KD. B and T cell memory cell development is likely involved as well given the low recurrence rate of KD and typically self-limited course of the disease.

There is no diagnostic test for KD, instead, the diagnosis of classic (or complete) Kawasaki disease is made utilizing clinical criteria (Table ​ (Table1) 1 ) and excluding other similar clinical entities. Individual clinical manifestations may not all present simultaneously. Careful review may reveal that one or more clinical features were present and resolved prior to presentation. Several other clinical manifestations may also be present which are not included in the diagnostic criteria (Table ​ (Table2 2 ).

Diagnostic criteria for Kawasaki disease

To be diagnosed with classic KD, the patient must have ≥ 5 days of fever as well as ≥ 4 of the 5 principal clinical features. In rare cases, experienced clinicians may be able to establish the diagnosis with less than the required duration of fever

Other (less common) clinical manifestations of KD

Patients who do not fulfill the complete diagnostic criteria for KD are referred to as incomplete or atypical KD. These patients may still be at risk for coronary artery abnormalities [ 37 ]. Therefore, any child with prolonged unexplained fever with any of the principal clinical features should be further evaluated for KD with consideration of echocardiography. The American Heart Associated (AHA) created an algorithm to aid in evaluation of suspected KD patients who do not meet the diagnostic criteria [ 38 •].

Kawasaki disease tends to be triphasic with an acute, subacute, and convalescent phase. The acute phase is characterized by high-spiking fevers (typically > 39.0 °C), with the other principal features listed in table ​ table1. 1 . The acute febrile phase lasts anywhere from 7 to 14 days. The subacute phase is often an asymptomatic period after the febrile episode subsides and extends approximately 4 weeks. During this phase, patients may still have desquamation of the digits, arthralgias, and abnormal lab findings. This is the period of time notable for the greatest risk (highest incidence) of developing cardiac sequelae, namely coronary artery aneurysms (CAA). The third, convalescent phase is typically an asymptomatic period, roughly 4–8 weeks after onset of initial illness. There is still a risk (but significantly decreased) of aneurysm development despite absence of clinical symptoms during this period.

The rate of KD recurrence is less than 3% of patients in Japan, [ 39 ] and roughly 1.7% of patients in the United States (3.5% in US KD patients of Asian and Pacific Islander descent) [ 40 ]. There is reportedly a higher risk of coronary artery sequelae with recurrent episodes [ 22 ].

Laboratory Analysis and Workup

Kawasaki disease is a clinical diagnosis based on set diagnostic criteria. Laboratory findings, although nonspecific, are useful in supporting a diagnosis of KD, particularly when the clinical manifestations are non-classic. Table ​ Table3 3 outlines several common laboratory findings seen in KD during different phases of disease [ 41 , 42 ].

Common laboratory findings in KD

Most children with KD will typically present in the acute phase with leukocytosis (elevated immature and mature granulocytes). Anemia is another common finding and tends to be normocytic and normochromic. Thrombocytosis is common after the first week of symptoms; counts peak in the third week, and may reach as high as 1,000,000 per mm 3 (average ~ 700,000 per mm 3 ) before normalizing in the subacute to convalescent phase. Acute phase reactants are elevated to varying degrees in nearly every patient with KD. Serum transaminases or gamma-glutamyl transpeptidase elevations occur in 40–60% of patients [ 2 , 43 ]. Urinalysis may show a sterile pyuria in up to 80% of children [ 44 ].

Some studies suggest use of N-terminal pro-brain natriuretic peptide as an adjunctive diagnostic marker of acute phase KD. Its suggested use is in the pediatric emergency room in patients with unexplained prolonged fever with suspected KD. However, it is a nonspecific test with no clear cut-point values for a positive result [ 45 – 47 ]. A recent study investigated the use of platelet-activating factor (PAF) and its acetyl-hydrolase (PAF-AH) in predicting KD. In this particular report, the authors found a statistically significant elevation in PAF and PAF-AH levels in the acute phase in children with KD as compared to controls [ 48 •].

