Abstract:

Kawasaki disease (KD) is a vasculitis with predilection for coronary arteries. Due to a lack of reliable confirmatory laboratory tests, the diagnosis of KD is based on a characteristic pattern of clinical findings that appear in a typical temporal sequence. The diagnostic criteria have been periodically modified and the American Heart Association has proposed the most recent guidelines for its diagnosis. However, patients may have incomplete or atypical forms of KD and diagnosis can often be difficult. Because oropharyngeal manifestations are a common and important feature for diagnosing KD and recent studies have hypothesized a possible association between KD and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in this review we highlight the importance of dentists in the diagnosis of KD and its potential association with SARS-CoV-2.

Keywords:
Mucocutaneous Lymph Node Syndrome; Coronavirus Infections; Dental Care

Introduction

Kawasaki disease (KD, OMIM #611775), a medium-sized vasculitis with coronary artery predilection, shows a variable incidence rate ranging from 4 to 300 per 100,000 children.¹1. Luca NJ, Yeung RS. Epidemiology and management of Kawasaki disease. Drugs. 2012 May;72(8):1029-38. https://doi.org/10.2165/11631440-000000000-00000
https://doi.org/10.2165/11631440-0000000... ^,22. Makino N, Nakamura Y, Yashiro M, Kosami K, Matsubara Y, Ae R, et al. Nationwide epidemiologic survey of Kawasaki disease in Japan, 2015-2016. Pediatr Int (Roma). 2019 Apr;61(4):397-403. https://doi.org/10.1111/ped.13809
https://doi.org/10.1111/ped.13809... It is more frequently diagnosed in boys and the diagnosis is based on clinical features, including recurrent fever, polymorphic rash, characteristic changes in the extremities (erythema of the hands and feet accompanied by desquamation of the fingers and toes), bilateral conjunctivitis, cervical lymphadenopathy, oropharyngeal changes, such as a ‘strawberry’ tongue (prominent lingual papillae), dry, erythematous or split-lips, and oropharyngeal mucosal erythema,³3. Dajani AS, Taubert KA, Gerber MA, Shulman ST, Ferrieri P, Freed M, et al. Diagnosis and therapy of Kawasaki disease in children. Circulation. 1993 May;87(5):1776-80. https://doi.org/10.1161/01.cir.87.5.1776
https://doi.org/10.1161/01.cir.87.5.1776... because there is no gold standard laboratory test.⁴4. Singh S, Jindal AK, Pilania RK. Diagnosis of Kawasaki disease. Int J Rheum Dis. 2018 Jan;21(1):36-44. https://doi.org/10.1111/1756-185X.13224
https://doi.org/10.1111/1756-185X.13224... KD was first identified in 1967 by Tomisaku Kawasaki in 50 Japanese children less than 5-years-old. Currently, nearly all racial groups are affected.⁵5. Burns JC, Kushner HI, Bastian JF, Shike H, Shimizu C, Matsubara T, et al. Kawasaki disease:a brief history. Pediatrics. 2000 Aug;106(2):E27. https://doi.org/10.1542/peds.106.2.e27
https://doi.org/10.1542/peds.106.2.e27...

