Kawasaki disease

Abstracts

A doença de Kawasaki é vasculite sistêmica e aguda de etiologia desconhecida. Constitui a principal causa de doença cardíaca adquirida em crianças nos EUA. Ocorre mais frequentemente em meninos, 80% dos casos em crianças com menos de cinco anos, sendo rara após os oito anos. Pode atingir crianças de todas as raças, tendo maior incidência entre os descendentes asiáticos. Caracteriza-se por febre, conjuntivite bilateral não exsudativa, eritema e edema de língua, lábios e mucosa oral, alterações de extremidades, linfonodomegalia cervical, exantema polimórfico. Aneurismas e estenoses de artérias coronárias são comuns em percentual que varia de 20 a 25% dos pacientes não tratados, podendo posteriormente levar a infarto agudo do miocárdio e morte súbita. O tratamento com imunoglobulina intravenosa é efetivo e deve ser iniciado precocemente a fim de evitar sequelas cardíacas. O desenvolvimento de testes diagnósticos, terapêuticas mais específicas e a prevenção dessa doença potencialmente fatal em crianças dependem dos contínuos avanços na determinação de sua etiopatogenia.

Aspirina; Aneurisma coronário; Exantema; Síndrome do linfonodo mucocutâneo

CONTINUING MEDICAL EDUCATION

Kawasaki disease

Patrícia Aparecida de Castro^I; Lílian Mendes Ferreira Urbano^II; Izelda Maria Carvalho Costa^III

^IResident Physician (3rd year), Department of Dermatology, Universidade de Brasília (UnB)-Brasilia (DF), Brazil

^IIResident Physician (2nd year), Department of Dermatology, Universidade de Brasília (UnB)-Brasilia (DF), Brazil

^IIIPhD in Dermatology, Tutor of the course of graduate studies in Healthcare Sciences, Universidade de Brasília (UnB)-Brasilia (DF), Brazil

^{Mailing Address}

ABSTRACT

Kawasaki disease is a systemic acute vasculitis of unknown etiology. It is the leading cause of acquired heart disease in children in the USA. It occurs more frequently in boys and eighty percent of the cases occur in children under five years of age. The disease rarely occurs after eight years and it can affect children of all races, with higher incidence among Asian descendants.

Kawasaki disease is characterized by fever, bilateral non-exudative conjunctivitis, redness and swelling of the tongue, lips and oral mucosa, abnormalities in the extremities, cervical lymph node, and polymorphic exanthema. Aneurysms and stenoses of coronary arteries occur in pproximately 20 to 25% of untreated patients and subsequently can lead to acute myocardial infarction and sudden death. Treatment with intravenous immunoglobulin is effective and should be initiated early to prevent cardiac sequel. The development of diagnostic tests, more specific treatment approaches and prevention of this potentially fatal disease in children depends on continuous advances in the determination of its pathogenesis.

Keywords: Aspirin; Coronary aneurysm; Exanthema; Mucocutaneous lymph node syndrome

INTRODUCTION

It is an acute and multisystemic vasculitis that impairs medium-sized vessels ¹. It is more frequent in children, especially those younger than 5 years, but there are reports in the literature of cases in adults. Kawasaki disease (KD) may cause vasculitis in different organs such as the lungs, intestines, biliary bladder, central nervous system and others, but heart impairment is the most significant in the formation of coronary aneurisms. The diagnosis is essentially clinical and clinical management, once it is started, leads to clinical improvement and reduces the risks of heart sequels.

HISTORY

KD was initially described in the medical literature by Tomisaku Kawasaki in 1967 ². At that time, there were 50 cases that had been followed up from 1961 to 1967 ³. It was believed to be a benign, self-limiting disease that had no sequels. The disease was named mucocutaneous lymph node syndrome ⁴. In 1970, there were 10 deaths of children younger than 2 years with KD, revealing the most aggressive aspect of the disease ^4,5. Noboru Tanaka, a pathologist, found out a case of coronary artery thrombosis during a necropsy of a child with previous diagnosis of KD.⁴ Takajiro Yamamoto, a pediatrician, observed gallop rhythm and congestive heart failure in one of his patients with KD. Yamamoto et al. published 23 cases of KD out of which 11 (48%) had electrocardiographic abnormalities, which made them conclude that heart involvement was a common characteristic in the syndrome ³. In 1974, Kawasaki had the first publication of KD in English ^3,6. Melish, in 1976, reported the first case of KD in the USA ⁴.

