Kawasaki Disease and the Importance of Family History

Abstract

Background

Kawasaki disease (KD), a coronary artery vasculitis, is rare in teenagers who nonetheless have an increased risk of coronary artery aneurysms.

Case Summary

A 19-year-old woman had a prolonged febrile illness that resolved without treatment. The diagnosis of KD was made at autopsy at 42 years of age after sudden cardiac death associated with calcified giant coronary artery aneurysm. An interview of the decedent's mother revealed a KD-compatible illness in the decedent's son at 5 years of age that also was not diagnosed.

Discussion

Susceptibility to KD is influenced by host genetics, and first-degree relatives of an index case have a 10-fold increased relative risk of disease. Pathognomonic changes in the coronary arteries discovered at autopsy should prompt counseling of family members.

Take-Home Messages

KD should be considered in adolescents and young adults with prolonged unexplained fever and mucocutaneous findings, including rash, conjunctival injection, oral changes, and extremity edema and erythema, and transthoracic or transesophageal echocardiography should be performed to evaluate the coronary arteries. Clinicians evaluating a patient with suspected KD should obtain a history regarding family members with antecedent, unexplained, and prolonged febrile illness that might have been undiagnosed KD.

Visual Summary

Visual Summary.

Timeline of the Case

KD = Kawasaki disease.

History of Presentation

A 42-year-old woman presented to the emergency department with a history of untreated hypertension and new onset chest pain with exertion. The electrocardiogram was unremarkable, and she was discharged with reassurance. Exertional chest pain continued, and she was scheduled for a stress echocardiogram. The day before the testing, the woman's son found her unresponsive in bed. Emergency personnel pronounced her dead at the scene.

Take-Home Messages

• •KD should be considered in adolescents and young adults with prolonged unexplained fever and mucocutaneous findings, including rash, conjunctival injection, oral changes, and extremity edema and erythema, and transthoracic or transesophageal echocardiography should be performed to evaluate the coronary arteries.
• •Clinicians evaluating a patient with suspected KD should obtain a history regarding family members with antecedent, unexplained, and prolonged febrile illness that might have been undiagnosed KD.

At autopsy, calcified aneurysms, measuring approximately 10 mm in diameter, were found within the proximal left anterior descending and mid–right coronary arteries. There was >95% stenosis with associated calcification in these segments. There was approximately 50% calcific stenosis of the circumflex artery with no evidence of atherosclerosis. There was no acute thrombosis of the vessel lumens. Near-transmural white-tan fibrosis was noted along the posterior left ventricular wall and patchy fibrosis extended over the lateral left ventricular wall and interventricular septum. The aorta had mild atherosclerosis, greatest in the lower abdominal region.

Histologic sections of the myocardium showed widespread interstitial fibrosis and subacute fibrosis with cardiomyocyte dropout, residual pigmented macrophages, and scattered lymphocytes (Figure 1A). Acute infarction was demonstrated through contraction band necrosis with no associated inflammatory cell infiltrate. The calcified aneurysms in the coronary arteries had regions of chronic thrombosis and recanalization, disruption of the elastic laminae, and arterial wall fibrosis (Figures 1B and 1C). There was adventitial chronic inflammation and focal chronic inflammation within the aneurysmal wall. No atheromatous plaque was found in the coronary arteries.

Figure 1.

Histologic Findings

(A) Cardiomyocyte dropout, residual pigmented macrophages, and scattered lymphocytes were seen in the myocardium. The magnified photograph in the black square area showed pigmented macrophages. Bar = 1 mm, HE staining. (B) The thrombosed and recanalized (blue arrows) coronary artery with calcification (black arrow). Bar = 1 mm, HE. (C) Elastica van Gieson staining showed disruption of elastic laminae and arterial wall fibrosis. Bar = 2.5 mm. HE = Hematoxylin-eosin; KD = Kawasaki disease.

Past Medical History

Medical records were not available for review, but the history was obtained from the decedent's mother. The decedent was hospitalized at 19 years of age for a prolonged febrile illness associated with rash, with no final diagnosis despite extensive testing. The fever and rash eventually subsided, and she was discharged after 2 weeks without any specific treatment or diagnosis. The decedent's mother also shared that the decedent's son had experienced a similar illness at 5 years of age, which prompted further investigation.

Investigations

Informed consent was obtained for the review of the medical records of the decedent's son and for the release of the decedent's tissues from the Medical Examiner's office. On day 2 of illness, he presented to urgent care with fever, unilateral neck pain, and swelling, and was diagnosed with lymphadenitis. A blood culture was drawn, and he received a dose of ceftriaxone. Fever and unilateral cervical lymph node enlargement persisted, and he developed an erythematous maculopapular rash and erythema of the palms and soles. The blood culture grew methicillin-sensitive Staphylococcus aureus, and he was admitted for intravenous antibiotics. The patient was started on vancomycin and remained febrile through day 5 of illness with worsening tachycardia and hypotension. Because of concerns for septic shock, the patient was transferred to the pediatric intensive care unit at another hospital. Physical examination on transfer revealed bilateral conjunctival injection; red, cracked, and bleeding lips; and a unilateral cervical lymph node mass. Laboratory values showed marked inflammation and elevated hepatobiliary enzymes (Table 1). A computed tomography (CT) scan revealed multiple nodes with no evidence of suppuration or fluid collection. An echocardiogram was performed to rule out endocarditis, which showed a left ventricular ejection fraction of 58% and a dilated proximal right coronary artery with a z-score (internal diameter normalized for body surface area) of 2.3. The left coronary artery system appeared normal. There were a small pericardial effusion and mild mitral and tricuspid valve insufficiency. No vegetations were appreciated. Repeat blood cultures revealed no pathogens. His fever curve gradually improved, and he was discharged on the 14th day of illness. The consensus of the infectious disease team was that the patient had experienced septic shock secondary to methicillin-sensitive S. aureus bacteremia although no focus was ever determined.