Although the etiology of KD is unknown, some studies have described an association with viral respiratory infections.⁶6. Turnier JL, Anderson MS, Heizer HR, Jone PN, Glodé MP, Dominguez SR. Concurrent respiratory viruses and Kawasaki disease. Pediatrics. 2015 Sep;136(3):e609-14. https://doi.org/10.1542/peds.2015-0950
https://doi.org/10.1542/peds.2015-0950... ^,77. Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Bradley Segal J, et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020 Jun;10(6):537-40. https://doi.org/10.1542/hpeds.2020-0123
https://doi.org/10.1542/hpeds.2020-0123... Turnier et al.,⁶6. Turnier JL, Anderson MS, Heizer HR, Jone PN, Glodé MP, Dominguez SR. Concurrent respiratory viruses and Kawasaki disease. Pediatrics. 2015 Sep;136(3):e609-14. https://doi.org/10.1542/peds.2015-0950
https://doi.org/10.1542/peds.2015-0950... for example, associated 28% of cases of KD with rhinovirus/enterovirus and 8.7% were attributed to parainfluenza. The association of KD and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was noticed after the first case of KD was diagnosed in a patient infected with the coronavirus disease 2019 (COVID-19) by Jones et al.⁷7. Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Bradley Segal J, et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020 Jun;10(6):537-40. https://doi.org/10.1542/hpeds.2020-0123
https://doi.org/10.1542/hpeds.2020-0123... Further more, a cluster of SARS-CoV-2-infected children presenting with KD-like symptoms has also been reported, as well as, multisystem inflammatory syndrome (MIS), KD shock syndrome, and toxic shock syndrome.⁸8. Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS, et al. Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City. JAMA. 2020 Jul;324(3):294-6. https://doi.org/10.1001/jama.2020.10374
https://doi.org/10.1001/jama.2020.10374... ^,99. McCrindle BW, Manlhiot C. SARS-CoV-2-related inflammatory multisystem syndrome in children: different or shared etiology and pathophysiology as Kawasaki disease? JAMA. 2020 Jul;324(3):246-8. https://doi.org/10.1001/jama.2020.10370
https://doi.org/10.1001/jama.2020.10370... ^,1010. Rivera-Figueroa EI, Santos R, Simpson S, Garg P. Incomplete Kawasaki disease in a Child with Covid-19. Indian Pediatr. 2020 Jul;57(7):680-1. https://doi.org/10.1007/s13312-020-1900-0
https://doi.org/10.1007/s13312-020-1900-... ^,1111. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, 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 Jun;395(10239):1771-8. https://doi.org/10.1016/S0140-6736(20)31103-X
https://doi.org/10.1016/S0140-6736(20)31... ^,1212. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020 Jul;324(3):259-69. https://doi.org/10.1001/jama.2020.10369
https://doi.org/10.1001/jama.2020.10369...

This association has worried the scientific community, since the COVID-19 pandemic has reached more of 19.4 million cases and 721,000 deaths (https://who.sprinklr.com, accessed on Aug 9^th, 2020). In Brazil, the first COVID-19 official case was reported on February 25, 2020, and currently the country has the most cases and deaths in Latin America (3,012,412 cases and 100,477 deaths as of August 8, 2020) (https://covid.saude.gov.br/), and these statistics are probably substantially underestimated.¹³13. The Lancet. COVID-19 in Brazil: “So what?”. Lancet. 2020 May;395(10235):1461. https://doi.org/10.1016/S0140-6736(20)31095-3
https://doi.org/10.1016/S0140-6736(20)31...

As orofacial manifestations are common and essential for diagnosing KD and a potential association with COVID-19 was reported, we highlight, in this critical review, the clinical and laboratory features of KD and its association with SARS-CoV-2.

Discussion

Diagnosis criteria

Two official guidelines for KD diagnosis have been developed by the Kawasaki Disease Research Committee (KDRC, 2002)¹⁴14. Ayusawa M, Sonobe T, Uemura S, Ogawa S, Nakamura Y, Kiyosawa N, et al. Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int. 2005;47(2):232-4. https://doi.org/10.1111/j.1442-200x.2005.02033.x
https://doi.org/10.1111/j.1442-200x.2005... and by the American Heart Association (AHA, 2017)¹⁵15. 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 Apr;135(17):e927-99. https://doi.org/10.1161/CIR.0000000000000484
https://doi.org/10.1161/CIR.000000000000... ^,1616. Correction to: Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2019 Jul;140(5):e181-4. https://doi.org/10.1161/CIR.0000000000000703
https://doi.org/10.1161/CIR.000000000000... (Tables 1 and 2). Those guidelines do not differ significantly from the original description by Kawasaki in 1967,¹⁷17. Kawasaki T. [Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children]. Arerugi. 1967 Mar;16(3):178-222. Japanese. and the main difference between the KDRC and AHA guidelines is that while fever for more than five days is an essential condition in the AHA’s guidelines, it is not recognized in the KDRC’s guidelines. However, in the AHA’s guidelines, the importance of fever for more than five days is minimized if the patient shows more than four of the principal clinical signs of inflammation in mucocutaneous areas, including the skin (feet and hands) and mucous membranes, such as the oral cavity and eyes.

