An overview of current theses and research surrounding the pathogenesis, presentation, and treatment of COVID-19 in children.
According to the Centers for Disease Control, from March 2020 to June 2022 in the United States, there were 2.5 million cases of pediatric infection from SARS-COV-2. Of the reported cases, 1310 infants and children lost their lives.
While a 0.05% mortality rate may seem like a small number, it is important to understand that among all-cause mortality for this population, COVID-19 is the leading cause of death among children 0-19 years of age.1 Unfortunately, lay populations could discount the urgency of the matter due to research suggesting that 15%-42% of children present with mild and even asymptotic progression of the illness, according to multiple studies cited in the Journal of Pediatrics and Child Health.2-4
The highly infectious nature of the virus, variability in immune response, as well as complications such as post-infectious inflammatory syndrome (PIMS-TS/MIS-C) and long COVID add an additional layer of complexity to the diagnosis, prognosis, and treatment for these patients. The purpose of this article is to familiarize providers to current theses and research surrounding the pathogenesis, presentation, and treatment of COVID-19 in children.
To begin to understand why COVID-19 looks so different in children versus adults, it is important to understand the similarities and differences in the progression of the disease. Similarities include that COVID-19 is a single stranded RNA virus. The virus uses a spike protein binding to the angiotensin converting enzyme 2 (ACE2) for entry into cells and replication.
ACE2 is present on several cell surface types including the GI and respiratory tract, as well as the endovascular epithelia.2 Another similarity is in the adaptive cellular immune response between pediatric and adult populations.2,6
If the pathogenesis and adaptive immune response are similar between adults and children, why are milder courses observed in children? Prior hypothesis evaluated the possibility of children having less ACE2 receptor expression, immunity acquired from other infections, coinfection causing the immune system to activate faster and more effectively, and/or maternal immunity.10,11
However, current research supports the hypothesis that children exhibit an almost super-powered nasal mucosa pre-activated for respiratory infections, such as COVID-19. In the study, researchers tested the nasal mucosa of both adults and children and found that innate immune cells exhibit enhanced viral sensing, innate immune cell activation in airway epithelial cells.2,7,11
Another hypothesis suggests the mild presentation is due to a less experienced adaptive immune system. Blood samples from COVID-19-positive subjects had a lower frequency and even depletion of adaptive immune cells in children compared to adult counterparts.
The theory is that due to decreased cytotoxic immune cells, the body does not exert the same hyperinflammatory characteristics that can lead to complications in severe courses of the disease.11 Although evidence suggests a stronger innate immune response and a dampened inflammatory response, efforts should still be made to ensure children are vaccinated and, if tested positive, treated according to the most up to date research findings.
As previously mentioned, COVID-19 typically presents in children as mild non-specific symptoms, such as other upper respiratory infections. These include fever (46%-64%), cough (32%-56%), rhinorrhea, sore throat, dyspnea (<10-20%), headache and malaise (60%), and GI symptoms (10-20%).
Progression and severity of the illness varies from patient to patient. However, patients with risk factors or comorbidity such as an age <1 year, obesity, asthma, diabetes mellitus, immunosuppression, chronic kidney disease, and/or sickle cell disease are at a higher risk for disease complication requiring hospitalization.2,10
The course of the illness becomes especially heinous if and when asymptomatic patients (typically between the ages of 9 and 102), 4-6 weeks after COVID-19 infection, begin to show signs and symptoms of PIMS-TS or MIS-C. Although the illness is reported in 1 in 3000 children infected, this severe hyperinflammatory illness, mimicking Kawasaki disease and toxic shock syndrome, can wreak havoc on several organ systems as the name suggests.
Key characteristics of the illness include fever, rash, and elevated bio markers, such as C-reactive protein, procalcitonin, ferritin, D-dimer, troponin, and proBNP.2,10,12 Of the populations suffering from the illness, 60%-70% are admitted to intensive care units and 1%-2% die.