Epidemiology

KD occurs universally ⁷. It may occur at any pediatric age range, but 85% of the cases affect children below the age of 5 years ^6,7. It is infrequent in patients younger than 6 months or older than 8 years, but in these cases there is increased risk of formation of coronary aneurysms ⁷. KD incidence varies in different parts of the world. It is more prevalent in Japan and in Japanese descendant children, with annual incidence of approximately 112 cases per 100,000 children < 5 years ^4,6,8,9. There were three major epidemics in Japan in 1979, 1982 and 1986. Its annual incidence in USA ranges from 9.1 to 32. 5 cases per 100,000 children < 5 years, and it is more common in American descendants of Asiatic or Pacific families (32.5 children/ 100,000 children < 5 years), intermediately common in African descendants (16.9/ 100,000 children < 5 years) and Hispanic descendants (11.1/ 100,000 children < 5 years), and not very common in Caucasians (9.1/ 100,000 children < 5 years). ⁸ It is the most common cause of acquired heart disease in children in the USA ^5,6. The ratio between boys and girls range from 1.5 to 1.7: 1 ^2,8. The recurrence index of KD in Japan is 3% and in North America it is about 1%.^2,3

A study in KD in a Japanese family showed that the incidence of a second case of the disease 1 year after the first one in the same family is significantly higher than in the general population ^2,4.

Approximately 50% of the second cases occur in the first 10 days after the onset of index case ^3,4. The risk of occurrence in twins is 13% ^1,2.

These findings suggest that genetic predisposition in interaction with the possible exposure to etiological and environmental agents would have a role in the etiopathogenesis of the disease. The disease is more common in winter and spring months ⁴.

Etiopathogenesis

The cause of Kawasaki disease remains unknown despite its clinical characteristics (self-limiting febrile disease) and epidemiological characteristics (seasonality and epidemic character of the disease), favoring the hypothesis of an infectious agent as the determining cause, without any confirmation yet.

There are some ongoing studies leading to disagreeing theories in the scientific arena. One of the theories is the coronavirus NL-63: in 2005, researchers from New Haven, in Connecticut, reported the presence of a human coronavirus (HCoV) detected using polymerase chain reaction (PCR) in respiratory secretion of 8 children out of a total of 11 patients with KD and only in 1 out of 22 control patients ¹⁰.

However, other five posterior studies did not find the same coronavirus in respiratory and nasopharyngeal tissue samples of KD patients with statistical significance meaning, which invalidated this virus as causal agent of the disease ¹¹.

The other advocated theory is of immune stimulation by bacterial superantigen such as staphylococcal and streptococcal toxins ¹². The superantigen binds to the antigen-presenting cell, intact and without any processing, through a major histocompatibility complex class II (MHC class II) and domain V, of T lymphocyte receptor (TcR) in different sites from those of common antigens and triggers an exacerbated immune activation with production and release of proinflammatory cytokines in excessive concentration, such as alpha tumor necrosis factor (TNF-alpha), interleukin 1 (IL-1) IL-2 and others ^11,13. It also has some functions to activate natural killer cells, polyclonal activation of lymphocytes B, marked accentuation of endotoxins and toxic effect of endothelium ^13-15. However, a multicenter study did not show differences in the isolation of superantigen producing bacteria among patients with KD and another febrile control group ¹⁶.

The third theory is of the oligoclonal IgA response in acute KD. The analysis of gene sequence of alpha heavy chain of immunoglobulins coming from inflammatory infiltrate of the arterial wall of patients with KD showed a limited number of immunoglobulin specific antibodies (IgA) present (oligoclonal response), indicating an immune-antigen directed response ¹⁷. To detect the antigen determining this oligoclonal response, synthetic antibodies were produced in vitro after cloning of the genes in the variable regions a and κ of the immunoglobulins present in the inflamed arterial wall of patients with KD. Synthetic immunoglobulin IgA detected the cytoplasmatic inclusions of bronchial ciliary epithelium of children with KD. The studies indicated that these inclusions were more consistent with viral protein aggregates and associated with nucleic acid 18. Cytoplasmatic inclusions have been identified in Asiatic and non-Asiatic patients from Japan and the United States with KD using synthetic monoclonal antibodies, confirming this theory of IgA response and the possibility of having KD caused by an infectious agent that has not been determined yet. ^11,18

The increase in frequency of KD among Asian patients and their descendants, as well as the high incidence of affected family members favor the idea of genetic predisposition in KD ¹⁹. A study revealed that there are 67 different genes associated with KD and involved in endothelial function, lipid metabolism, platelet adhesion and immune activation ²⁰. Some gene alleles (of genes CCR3, CCR2, CCR5 that are receptors of cytokines) showed significant association with KD, which suggested genetic susceptibility ²¹.

The polymorphism of interleukin 1 receptor gene (IL-1R) has also been implied in the pathogenesis of KD ²².

There are many studies trying to elucidate in details the pathogenesis and through this knowledge, find more directed therapeutic approaches and preventive measures against heart sequels. The studies have shown that high levels of alpha tumor necrosis factors (TNF-α) are significant in coronary vessels of the patients with heart lesions, which may imply more specific therapy (anti-TNF alpha) in cases of heart impairment or refractory response to treatment ²³.