Although a specific diagnostic test does not exist, some findings may help to distinguish KD from other similar conditions.¹⁸18. Cohen E, Sundel R. Kawasaki disease at 50 years. JAMA Pediatr. 2016 Nov;170(11):1093-9. https://doi.org/10.1001/jamapediatrics.2016.1446
https://doi.org/10.1001/jamapediatrics.2... The disease usually shows three stages (average duration of 6 to 8 weeks) and different laboratory findings can occur. The first stage is the acute febrile period that lasts one to two weeks, with nonspecific results, but may help support the diagnosis in children who do not fulfil clinical criteria. There is an increase in the erythrocyte sedimentation rate, C-reactive protein, blood cell count (predominance of neutrophils), serum transaminase levels associated with hypoalbuminemia, thrombocytosis (this finding usually occurs more in the subacute phase), and anemia. The subacute period (around 25 days) is characterized by thrombocytosis in association with periungual desquamation of the fingers or toes. The last phase (convalescent phase, around four to eight weeks) shows a normal sedimentation rate and platelet count.¹⁹19. Scuccimarri R. Kawasaki disease. Pediatr Clin North Am. 2012 Apr;59(2):425-45. https://doi.org/10.1016/j.pcl.2012.03.009
https://doi.org/10.1016/j.pcl.2012.03.00...

Findings on high-resolution echocardiography also provide important information for KD diagnosis and treatment.²⁰20. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, 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, America Heart Association. Circulation. 2004 Oct;110(17):2747-71. https://doi.org/10.1161/01.CIR.0000145143.19711.78
https://doi.org/10.1161/01.CIR.000014514... Among the most common cardiac complications are coronary artery aneurysm, decreased myocardial contractility, congestive heart failure, arrhythmias, pancarditis, pericardial effusion, and myocardial ischemia.²¹21. Cox JR, Sallis RE. Recognition of kawasaki disease. Perm J. 2009;13(1):57-61. https://doi.org/10.7812/TPP/08-042
https://doi.org/10.7812/TPP/08-042... According to AHA guidelines, children with fever for more than five days and two or more clinical signs of mucocutaneous inflammation, plus coronary artery dilation and/or characteristic laboratory test results (Table 3) should be considered for KD diagnosis.

Etiology and the relationship with SARS-CoV-2

Although the etiology of KD is unknown, bacterial and viral infections are considered the most likely triggers of the disease.²²22. Agarwal S, Agrawal DK. Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Rev Clin Immunol. 2017 Mar;13(3):247-58. https://doi.org/10.1080/1744666X.2017.1232165
https://doi.org/10.1080/1744666X.2017.12... Among bacteria related to KD are Staphylococcus aureus, Streptococcus A, Yersinia pseudotuberculosis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Chlamydiae pneumoniae, Mycoplasma pneumoniae and Rickettsial. The viruses frequently associated with KD are Parvovirus B19, Epstein Barr virus, Cytomegalovirus, Human herpesvirus 6, Rhinovirus/Enterovirus, Retrovirus, Rotavirus, Parainfluenza virus, New Haven coronavirus, Measles, Chickenpox, and Dengue virus, where 28% of KD cases are associated with Rhinovirus/Enterovirus.⁶6. Turnier JL, Anderson MS, Heizer HR, Jone PN, Glodé MP, Dominguez SR. Concurrent respiratory viruses and Kawasaki disease. Pediatrics. 2015 Sep;136(3):e609-14. https://doi.org/10.1542/peds.2015-0950
https://doi.org/10.1542/peds.2015-0950... ^,2323. Chang LY, Lu CY, Shao PL, Lee PI, Lin MT, Fan TY, et al. Viral infections associated with Kawasaki disease. J Formos Med Assoc. 2014 Mar;113(3):148-54. https://doi.org/10.1016/j.jfma.2013.12.008
https://doi.org/10.1016/j.jfma.2013.12.0...

