In the midst of the coronavirus disease 2019 (COVID-19) pandemic, we are seeing widespread disease burden affecting patients of all ages across the globe. However, much remains to be understood as clinicians, epidemiologists, and researchers alike are working to describe and characterize the disease process while caring for patients at the frontlines. We describe the case of a 6-month-old infant admitted and diagnosed with classic Kawasaki disease, who also screened positive for COVID-19 in the setting of fever and minimal respiratory symptoms. The patient was treated per treatment guidelines, with intravenous immunoglobulin and high-dose aspirin, and subsequently defervesced with resolution of her clinical symptoms. The patient’s initial echocardiogram was normal, and she was discharged within 48 hours of completion of her intravenous immunoglobulin infusion, with instruction to quarantine at home for 14 days from the date of her positive test results for COVID-19. Further study of the clinical presentation of pediatric COVID-19 and the potential association with Kawasaki disease is warranted, as are the indications for COVID-19 testing in the febrile infant.
The rapid spread of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has led to a global pandemic, with infected individuals of all ages residing in almost every country in the world. The pediatric population appears to be affected in much smaller proportions than adults, with only 2% of cases described in patients younger than age 20.1 In an epidemiological report, authors described 731 confirmed COVID-19 cases in the pediatric population, with >90% of patients characterized as asymptomatic, mild, or moderate cases.2 The authors looked at a total of 2143 patients, 1412 of whom had suspected but unconfirmed COVID-19 infection, but there was little description of co-incidence with other clinical conditions and no cases reported of concurrent Kawasaki disease (KD).
We describe here the case of a pediatric patient diagnosed and treated for classic KD in the setting of confirmed COVID-19 infection, published with parental permission.
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).
Dr Jones provided direct care to the patient in this report, conceptualized and outlined the manuscript, reviewed existing literature, and drafted the initial manuscript; Dr Mills reviewed existing literature and drafted the initial manuscript; Dr Suarez provided direct care to the patient in this report and contributed to the drafting of the initial manuscript; Dr Hogan contributed to the drafting of the initial manuscript; Drs Yeh, Segal, Nguyen, and Barsh provided direct care to the patient in this report; Dr Maskatia is providing ongoing care to the patient; Dr Mathew conceptualized and outlined the manuscript; and all authors reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
RE: COVID-19 and Kawasaki Disease: Novel Virus and Novel Case
I read with great interest the paper of Jones et al. (1) about Covid-19–associated Kawasaki Disease, an autoimmune disease related to molecular mimicry phenomena (2, 3).
It is now evident that COVID-19, at least in a subset of patients, is a systemic disease. These subjects present signs and symptoms related to autoimmunity.
Since molecular mimicry was already shown to have a role in viral pathogenicity, including that of SARS-CoV (4) (the coronavirus determining another serious epidemic in 2002-2004), the scientific community should be advised about the fact that molecular mimicry phenomena might occur also in SARS-CoV-2.
If confirmed, as already postulated (5), this could explain also the acute pulmonary embolism as well as the multi-organ microvascular thrombosis that some patients experience. In my modest opinion, it is necessary to prompt the searching of human epitopes which can turn into autoantigens. This paper about Kawasaki Disease in COVID-19 patients can offer useful clues.
University of Palermo
1: Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Bradley Segal J, Nguyen EL, Barsh GR, Maskatia S, Mathew R. COVID-19 and Kawasaki Disease: Novel Virus and Novel Case. Hosp Pediatr. 2020 Apr 7. pii: hpeds.2020-0123. doi: 10.1542/hpeds.2020-0123.
2: Sireci G, Dieli F, Salerno A. T cells recognize an immunodominant epitope of heat shock protein 65 in Kawasaki disease. Mol Med. 2000 Jul;6(7):581-90.
3: Marrani E, Burns JC, Cimaz R. How Should We Classify Kawasaki Disease? Front Immunol. 2018 Dec 14;9:2974. doi: 10.3389/fimmu.2018.02974.
4: Chew FT, Ong SY, Hew CL. Severe acute respiratory syndrome coronavirus and viral mimicry. Lancet. 2003 Jun 14;361(9374):2081.
5. Cappello F. Is COVID-19 a proteiform disease inducing also molecular mimicry phenomena? Cell Stress Chaperones. 2020 Apr 20. doi: 10.1007/s12192-020-01112-1.
RE: COVID-19 and Kawasaki cases here and in the news
I read with interest the recent case report “COVID-19 and Kawasaki Disease: Novel Virus and Novel Case” (Jones, Mills et al. 2020). As we still struggle to grasp what Kawasaki disease really is, case reports will continue to add fruitful information to our knowledge base.
The author’s case would obviously been bolstered by echocardiographic findings supportive of Kawasaki Disease. We have had cases initially considered for Kawasaki Disease that were SARS-CoV-2 and attributed the findings to the later. In this case presented, I appreciate that the author’s provided pictures. The rash is impressive, and outside of vesicles, many rashes have been associated with Kawasaki disease. However, the feet are fairly normal appearing. With the extensive nature of the rash, I am not surprised by more general lower extremity edema. On the provided clinical description, prominent papilla of the tongue without notation of erythema of the oropharynx would generally not fulfill the criteria of oropharyngeal inflammation in our practice. Lacking prominent unilateral lymphadenopathy, would make this case be at best incomplete Kawasaki Disease if following guideline descriptions (McCrindle, Rowley et al. 2017). A follow up for late pealing would be of interest, however, generalized edema and other viruses can also be associated with late pealing. This is the continued challenge of Kawasaki disease: all of these associations are not truly specific to Kawasaki disease on their own.
As a number of SARS-CoV-2 infected persons are asymptomatic, this could be an unrelated finding in a case of incomplete Kawasaki Disease, although the upper respiratory symptoms speak against this. Previous reports on Kawasaki disease have shown both preceding viral illness in outbreaks (Bell, Brink et al. 1981) and cases associated not uncommonly (roughly 10% of cases) with concomitant respiratory viruses (Jordan-Villegas, Chang et al. 2010). We have seen associations of roughly 10% of cases ourselves (Engelberg, Martin et al. 2017). With recent reports of clinical overlap of Kawasaki Disease and COVID-19, we will likely see similar case reports going forward. With the epidemiology of Kawasaki disease presumably unchanged, overlaying millions of cases of COVID-19 throughout the United States, there will be overlap of cases. So, my interpretation of this case is this is solely COVID-19 associated inflammation.
As both conditions appear to incite a large inflammatory response in certain children, continued research is needed to provide the ‘how’ for SARS-CoV-2 associated inflammation and the ‘what’ for the etiology of Kawasaki disease.
Bell, D. M., et al. (1981). "Kawasaki syndrome: description of two outbreaks in the United States." N Engl J Med 304(26): 1568-1575.
Engelberg, R., et al. (2017). "Observational study of Interleukin-21 (IL-21) does not distinguish Kawasaki disease from other causes of fever in children." Pediatric Rheumatology Online Journal 15(1): 32.
Jones, V. G., et al. (2020). "COVID-19 and Kawasaki Disease: Novel Virus and Novel Case." Hosp Pediatr.
Jordan-Villegas, A., et al. (2010). "Concomitant respiratory viral infections in children with Kawasaki disease." Pediatr Infect Dis J 29(8): 770-772.
McCrindle, B. W., et al. (2017). "Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association." Circulation 135(17): e927-e999.