Matrix metalloproteinases (MMP) are zinc-dependent endopeptidases involved in the degradation of extracellular matrix such as collagen and elastic fibers. These enzymes are produced by smooth muscle cells of arterial wall during inflammatory response and suffer up-regulation owing to alpha tumor necrosis factor. Studies have shown that MMP-9 is related with coronary vascular damage ²⁴. Gene polymorphism of MMP-13 (some genotypic frequencies) is significantly associated with formation of coronary aneurysms ²⁵.

There is a family of proteins (S100) released by neutrophils and monocytes during the inflammatory cascade that are responsible for the migration of inflammatory cells through the vascular wall; they act by binding to the endothelial cell receptor (named RAGE). There is an inhibitory factor (s-RAGE) or RAGE receptor that prevents the binding of protein S100A12 to the receptor, balancing the inflammatory response. However, in the acute phase of the disease, the serum level of s-RAGE is reduced especially in those patients that do not respond to the treatment. It is known that s-RAGE levels are negatively correlated with those of S100A12 proinflammatory protein ^26,27.

The most acceptable etiopathogenic hypothesis is that KD is caused by an infectious agent, not identified yet, that determines clinical affections in genetically susceptible subjects in case of Asian descendants.

Pathology

Histological abnormalities found in KD consist of generalized systemic vasculitis, affecting predominantly medium-sized vessels, preferably coronary arteries ^1,2,3,4,6. Systemic inflammatory abnormalities may be observed in many organs causing myocarditis, vasculitis, aseptic meningitis, pneumonitis, lymphadenitis and hepatitis ^4,6.

In the initial stages of vasculitis, there is edema of endothelial cells with nuclear degeneration followed by edema and inflammation of adventitia layer⁴. Internal elastic lamina remains intact ². There is initial neutrophilic inflammatory infiltrate (within the first 7 to 9 days), with quick transmission to mononuclear predominance of cytotoxic T lymphocytes CD8+ and immunoglobulin IgA ^2,3.

In the coronary arteries, there are inflammatory affections detected on the medium layer with edema and necrosis of muscle cells; then, there is progression of inflammatory process that involves the whole vessels ^3,4. In this stage, there is destruction of internal and external elastic lamina, making the vessel layers become indistinguishable ². As a result of loss of structural integrity, there is formation of aneurysms ⁴. There is also proliferation of fibroblasts. Matrix metalloproteinases (MMP) have an important role in the process of arterial remodeling ^2,3. As a result of remodeling, there may be cases of stenosis, calcifications and formation of thrombi. Inflammatory activity remains for weeks and months with progressive fibrosis ³.

Clinical and laboratory diagnosis

In the absence of specific diagnostic tests or pathognomonic clinical finding of KD, researchers, based on epidemiological studies, have defined clinical criteria to facilitate the diagnosis (

Chart 1)

^2,7,28,29. The presence of persistent fever for 5 days or more, associated with 4 of the 5 clinical criteria closes the diagnosis of KD. There are no specific clinical diagnostic tests for KD, but there are characteristic laboratory findings (

Chart 2).

There are some patients that are diagnosed as having atypical or incomplete KD once they do not comply with all proposed diagnostic criteria ^2,29,30. The most appropriate term is incomplete KD, because patients have some typical symptoms of the disease and not atypical manifestations. Incomplete KD should be considered in all children with unexplained fever for more than 5 days associated with 2 or 3 of the main clinical findings of KD ^1,30. The incomplete form is more frequent in children below 6 months of age ³. The diagnosis of incomplete KD is based on echocardiographic findings of coronary artery affections; however, even in patients with fewer than 3 diagnostic criteria but with coronary lesion, treatment is indicated with intravenous immunoglobulin. The conventional diagnostic criteria proposed by the American Heart Association fail to recognize the incomplete form of the disease. ^5,32,33

Electrocardiogram may be normal or show arrhythmia, prolongation of PR interval or non-specific findings of ST segment and T wave ^2,8. Chest x-ray is normally normal but in 14.7% of the cases, there are abnormalities such as reticulogranular infiltrate pattern or peribronchial infiltrate, pleural effusion or atelectasia. Such abnormalities are detected after 10 days from onset of the disease and show radiological resolution after 10 to 50 days from beginning of the presentation ⁶.

Clinical presentation

In Kawasaki disease the fever, which is a characteristic sign of the acute phase of the disease, is normally high (above 39-40º C), remittent and followed by extreme irritability

^34,35. The first day of fever is considered the first day of the disease, but in some patients, there might be clinical manifestations before the febrile presentation

^3,4. The duration of fever is on average one to two weeks; in the absence of treatment, it may extend for three to four weeks. It responds partially to antipyretic drugs and does not cease with the introduction of antibiotics. However, when appropriate therapy is started – intravenous immunoglobulin (IVIG) and aspirin – the fever is gone after two days

^2,4,36.