Epidemiological data from many countries show that children are affected by SARS-CoV-2 in far smaller proportions than adults, with only 2% of cases described in patients under the age of 20.²⁴24. Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020 Jun;145(6):e20200702. https://doi.org/10.1542/peds.2020-0702
https://doi.org/10.1542/peds.2020-0702... Recently, in some countries, there has been an apparent cluster of children presenting with symptoms of KD, which seems related to the COVID-19 pandemic.⁷7. Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Bradley Segal J, et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020 Jun;10(6):537-40. https://doi.org/10.1542/hpeds.2020-0123
https://doi.org/10.1542/hpeds.2020-0123... ^,1212. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020 Jul;324(3):259-69. https://doi.org/10.1001/jama.2020.10369
https://doi.org/10.1001/jama.2020.10369... ^,2525. Xu S, Chen M, Weng J. COVID-19 and Kawasaki disease in children. Pharmacol Res. 2020 Sep;159:104951. https://doi.org/10.1016/j.phrs.2020.104951
https://doi.org/10.1016/j.phrs.2020.1049... ^,2626. Toubiana J, Poirault C, Corsia A, Bajolle F, Fourgeaud J, Angoulvant F, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ. 2020 Jun;369:m2094. https://doi.org/10.1136/bmj.m2094
https://doi.org/10.1136/bmj.m2094... ^,2727. Labé P, Ly A, Sin C, Nasser M, Chapelon-Fromont E, Ben Saïd P, et al. Erythema multiforme and Kawasaki disease associated with COVID-19 infection in children. J Eur Acad Dermatol Venereol. 2020 Oct;34(10):e539-41. https://doi.org/10.1111/jdv.16666
https://doi.org/10.1111/jdv.16666... ^,2828. Moreira A. Kawasaki disease linked to COVID-19 in children. Nat Rev Immunol. 2020 Jul;20(7):407. https://doi.org/10.1038/s41577-020-0350-1
https://doi.org/10.1038/s41577-020-0350-... A French center, for example, diagnosed 17 cases in 11 days, in contrast to an average of two cases per month in 2018-2019.²⁸28. Moreira A. Kawasaki disease linked to COVID-19 in children. Nat Rev Immunol. 2020 Jul;20(7):407. https://doi.org/10.1038/s41577-020-0350-1
https://doi.org/10.1038/s41577-020-0350-... Similarly, Verdoni et al.¹¹11. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, 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 Jun;395(10239):1771-8. https://doi.org/10.1016/S0140-6736(20)31103-X
https://doi.org/10.1016/S0140-6736(20)31... have described KD-like symptoms in 10 SARS-CoV-2 positive Italian children in two months, in contrast with 19 cases diagnosed in the past five years. Of the children evaluated in the report by Verdoni et al.,¹¹11. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, 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 Jun;395(10239):1771-8. https://doi.org/10.1016/S0140-6736(20)31103-X
https://doi.org/10.1016/S0140-6736(20)31... five showed typical KD features, including non-purulent conjunctivitis, polymorphic rash, mucosal changes and swollen extremities, and another five children showed fewer than three of the minimal clinical signs for KD diagnosis. There were also a high proportion of patients experiencing shock, with five out of ten children showing fluid resuscitation hypotension and two needing inotropic support. These differences raise the question of whether this cluster is KD triggered by SARS-CoV-2, or if it represents features related to multisystem inflammation.

While the SARS-CoV-2 could become endemic, like HIV, the WHO, warn against any attempt to predict how long it may remain in circulation. This virus may become another endemic virus in our communities and may never go away (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Due to the time interval of studies on the pandemic and the immunological mechanisms resulting from viral infection, many effects may be discovered.

Principal clinical findings

Usually, KD starts with a sudden, unremitting fever, of high intensity, lacking an antimicrobial response, and followed by inflammation of the mucosa. Although most children with KD have a fever which typically lasts longer than five days, however, this number is somewhat arbitrary.²⁹29. Yoshino A, Tanaka R, Takano T, Oishi T. Afebrile Kawasaki disease with coronary artery dilatation. Pediatr Int (Roma). 2017 Mar;59(3):375-7. https://doi.org/10.1111/ped.13214
https://doi.org/10.1111/ped.13214... Thus, an experienced physician can diagnose KD on day three or four of the illness, in association with other clinical features.¹⁵15. 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 Apr;135(17):e927-99. https://doi.org/10.1161/CIR.0000000000000484
https://doi.org/10.1161/CIR.000000000000... Such features include, bilateral exudative conjunctival injection with limbal sparing and the presence of erythema in the oral cavity and lips, with lip cracking found in 96% of patients.³⁰30. Saguil A, Fargo M, Grogan S. Diagnosis and management of kawasaki disease. Am Fam Physician. 2015 Mar;91(6):365-71.