Diagnostics/Imaging

The most feared sequelae of KD is development of coronary artery abnormalities, which occurs in 20–25% of untreated children [ 49 ]. Echocardiography remains the standard imaging modality to evaluate for both coronary artery dimension as well as other cardiac abnormalities. It is a non-invasive study without risk of radiation and high sensitivity and specificity for identifying coronary artery lesions (CALs). The Japanese Ministry of Health criteria is widely used to classify coronary artery sizes according to age [ 50 ]. In children younger than 5 years, coronary artery lumen diameter is abnormal if exceeding 3 mm. In children 5 years of age and older, a lumen diameter greater than 4 mm is considered abnormal. In addition to absolute luminal dimensions, both the Japanese ministry of Health and the American Heart Association also utilize Z scores when classifying CALs. Z scores are coronary dimensions that are adjusted for body surface area, as coronary artery dimensions will change with the size of the child. Overall, aneurysms < 5 mm luminal diameter are considered small, 5–8 mm luminal diameter are considered medium-sized, and aneurysms > 8 mm in luminal diameter are considered large.

Echocardiography surveillance is typically performed at diagnosis, 1–2 weeks after diagnosis, and then again 6–8 weeks later (assuming no complications). There are several factors associated with increased risk of developing CALs including male sex, age < 12 months or > 8 years, fever duration > 10 days, leukocytosis > 15,000 per mm 3 , low hemoglobin (< 10 g/dL), thrombocytopenia, hypoalbuminemia, hyponatremia, and persistent fever or recurrence of fever > 36 h after IVIG administration [ 51 , 52 ]. Children at higher risk, and those with previously noted CALs, will be screened more often. Other imaging modalities utilized include magnetic resonance angiography, computed tomographic angiography, and cardiac catheterization if warranted.

Differential

Several other illnesses share similar clinical features to KD (Table ​ (Table4) 4 ) and must be considered prior to diagnosis. Clinical manifestations that do not align with the diagnostic criteria for KD should prompt investigation of other causes. It must also be noted, that children affected by KD may have a concurrent infection with another pathogen, i.e., viral respiratory pathogen as previously described.

Differential diagnosis of Kawasaki disease

Multisystem inflammatory syndrome in children (MIS-C) is a newly reported inflammatory condition with Kawasaki-like features and an association with the 2019 Coronavirus (COVID-19). First described April 2020 in the UK, MIS-C cases are now reported in Italy, France, Spain, and the United States. Affected children tend to present with persistent fever, conjunctivitis, mucositis, lymphadenopathy, rash, evidence of multisystem organ involvement, and elevated inflammatory markers. Respiratory symptoms and abdominal pain are also common features [ 53 •, 54 •, 55 •, 56 •, 57 •]. The Centers for Disease Control (CDC) case definition for MIS-C includes individuals less than 21 years of age presenting with fever (> 38.0 °C), laboratory evidence of inflammation, and clinically severe illness requiring hospitalization with multisystem organ involvement. Patients must have evidence of exposure to COVID-19 within 4 weeks prior to onset of symptoms, and practitioners must exclude plausible alternative diagnoses [ 58 •].

MIS-C appears to present as a late manifestation of disease (weeks after the COVID-19 exposure) and may be more related to immune activation during the convalescent period. It remains unknown if COVID-19 triggers KD features, if it is a completely separate entity, a spectrum of disease, related to macrophage activation, or an overlap syndrome. One of the most interesting aspects of this disease is that countries with the highest incidence of KD, i.e., Japan and China, have no reported cases despite excellent surveillance systems. Other notable differences compared to KD: MIS-C typically presents after the age of 5, and there appears to be a higher incidence in children of Afro-Caribbean descent [ 54 •, 57 •]. Little information is currently known about the pathogenesis and optimal treatment regimen for MIS-C. Most practitioners are utilizing standard Kawasaki protocols if clinically similar to KD in addition to supportive therapy [ 54 •, 55 •, 56 •, 57 •]. Several international registries are collecting surveillance data to learn more about this new entity. The hope is that discoveries in MIS-C may provide insight into our understanding of the trigger, genetics, and pathophysiology of KD.

Primary Treatment

Intravenous immunoglobulin (ivig).

Early identification of KD is paramount as timely administration of treatment has greatly reduced the incidence of coronary artery lesions (CALs). IVIG is most effective when administered within 10 days of onset of fever, and its use decreases the risk of coronary artery aneurysm formation from 20–25% to 3–5% in those who are appropriately treated [ 59 , 60 ]. Effective initial treatment consists of a single infusion of high-dose IVIG at 2 g/kg together with acetylsalicylic acid (ASA) [ 60 – 62 ].