Bilateral non-exsudative conjunctivitis involves primarily the bulbar conjunctiva in relation to palpebral and tarsal conjunctiva, it is not painful and occurs in the acute stage of the disease. Iridocyclitis may follow, with quickly resolution and rarely associated with photophobia ^2,3,6,8.

The abnormalities found in the labial semimucosa are characterized by erythema, edema with fissures, desquamation and exsudation (Figure 1); the oropharynx mucosa has enanthema and the tongue maintains a raspberry-aspect (marked erythema with prominent gustative papillae). Pharyngeal ulcerations and exsudate are not observed ^2-4.

In the acute phase of the disease, erythema and/or indurations of palmar and plantar regions are also described, followed by increase in pain sensitivity; after 2-3 weeks of the disease – the subacute phase – there is periungual desquamation of hands and feet that progresses to hand palms and feet (Figure 2) ^3-8. After 1-2 months, there might be Beau's lines in affected nails ².

The cutaneous rash observed in patients with KD is non-specific, polymorphic, non-pruriginous and normally observed up to the 5th day of fever. Cutaneous exanthema may comprise macular-papular erythematous and fissure lesions, the most common type, in addition to urticariform type rash, scarlatiniform, erythrodermic, purpuric, multiform-like erythema ⁷, and more rarely, description of cases with micropustules on the extensor surface of the limbs ^37,38. There are no reports in the literature about vesicle-bullous lesions. The rash comprises mainly the trunk and the extremities with predilection for inguinal and perineal regions that present, throughout the clinical progression, desquamation in the acute stage of the disease (Figure 3) ^2,3,4,6. Neck lymphadenopathy is the most uncommon diagnostic criterion, which affects 50-75% of the patients, whereas the other clinical criteria are seen in 90% of the cases. It is normally unilateral and located on the anterior cervical triangle. According to the definition of the diagnostic criteria, there should be more than one impaired lymph node and > 1.5 cm in diameter. Affected lymph nodes are not painful or little painful, not-fluctuating and non-suppurative; erythema of the neighboring skin may occur. We should be attentive to those children with fever and neck adenitis that do not respond to antibiotics, because Kawasaki disease should be part of the differential diagnoses ^2,6,7.

KD is divided into three clinical phases: acute, subacute and convalescence. The cute phase lasts 1-2 weeks, comprises fever plus two more diagnostic criteria in addition to clinical findings associated with myocarditis, pericardial effusion, aseptic meningitis (1-25%), diarrhea (15%), liver dysfunction (5%); uveitis (17%), and arthritis and/or arthralgia (30%). The subacute phase starts when fever, rash and lymph adenopathy are resolved, after 1-2 weeks from the beginning of the disease, but there is irritability, anorexia and conjunctivitis. In this stage, there is periungual desquamation, thrombocytosis, formation of coronary aneurysm, and risk of sudden death is greater – this phase lasts for about 4 weeks. In this phase, neurological complications can be seen in 1% of the cases and include facial palsy, ataxia, encephalopathy, hemiplegia and cerebral infarction. The convalescence phase starts when clinical signs disappear and it lasts up to normalization of erythrocyte sedimentation rate (ESR), usually ^6-8 weeks after the onset of fever ^4,6,39. The occurrence of the disease in adults is uncommon – there are approximately 60 cases reported in the literature with ages ranging from 18-30 years and greater incidence of reports in Europe, and there are no reports of death in adults in the acute phase ^39,40,41. Diagnostic criteria were defined for children and are not validated for adults, but they are used in clinical practice.

Seve et al.⁴¹, after studying 57 adults, defined the differences in clinical presentation between adults and children: adults have more affection of neck lymph nodes (93% of adults versus 15% of children); hepatitis (65% versus 10%), and arthralgia (61% versus 24-38%). The diagnostic definition of KD in adults is difficult to make and it should take into account a set of information, such as absence of infection, no clinical improvement with antibiotics, and presence of diagnostic criteria similar to these in children.

Many clinical manifestations resulting from systemic vasculitis may be described in KD – they are secondary findings and do not comprise the diagnostic criteria (Chart 3) ^2,3,4,6,8,42. Hemophagocytic syndrome, which is characterized by persistent fever, cytopenia, hepatosplenomegalia, liver dysfunction secondary to excessive activation of macrophages, is a rare and severe complication of KD that seems to occur in patients with recurrent fever or refractory to treatment ⁴³.