In addition, children with KD often have a non-specific erythema of the palms and soles and characteristic edema of the hands and feet, that usually subsides within a few days. Periungual skin peeling is a pathognomonic symptom of KD usually occurring during the second or third week of illness. Although there is a report of periungual desquamation within 10 days,³¹31. Kushner HI, Macnee R, Burns JC. Impressions of Kawasaki syndrome in India. Indian Pediatr. 2006 Nov;43(11):939-42. this is not very useful for an early diagnosis.³²32. Chao SM, Phua KB. Perineal eruption as an early sign of Kawasaki disease. Ann Acad Med Singap. 1991 Mar;20(2):244-7. Another non-specific lesion is the diffuse erythematous polymorphic rash that typically occurs in the first few days of illness. It can be seen in up to 96% of patients. However, it is often intermittent and may therefore be overlooked, particularly in children with dark skin.³⁰30. Saguil A, Fargo M, Grogan S. Diagnosis and management of kawasaki disease. Am Fam Physician. 2015 Mar;91(6):365-71. Unilateral cervical lymphadenopathy is a characteristic clinical sign of KD, but is seen in only 60% of patients and often mistaken for suppurative lymphadenitis.³⁰30. Saguil A, Fargo M, Grogan S. Diagnosis and management of kawasaki disease. Am Fam Physician. 2015 Mar;91(6):365-71.

Role of dentists on KD diagnosis

Among mucocutaneous lesions found with KD, the most common occur in the orofacial region and can be found in most cases at time of diagnosis.¹⁶16. Correction to: Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2019 Jul;140(5):e181-4. https://doi.org/10.1161/CIR.0000000000000703
https://doi.org/10.1161/CIR.000000000000... ^,3333. Bhatnagar SK, Paul G, Subramanian R, Al Hosni MS, Al Khusaiby SM. Kawasaki disease in Oman: a clinical study. J Trop Pediatr. 2003 Dec;49(6):361-6. https://doi.org/10.1093/tropej/49.6.361
https://doi.org/10.1093/tropej/49.6.361... ^,3434. Scardina GA. Oral manifestation of Kawasaki disease. Res J Biol Sci. 2007;2(4):431-3. The changes in the lips, including erythema, dryness, cracking, peeling, vertical cracking and bleeding, and changes in the mouth, such as strawberry tongue with erythema and prominent fungiform papillae, and diffuse oropharyngeal mucosa erythema, can occur both in the acute (0-9 days) and convalescence stages (> 25 days).²⁰20. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, 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, America Heart Association. Circulation. 2004 Oct;110(17):2747-71. https://doi.org/10.1161/01.CIR.0000145143.19711.78
https://doi.org/10.1161/01.CIR.000014514... Oral mucositis, characterized by typical necrotizing microvasculitis with fibrinoid necrosis, is common in KD.³⁴34. Scardina GA. Oral manifestation of Kawasaki disease. Res J Biol Sci. 2007;2(4):431-3. Whittaker et al.¹²12. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020 Jul;324(3):259-69. https://doi.org/10.1001/jama.2020.10369
https://doi.org/10.1001/jama.2020.10369... have reported that 17 (29%) of the patients with MIS presented mucus membrane changes and red, cracked lips, Cheung et al. (2020)⁸8. Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS, et al. Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City. JAMA. 2020 Jul;324(3):294-6. https://doi.org/10.1001/jama.2020.10374
https://doi.org/10.1001/jama.2020.10374... have found that 53% of their patients presented lip-redness, and Verdoni et al. (2020)¹¹11. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, 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 Jun;395(10239):1771-8. https://doi.org/10.1016/S0140-6736(20)31103-X
https://doi.org/10.1016/S0140-6736(20)31... have described that four of five patients (80%) displayed associated changes of the lips or oral cavity, or both. These oral changes can be identified by dentists, and considering these together with the medical history, patients should be referred to the pediatrician for confirmation of a KD diagnosis.²⁰20. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, 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, America Heart Association. Circulation. 2004 Oct;110(17):2747-71. https://doi.org/10.1161/01.CIR.0000145143.19711.78
https://doi.org/10.1161/01.CIR.000014514...

