Autoptic Findings in Cases of Sudden Death Due to Kawasaki Disease

Kawasaki disease (KD) is the second-most-common childhood vasculitis, and its etiology is still unknown today. Even though the acute illness is usually self-limiting, sometimes, it can generate complications, such as coronary artery aneurysms (CAA), acute myocardial infarction (AMI), heart failure, or arrhythmias, and can rarely cause sudden or unexpected deaths. We present a review of the literature, which collects autoptic and histopathological data relating to many of the cases of these deaths. On the basis of the titles and abstracts, we selected 54 scientific publications for a total of 117 cases. Among them, as expected, the majority of the deaths were due to AMI (41.03%), arrhythmia (8.55%), acute coronary syndrome (8.55%), and CAA rupture (11.97%), involving mostly 20-year-olds or younger individuls (69.23%). This is not surprising since the CAs are the most involved arteries. Gross autoptic and histopathological findings are reported in the paper. Our work revealed that, when compared with the incidence of KD, only a few cases suffered from sudden death, underwent an autoptic examination, and were then described in the literature. We suggest that researchers should perform autopsies to gain a better understanding of the molecular pathways involved in KD so as to propose further innovative therapeutic protocols or implement more appropriate prevention schemes.


Introduction
Kawasaki disease (KD), or mucocutaneous lymph node syndrome, is an acute, selflimited vasculitis of medium-sized vessels, affecting mainly the coronary arteries. It mostly occurs during childhood [1,2]. and it is the second-most-common childhood vasculitis. As a matter of fact, it is second only to immunoglobulin A (IgA) vasculitis (Henoch-Schönlein purpura) [3]. It was discovered by Dr. Tomisaku Kawasaki, who studied the first case in 1961: A 4-year-old boy unusually presenting with rash and fever. In 1967, he published his first study, conducted on 50 similar cases, which brought him to a definition of this pathology. His study was first published in Japanese [4] and subsequently translated into English in 1974 [5].
Although many years have passed since Dr. Kawasaki's first study, the KD etiology is still unknown today, but several theories have been proposed [6]. The hypothesis that it is caused by a transmissible agent (e.g., Parvovirus B19 [7], Propionibacterium [8], Human Bocavirus [9]) is the most debated. As a matter of fact, it has been proposed

Materials and Methods
The present systematic review was carried out according to the Preferred Reporting Items for Systematic Review (PRISMA) standards [25]. A systematic literature search and critical review of the collected studies were conducted. An electronic search of PubMed, Science Direct Scopus, Google Scholar, and Excerpta Medica Database (EMBASE) was performed from database inception until February 2023. The search terms were "Kawasaki disease + sudden death", "Kawasaki disease + fatal", "Kawasaki disease + sudden cardiac death", "Kawasaki disease + sudden infant death", "Kawasaki disease + unexpected death", "Kawasaki disease + autopsy", "mucocutaneous lymph node syndrome + sudden death", "mucocutaneous lymph node syndrome + fatal", "mucocutaneous lymph node syndrome + sudden cardiac death", "mucocutaneous lymph node syndrome + sudden infant death", "mucocutaneous lymph node syndrome + unexpected death", and "mucocutaneous lymph node syndrome + autopsy", and these terms were searched in the titles, abstracts, and keywords. The bibliographies of all located papers were examined and cross-referenced to further identify relevant literature. A methodological appraisal of each study was conducted according to the PRISMA standards, including an evaluation of bias. The data collection process included study selection and data extraction. The following inclusion criteria were used: (1) original research articles, (2) reviews and mini-reviews, (3) case reports or case series, (4) only papers written in English, (5) only cases of sudden or unexpected death related to KD, (6) cases where the cause of death was certainly attributable to KD, and (7) only cases affected by primary KD. Non-English papers, papers regarding cases of survived patients, papers in which the cause of death was not directly attributable to KD, papers in which the subject had secondary KD, and papers presenting cases where death occurred after a long hospital stay (>3 days) following the acute event were excluded. The latter were excluded, because the purpose of the review is to highlight the main anatomical and histopathological findings on sudden or unexpected deaths due to Kawasaki. A long hospital stay was therefore considered a possible source of bias in data interpretation. Two researchers (G.V. and F.S.) independently examined the papers with titles or abstracts that appeared to be relevant and selected those that analyzed sudden or unexpected deaths due to KD. Disagreements concerning eligibility among the researchers were resolved by consensus. Preprint articles were included. Data extraction was performed by two investigators (A.C.M. and A.M.) and verified by other investigators (G.V., F.S. and F.D.D.). This study was exempt from institutional review board approval, as it did not involve human subjects.

