The characteristics of scientific progress is our knowing that we do not know
In just a few short months, the disease caused by severe acute respiratory syndrome coronavirus 2, commonly known as coronavirus disease 2019 (COVID-19), has morphed from a vague foreign contagion to a global pandemic devastating economies and the health of citizens across the globe. Children have been spared the severe burden of disease, and critical illness and mortality have been substantially less as compared with adults (1). However, the transmissibility and pathogenicity of COVID-19 is slowly emerging and the final chapter on its toll on children is sketchy. Much has been written about the devastating consequences to healthcare delivery and outcomes, especially in adults and recently a large volume of reports of COVID-19 in children is slowly unveiling the clinical features and varying disease manifestations.
The reports on children published from countries that represented the first wave of the disease such as China (2), Italy (3), provide some data, but understandably scant information from rigorously conducted trials to explain pathogenesis and guide therapies. The hope is that this avalanche of manuscripts outlining clinical experience will eventually lead to an interconnected leitmotif and to a better understanding of COVID-19 in children. As of this writing (June 15), there was a total of 1,124 manuscripts on PubMed relating to COVID-19 in children, yet no clinical trials, 186 reviews, and 29 systematic reviews, most of which have been published in 2020 (4). Granted these are early days and as more experience is reported and data are converted into information, it is likely that the seemingly unrelated threads will yield a tapestry.
An example of such experience is an observational study reported in this issue of Pediatric Critical Care Medicine by Bhumbra et al (5). Bhumbra et al (5) outline their experience in providing care for seven critically ill children with COVID-19. Although a small number of cases, several interesting nuggets of information can be gleaned from this report as follows:
- 1) Of 407 children tested for COVID-19, only 24 were positive, 19 were hospitalized, and only seven were critically ill
- 2) African Americans and Hispanics combined (71%) were disproportionately affected when one considers the African American and Hispanic populations represents 9.8% and 7.1% of the population of Indiana
- 3) Critically ill children were older (4/7) over 15 years old
- 4) All four critically ill ventilated children had complicated courses (mechanical ventilation for a mean duration of 14 d), secondary bacterial infection in two, significant rhabdomyolysis in one, and one death
The role of various therapies cannot be informed by the study of Bhumbra et al (5) because of small numbers and therapy of dubious benefits offered on a compassionate basis. However, several issues emerging from the study by Bhumbra et al (5) are worthy of discussion and further exploration such as the predilection for racial minorities, similarities and differences to sepsis, wide expression of clinical disease, and the conundrum of providing family centered care.
Much has been written about the issue of racial disparities in the U.S. healthcare system and COVID-19 has revealed its ugly underbelly (6). The high burden in minority communities may be due to structural inequities (racism, neighborhood segregation, income disparities, housing and education inequality, and poorer access to care) or individual factors such as genetics, comorbidities, and other healthcare issues likely related to social vulnerabilities (7,8). These inequities are also likely to plague children in these communities and likely explain the disproportionate contribution of African American and Hispanic children to critical illness in this report. Indeed that children of minority populations are more prone to severe disease is not unique to the United States. A report from the United Kingdom of eight children suffering from Multisystem Inflammatory Syndrome in children (MIS-C) from COVID-19 reveals that all eight children were minorities (six of Afro-Caribbean descent, one Asian, and one Middle-Eastern) (9). The socioeconomic circumstances of the U.K. cohort were not reported and hence whether there are other reasons such as an underlying genetic basis to explain disease predilection is unclear.
That issues of racial disparities and inequities seem to result in higher burden of critical illness in children are important, and funding agencies are starting to invest in COVID-19 research (including Implementation Science) in both rich and poor countries. The importance of this research is underlined by the fact that in low- and middle-income countries which have the substantially greater number of children many with comorbidities such as malnutrition, malaria, anemia, and tuberculosis, poorly or nonresilient health systems, and gross inequities, COVID-19 may result in an estimated increase of anywhere between 253,500 and 1,157,000 additional deaths in children (10)
The issue of coinfections in critically ill children in this report, as well as other reports (5,11), underlines the importance of considering sepsis in all children with COVID-19 until this is proven to be the only cause of illness by ruling out other pathogens. Hence, broad-spectrum antibiotic administration and cardiorespiratory support as outlined in the pediatric surviving sepsis campaign guidelines (12) should be instituted in view of the fact that bacterial sepsis more commonly results in critical illness in the United States rather than COVID-19 (1,13). There is a high risk of diagnostic fixation or anchoring bias that a child with cardiopulmonary dysfunction is solely due to acute COVID-19 illness or MIS-C without consideration of sepsis as a possibility (14). This is especially true in MIS-C which may be associated with severe cardiovascular dysfunction (9). In addition, therapies such as corticosteroids and anticoagulants may be of no or dubious benefit in sepsis but may be useful in MIS-C. Thus, in cases where there is doubt, treatment should be immediately started for as per sepsis guidelines and consultation with the appropriate specialties be obtained as soon as possible.