Cardiovascular manifestations and imaging tests

Heart manifestations may be exacerbated in the acute phase determining increase in long-term mortality and morbidity. KD is the main cause of heart disease acquired in childhood in the USA and in Japan, and it is an important cause in adults in which the incidence of the disease is common. There may be myocarditis, pericarditis, endocarditis, valvular and coronary impairment with hemodynamic repercussions. The clinical examination of children with cardiac affection may reveal hyperdynamic precordium with tachycardia, pansystolic rumor in cases of mitral regurgitation and gallop rhythm owing to onset of heart failure ^2,6. Myocarditis is detected in 50-70% of the patients using exams with radioisotopes. Severity of myocardial inflammation does not seem to be related with risk of formation of coronary aneurysm. Even though most children have abnormal myocardial contractility shown by echocardiography in the acute phase, the heart function is soon restored by the introduction of IVIG.⁴⁴

Coronary damage, which may vary from dilation, stenosis to formation of aneurism, occurs in 5% of the patients appropriately treated and in 20-25% of those untreated cases ^2,6,45. The frequency of coronary involvement is greater in infants below 6 months of age compared to those aged 6-12 months. Coronary dilation, if present, may be evidenced by bi-dimensional echocardiography on day 10 of the disease and the peak of occurrence of the dilation or aneurysm is on week 4. In 1% of the cases, there is formation of giant aneurysms ^3,4. Spindle-shaped and saccular aneurysms appear between 18-25 days of the disease. A study with 598 children with KD showed the involvement of left coronary artery in 12% of the cases, the right coronary artery in 3%, and both in 8% ⁴⁶.

According to the classification of the American Heart Association², aneurysms are classified into small (internal diameter of vessel wall <5mm), medium (diameter ranging from 5-8mm), and giant (diameter > 8mm). In general, small and spindle-shaped aneurysms tend to suffer regression, whereas giant and saccular aneurysms have poor prognosis, including the risk of thrombosis and stenosis ^42,47. Aneurysms may be less frequently formed in other arteries such as subclavian, brachial, axillary, iliac, femoral and even abdominal or renal aortas ³.

There are evidences of risk factors related with the formation of coronary aneurysms such as recurrent fever despite the use of IVIG, increased ESR, anemia and hypoalbuminemia, male gender, age < 1 year, hyponatremia and thrombocytopenia ⁴⁸.

In view of the risks of heart sequels resulting from KD, cardiovascular monitoring using imaging techniques is essential.

The key non-invasive high sensitivity and specificity test to detect abnormalities of proximal segments of coronary arteries is echocardiography (level of evidence C). Echocardiogram is essential in the assessment of children with fever and other KD findings. The exam may show perivascular enhancement, ectasia or narrowing of coronary arteries that represent coronary arteritis before the formation of aneurysm, which is rarely seen before the disease has been in place for at least 10 days. Reduction of myocardial contractility of left ventricle, regurgitation of mitral valve and pericardial effusion are frequent echocardiographic findings in patients with KD in acute phase.

To cases without cardiac impairment, echocardiogram should be performed at the moment of diagnosis, on week 2 and on week 6-8 after onset of manifestations.

It is important to recognize the limitations of echocardiogram in visualizing thrombosis and stenosis of coronary distal segments ^2,42. There are other diagnostic options such as magnetic resonance imaging (MRI), angioresonance, high resolution computed tomography, and angiography that are used according to their availability, advantages, severity and indications in each case. Both MRI and angioresonance are capable of detecting aneurysms in the distal branches of the coronary, and the latter can be useful in early stages of the disease even in children < 6 months ⁴⁹. Recently, high resolution computed tomography has been recommended rather than transthoracic echocardiogram or MRI. It has the advantage of detecting calcifications on the arterial wall, quick acquisition of images and it simplifies the interpretation of the images, whereas MRI requires prolonged anesthetic time in children for collection of images ^2,50,51. The objective of the exams is to primordially detect the heart affections to detect risk stratification for appropriate therapeutic management ⁵¹.

Angiography is the gold standard to assess heart impairment, but it is an invasive test and has obvious risks, requiring specific indications of use. In patients with medium and spindle shaped aneurysms visualized by echocardiography and showing tendency to regression, there is no indication of this exam. The indications to angiography depend on the abnormalities seen in non-invasive tests such as signs of myocardial ischemia in stress echocardiogram, failure in visualizing the distal branches of coronary arteries, multiple aneurysms, giant aneurysm, coronary stenosis and follow up after myocardial revascularization (level C of evidence) ⁶. The ideal time for performing the test varies depending on the hospital Center; however, it is normally recommended after 6-12 weeks of the disease and after resolution of the acute inflammatory process (level of evidence C).