Results
The search identified 216 articles, which were screened to exclude duplicates. The resulting 152 references were then screened based on the titles and abstracts of the articles. This procedure left 88 articles for further consideration. These publications were carefully evaluated, considering the main aims of the review. This evaluation left 54 scientific papers comprising original research articles, case reports, and case series. Figure 1 illustrates our search strategy. We found a total of 117 cases of sudden or unexpected death related to KD in the literature. In Table 1, brief descriptions of the studies included in this review are reported. Hospitalized for fever and cervical lymphadenopathy. During the hospital stay, the patient developed heart failure and suddenly died.
Heart: fibrinous exudate in the pericardial sac. Dilated and thrombosed CAAs (located in the LCA, LAD, and RCA).
Heart: CAAs showed focal thinning and necrosis of the walls and thrombi in the lumen. CAs had focal acute vasculitis, chronic inflammation with destruction of the media, and fresh proliferating tissue. Focal eosinophilia and a few areas of frank necrosis with neutrophils in the myocardium. Heart: fibrosis at the posterior and lateral walls of the LV. Dilative hypertrophy of the RV, Weight of the heart: 340 g. Coronary arteries: LCA aneurysm with total occlusion, RCA aneurysm.

ACF
Heart: myocardial fibrosis. AMI  Autoptic and histopathological findings were reported for 67 and 72 cases, respectively. As shown in Table 2, which summarizes the main characteristics of the cases included in this review, there were 86 males (73.50%), 20 females (17.09%), and for 11 people, gender was not specified (9.40%). The age of the subjects was specified in only 102 out of the 117 cases. Among them, the most affected age group was the <20-year-old population (69.23%). Out of these, 28 subjects (23.93%) were <5 years old, 26 (22.22%) were 6-12 years old, and 27 (23.08%) were 13-20 years old. Age was not available in 15 cases (12.82%). A total of 80 subjects had an in-life diagnosis. Among them, 37 were treated (31.63%), 7 were not treated (5.98%), and no treatment data were available for 36 of them (30.77%). Thirty-seven cases had a postmortem diagnosis (31.62%).
As shown in Table 3, there were 48 deaths due to AMI (41.03%), 7 deaths due to acute cardiac failure (ACF) (5.98%), 2 deaths due to pericarditis (1.71%), 2 deaths due to pancarditis (1.71%), 6 deaths due to myocarditis (5.13%), 10 deaths due to arrhythmia (8.55%), 10 deaths due to acute coronary syndrome (8.55 %), 14 deaths due to CAA rupture (11.97 %), 1 death due to cardiac tamponade (0.85%), 1 death due to acute encephalitis (0.85%), 1 death due to cerebral hemorrhage (0.85%), 1 death due to cerebral hypoxia (0.85%), and 14 deaths with undefined causes (11.97%). A pie chart on the causes of death is presented in Figure 2.  As previously stated, autopsy investigations and histological examinations were reported for 67 and 72 cases, respectively. In Table 4, a summary of the main gross findings is shown. Among the most frequent findings, out of 65 cardiac death cases, 19 presented with an enlarged heart, 21 had signs of myocardial fibrosis, and 18 had coronary stenosis. Moreover, CAAs affected 46 people, and CAA rupture was reported in 14 cases.  Among the most frequent microscopic findings, out of 72 cardiac death cases, AMI was reported in 17 cases, myocardial fibrosis was reported in 17 cases, coronary artery stenosis was reported in 16 cases, coronary artery thrombosis was reported in 19 cases, coronary artery wall inflammatory infiltrates were reported in 26 cases, and CAA thrombosis was reported in 17 cases. In Table 5, a summary of the main microscopic findings is reported.

