Introduction

Kawasaki disease is the most common childhood vasculitis affecting the medium-sized arteries. The estimated incidence is 25 per 100,000 in North America [1]. Intravenous immunoglobulin (IVIG) and aspirin remain the mainstay of treatment, as prompt administration has decreased the incidence of the development of coronary artery aneurysms [1, 2]. However, patients unresponsive to IVIG are at higher risk of developing coronary artery aneurysms.

The second-line treatment for these patients has been studied, yet the optimal treatment has not been determined. Here, we describe a young infant with acute Kawasaki who developed large coronary aneurysms despite initial defervescence after treatment [3].

Case report

A two-month-old male infant presented to the local hospital with a two-day history of pyrexia up to 40°C, a concurrent mild diarrheal illness, and slightly decreased feeding. He had received the first dose of the routine childhood immunization of the hexavalent vaccine twenty-four hours prior to the symptoms. There was no history of viral infection.

He was born at 37 + 2 weeks of gestation with an elective cesarean secondary to a previous cesarean with a birth weight of 2,820 g. He is the third child of non-consanguineal healthy parents. Prior to the admission, he had been gaining weight appropriately.

His present weight was 5,200 g, height 54 cm, and head circumference 40 cm.

On examination, he was pyrexial with a fever of 38°C. On inspection, he had a blanching maculopapular rash, with a heart rate of 100 bpm, and blood pressure of 100/57 mmHg. The chest was clear with normal vesicular sounds, and the heart sounds were normal. The femoral arteries were palpable.

A few hours after admission, he had a new onset of pyrexia up to 39.5°C and a pulsating fontanelle. A lumbar puncture was undertaken, showing leucocytes 10/μL, RBC 4,800/μL, glucose 87 mg/dL, protein 50.6 mg/dL, negative culture, and antibiotic treatment was commenced with cefotaxime.

An extended nasopharyngeal viral panel, including SARS-CoV-2, was negative. More, cerebrospinal fluid PCR was negative for extended viral panel as well as bacterial Neisseria meningitides, Streptococcus pneumonia, Hemophilus influenzae type b, and Listeria monocytogenes.

However, two days later, four days after the onset of the fever, the patient developed strawberry tongue, cheilitis, and widespread maculopapular blanching rash over the limbs and torso. An initial echocardiogram was normal, but an abdominal echo showed edema surrounding the gallbladder. A diagnosis of incomplete Kawasaki was made. The patient was treated with IVIG 2 g/kg and high-dose aspirin 80 mg/kg/day. The fever subsided after 72 hours; however, he did develop peripheral and scrotal edema, which resolved.

Despite being afebrile, two days after the initial fever resolution, on the ninth day of illness, a new onset of fever was noted up to 38.2°C, so oral prednisolone was commenced at a dose of 2 mg/kg/day. Subsequently, desquamation of the fingers was noted.

On the 11th day of admission, 13 days after the initial pyrexia, a new echocardiogram showed dilation of the left coronary artery (LCA) with a 2.3 mm diameter (previously 1.7 mm), z score 2.9, and the left anterior descending (LAD) branch had a diameter of 2.2 mm with a z score of 3.87. The right coronary artery (RCA) measured 2.1 mm (previously 1.7 mm) with a z score of 2.9 (Dallaire and Dahdah, JASE 2011 [4]). The next day, as he continued to be pyrexial with a fever up to 37.7°C, he was transferred to our hospital (Table 1).

At our hospital, a new echocardiogram was performed. It showed good systolic function of the left ventricle, mitral and tricuspid regurgitation, and a small aneurysm of LCA 2.6 mm (z score 3.86), a medium aneurysm of the LAD 3.4 mm (z score 6.41), and RCA 3.1 mm (z score 6.94) (Figure 1A and 1B). Subsequently, a second dose of immunoglobulin was given. The oral prednisolone was changed to intravenous methylprednisolone, followed by a single dose of infliximab. More, anakinra was added 8 mg/kg as it was felt that an intensification of therapy was warranted due to the rapid appearance of medium-sized aneurysms, the persistence of a high white cell count and platelets, and high inflammatory markers. However, the coagulation screening was normal. Regarding the cardiac markers, the troponin was borderline raised (15.9 pg/mL, normal < 14 pg/mL), and the NT proBNP was raised to 220 pg/mL. Finally, the patient’s young age < 6 months placed him in a higher risk category (Table 2). As per American Heart Association (AHA) guidelines, the patient was also given tinzaparin and anakinra, continued at a reduced dose of 4 mg/kg/day.

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Figure 1. Echocardiogram on day 14. (A) Dilation of the left coronary artery and the left anterior descending branch. (B) Dilation of the right coronary artery.

The antibodies for SARS-CoV-2 IgG2 taken on day 17 were positive at 23,847.2 AU/mL (negative < 50 AU/mL).

On day 23, a repeat echocardiogram showed mild mitral and tricuspid regurgitation, LCA 2.6 mm (z score 3.86), LAD ectasia, measuring 3.9 mm (z score 9.66), and RCA with dilation of the proximal part of 4 mm (z score 8.94). The distal part was 2.9 mm (z score 4) (Figure 2).