Even with prompt IVIG therapy, up to 20% of children will develop recurrent or persistent fevers. These children are termed IVIG-resistant [ 61 – 63 ]. There are several risk factors for IVIG-resistant KD including delayed initial IVIG administration, increased ESR, decreased hemoglobin and platelet levels, oral mucosal alterations, cervical lymphadenopathy, extremity swelling, and polymorphous rash [ 64 •]. It is recommended that these children are administered a second dose of IVIG to help prevent sequelae [ 61 ]. Additional considerations regarding IVIG therapy: active vaccinations, i.e., measles and varicella vaccinations are contraindicated for 11 months after administration of IVIG and known physiologic ESR elevations after IVIG preclude its use to assess response to therapy.

Moderate-dose (30–50 mg/kg/day) or high-dose (80 to 100 mg/kg/day) ASA is generally utilized until the patient is afebrile in the United States, Japan, and Western Europe. There does not appear to be a significant difference between low-dose (3-5 mg/kg/day) ASA versus high-dose ASA in regard to incidence of CALs, duration of fever, or duration of hospitalization [ 65 •]. There is also no clear evidence that any dose of ASA will decrease development of CALs [ 66 ].

Therefore, it may be reasonable to give the moderate-dose ASA to avoid potential toxicities seen in high-dose ASA. Regardless of dose, ASA and IVIG remain the standard initial management. ASA is typically scheduled every 6 h during the acute phase of illness. Some clinicians will continue high-dose ASA until the 14th day of illness, even after fever defervescence. After the acute phase, children are transitioned to low-dose (3–5 mg/kg) ASA for anti-platelet effect. Patients remain on low-dose ASA into the convalescent phase. The decision to continue or discontinue therapy is usually made around 6–8 weeks pending any CALs on echocardiogram. Patients who are at high risk of treatment resistance and/or patients with coronary sequelae may benefit from adjunctive treatments (which are discussed below).

Adjuvant Therapy and Treatment Options for Cases Refractory to IVIG and ASA

Corticosteroids.

Corticosteroids are well-utilized in most vasculitides given their relatively fast onset, strong anti-inflammatory properties, and overall improved outcomes. Their use in KD is more controversial, but emerging data suggests that patients at particularly high risk for development of CALs may benefit from early use of corticosteroids as primary adjunctive therapy with IVIG and ASA. A 2016 meta-analysis of 16 studies by Chen et al. looked at early intervention with corticosteroids plus IVIG versus corticosteroid use in IVIG-resistant cases. They found that the incidence of CALs was lower in patients who received corticosteroids as adjunctive primary therapy compared to the IVIG only group [ 67 ]. A 2017 Cochrane review also demonstrated reduced incidence of CALs in KD patients treated with corticosteroids during the acute phase. Additionally, they found that corticosteroid use was associated with decreased duration of fever, length of hospitalization, and time to normalization of CRP [ 68 •].

There is significant heterogeneity in studies assessing corticosteroids use in KD with regard to dose, duration, and timing of use. Despite this fact, there are several notable consistencies when comparing results. Studies that utilized a single dose of intravenous methylprednisolone [ 69 , 70 ] did not demonstrate the same benefit of reduced incidence of CALs seen in studies which utilized moderate to high dose (i.e., 1–6 mg/kg/day prednisolone equivalent doses) over an extended course (i.e., greater than 3 days) [ 71 , 72 ]. Early use of corticosteroids during the acute phase appears to be more beneficial than in refractory (IVIG-resistant) cases [ 67 , 73 ]. Patients at higher risk of poor coronary outcomes have the greatest magnitude of benefit from early adjunctive corticosteroid therapy [ 68 , 69 , 72 , 74 ]. Overall results demonstrate good tolerability and safety with corticosteroid use and no evidence of increased incidence of adverse outcomes. There is currently no consensus on corticosteroid dosing for treatment of KD. The most recent AHA guidelines note that a longer course of corticosteroids may be considered in high risk patients as primary adjunctive therapy or in IVIG-resistant cases [ 38 •].

Tumor Necrosis Factor (TNF) Inhibition

TNF and IL-1 beta have both been implicated in the vascular endothelial cell damage and CALs seen in acute KD [ 75 ]. Several small studies reported potential beneficial effects of TNF blockade during the acute phase of KD, either as primary therapy or in cases refractory to IVIG. The most well-studied agent is infliximab, whose use may decrease the duration of fever and the length of hospitalization as well as aid in normalization of acute phase reactants. No studies to date, however, have reported decreased CALs with the use of infliximab [ 76 , 77 ].