That the four critically ill in this report (5) had a more complicated course and longer periods of mechanical ventilation is in contradistinction to the report and to the limited experience of eight MIS-C cases in the United Kingdom (9). In the U.K. group, all children exhibited cardiac dysfunction on echocardiogram which was clinically significant resulting in the need for cardiorespiratory support (two or more inotropes or vasotonic drugs in seven), broad-spectrum antibiotics in eight and IV immunoglobulin in eight. Despite severe physiologic cardiac derangements, there was a quick resolution of disease with the length of pediatric critical care stay of only 4–7 days as compared with an average of 14 days in the study by Bhumbra et al (5). The late presentation of MIS-C following COVID-19 infection and the common features shared with Kawasaki disease may point to a different path of physiologic mechanism of COVID-19 sepsis and COVID-19 MIS-C; however, this is yet to be proven (15).
One issue of major importance that is not addressed in the study by Bhumbra et al (5) is the family centered care in critically ill children with COVID-19 (16) Public safety measures demand restricting physical presence of families, however, critically ill children are especially vulnerable to social isolation and consideration of methods to support the presence of family members is important to both immediate and long-term consequences of isolation.
There are many questions raised by the current study of Bhumbra et al (5). For instance, what are the target organs in COVID-19 critical illness in children? How is COVID-19 MIS-C, related to sepsis? What is the optimal combination of therapies for critically ill children? What determines which children will be severely affected? These are salient questions that beg answers. The COVID-19 and critical illness story in children will continue to evolve, hopefully leading to a more complete understanding but more importantly to prevention and treatment options. Unraveling the mysteries of COVID-19 in children will take us along a tortuous path but knowing that we do not know is the first step on this journey.
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2. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China. Pediatrics. 2020. 145:e20200702
3. Parri N, Lenge M, Buonsenso D; Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) Research Group. Children with Covid-19 in Pediatric Emergency Departments in Italy. N Engl J Med. 2020. 383:187–190
4. PubMed.gov website: COVID-19 AND children. Available at: https://pubmed.ncbi.nlm.nih.gov/?term=COVID-19+AND+children
. Accessed July 16, 2020
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10. Roberton T, Carter ED, Chou VB, et al. Early estimates of the indirect effects of the COVID-19 pandemic on maternal and child mortality in low-income and middle-income countries: A modelling study. Lancet Glob Health. 2020. 8:e901–e908
11. Kim D, Quinn J, Pinsky B, et al. Rates of co-infection between SARS-CoV-2 and other respiratory pathogens. JAMA. 2020. 323:2085–2086
12. Weiss SL, Peters MJ, Alhazzani W, et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 2020. 21:e52–e106
13. Hartman ME, Linde-Zwirble WT, Angus DC, et al. Trends in the epidemiology of pediatric severe sepsis*. Pediatr Crit Care Med. 2013. 14:686–693
14. Mamede S, van Gog T, van den Berge K, et al. Why do doctors make mistakes? A study of the role of salient distracting clinical features. Acad Med. 2014. 89:114–120
15. Ramcharan T, Nolan O, Lai CY, et al. Paediatric inflammatory multisystem syndrome: Temporally associated with SARS-CoV-2 (PIMS-TS): Cardiac features, management and short-term outcomes at a UK tertiary paediatric hospital. Pediatr Cardiol. 2020 Jun 12. [online ahead of print]
16. Hart JL, Turnbull AE, Oppenheim IM, et al. Family-centered care during the COVID-19 era. J Pain Symptom Manage. 2020 Apr 22. [online ahead of print]