Discussion
Our review identified 117 cases of sudden death from KD in the literature. Unfortunately, only some of them have been completely described (67 and 72 with autoptic and histopathological reports, respectively). The first article about KD dates back to 1967, with the report of an acute febrile mucocutaneous syndrome with lymph node enlargement and cutaneous manifestations [4,80]. In almost 60 years, a lot has been discovered about this peculiar disease, and significant progress has been made in terms of diagnosis, prevention, treatment, and follow up of the disease. Indeed, only a few autoptic reports are present in recent literature, also due to the fact that the pathology is, to date, rarely fatal. Nowadays, it is well-known that autopsy is a fundamental tool to understand the physiopathology of diseases better and deeply [81]. As a matter of fact, autoptic data have been fundamental to provide essential information about the molecular pathways of pathological features, allowing targeted therapies and specific diagnostic protocols [82].
The present systematic review revealed that, when compared with the incidence of KD [83,84], only a few cases suffered from sudden death, underwent an autoptic examination, and were then described in the literature, mainly through case reports or series. Ayusawa et al. described cases of sudden death among students between 1990 and 1999 and then between 2000 and 2009, in Japan [79]. Their research is very interesting, because it is one of the largest case series. The authors did not provide any autoptic data, meaning that these findings are still not considered to be fundamental for understanding a disease. However, their studies seem to show a reduction in sudden death cases of about 50% for all new diagnoses of KD and a reduction of approximately 80% in patients also affected by CAA. This may be due to the increased knowledge about KD, which allows earlier diagnosis and better in-life treatment. Suda et al. stated that the introduction of anticoagulant therapy, particularly warfarin, helps to reduce the incidence of myocardial infarction [85].
Two decades after its discovery, KD surpassed rheumatic fever as the most common cause of acquired heart disease in children in Asia [86]. As a matter of fact, we identified 81 cases of death due to KD among people aged younger than 20 years, which represents 69.23% of all identified cases, and most of these cases involved Asian subjects.
Furthermore, an aspect of non-negligible importance is the psychological impact that the disease has on these young subjects. As reported by Shain B.N., adolescents living with chronic disease have a greater risk of suicide attempts [87]. King et al. showed that kids affected by KD are more likely to present with social problems and experience anxiousdepressed behavior and attention difficulties compared with their healthy siblings [88].
Further studies [89,90] support the findings about the negative impact of KD on behavior. Alves et al. showed that 20% of these patients experience frequent irritability, aggressiveness, attention deficit, learning deficit, and antisocial behaviour [90]. A central nervous system pathology related to cerebral vasculopathy has been taken into consideration to explain a possible physiopathology of the problem [89].
Kato et al. studied the natural course of coronary lesions in KD patients, suggesting that the cause of intimal proliferation and obstruction could be vascular remodeling [91].
Burns et al. and Sasaguri and Kato, in their morphologic postmortem studies related to the acute phase of the disease, showed that intimal obstruction is caused by chronic and persisting activity of inflammatory infiltrates on the endothelium and artery wall. Such inflammatory activity, associated with remodeling activity, results in aneurysm, thrombosis, or intimal proliferation, similar to atherosclerotic coronary disease [92,93]. Nakamura et al. followed up 6576 patients with KD after their first medical examination. At the end of the observational study, both deceased patients and still-alive patients were taken into consideration for the data analysis. The study found out that the mortality rate did not increase significantly after the acute phase of the disease [94].
In this paragraph, we present a detailed overview of the main molecular mechanisms involved in the pathology. In its acute phase, KD is characterized by abnormal activation of immunocompetent cells such as monocytes/macrophages and lymphocytes, leading to the secretion of inflammatory cytokines and chemokines, such as tumor necrosis factor α (TNFα), interferon-γ (IFN-γ), interleukins (e.g., IL-6), and monocyte chemoattractant protein (MCP)-1. These molecules activate immune cell interactions and the endothelial cells, causing, on the surface of the latter, the expression of adhesion molecules. As a result, the leucocytes adhere firmly to them and, eventually, migrate through the vascular walls. A vasculitis process hence begins, and endothelial cells and smooth muscle cells are damaged. Additionally, various vasoactive substances, including growth factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), as well as endothelin and nitric oxide, are produced, allowing the induction of migration and the proliferation of intimal smooth muscle cells. Moreover, these substances lead to an increase in vascular permeability, causing coronary artery dilation [6].
The histological findings collected through this review corroborate this interpretation, showing that the arterial wall is involved in chronic and persistent inflammatory activity. As a matter of fact, while limited by a small number of cases, our data show CA wall inflammatory infiltrates and various degree of perivascular myocardial inflammation in most cases, as well as systemic vessel inflammatory infiltrates. Inflammation is mainly supported by lymphocytes and granulation tissue.
Tsuda et al. showed that the left coronary artery is the most affected and that the aneurysm size is one of the major predictive factors for the development of myocardial infarction [95].
As expected, the most common cause of death, in the cases reported in this review, involved the heart, presenting as sudden or unexpected cardiac death. This is not surprising, since the CAs are the most involved arteries [96,97].
Early sudden cardiac death may end a clinically silent course of disease or deteriorate a symptomatic clinical spectrum, such as AMI, arrhythmia, or heart failure [98]. Although sudden death mainly affects children and adolescents, it can also occur 10 to 20 years after diagnosis, making KD unsafe at any age [99].
The chronic evolution of CAA caused by KD may develop in two ways: it may either resolve through intimal thickening or progress to lumen enlargement without remodelling, leading to acute thrombosis at a later stage [35,53]. CAA rupture is considered to be an exceptional complication of KD [58].
Some authors found that treatment with IVIG combined with acetylsalicylic acid (ASA) is an effective strategy to prevent CA lesions [100,101].
Newburger et al. recalled that some clinical trials performed in the 1980s showed a possible reduction in CAA formation from 25% to 5%, thanks to the use of high doses of IVIG and ASA, if administered within the first 10 days after fever onset [102]. The efficacy of high-dose IVIG treatment for acute-stage KD has become widely recognized [103], and today it is administered to 85% of children with acute-stage KD [6]. Simultaneously, IVIG therapy has led to a decrease in the mortality rate from KD by reducing the formation of lesions that affect the CA [6].
However, it should be reported that, although IVIG infusion is an effective treatment for KD, some patients (4%) still develop CAAs [104].
Our review shows that only 31.62% of sudden deaths (37 cases) did not have an ante-mortem diagnosis. This means that in the remaining 68.38% (80 cases), the diagnosis was performed during life. Among them, seven patients (5.98%) were not under treatment for KD. Unfortunately, we do not know if patients received treatment in 36 cases (30.77%). This lack of information in the papers included in this review does not allow us to further discuss the correlation between the incidence of sudden death and in-life treatment or the possibility that a proper therapy program could significantly prevent sudden death in such patients.
Another aspect that needs to be highlighted is that most of the cases of sudden death reported in the literature were males. Indeed, 73.50% of the cases included in this review were males. This is in accordance with previous research, which showed that KD is more common in boys, with a male:female ratio of about 1.6:1 [105,106]. Furthermore, according to Nakamura et al., males suffering from cardiac complications caused by KD experience a higher mortality rate in comparison to the general population, whereas the mortality rates for females with complications and for both males and females without complications were not increased [94].
The present study is limited by the small number of included cases, which did not allow for a relevant statistical analysis. In particular, it was not possible to compare differences by country or ethnicity. Moreover, there is no uniformity among papers concerning the demographic information provided, and this is another limit of the current study. The scarcity of sudden or unexpected death cases in KD patients, despite its significance as a public health issue, particularly among young people, may be attributed to the perception that an autopsy is unnecessary when the diagnosis has already been established. However, we suggest that researchers should also perform autopsies when an in-life diagnosis is present in order to share their important findings. Postmortem investigations could provide precise information about the molecular mechanisms causing the alterations of the vascular walls and the specific pathophysiology that causes death in those patients. Additionally, conducting autoptic investigations could significantly improve the understanding of both the molecular mechanisms behind the disease as well as the effectiveness of the various treatment options. Thankfully, as mentioned earlier, the number of deaths related to KD has decreased in the past several decades. As a result, it would be beneficial to thoroughly investigate any rare case of fatality in order to apply new histopathological investigation techniques and other diagnostic examinations such as the post-mortem computed tomography [107].