A review estimated the incidence of myocardial acute infarction in pregnant women in 1: 10.000.⁵² There are few studies about pregnancy and delivery in pregnant women with coronary disease caused by KD. A study of 13 pregnant women with KD in childhood and coronary lesion showed that none of the patients presented coronary thrombosis by using low doses of aspirin, which is considered safe for pregnancy and delivery. Nine pregnant women had vaginal delivery, with epidural anesthesia and no cardiac complications. Analgesia is indicated in the delivery of women with heart disease because it maintains the hemodynamic function and reduces the cardiac activity during labor. In symptomatic cases, a C-section may be considered ⁵³.

Differential Diagnosis

The main differential diagnoses are found in chart ^4.4.

Chart 4 Differential diagnosis of Kawasaki disease

• Síndrome de Stevens Johnson

• Pharmarmacodermia

• Febrile viral exanthemas (measles, adenovirus, enterovirus, Epstein-Barr virus)

• Juvenile rheum atoi d arthritis

• Staphylococcal sal ded skin syndrome

• Toxic shock syndrome

• Leptospirosis

• Mercury poisoning

• Measles

• Scarlet fever

• Recurrent toxin-mediate perineal erythema

• Bacterial neck lymphadenitis

Laboratory abnormalities and clinical peculiarities should support the diagnostic exclusion of each disease. An important differential diagnosis to dermatologist is with scarlet fever owing to clinical similarities. Both present exanthema with palmo-plantar desquamation, enanthema of oral mucosa with raspberry-like tongue and lymph node enlargement. However, scarlet fever reveals exsudative pharyngitis caused by group A Streptococcus and good clinical response within 24-48 hours from beginning of antibiotic therapy.

There is toxin-mediated recurrent perineal erythema that is a cutaneous disease mediated by superantigens produced by streptococcus and staphylococcus and clinically similar to KD. In this disease there is perineal erythema with desquamation, oral mucosa enanthema with raspberry-like tongue and desquamative palmar-plantar erythema, which are common signs of KD. However, the differential diagnosis is based on absence of fever, exanthema, conjunctivitis and lymph node enlargement in toxin-mediated perineal erythema ⁵⁴.

Evolution and prognosis

The progressive course of coronary lesions in KD is temporarily modified. Angiographic resolution after 1-2 years from the beginning of the presentation is observed in 50 to 67% of the vessels with coronary aneurysms ^2,46. There are some factors associated with the possibility of regression of aneurysms in children below the age of one year, small and medium aneurysms, spindle morphology and aneurysms located in the distal segment of coronary arteries. Aneurysms may progress unfavorably with persistence leading to stenosis, occlusion or tortuosity.

Whereas aneurysms tend to regress in most cases, stenosis - representing a proliferation of the intimal and medium layers, is progressive. Giant and persistent aneurysms tend to frequently progress with stenosis.

In a prospective study, Kato et al. ⁴⁶ reported the presence of coronary stenosis in patients with persistent aneurysm after 10 to 21 years of acute stage of the disease. Acute myocardial infarction (AMI) caused by thrombotic occlusion of aneurysm or coronary stenosis is the main cause of death in KD ⁵⁵. High risk of AMI is present primarily in the 1st year of life after the disease and most fatal cases are due to obstruction of coronary artery on the left and both right coronary and anterior descending arteries. In these patients with significant coronary disease there is the need to perform stress echocardiogram to assess the myocardial function so as to decide about the indication of angiography and surgical intervention ^2,4,56.

AMI in children has different clinical presentation from that in adults. A review of 195 cases of AMI caused by KD in children hospitalized in Japan showed that the main symptoms were hypotension, vomiting, malaise and abdominal pain; chest pain occurred more frequently in older children ⁴. In 37% of the cases, there were no previous symptoms. These findings emphasize the importance of diagnostic suspicion of AMI in children with KD or previous disease or coronary disease with positive epidemiology for KD, because early and correct intervention may reduce mortality of these children.

The long-term implications of aneurysms that regress are unknown. The impaired arteries have less distensibility and reduced vasodilation to infusion of isosorbide dinitrate in relation to the blood vessels that are not affected by the disease ^57,58. Echocardiogram reveals areas in which the aneurysm suffers regression, with irregular thickness of intimal-medium layer. The clinical pathology reveals such thickness of vessel wall, despite the normal arterial lumen. The association between KD and progression of atherosclerosis in adults with previous disease is still unknown ^4,59. There are cases of young adults with coronary ischemic disease consistent with Kawasaki sequels.

There are some factors that suggest worse prognosis, with risk of forming aneurysms, which are: duration of fever for more than 16 days, recurrence of fever after at least 48 hours without it, arrhythmia, male gender, age younger than 1 year, presence of cardiomegalia and laboratory affections such as platelet reduction, anemia and hypoalbuminemia at the disease onset ⁴.

Some researchers have studied the coronary physiology in the patients with KD and no cardiac lesions. Muzik et al. showed that these children have lower myocardial flow and greater resistance to coronary arteries when compared to the control group ⁶⁰.

