COVID-19 and Kawasaki Disease: Novel Virus and Novel Case

The patient is a 6-month-old, term, previously healthy and fully immunized girl who initially presented to pediatric urgent care with 1 day of fever, fussiness, and refusal to eat. She did not exhibit cough, congestion, or rhinorrhea. Examination revealed a fussy infant with a temperature of 38.8°C, with no focal signs of infection. Laboratory evaluation included a rapid influenza swab and a catheterized urinalysis with urine culture, all of which had negative results. She was diagnosed with a viral infection.

On day 2 of fever, she developed an erythematous, seemingly nonpruritic, blotchy rash. She re-presented to care on day 4 of fever with persistent rash. Although she remained free of cough, there was possible mild congestion. Vital signs revealed a temperature of 38.3°C, sinus tachycardia (200 beats per minute), and tachypnea with an oxygen saturation of 100%. Examination was notable for irritability, limbic sparing conjunctivitis, and dry cracked lips. There was no appreciable lymphadenopathy, and, at the time, she had normal extremities. She had mild subcostal retractions, although she had normal breath sounds. Laboratory testing revealed a left-shifted white blood cell count with bandemia, normocytic anemia, normal platelets, markedly elevated C-reactive protein of 13.3 mg/dL, and erythrocyte sedimentation rate of 118. She had hyponatremia (sodium at 133) and hypoalbuminemia (albumin at 2.8), with otherwise normal chemistries, including liver function tests. Results from respiratory pathogen testing by reverse transcription polymerase chain reaction (RT-PCR) test and blood culture were negative. A chest radiograph revealed a faint opacity in the left midlung zone. Throughout this period of illness, she had no sick contacts. Her 9-year-old sibling had upper respiratory symptoms 3 weeks before. The family had self-isolated because of the COVID-19 pandemic for the week before, without leaving home for school or work. There was no history of recent travel.

The patient was referred for admission for KD evaluation. Given her fever, possible mild congestion, and chest radiograph findings, she was sent to the emergency department for COVID-19 testing before admission to the pediatric floor. On arrival, the patient was on day 5 of fever and had limbic sparing conjunctivitis (Fig 1); prominent tongue papilla; a blanching, polymorphous, maculopapular rash (Fig 2); and swelling of the hands (Fig 3) and lower extremities (thus meeting classic criteria for KD). She was treated with a single dose of 2 g/kg intravenous immunoglobulin and high-dose acetylsalicylic acid (20 mg/kg 4 times daily), according to treatment guidelines.³  Her last elevated temperature was 38.3°C, just after completing intravenous immunoglobulin. An echocardiogram was normal without any evidence of coronary dilation or aneurysm, no pericardial effusion, and with normal valvar and ventricular function.

The evening before discharge, RT-PCR testing for COVID-19 resulted positive from the Stanford Health Care Clinical Virology Laboratory. The public health department was notified, and the family was instructed to quarantine at home for 14 days from the positive test result date. She was discharged on low-dose acetylsalicylic acid (3 mg/kg daily), with plans to follow-up with pediatric cardiology for repeat echocardiographic evaluation 2 weeks after discharge, timed to occur after the mandated 14-day quarantine.

To our knowledge, this is the first described case of KD with concurrent COVID-19 infection. KD is an acute vasculitis of childhood and the leading cause of acquired heart disease in children in developed countries, with 50% of cases occurring in those <2 years of age and 80% in those <5 years of age.⁴  The diagnosis of “classic” KD is considered in patients presenting with fever for 5 days together with at least 4 out of 5 clinical criteria in the absence of an alternate diagnosis.

The cause of KD remains unknown despite several decades of investigation. Some evidence suggests an infectious trigger, with winter to spring seasonality of the disease, and wavelike spread of Japanese epidemics of KD.⁴  In various studies, authors have described an association between viral respiratory infections and KD, ranging from 9% to as high as 42% of patients with KD testing positive for a respiratory viral infection in the 30 days leading up to diagnosis of KD.^5–7  Interestingly, Turnier et al⁵  in 2015 described that 28% of positive results were attributable to rhinovirus and/or enterovirus, and 8.7% were due to parainfluenza; results for the remaining pathogens (respiratory syncytial virus, influenza, adenovirus, and human coronavirus [strains 229E, HKU1, NL63, OC43]) were each positive <5% of the time.

Although the clinical significance of our patient’s positive COVID-19 test result in the setting of her KD is not clear, her testing for COVID-19 appears accurate. The Stanford Health Care Clinical Virology Laboratory serves pediatric and adult tertiary-care hospitals and affiliated clinics in northern California. In early January 2020, 2 multiplex RT-PCR assays were validated on the basis of a modified published protocol.⁸  These assays are used to target the envelope and RNA-dependent RNA-polymerase genes, respectively. Analytical sensitivity from nasopharyngeal swabs eluted in viral transport medium was shown to be good, with a lower limit of detection ranging between 500 and 700 copies per mL. Furthermore, analytical specificity was high, with no cross-reactivity observed in >50 tested samples with seasonal coronaviruses or other respiratory viruses. Samples revealing late cycle threshold values (cycle threshold ≥40) are repeated for confirmatory testing to prevent false-positive results. Although direct comparison data between this assay and the Centers for Disease Control and Prevention’s assay (which targets 2 regions of the nucleocapsid gene) have not yet been published, preliminary data suggest similar analytic performance.^8,9 

At the time of this patient’s hospital discharge, the World Health Organization reported almost 180 000 global cases of confirmed COVID-19, with 7426 deaths.¹⁰  Despite the growing number of reported cases, there remains a knowledge gap regarding the infectious, epidemiological, and clinical features associated with COVID-19 illness, particularly in the pediatric population. To date, the most common pediatric presentation of COVID-19 is an array of signs and symptoms including completely asymptomatic to symptoms of acute upper respiratory tract infection such as fever, fatigue, cough, sore throat, rhinorrhea and congestion, and shortness of breath. In more severe cases, symptoms can include gastrointestinal symptoms and patients can progress to respiratory failure, shock, coagulation dysfunction, and renal injury.² 

With regard to her COVID-19 infection, our patient’s clinical course and presentation were mild. Throughout her hospitalization, she did not have any notable respiratory symptoms, and repeat chest radiograph was not obtained. Her mother was in close contact with the infant throughout hospitalization and has no respiratory symptoms as of 2 weeks after hospital discharge. When coronary involvement appears with KD, it typically occurs after the initial presentation. As such, recommendations for monitoring include echocardiography in 1 to 2 weeks and 4 to 6 weeks after treatment.³ 

As we continue to see the spread of COVID-19 and increase in cases worldwide, clinical criteria for testing for COVID-19 may be restricted to those with respiratory symptoms because of constraints such as testing availability. In pediatrics, with the clinical spectrum yet to be clearly defined, patients presenting with fever alone or primarily with other organ system involvement such as gastrointestinal symptoms may be missed if testing is restricted to those with respiratory complaints alone.

This case report may serve as a useful reference to other clinicians caring for pediatric patients affected by COVID-19 as understanding of the clinical presentation patterns continues to evolve. Further description of the clinical course of pediatric patients diagnosed with COVID-19 remains necessary, particularly regarding the potential association with KD.

We thank the patient and her family for their willingness to share this case and the images. We also thank all the members of the health care team who contributed to the care of the patient discussed in this case report. In particular, we thank Dr Katherine Fry (Palo Alto Medical Foundation pediatric hospitalist).