Understanding the biological effects of SARS-CoV-2 persistence in children

In a study published in The Lancet Microbe, researchers analyzed the most recent knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen or ribonucleic acid (RNA) persistence in SARS-CoV-2-infected children.

Study: Viral persistence in children infected with SARS-CoV-2: current evidence and future research strategies. Image Credit: FamVeld/Shutterstock.com

Background

Although the knowledge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its human interaction has advanced a lot since its emergence in December 2019, many unanswered questions regarding the virus could significantly impact both children’s and adults’ health.

The post-coronavirus disease 2019 (COVID-19) (post-COVID-19) or long COVID condition, where the virus persists in the body, presents one of the biggest hurdles for researchers and patients, including adults and children. The development of long COVID has been associated with a number of biological abnormalities.

Nonetheless, the precise pathogenesis is yet unknown. Presently, the focus is on the persistence of the virus or its components in the human body following initial infection. 

About the study

In the present research, the authors evaluated the current data on potential SARS-CoV-2 persistence in pediatric patients, how it may impact the patient, and how it may result in post-COVID-19 conditions.

The researchers performed a literature review and analyzed studies on the presence of SARS-CoV-2 antigen or RNA in children undergoing surgery, biopsy, or autopsy for either death from the multisystem inflammatory syndrome or COVID-19 or evaluations for post-COVID-19 or other conditions in PubMed.

The review contained 21 articles following the screening and selection of identified studies. The age range of patients who underwent tissue biopsies or autopsies was one day to 17 years.

The team also analyzed why these findings may serve as a basis for future therapeutic and diagnostic studies on SARS-CoV-2 infection. They also included the personal experience of a doctor and patient in the study.

SARS-CoV-2 persistence in adults

Studies evaluating viral persistence and immunopathology in COVID-19 patients that died weeks to months following the initial infection, for any reason, showed compelling evidence that the viral parts could persist in the body.

Recent evidence reveals less efficient or lower SARS-CoV-2 clearance in non-respiratory tissues. Thus, comprehending how SARS-CoV-2 bypasses immune detection is vital for directing future therapeutic methods to promote viral clearance.

In addition, several immunological and anatomopathological studies in immunocompetent and immunocompromised adults demonstrated that SARS-CoV-2 antigens and RNA could persist in pulmonary and extra-pulmonary regions. 

These events have been observed in patients with the SARS-CoV-2 pre-Omicron variant infections. Hence, these results might not apply to individuals with the Omicron variant infection.

Nevertheless, since there is proof that even Omicron-infected patients develop post-COVID-19 conditions, until disproven, viral persistence might be a possibility even among newly infected patients.

Presence of SARS-CoV-2 in pediatric populations 

Of the 21 studies in the present review, eight articles addressed the post-mortem histopathological results and the SARS-CoV-2 RNA detection by reverse transcription polymerase chain reaction (RT-PCR) in tissues of children who had undergone autopsy due to fatal acute illness complications.

Six publications demonstrated the presence of viral RNA in the central nervous system (CNS) and other organs and tissues. Further, no SARS-CoV-2 RNA was identified in samples of the blood, cerebrospinal fluid (CSF), lungs, or brain tissue of a pediatric patient who died due to acute fulminant cerebral edema associated with COVID-19.

In three studies, pediatric patients with COVID-19-linked pneumonia showed RT-PCR-confirmed viral infection of respiratory tissues.

Furthermore, the authors noted that according to 11 studies in the present research, following an acute SARS-CoV-2 infection, the virus or at least its parts persisted for weeks to months in children’s biological fluids and tissues.

In addition, three articles depicted the post-mortem discovery of SARS-CoV-2 RNA in tissues of children with multisystem inflammatory syndrome. One case report demonstrated SARS-CoV-2 nucleocapsid proteins in the intestinal lamina propria of a young girl with ongoing gastrointestinal symptoms three months following acute SARS-CoV-2 infection.

Two articles described RT-PCR-confirmed SARS-CoV-2 persistence in adenoids and palatine tonsils of children with mild or asymptomatic acute infection. Furthermore, another study depicted SARS-CoV-2 RNA detection by RT-PCR in the CSF of a 17-year-old girl with Guillain-Barrè syndrome associated with acute COVID-19.

Two included publications examining the presence of SARS-CoV-2 RNA in tissues of stillborn babies who died following maternal COVID-19 during pregnancy detected viral RNA in their organs. The most frequent anatomopathological observations were associated with intrauterine hypoxia, asphyxia, hemosiderosis, and hepatocellular damage.

An extremely preterm baby who died four days following birth, whose mother had severe acute SARS-CoV-2 infection, had viral RNA in the neonatal liver and heart vascular endothelium, and various placental and neonatal samples.

Potential effects of SARS-CoV-2 or its particles persistence

Although the biological impacts of SARS-CoV-2 RNA persistence are uncertain, preliminary data indicate that these viral components could stimulate immune responses. A study found that the CXCR5+ CD8+ T cells may act as SARS-CoV-2 spreaders in various body regions concealing the virus or an inflammation source in long COVID.

Additionally, a pilot study documented that a subgroup of children with post-COVID-19 had an impaired capacity to switch from non-specific to acquired immune responses. 

Moreover, evidence suggests that long-term SARS-CoV-2 antigenemia can result in a hyperinflammatory presentation in multisystem inflammatory syndrome and long COVID among pediatric populations.

Although observational studies discovered a spike in new-onset immune-mediated diseases among children with a history of COVID-19, like type 1 diabetes, a clear association and causal impact between SARS-CoV-2 infection and type 1 diabetes is lacking.

Antiviral consideration for pharmacological studies in long COVID

An oral antiviral agent, nirmatrelvir, targets the SARS-CoV-2 3-chymotrypsin-like cysteine protease enzyme (Mpro), essential to the viral replication cycle. Nirmatrelvir therapy was linked to a lower risk of long COVID. A case series of four long COVID patients demonstrated improved symptoms following treatment with nirmatrelvir.

Other promising treatment options in the long COVID include immunomodulatory drugs lowering chronic inflammation, such as immunoglobulin G4 monoclonal antibody.

Although SARS-CoV-2 vaccination may not be an immunomodulatory therapy, a 2023 systematic review discovered that it has therapeutic impacts on long COVID through rebalancing and boosting the immune system. Nonetheless, no research has been published examining the same effects in pediatric populations.

Comparing long COVID to other viral infections

A study compared the symptoms of long COVID patients with psychosomatic or psychiatric patients with other infections, such as Ebola, Lyme, influenza, and chikungunya.

These clinical findings show that many people who survived infections may have long-term, detrimental effects on their health. Further, no study indicates that COVID-19 could result in symptoms as severe as post-measles subacute sclerosing panencephalitis.

Conclusions

The current study shows SARS-CoV-2 could circulate systemically and persist for weeks or months in children, regardless of the severity of the disease. Viral RNA has been found in pediatric patients who died due to critical acute SARS-CoV-2 infection and children with multisystem inflammatory syndrome with mild or asymptomatic COVID-19.

The authors discussed what is presently known about the biological impacts of SARS-CoV-2 persistence on different viral infections and outlined novel scenarios for basic, clinical, and pharmacological research exploration.

A strategy like this will help with post-viral syndrome management and comprehension. The persistence of SARS-CoV-2 RNA following infection is well known. Nevertheless, its impact on immunity, health, and chronic diseases is still not entirely understood.

The researchers suggest that the enormous scientific interest in SARS-CoV-2 presents a unique chance to learn more about the biological, therapeutic, and clinical effects of viral persistence in humans.