Owing to the likely risk of greater morbidity and mortality in adults with previous KD, it is recommended that all children (including those without cardiovascular involvement) are followed up for each 3-5 years using tests. The frequency of follow up in children with coronary artery abnormalities should be more periodic and ranges according to each case. In these cases, there should be a follow up with cardiac pediatrician and routine testing (electrocardiogram and echocardiogram), plus stress test and myocardial perfusion tests for children older than 10 years of age. If the stress test is not compatible with myocardial ischemia, coronary angiography is indicated ⁸.

Nakamura et al. ⁶¹ designed a study, after following up 6,576 patients with KD, for a period of 12-22 years that showed mortality rate greater for men with heart sequels, whereas women with such sequels and the group (men and women) without heart sequels did not show increase in mortality rate compared to the general population. The level of prevalence of morbidity was 0.57%, and in men (0.63%) it was greater than in women (0.32%) ⁶².

In Japan, a study was performed with 9,965 freshmen of University of Tokyo by sending questionnaires to students and parents about the identification of previous KD, or the diagnosis was made based on the spontaneous report of the parents about KD in childhood. The results showed that spontaneous report of parents was uncertain about the occurrence of the disease and that medical and directed assessment of patients could detect previous KD; the study suggested that 1 in each 200 students in Japan might have had the disease and there is the need to recognize this fact because of the risks of heart sequels and death ⁶².

The level of lethality in Japan is 0.8%. ⁴ In the USA, intra-hospital mortality of patients with KD is approximately 0.17%. Deaths are resultant from heart sequels. The peak of mortality occurs between 15 and 45 days from onset of the fever, but in many cases there is late death caused by acute myocardial infarction secondary to coronary thrombosis in areas of aneurysm or, more recently, by rupture of aneurysm.

TREATMENT

The treatment of KD in the acute phase aims at reducing the inflammatory response of the coronary artery wall and prevent vasculitis and its consequences (thrombosis and aneurysm), whereas therapy in subacute and convalescence phases aims at preventing myocardial ischemia and infarction ³.

Intravenous immunoglobulin (IVIG) is the main drug used to treat KD. It is used in the acute phase, preferably within the first 7-10 days of the disease to reduce the prevalence of coronary artery abnormalities and to reduce the duration of clinical symptoms ^42,63-66. It may also quickly normalize the inflammatory proteins of the acute phase, except the erythrocyte sedimentation rate (ESR), and to improve myocardial function ^4,66.

In a recent retrospective study, it was concluded that late onset of IVIG use, after day 8 of the disease, reduces the likelihood of therapeutic success ⁶⁷. The action mechanisms of IVIG are still unknown; many theories have been advocated as possible mechanisms such as suppression of macrophages and activated monocytes, block of the interaction between the endothelium and natural killer cells, stimulation of inhibitory receptors, modulation of cytokine production, neutralization of bacterial superantigens, reduction of antibody synthesis and increase in suppressant T lymphocyte activity ^68,69.

Patients should be treated with IVIG at 2g/Kg dose in single infusion every 10-12 hours (level of evidence A), together with aspirin (AAS) at 80-100mg/Kg dose.2,3 IVIG infusion before day 5 of the disease does not prevent heart sequels more than the treatment prescribed on days 5-7 of the disease; in fact, early infusion increases the need for retreatment ^70,71.

IVIG may lead to some minor adverse events, such as vasomotor symptoms – headache, fever and shivers, hypotension, in addition to other transient affections such as leucopenia, neutropenia or proteinuria ^3,42,72. There are rare severe complications such as aseptic meningitis, thrombosis, anaphylactic shock, and acute renal failure. Dermatological adverse effects are also uncommon, such as pruritus, eczematous dermatitis, alopecia, and multiform erythema ⁷².

Vaccinations with attenuated live virus (measles, rubella, mumps and varicella) should be postponed at least for 11 months after administration of IVIG, owing to reduced immunogenicity caused by the passive antibodies of the drug ⁷³.

AAS in high doses has antiinflammatory effect and in low doses it causes inhibition of platelet aggregation in children with KD; thus, in the acute phase, aspirin is used at a 80-100mg/Kg/day dose, divided into 4 daily doses to maximize the antiinflammatory effect of IVIG, but it does not reduce the frequency of coronary abnormalities ². The duration of use of aspirin in high doses range from institution to institution, and many hospital centers reduce the dose 48-72 hours after the child has no more fever, whereas other centers maintain high dose AAS for 14 days and starting 48-72 hours after the fever is gone. The reduction of AAS dose should be made to 3-5 mg/Kg/ day and maintained for 6-8 weeks from the beginning of the disease (level of evidence C). To those children with heart abnormalities, aspirin is maintained indefinitely (Level of evidence B) ^2,3.

