What is Kawasaki disease
Kawasaki disease (KAD) is a systemic vascular disease that typically affects medium and small vessels. KAD is typically self-limiting and the highest incidence is seen in children less than 5 years of age. KAD is currently recognized as a systemic vasculitis with a particular preference for coronary arteries and, in Western countries, is the most frequent cause of heart disease in children. The etiopathogenesis of KAD is not entirely clear although recent research has focused on the causes and treatment strategies.
The KAD was first defined by Kawasaki in Japan in 1967 but has since been documented in several geographic areas; there are, however, distinct manifestations between the different regions. Inhabitants of Asian descent have the highest incidence of KAD. Makino et al. found that the incidence of KAD continues to rise in Japan; in this country the incidence rate was 243 per 100,000 inhabitants aged 0-4 in 2011, increased to 265 in 2012. The cumulative incidence of KAD in Japan is 1.5 / 100 boys and 1.2 / 100 10-year-old girls. Unlike other rheumatic disorders, there is evidence from several studies that KAD affects more boys than girls. In Northeast Asian countries, such as Korea and Japan, the reported incidence of KAD is much higher than that of western countries with a growing trend, while in Australia, USA and Europe the previously recorded growth in incidence of KAD seems to have plateaus.
KAD is hypothesized to occur in genetically predisposed individuals who are exposed to an as yet unidentified, possibly infectious, trigger. The concept of an underlying genetic predisposition to KAD is based on two key observations. First, there is an increased risk of KD in patients who have a first degree relative with a history of KAD. Similarly, parents of a child with KAD are twice as likely to have a history of KAD than the general population. Second, KAD has a significantly higher incidence in some ethnic groups, which persists even after their transfer to other regions of the world. This is exemplified by the case of Hawaii, where the incidence of KAD in those of Japanese descent was 210 cases per 100,000 children in the period 1996-2006. This is comparable to the incidence observed in Japan and contrasts markedly with the incidence reported in white children in Hawaii during the same time period – 13.7 cases per 100,000 children – which is similar to the incidence rate among white children in the innerside of United States.
The infectious trigger concept is supported by KAD symptomatology resembling common childhood infections, region-specific incidence rates, seasonality, occurrence of outbreaks, and low incidence of recurrence. A study that analyzed KAD in 25 countries for more than 40 years found a statistically significant and consistent seasonal fluctuation in KAD case numbers with higher numbers observed in winter in the extra-tropics of the Northern Hemisphere, suggesting seasonal exposure. to a (possibly infectious) environment agent. The fact that 80% of KAD occurs in individuals less than five years of age may be due to the immature immune system failing to protect itself from this agent. Rowley et al published a series of articles that revealed the presence of IgA plasma cells and an oligoclonal IgA response in the arterial tissues of patients with KAD, suggesting an antigen-driven response driven by the entry of a pathogen into a mucosal respiratory trait.
Although an association between KAD and environmental and genetic factors has been shown, the exact etiology of this condition is still unclear. The seasonal cluster is evident among different ethnic groups, such as the summer / spring peak in China and the winter / spring peak in Japan. Seasonal variation can be caused by various infectious agents. Recent studies have hypothesized that tropospheric wind patterns and air pollution may trigger immunopathological pathways in children genetically susceptible to variable agents. Additionally, the current coronavirus 2 (SARS-CoV-2) infection has been reported to trigger KAD although evidence is still scant. Observation of an increased incidence among Japanese descendants residing outside of Japan and better incidence of a history of KAD among the parents of a KAD patient suggest a genetic component in KAD. Genomic Association Studies (GWAS) have also tried to explain the molecular alteration in KAD.
The immune response
Despite decades of research, the underlying immune-pathogenic mechanism for KAD is not fully understood. The proposed paradigm is an exaggerated immune response (both innate and adaptive systems) observed in genetically susceptible individuals following an encounter with an infectious agent leading to an imbalance between pro-inflammatory and anti-inflammatory pathways. For example, the IL-1 signaling pathway appears to be the key to the pathogenesis of KAD; upregulated IL-1 pathway genes and increased IL-1 concentrations have been demonstrated in the peripheral blood of patients with KAD during the acute phase of the disease. It was also found that TNF-alpha is significantly increased in peripheral blood monocytes in KAD patients compared to healthy controls.
The self-limiting nature of the disease and the low recurrence rate suggest memory emergence of T and B lymphocytes which is protective. Farh et al. proposed the role of B lymphocytes in the pathogenesis of KAD. Decreased messenger RNA expression from the common risk haplotype of BLK and increased expression of the whole, membrane-bound isoform of CD40 on B lymphocytes may result in increased B cell activity. Understanding the exact underlying mechanism it is critical as this informs potential therapeutic targets, for example, anakinra (an IL-1 receptor antagonist) and anti-TNF-alpha agents.
Typically, patients with KAD have fever ranging from 38 ° C to 40 ° C and often without prodromal symptoms such as runny nose, coughing and sneezing. Bilateral conjunctival injection without exudate appears within 2-4 days of the onset of the disease. Changes in the oral cavity are typically defined by lip bleeding, redness, cracking and dryness, strawberry-like tongue without blisters or pseudo-membrane formation, canker sores or ulcerations, and diffuse erythema of the oropharyngeal mucosa. Polymorphic erythema develops on the body and / or extremities, from the first to the fifth day after the onset of fever. Several types of rash have been described: a morbilliform maculopapular rash, an urticarial rash with large erythematous plaques, or, less frequently, an erythema multiforme with central clearing or iris lesions. After a week of starting, a diffuse erythema develops on the palms and soles of the hands and feet. Cervical lymphadenopathy was reported in nearly half of KAD patients in the United States and 70% in Japan, while other major symptoms were described in> 90% of patients. Lymphadenopathies are generally unilateral and 2-5 cm in diameter.