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Figure 2. Echocardiogram on day 23. (A) Dilation of the left coronary artery and left anterior descending branch. (B) Remaining right coronary artery dilation.

He continued to be stable until discharge and follow-up.

One year later, the repeat echocardiogram showed improvement of the aneurysms with the LCA measuring 1.72 mm (z score 1.07) and the RCA measuring 1 mm (z score 0.53) (Figure 3).

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Figure 3. Echocardiogram one year later showing full resolution of the aneurysms. (A) The LCA aneurysm has fully resolved. (B) Similarly, the RCA now has a normal diameter. LCA: left coronary artery; RCA: right coronary artery.

Discussion

Kawasaki disease and multisystem inflammatory syndrome in children (MIS-C) appear to share some of the host immunological responses to a viral infection and subsequently clinical patterns. However, they also diverge in epidemiology, clinical presentation, and laboratory characteristics [5, 6].

Initial observations mentioned the decreased incidence of thrombocytosis in MIS-C [7, 8]. MIS-C patients typically have lower lymphocyte, platelet, and albumin levels but higher C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin, D-dimers, and cardiac markers than patients with Kawasaki disease [9].

Moreover, there are differences in epidemiology and clinical presentation of these two conditions. Both conditions have a predilection for boys. Kawasaki disease is more prevalent in Asians, whereas MIS-C is more frequent in Hispanic/African children [10].

Although both conditions may result in coronary aneurysms, they are more frequent in Kawasaki disease than in MIS-C. On the contrary, cardiac dysfunction such as ventricular dilation and need for vasopressors and intensive care admission are more likely to be associated with MIS-C. That is confirmed in laboratory indices such as high levels of NT proBNP and troponin levels [9, 10]. Moreover, multiorgan dysfunction is more likely in MIS-C. Pulmonary dysfunction is usually absent in Kawasaki but is frequently present in MIS-C [11]. Gastrointestinal complaints are more persistent in MIS-C [11–13].

Both conditions are characterized by increased CRP and ESR. However, increased white cell count, thrombocytosis, and eosinophilia are often observed in Kawasaki disease. In MIS-C, however, bone marrow suppression results in leucopenia and thrombocytopenia. Fibrinogen and ferritin levels are also elevated [11–13].

Due to the high titers of SARS-CoV-2 antibodies and the absence of any other virus, the diagnosis of MIS-C associated with SARS-CoV-2 and hyperinflammation in pediatric COVID-19 was considered. Although fever was present, apart from the skin changes, there was no other notable multisystem involvement that would contradict the definitions of MIS-C set by the Centers for Disease Control, Royal College of Pediatric and Child Health, and the World Health Organization, respectively [14–17]. Moreover, the age of the patient is more in keeping with Kawasaki disease rather than MIS-C. He did not fulfill the criteria for neonatal MIS [18]. The mucocutaneous symptoms of the baby were reminiscent of the classically described Kawasaki disease [19–21]. Finally, our patient showed a white cell count and high lymphocyte counts. There was thrombocytosis. Although the inflammatory markers were raised, the cardiac function markers were not significantly raised. Also, the fibrinogen was normal (Table 2). Resistance to immunoglobulins is associated with the development of coronary aneurysms. Therefore, adjunct therapies are being evaluated [22]. Interleukin 1 (IL-1) receptor blockade has proven to be beneficial in preventing myocardial dysfunction [23].

That is not unprecedented, given the pivotal role that IL-1α plays in the proinflammatory cycle of many tissues [24]. IL-1 blockade has been used in polygenic autoinflammatory disorders such as systemic juvenile idiopathic arthritis, adult-onset Still’s disease, idiopathic recurrent pericarditis, Behcet syndrome, and gout [25]. Anakinra, an IL-1α receptor antagonist, has been used as a second-line therapy in giant coronary artery aneurysms in Kawasaki disease [26]. Anakinra has been used as an off-label therapy for the treatment of IVIG-resistant Kawasaki disease in doses of 1–9 mg/kg/day [27]. Similarly, other studies report dosing schedules from 1–8 mg/kg/day [28]. There is less information about neonatal dosing. However, off-label anakinra has been used in neonates with Kawasaki disease from 1 to 6–9 mg/kg/day [29].

Indeed, anakinra has been used in IVIG-resistant Kawasaki to promote apyrexia and prevent the appearance of coronary aneurysms [30]. More relevant, anakinra has been used as a second-line treatment in the case of infants with resistant Kawasaki and giant aneurysms. The result was improvement and stability, but not complete resolution [31, 32]. In older infants, however, with resistant Kawasaki and medium to giant aneurysms treated with anakinra, there was complete resolution of the aneurysms [33–35]. Recurrent Kawasaki has been successfully treated with adjunctive anakinra, with full resolution of medium-sized aneurysms [36]. Treatment with anakinra has also resulted in the resolution of medium-sized aneurysms in older children as well [37, 38]. In a case series of 11 children with ages from 4 months to 9 years, all patients exhibited improvement with variable regression of the coronary aneurysms, with one exception, who died from complications of coronary artery rupture [39]. A trial of anakinra in refractory Kawasaki has shown some improvement in the dilation of coronary arteries and improvement of fever [40] (Table 3).

Future and existing trials will help clarify the potential role of prompt treatment to prevent coronary aneurysm formation.