Early diagnosis of KD is essential, because the intravenous immunoglobulin (IVIG) administration within the first 10 days has shown to reduce the incidence of cardiac complications.²¹21. Cox JR, Sallis RE. Recognition of kawasaki disease. Perm J. 2009;13(1):57-61. https://doi.org/10.7812/TPP/08-042
https://doi.org/10.7812/TPP/08-042... ^,3333. Bhatnagar SK, Paul G, Subramanian R, Al Hosni MS, Al Khusaiby SM. Kawasaki disease in Oman: a clinical study. J Trop Pediatr. 2003 Dec;49(6):361-6. https://doi.org/10.1093/tropej/49.6.361
https://doi.org/10.1093/tropej/49.6.361... Furthermore, a recent meta-analysis showed that changes in the oral mucosa is a clinical indicator of IVIG resistant in Asian patients and other alternative therapeutics are needed for those patients.³⁵35. Li X, Chen Y, Tang Y, Ding Y, Xu Q, Sun L, et al. Predictors of intravenous immunoglobulin-resistant Kawasaki disease in children: a meta-analysis of 4442 cases. Eur J Pediatr. 2018 Aug;177(8):1279-92. https://doi.org/10.1007/s00431-018-3182-2
https://doi.org/10.1007/s00431-018-3182-... Recurrence is reported at rates of 0.8% to 3%, and oral manifestations can occur.³⁶36. Verma L, Passi S, Kaur G, Gupta J, Joshi M. Recurrent Kawasaki disease presenting to dentists: “think beyond dentition”. Int J Clin Pediatr Dent. 2018 Nov-Dec;11(6):532-5. https://doi.org/10.5005/jp-journals-10005-1571
https://doi.org/10.5005/jp-journals-1000... Dry, cracked, red and swelling lips, and strawberry tongue are the most common signs of recurrence.³⁶36. Verma L, Passi S, Kaur G, Gupta J, Joshi M. Recurrent Kawasaki disease presenting to dentists: “think beyond dentition”. Int J Clin Pediatr Dent. 2018 Nov-Dec;11(6):532-5. https://doi.org/10.5005/jp-journals-10005-1571
https://doi.org/10.5005/jp-journals-1000... ^,3737. Faden A. Recurrent lip swelling as a late presentation of Kawasaki disease: case report and review of literature. Saudi Dent J. 2013 Jan;25(1):43-7. https://doi.org/10.1016/j.sdentj.2012.10.001
https://doi.org/10.1016/j.sdentj.2012.10... Dentists should be aware that patients with KD can also have cardiac sequelae, requiring prophylactic antibiotics before invasive dental procedures.

Being a rare disease, some cases go unnoticed due to a lack of knowledge. Proper information assists in the timely diagnosis and reduces the mortality rate caused by the disease. Thus, the requirement of dentists to recognize KD is essential.