As of February 2020-May 2022, there were 8529 cases and 69 deaths in the United States.1 Again, although the incidence is small, it is important that providers understand the signs, symptoms, and diagnostic criteria as a method for treating patients and counseling parents of children with COVID-19.
Treatment of COVID-19 in the Ambulatory Care Setting
Treating COVID-19 in pediatric patients poses an especially complicated challenge. The treatment of COVID-19 in children in ambulatory care settings is largely guided based on therapy in adults because of the lack of data and inclusion in randomized trials.2,5
Recommendations have been deduced by weighing risks and benefits, considering expert opinion, and integrating knowledge obtained from similar infections.5 According to current guidelines, the treatment of mild to moderate COVID-19 in children is directed by severity, age, vaccination status, and comorbidities.
These factors categorize pediatric patients into low-, intermediate-, and high-risk groups, each corresponding with the probability of the patient progressing to a severe disease state. Those categorized into the high-risk group are child patients who experience obesity, patients who rely on respiratory assistance, those with severe disability that effects respiratory activity or activities of daily life, individuals with severe chronic lung disease, severe cardiac disease, or multiple moderate to severe chronic diseases and who have not been vaccinated.
The high-risk designation changes to intermediate-risk if patients have completed the primary series or are up to date on COVID-19 vaccination boosters. If patients are less than 1 year of age, less than or equal to 2 years of age born prematurely, experience sickle cell disease, poorly controlled diabetes, non-severe cardiac disease, non-severe neurologic disease, or non-severe metabolic disease, they are considered intermediate-risk regardless of vaccination status.
Pediatric patients who are overweight, suffer from mild asthma, or experience well-controlled diabetes are categorized as low risk. If a child is moderately to severely immunocompromised, the patient is automatically determined to be placed in the high-risk group.
Based on risk categorization, health care professionals can tailor their treatment strategy. Initially, all patients who are symptomatic should be provided with supportive care.
Supportive care is described as managing symptoms, ensuring proper nutrition, and applying social isolation as much as possible. For example, management of symptoms such as cough can be achieved using OTC antitussives.
Low-risk patients can be managed with supportive care alone. For the intermediate-risk group, there is insufficient evidence to make recommendations for a medication in any child age group.5
Patients determined to be high-risk and between 12 and 17 years of age are recommended to use either ritonavir-nirmatrelvir or remdesivir. Remdesivir is to be initiated within 7 days whereas ritonavir-nirmatrelvir should be initiated within 5 days of symptom onset.5,8,9
For high-risk patients less than 12 years of age, ritonavir-nirmatrelvir has not been approved for this age group.5,9 However, in April 2022, remdesivir (Veklury; Gilead Sciences) received FDA approval for the treatment of pediatric patients who are older than 28 days, weighing at least 3 kg, and are either hospitalized with COVID-19 or have mild-to-moderate COVID-19 and are considered high risk for progression to severe COVID-19, including hospitalization or death.13
Long COVID in Children: What We Know
Long COVID refers to symptoms of the acute COVID-19 disease that persists even after viral clearance.11 Many studies have tried to determine the prevalence of long COVID in children with many reaching differing conclusions.
Symptoms of long COVID are seen more in children with severe COVID-19 symptoms but can be seen in instances of asymptomatic children as well. Some of the more common symptoms associated with long COVID include fatigue, chest pain, and headache.
Based on current literature, symptoms can persist for a prolonged amount time, 4 weeks or more, but duration is not explicitly defined.11,12 At this time, there is no strict definition of time or symptoms needed to diagnose long COVID in children.12
Children who are infected with SARS-CoV-2 are at risk of developing symptoms of COVID-19 and normal function in many physiological systems can be disrupted for an uncertain amount of time.12
In the case of COVID-19 and children, it becomes an especially more complex and difficult disease to analyze. Compared to adults, children have different responses when confronted with the SARS-CoV-2 virus.
