By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN
SYNOPSIS: Findings consistent with long COVID occur in 4.5% of infected children. COVID vaccination reduces the risk of long COVID by 50% in adolescents and by 24% in children aged 5 to 11 years.
SOURCE: Razzaghi H, Forrest CB, Hirabayashi K, et al. Vaccine effectiveness against long COVID in children. Pediatrics 2024; Jan 16. doi: 10.1542/peds.2023-064446. [Online ahead of print].
In the United States, more than 2,100 children died of COVID-19, and 2.1% of SARS-CoV-2-infected children had severe illness. Pediatric patients, like their adult counterparts, can experience long COVID, post-acute sequelae of SARS-CoV-2 with symptoms such as brain fog, dyspnea, pain, fatigue, and gastrointestinal dysfunction. Anecdotal reports suggest that long COVID is more common in adults than in adolescents and more common in adolescents than in younger children.
SARS-CoV-2 vaccination reduces the risk of severe and complicated COVID illness. Different studies give differing results about whether vaccination prevents long COVID in adults. In a study of 6,500 children in the United Kingdom, COVID vaccine was not associated with whether a child had post-COVID symptoms six months after the acute SARS-CoV-2 illness.
To better understand links between COVID vaccination and long COVID, Razzaghi and colleagues evaluated data from a large-scale, multi-institution collaborative study in the United States (the National Institutes of Health Researching COVID to Enhance Recovery [RECOVER] Initiative). The investigative team made retrospective use of electronic health record data of more than 25 million children from 41 health systems who had had COVID, a respiratory illness, SARS-CoV-2 testing, or a SARS-CoV-2 vaccine.
Children were enrolled in the study sample if they were 5 to 18 years of age and eligible for COVID vaccination, if they had medical contact during the two years prior to study entry, and if they had an in-person medical visit 28 to 179 days after entry into the cohort (whether vaccinated or not). Patients were not included in the cohort if they had COVID illness during the 28 days just after being vaccinated. Outcomes were characterized as diagnosed long COVID or as having probable long COVID (having other diagnoses consistent with long COVID) during the first 12-18 months after entry into the study cohort. Thus, they compared long COVID outcomes of vaccine-eligible children who either did or did not receive vaccination.
The actual study sample included 480,498 children aged 5 to 11 years and 719,519 adolescents (aged 12 to 18 years). Of these children, 55% had at least one vaccine; of those who were vaccinated, 84% had two or more vaccine doses.
Statistically, children in the vaccinated group were more likely to be girls with self-reported Asian or Hispanic background. In addition, vaccinated children were older and had fewer chronic health problems than did those who did not receive vaccination. For children who had COVID-19 after entry into the study, 0.8% were diagnosed as having long COVID and another 3.7% had probable long COVID. For children with no history of COVID prior to study entry, vaccine effectiveness was 35% in preventing long COVID during the year following study entry. Vaccination was similarly effective in preventing long COVID in children and adolescents who had symptomatic COVID prior to study enrollment. However, the protection against long COVID seemed to wane over time, with less protection at 12 months than at six months after vaccination and with less protection remaining at 18 months than at 12 months after vaccination.
In summary, COVID vaccine was effective, although imperfectly, in preventing long COVID in children and, especially, in adolescents. Vaccine was protective against long COVID regardless of whether the child had had COVID illness prior to being vaccinated.
COMMENTARY
We have emerged into what some people consider a post-COVID or post-pandemic era.1 Indeed, it is good to have many burdens of the pandemic in our figurative rear-view mirror. But it is really just the era following the COVID emergency; even the lay press reminds us of the ongoing importance of COVID.1
Indeed, we should not let our patients relax their preventive measures too much as activity restrictions are eased. This new data analysis from Razzaghi and colleagues provides practical lessons to guide prevention of future health compromises due to SARS-CoV-2. First, COVID vaccine is effective in preventing long COVID, even as it also helps prevent severe acute infection. Second, the benefit of COVID vaccine in preventing long COVID is even greater for adolescents (who might tend to neglect routine healthcare interventions) than for younger children. Third, COVID vaccine helps prevent long COVID even when the individual had COVID prior to vaccination. Finally, the protective effect of COVID vaccine against long COVID wanes during the year and a half following vaccination; patients should be encouraged to stay current with ongoing COVID vaccination.
Post-acute sequelae of COVID are estimated to affect 5.8 million children in the United States.2 These sequelae are more common after symptomatic SARS-CoV-2 illness but also can occur following asymptomatic infection.2 Fatigue, post-exertional malaise, difficulty concentrating (“brain fog”), dyspnea, and pain are common symptoms and can be debilitating.2,3 Some patients have post-COVID postural orthostatic tachycardia syndrome (POTS), which manifests similarly to POTS that began following other triggering infections and injuries prior to the COVID-19 pandemic.2
The pathogenesis of pediatric long COVID has not been well characterized.3 Acute fatal SARS-CoV-2 infection is associated with microglial inflammation in many parts of the brain, including the medulla.4,5 The hypothalamus (especially the paraventricular nucleus) connects through neuropathways to the rostral medulla oblongata and has been linked to both autonomic dysfunction and chronic pain.6-8 One could speculate that when microglial inflammation is unusually significant in the hypothalamus during and following acute SARS-CoV-2 infection, this inflammation can cause autonomic dysfunction-induced fatigue, malaise, orthostatic intolerance, and gastrointestinal dysmotility as well as the chronic pain of long COVID. Eventual histopathology studies of individuals with long COVID might be able to determine if microglial changes in the hypothalamus are, indeed, associated with long COVID.
REFERENCES
- McBride K. What is ‘post-pandemic’? NPR News. July 13, 2023 https://www.npr.org/sections/publiceditor/2023/07/13/1187493251/what-is-post-pandemic
- Rao S, Gross RS, Mohandas S, et al. Postacute sequelae of SARS-CoV-2 in children. Pediatrics 2024; Feb 7:e2023062570. doi: 10.1542/peds.2023-062570. [Online ahead of print].
- Toepfner N, Brinkmann F, Augustin S, et al. Long COVID in pediatrics - epidemiology, diagnosis, and management. Eur J Pediatr 2024; Jan 27. doi: 10.1007/s00431-023-05360-y. [Online ahead of print].
- Matschke J, Lahann H, Krasemann S, et al. Young COVID-19 patients show a higher degree of microglial activation when compared to controls. Front Neurol 2022; Jun 16;13:908081. doi: 10.3389/fneur.2022.908081.
- Agrawal S, Farfel JM, Arfanakis K, et al. Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases. Acta Neuropathol Commun 2022;10:186.
- Nunn N, Womack M, Dart C, Barrett-Jolley R. Function and pharmacology of spinally-projecting sympathetic pre-autonomic neurones in the paraventricular nucleus of the hypothalamus. Curr Neuropharmacol 2011;9:262-277.
- Reisert M, Weiller C, Hosp JA. Displaying the autonomic processing network in humans — a global tractography approach. Neuroimage 2021;231:117852.
- Kong J, Huang Y, Liu J, et al. Altered functional connectivity between hypothalamus and limbic system in fibromyalgia. Mol Brain 2021;14:17.