A recent trial with etanercept for acute phase KD showed no significant benefit in cases refractory to IVIG. However, there did appear to be an improvement in coronary artery dilation and disease progression in patients 1 year out from onset. This effect seemed especially true in patients with baseline abnormalities on coronary imaging [ 78 •]. Use of TNF inhibitors is not mainstream for reasons besides lack of effect on CALs, namely association with malignancy and infection risk.

Interleukin 1 Inhibition

Several small case studies have reported successful use of anakinra, an IL-1 receptor antagonist, in the treatment of refractory KD [ 79 – 81 ]. Prospective trials are underway to further investigate.

Calcineurin Inhibition

Calcineurin inhibitors like cyclosporine may be beneficial as adjunctive primary treatment or in cases refractory to IVIG [ 82 •, 83 , 84 ]. The 2019 Hamada et al. study was a randomized control trial that showed reduced incidence of CALs in higher risk patients treated with IVIG plus cyclosporine versus standard therapy with IVIG alone. Additionally, the authors found no increased incidence of adverse events between the two groups [ 82 •]. Calcineurin inhibition therapy has promise given the important role the adaptive immune system, specifically T cells, plays in the pathogenesis of KD. More studies need to be conducted to assess effectiveness and safety.

Other Therapies

Several other immunosuppressive agents are reported to be effective in patients with refractory KD including: plasma exchange, cyclophosphamide, methotrexate, and even rituximab. Use of these agents is not widespread given toxicity risks and lack of staunch prospective clinical trials [ 85 – 87 ]. IL-6 inhibitors are not currently used in refractory cases of KD. A 2017 prospective case series by Nozawa et al. reported progressive development of giant coronary artery aneurysms in 2 out of 4 children treated with tocilizumab with refractory KD. While this was a single small series, there is a suggestion than tocilizumab may accelerate formation of CALs [ 88 ].

Primary Prevention of Thrombosis

Patients with no evidence of CALs are maintained on low-dose ASA therapy throughout the acute phase of illness. At the 6–8 week follow-up appointment, ASA may be discontinued so long as no adverse changes are seen on the final cardiac imaging (echocardiogram). Patients with small CALs are typically continued on low-dose ASA monotherapy past this period. Those with moderate-sized aneurysms are managed with ASA and an ADP receptor antagonist, i.e., clopidogrel. Children with persistent large or giant aneurysms (internal luminal diameter ≥ 8 mm) may be treated with an antiplatelet agent plus anticoagulant therapy (i.e., warfarin or LMWH). The latter regimens are implemented in collaboration with pediatric hematology specialists. It is important to note that nonsteroidal anti-inflammatory drugs, which utilize the cyclooxygenase pathway, may interfere with the antiplatelet effect of ASA and should be avoided.

Studies are underway assessing the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in children with KD and CALs. Statins may have potential beneficial effects on inflammation, platelet aggregation, coagulation, and endothelial function in addition to their known cholesterol lowering effects. Studies have shown both safety and tolerability, but long-term prospective trials are needed prior to recommending their routine use in KD [ 89 , 90 ].

Prognosis and Long-Term Management

The prognosis for children diagnosed with Kawasaki disease is primarily based upon extent and severity of coronary artery involvement at diagnosis and at follow-up. The case-fatality rate in the United States and Japan is less than 0.2%, and the principal cause of death is myocardial infarction resulting from coronary artery occlusion [ 91 ]. The AHA 2017 guidelines for diagnosis, treatment, and management of KD provide a detailed risk classification scheme that can be utilized for follow-up guidance [ 38 •]. The classification system is divided into five risk categories utilizing both Z scores and absolute luminal dimensions.

The lowest risk level is 1, indicating no involvement of the coronary arteries ( Z score < 2). These patients are screened with echocardiogram during the acute illness, and then again at 6–8 weeks after onset. These patients appear to have a similar risk profile to patients without a diagnosis of KD [ 49 ]. ASA can be discontinued in this group so long as there are no adverse changes in the risk classification. The highest risk group is risk level 5 with large or giant aneurysms ( Z score ≥ 10 or absolute dimension ≥ 8 mm). These patients naturally require much closer cardiac monitoring, and even addition of anticoagulants if persistence of aneurysms as outlined above [ 38 •].

Compliance with Ethical Standards

The authors declare that they have no conflicts of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.

This article is part of the Topical Collection on Vasculitis

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