In patients with KAD, the main symptoms for diagnosis are persistent fever associated with polymorphic exanthema, lip and oral changes, cervical lymphadenopathy, non-purulent conjunctival injection, and extremity changes such as redness and swelling of the palms and desquamation during the subacute phase. According to American Heart Association (AHA) guidelines, “complete” KAD is described as persistent fever ≥5 days and at least 4 other symptoms. It is essential to understand that clinical manifestations can occur sequentially or simultaneously. These guidelines emphasized the importance of coronary artery imaging. The AHA has produced a process for making the diagnosis of “incomplete” KAD if three or fewer diagnostic criteria are present.
Echocardiography is the cornerstone of cardiac imaging during the acute phase. When abnormal, it is a useful adjunct to aid diagnosis if not all clinical features are present, or to aid early diagnosis if the fever has not yet lasted 5 days. It can be replaced by a criterion for making a diagnosis of complete KAD. However, where echocardiography is normal in the first week of illness, this does not preclude the subsequent development of coronary aneurysms and should therefore be repeated at intervals of 1-2 weeks and 4-6 weeks after initial treatment, or more frequently in patients at high risk for coronary aneurysms or if they are present in the baseline study. Coronary artery abnormalities occur in 15–25% of untreated patients and a significant percentage of these will have additional cardiovascular manifestations including pericarditis, myocarditis, pericardial effusion, electrocardiographic abnormalities and / or even myocardial infarction. Valvular dysfunction occurs in about a quarter of children with KAD and most commonly involves the mitral valve.
There are no specific laboratory tests available to diagnose KAD and the diagnosis is based only on clinical observation and symptoms. Recent studies have proposed inflammatory, proteomic and genetic biomarkers that may be useful in the diagnosis and management of KAD. Parthasarathy et al. in their review, they analyzed biomarkers that can be used to uncover the gold standard test for diagnosing KAD. The results suggest that NT-proBNP is currently a very favorable biomarker for future investigations; However, further studies are needed to find specific tests that allow for an early and accurate diagnosis of KAD.
Available medical therapies
The gold standard for the treatment of KAD is a high dose of 2g / kg of intravenous immunoglobulin (IVIG), administered over 8-12 hours. The aim of therapy is to inhibit the progress of coronary artery abnormalities. The efficacy of IVIG is likely due to the activation of an immature myeloid population of dendritic cells producing IL-10, the modulation of regulatory T cells, and the decrease in cytokine production. Early treatment with IVIG can considerably reduce the occurrence of coronary artery abnormalities. In addition to IVIG, the AHA recommends high-dose aspirin, although confirmation for further reduction in the risk of coronary artery aneurysms is lacking. Most patients respond quickly to IVIG. The Kobayashi score is the most popular scoring system for predicting patients resistant to IVIG, while this score has not proved useful in Western ethnicities.
Corticosteroids can be used as a second-line treatment alone or in combination with a second dose of IVIG. A recent meta-analysis concluded that steroids were more effective than IVIG in reducing fever but that there was no significant difference in the risk of coronary aneurysm formation. Serum TNF-alpha increases in KAD patients and higher serum levels have been shown to correlate with the development of cardiac complications. Infliximab is a chimeric mouse / human IgG1 monoclonal antibody that specifically binds to TNF-alpha with high affinity. It was evaluated as an adjunct to IVIG therapy in a randomized, double-blind, placebo-controlled Phase III study; it did not reduce resistance to treatment but did reduce the duration of the fever. In studies comparing rescue infliximab with a second dose of IVIG in patients resistant to IVIG, infliximab reduced fever duration, but the groups had similar coronary outcomes.
The disadvantage of etanercept, another TNF-alpha antagonist, is that it only binds to circulating and non-cell bound TNF-alpha, which could potentially compromise its efficacy. An open-label prospective study demonstrated its safety as an adjunct to standard therapy. Fifteen patients completed the study and none demonstrated resistance to IVIG therapy. The NFAT-calcineurin immune pathway is implicated in the pathogenesis of KAD. Therefore, cyclosporine, a calcineurin inhibitor, has been studied as both an adjunct therapy and a rescue therapy for KAD. A retrospective case series reported defervescence and resolution of inflammation in all 9 patients treated with cyclosporine following failure of multiple other therapies.
Statins lower low-density lipoprotein cholesterol, improve endothelial function, reduce oxidative stress, and inhibit inflammation. Several observations have led to an interest in atorvastatin as a potential adjunct therapy to inhibit the progression of aneurysms in KAD. Genetic studies have demonstrated an association between polymorphisms in matrix metalloproteinase (MMP) genes and both KAD susceptibility and aneurysm formation. In a mouse model, atorvastatin inhibited the secretion of MMP-9 in the blood vessel wall. It has also been shown to attenuate MMP-9 gene expression in vitro in human endothelial cells. Cyclophosphamide, methotrexate, and plasmapheresis have also been used in treatment-resistant KAD cases. Cyclophosphamide carries a high risk toxicity and therefore should only be considered in severe refractory cases.
According to AHA guidelines, high-dose pulse steroids, infliximab, cyclosporine, and anakinra should be considered in patients who have not responded to standard therapy. Several studies have looked at the results after KAD. Baker et al. studied 110 KAD children and reported that the general physical and psychosocial health characteristics of KAD patients without coronary artery aneurysms were similar to the general population. Only cases with giant coronary artery abnormalities had a lower physical score. However, the parents claimed a lower perception of health. King et al. studied 38 KAD patients and found deficits in attentional behavior and internalization, but did not describe significant differences in academic performance and cognitive development. However, self-assessment of older KAD children showed no differences with controls.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Biochemistry.
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