Conclusions
KD mostly occurs during childhood and is the second-most-common childhood vasculitis. Even though the acute illness is usually self-limiting, it can sometimes generate severe complications, such as CAA, AMI, heart failure, arrhythmias, and hemodynamic instability. These complications can be life threatening and can sometimes lead to sudden death. The advent of IVIG therapy brought a consistent decrease in KD complications and, consequently, the mortality rate.
Despite a high incidence of KD in society, particularly in Asian societies, the scientific papers reviewed in this study indicate that there is not a significant number of documented cases of sudden death resulting from KD in the literature. Moreover, the present systematic review reveals that only a few cases underwent an autoptic examination. However, from our findings it is evident that cardiac involvement was present in almost all cases and that most sudden or unexpected deaths were attributable to AMI, acute coronary syndrome, arrhythmia, or CAA rupture. Little histopathological data are reported in the literature on this topic, but our results underline that the arterial wall is involved in chronic and persisting inflammatory activity in almost all the cases.
Although the number of cases examined was limited, this study aimed to encourage further research on postmortem investigations. As a matter of fact, only through this type of research can more detailed and precise information be obtained to better understand and investigate the molecular pathways that cause alterations in the main vascular walls. The ultimate goals of this new knowledge could include the development of innovative therapeutic protocols and the implementation of more appropriate prevention schemes.

Data Availability Statement:
No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest:
The authors declare no conflict of interest.