Medical treatment and prognosis

The treatment in the acute phase aims to reduce the inflammatory response in the coronary artery wall, preventing the consequences of this vasculitis, including thrombosis and aneurysm.²²22. Agarwal S, Agrawal DK. Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Rev Clin Immunol. 2017 Mar;13(3):247-58. https://doi.org/10.1080/1744666X.2017.1232165
https://doi.org/10.1080/1744666X.2017.12... A combination of a high-dose of IVIG (a single dose of 2 g/kg) and high-doses of acetylsalicylic acid (AAS; 80-100 mg/kg/day until the fourteenth day of illness and at least 48 to 72 hours after cessation of fever) which are administered within 10 days of illness or later if the patient has persistent fever, aneurysms or inflammation, is recommended.¹⁵15. 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 Apr;135(17):e927-99. https://doi.org/10.1161/CIR.0000000000000484
https://doi.org/10.1161/CIR.000000000000... Subsequently, low-doses of AAS at 3 to 5 mg/kg/day is administrated for six to eight weeks, or throughout life if coronary complications occur.³⁰30. Saguil A, Fargo M, Grogan S. Diagnosis and management of kawasaki disease. Am Fam Physician. 2015 Mar;91(6):365-71. Although the anti-inflammatory role of AAS has been called into question and the IVIG’s mechanism of action is unclear,¹⁵15. 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 Apr;135(17):e927-99. https://doi.org/10.1161/CIR.0000000000000484
https://doi.org/10.1161/CIR.000000000000... this approach reduces the incidence of coronary artery defects from approximately 25% to less than 5%, and giant aneurysms to 1%.²²22. Agarwal S, Agrawal DK. Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Rev Clin Immunol. 2017 Mar;13(3):247-58. https://doi.org/10.1080/1744666X.2017.1232165
https://doi.org/10.1080/1744666X.2017.12... However, it was reported that among 20-40% of patients with KD are resistant to IVIG therapy and have a significantly higher risk in developing coronary artery abnormalities than nonresistant patients.²⁰20. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, 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, America Heart Association. Circulation. 2004 Oct;110(17):2747-71. https://doi.org/10.1161/01.CIR.0000145143.19711.78
https://doi.org/10.1161/01.CIR.000014514... ^,3838. Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr. 2008 Jul;153(1):117-21. https://doi.org/10.1016/j.jpeds.2007.12.021
https://doi.org/10.1016/j.jpeds.2007.12.... For IVIG-resistant KD patients, the protocol involves a second infusion of IVIG (2 g/kg) plus prednisolone (2 mg/kg divided every 8 h until afebrile, then prednisone orally until C-reactive protein is normalized, then tapered over 2-3 weeks), or Infliximab (5 mg/kg given over 2 h). Other alternative treatments are also used, such as cyclosporine, anakinra, cyclophosphamide, and plasma exchange.¹⁵15. 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 Apr;135(17):e927-99. https://doi.org/10.1161/CIR.0000000000000484
https://doi.org/10.1161/CIR.000000000000... However, the roles of the repeated use of IVIG and other adjunctive therapies are uncertain, even though some evidence reports good results.³⁰30. Saguil A, Fargo M, Grogan S. Diagnosis and management of kawasaki disease. Am Fam Physician. 2015 Mar;91(6):365-71.

KD patients in the subacute and convalescence phases with coronary aneurysms need to prevent thrombosis (platelet activation) and vessel stenosis. For this, low-dose aspirin (3-5 mg/kg/day) is the main therapy for children with small and medium aneurysms.²⁰20. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, 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, America Heart Association. Circulation. 2004 Oct;110(17):2747-71. https://doi.org/10.1161/01.CIR.0000145143.19711.78
https://doi.org/10.1161/01.CIR.000014514... Other antiplatelet agents are also used (clopidogrel, ticlopidine, dipyridamole) and their association with aspirin have been shown to be more effective in blocking platelet aggregation.²⁰20. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, 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, America Heart Association. Circulation. 2004 Oct;110(17):2747-71. https://doi.org/10.1161/01.CIR.0000145143.19711.78
https://doi.org/10.1161/01.CIR.000014514... Furthermore, the long-term risk of coronary disease results from intimate thickening and stenosis in regions adjacent to giant aneurysms and in areas with smaller aneurysms resolved.³⁹39. Gersony WM. The adult after kawasaki disease the risks for late coronary events. J Am Coll Cardiol. 2009 Nov;54(21):1921-3. https://doi.org/10.1016/j.jacc.2009.06.057
https://doi.org/10.1016/j.jacc.2009.06.0... Patients without aneurysms or stenosis do not appear to have subsequent complications, while long-term atherosclerotic risk evidence is mixed, and the follow-up needs to be done according to the clinical presentations.²⁰20. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, 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, America Heart Association. Circulation. 2004 Oct;110(17):2747-71. https://doi.org/10.1161/01.CIR.0000145143.19711.78
https://doi.org/10.1161/01.CIR.000014514... ^,3030. Saguil A, Fargo M, Grogan S. Diagnosis and management of kawasaki disease. Am Fam Physician. 2015 Mar;91(6):365-71.

Conclusion

Due to the orofacial manifestations, the participation of dentists, especially those specializing in oral medicine and pediatric dentistry, is essential for the early diagnosis of KD. In the face of the crisis caused by COVID-19 and the subsequent sequelae caused by the virus, it is necessary to consider the orofacial lesions related to KD. This is the first paper drawing attention to the importance of recognizing KD and KD-like symptoms in dentistry. Further studies will be needed to better understand the relationship between SARS-CoV-2 and these conditions.

Acknowledgment

The Minas Gerais State Research Foundation (FAPEMIG, Minas Gerais, Brazil), the National Council for Scientific and Technological Development (CNPq, Brazil) and the Coordination of Training of Higher Education Graduate Foundation (CAPES, Brazil).

References

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History