This changes how children present with the disease and puts patients at risk of experiencing the long-term risks of COVID-19, which include both long COVID and MIS-C. The treatment of COVID-19 in the outpatient setting also changes dramatically in children.
Medications are often not tested in the pediatric population, leading our decision-making to be directed from adult data. There are also limitations of age placed on specific medications that alter how treatment is utilized.
When deciding treatment modalities in children with COVID-19, each case deserves to be analyzed carefully taking into consideration risk factors, vaccination status, and age. As we continue to learn more about COVID-19, treatment opportunities will evolve and health care professionals can maintain providing the optimal individualized patient-centered care.
1. Fleming-Dutra, K. E. (2022, June 17). Covid-19 epidemiology in children ages 6 months– 4 years. COVID-19 epidemiology in children ages 6 months– 4 years. Accessed 12/22/2022 https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-06-17-18/02-COVID-Fleming-Dutra-508.pdf
2. Howard‐Jones, A. R., Burgner, D. P., Crawford, N. W., Goeman, E., Gray, P. E., Hsu, P., ... & Britton, P. N. (2022). COVID‐19 in children. II: Pathogenesis, disease spectrum and management. Journal of Paediatrics and Child Health, 58(1), 46-53.
3. Wurzel D et al. COVID-19 and its multi-system inflammatory complications in children - a multi-centre nationwide Australian study. BMJ Open. 2021; in press
4. Viner, R. M., Ward, J. L., Hudson, L. D., Ashe, M., Patel, S. V., Hargreaves, D., & Whittaker, E. (2021). Systematic review of reviews of symptoms and signs of COVID-19 in children and adolescents. Archives of disease in childhood, 106(8), 802-807.
5. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed 12/22/2022
6. Tosif S, Neeland MR, Sutton P et al. Immune responses to SARS-CoV-2 in three children of parents with symptomatic COVID-19. Nat. Commun. 2020; 11: 5703.
7. Loske J, Röhmel J, Lukassen S et al. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat. Biotechnol. 2021 https://doi.org/10.1038/s41587-021-01037-9.
8. Remdesivir. In: Lexi-Drugs. Lexi-Comp [Online Database]. Waltham (MA): UpToDate; 2022. Available from: https://online.lexi.com Accessed: 12/22/2022
9. Nirmatrelvir and Ritonavir. In: Lexi-Drugs. Lexi-Comp [Online Database]. Waltham (MA): UpToDate; 2022. Available from: https://online.lexi.com Accessed on: 12/17/2022
10. Goldwire, M. A., & Leeds, M. K. (2022, August 1). Lesson: Covid-19 infection in children. COVID-19 Infection in Children. Accessed 12/22/2022 https://journalce.powerpak.com/ce/covid-19-infection-in-children?wc_mid=6220%3A707726&wc_rid=6220%3A880565
11. Fainardi, V., Meoli, A., Chiopris, G., Motta, M., Skenderaj, K., Grandinetti, R., Bergomi, A., Antodaro, F., Zona, S., & Esposito, S. (2022). Long COVID in Children and Adolescents. Life (Basel, Switzerland), 12(2), 285. https://doi.org/10.3390/life12020285
12. Pierce, C. A., Herold, K. C., Herold, B. C., Chou, J., Randolph, A., Kane, B., ... & Hensley, S. E. (2022). COVID-19 and children. Science, 377(6611), 1144-1149.
13. Veklury® (Remdesivir) is First and Only Approved Treatment for Pediatric Patients Under 12 Years of Age with COVID-19. Foster City, CA: Gilead Sciences; April 15, 2022. Accessed January 11, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2022/4/veklury-remdesivir-is-first-and-only-approved-treatment-for-pediatric-patients-under-12-years-of-age-with-covid19
Editor's Note: This article was updated on January 11, 2023 at 9:35 AM ET.