Ibuprofen should not be administered together with aspirin, given that the former antagonizes the irreversible platelet inhibition of aspirin 74. Another important element in children taking high doses of aspirin is the possibility of Reye syndrome if the child gets infected by varicella or influenza. Parents should be instructed to go to the pediatrician if the child has any of these infections while taking AAS ^2,3.

Corticoids have been used in cases in which the patients do not respond to initial treatment with IVIG plus aspirin ⁷⁵. However, the results after using corticoids are still controversial. A randomized multicenter placebo-controlled and double-blind study showed that corticoids reduce the plasma levels of acute phase proteins (ESR and C reactive protein), but it does not reduce the risk of heart abnormalities, length of hospital stay, length of fever, and number of adverse events ⁷⁶.

Studies have recommended the use of corticoids to those cases in which patients have taken 2 doses of IVIG and there was no clinical response (Kawasaki refractory). The most widely used regimen is pulse therapy with methylprednisolone 30 mg/Kg/day infused for 2-3 hours once a day for 3 days.

Approximately 10% of the patients with KD do not respond to first dose infusion of IVIG, that is, there is persistence of fever and recurrence after 36 hours of the 1st infusion of IVIG. These patients are considered non-respondents to initial therapy and present higher risk of coronary abnormalities. In these cases, researchers recommend retreatment, that is, take the 2nd dose of IVIG 2g/Kg single dose (level of evidence C). ^77,78 Some centers have made the 3rd dose of IVIG but the clinical response is variable – fever may persist ⁷⁹.

There are no protocols directed to treating refractory KD. Other drugs have been used in such cases with favorable results, but all of them based on case reports or non-randomized and non-controlled studies. There are reports of treatment with plasmapheresis and effective clinical response to reduce incidence of coronary aneurysms 80. However, because of the ongoing risks, plasmapheresis is not frequently recommended (level of evidence C).

Immunosuppressants are also used, such as cyclophosphamide or cyclosporine associated with prednisone or methylprednisolone with improvement of fever, but without affecting heart abnormalities ^42,78,79. Cytotoxic agents present significant adverse effects and should be important in the cost-benefit ratio of a child with KD and heart affection. There are reports of use of methotrexate (10mg/ body surface 1x/ week) with clinical effectiveness – cessation of fever and no progression of dilation of coronary arteries ^81,82.

In Japan, Ulinastatin - which is a glycoprotein that inhibits the elastasis of neutrophils - was used in some cases of refractory KD, but some results need to be confirmed. Abciximab, inhibitor of platelet glycoprotein IIb/IIIa receptor, which has been used in patients in acute/ subacute phase with large aneurysm, showed good progression of diameter of aneurysm suggesting that the drug would promote vascular remodeling ^2,83. A new class of biological agents is being administered, among which there is infliximab (Remicade^®), a monoclonal antibody against alpha tumor necrosis factor (TNF-^α) with partial results in the few treated cases, leading to improvement of fever and aneurysms. However, there is need for controlled studies to assess and confirm these indications of use .^79,84

Treatment of subacute and convalescence phases of the patients with coronary aneurysms aim at preventing thrombosis (platelet activation) and vessel stenosis. Low dose aspirin (3-5mg/Kg/ Day) is the main therapy recommended in small children with small and medium aneurysms ^2,3,6,42. Other antiplatelet agents are also used (clopidogrel, ticlopidine, dipiridamole) and when associated with aspirin they have proved to be more effective in blocking platelet aggregation ^2,3,42.

Randomized studies are necessary to define the role of agents as low molecular weight heparin, warfarin and monoclonal antibodies against receptor IIb/ IIIa in managing children with giant aneurysms. The most common antithrombotic regimen for patients with giant aneurysms is low dose aspirin associated with warfarin to maintain INR (international normalized ratio) between 2.0 and 2.5 (level of evidence C).^2,85

CONCLUSION

Kawasaki disease is a systemic vasculitis with cutaneous manifestations through polymorphic exanthema and because of that, it should be part of the current knowledge of dermatologists as differential diagnosis of viral exanthema and scarlet fever. The likely consequence of vasculitis is to trigger the formation of coronary aneurysm with the inherited risk of obstruction and stenosis of these vessels and increase in morbidity and mortality. The main challenge of the physician is early diagnostic suspicion because onset of treatment with IVIG within the first ten days modifies the natural history of the disease.

REFERENCES

Conflict of interest: None

Financial funding: None

How to cite this article: Castro PA, Urbano LMF, Costa IMC. Doença de Kawasaki. An Bras Dermatol. 2009;84(4):317-31.

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Publication Dates

• Publication in this collection
  19 Oct 2009
• Date of issue
  Aug 2009