Table 1.

Baseline Laboratory Findings Upon Transfer to Intensive Care Unit for the Son at Age 5 y With Kawasaki Disease

Parameter	Value
White blood cell count	5.1 × 103 mL
Neutrophils	45%
Band neutrophils	36%
Monocytes	14%
Eosinophils	5%
Hemoglobin	8.4 g/dL
Hematocrit	26.3%
Platelet count	1.28 × 105
C-reactive protein	19.5 mg/dL
Erythrocyte sedimentation rate	75 mm/h
Albumin	2.8 g/dL
Alanine aminotransferase	140 U/L
Gamma-glutamyl transferase	128 U/L

After review of the mother's autopsy report, the family was contacted and a repeat echocardiogram of the son at 8 years of age showed a normal left ventricular ejection fraction of 69% and all coronary artery z-scores to be within 2 standard deviations of the mean.

Differential Diagnosis

After reviewing the gross anatomic and histologic findings, the decedent's febrile illness at 19 years of age was determined to be Kawasaki disease (KD), and her death was attributed to chronic and acute ischemia from the vasculitis. The retrospective diagnosis of KD for the decedent's son was supported by laboratory and clinical criteria that met the American Heart Association criteria for complete KD.¹

Outcome and Follow-Up

As the repeat echocardiogram for the decedent's son showed normal coronary artery internal dimensions, no further procedures were recommended. Genetic counseling was provided to the patient and the family to help explain the illness in both the mother and the son.

Discussion

These 2 cases present a series of diagnostic challenges. KD was not considered in the differential diagnosis of the mother when she presented at age 19 years with a prolonged febrile illness associated with mucocutaneous features consistent with the clinical case definition of KD. Similarly, a diagnosis of KD was not given to the son, whose management was dictated by a single blood culture that was likely a skin contaminant. If KD had been correctly diagnosed in the son and an appropriate family history had been obtained, the diagnosis of KD in the mother could have been suspected. The appropriate testing for the mother in that scenario would have been a CT coronary artery calcium score. An elevated score in a young adult without major risk factors for atherosclerosis would have prompted a CT angiogram, and the aneurysms would have been discovered. Thus, taking a family history could have saved a life.

In a review of KD epidemiology in the United States using the National Kids Inpatient Database for the years 2009 and 2012, only 1% of the 10,486 cases of KD were aged 16 to 18 years. However, the highest rate of coronary artery aneurysm (CAA) (8.6%) in these patients with treated KD occurred in this older age group.² Unfortunately, the diagnosis of KD was not considered in the 19-year-old woman presented here. In addition, her ischemic symptoms were not taken seriously when she presented with that chief complaint at 42 years of age. Untreated KD may remain clinically silent for years until progressive remodeling of the arterial lesions results in ischemic symptoms or sudden, unexpected death. In a multicenter study of adults aged <40 years evaluated by cardiac catheterization for suspected myocardial ischemia, 5% had lesions consistent with sequelae of KD.³ These findings demonstrate that CAA secondary to KD may go unrecognized until ischemic symptoms present later in life.

The discovery of KD in the mother prompted a retrospective re-evaluation of her son's illness. Susceptibility to KD is influenced by a complex genetic pattern that may be passed from parent to child.⁴ In the Japanese nationwide survey reporting the epidemiology of KD during 2017 and 2018, 1.3% of the 32,528 cases had a parent with a history of KD.⁵ Although inheritance patterns are complex and incompletely defined, these findings support a heritable predisposition and the value of obtaining a family history in guiding evaluation in cases of suspected KD. Currently, there is no genetic testing available for KD. Patients with a personal history of KD should be counseled regarding the risk of transmission of the complex genetic pattern to offspring.

In this case, postmortem examination was essential for linking remote KD as the primary cause of fatal coronary pathology. Shimizu et al⁶ reported 2 of 154 (1.3%) medical examiner cases aged <35 years whose death was attributable to coronary sequelae of antecedent KD diagnosed only at autopsy. Characteristic histopathologic features included CAA with calcification, thrombosis, and recanalization, as well as luminal myofibroblast proliferation.

Conclusions

KD, although rare in adolescents and young adults, should remain in the differential diagnosis of prolonged fever with mucocutaneous features and a negative evaluation for infectious diseases. When a child is diagnosed with KD, clinicians should inquire about family members with similar unexplained illnesses. Had the child been correctly diagnosed with KD and an appropriate history obtained from the mother, her death could potentially have been prevented with appropriate medical management.⁷

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.