Early viral activity plays critical role in long COVID, study suggests

By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Sep 2 2024

In a recent study published in Nature Communications, researchers explored the roles of acute-phase virological dynamics and host immunological responses in post-acute infection sequelae of coronavirus disease 2019 (PASC).

Background

Persistent symptoms following acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 infection) characterize PASC. The pathophysiology of PASC is uncertain, with numerous theories under investigation. Recent research suggests that PASC patients have SARS-CoV-2 antigens in their serum after acute infection, with subgenomic ribonucleic acid (RNA) found in tissues six months after COVID-19.

Studies comparing PASC patients to those with complete COVID-19 recovery have revealed elevated levels of inflammatory markers lasting at least 12 months. However, biological specimens to identify PASC determinants from acute and initial post-acute COVID-19 periods are scarce, with most research evaluating short-term outcomes among hospitalized patients.

About the study

In the present study, researchers analyzed a household cohort of acute COVID-19 patients to investigate early biological predictors of post-acute COVID-19 sequelae by comparing individuals who developed PASC to fully recovered individuals. They investigated whether specific biological mechanisms during acute infection led to prolonged symptomatology after acute sickness.

Between September 2020 and May 2022, the researchers enrolled 136 participants within five days of their initial SARS-CoV-2-positive real-time polymerase chain reaction (PCR) report from San Francisco. Participants self-obtained up to 21 nasal specimens in the initial four weeks post-symptom onset. Study questionnaires and serum samples were collected at baseline, nine days, two weeks, three weeks, four weeks, four months, and eight months following symptom onset. The questionnaires provided data on sociodemographic characteristics, medical history, COVID-19 symptoms, SARS-CoV-2 vaccinations, and quality of life.

The researchers ascertained PASC based on COVID-19-related symptom presence two to six months after acute infection. Researchers compared viral biomarkers and host immunological markers among individuals who developed PASC and those who did not. Viral markers included the duration and quantity of nasal SARS-CoV-2 RNA, infectious viral load, and serum N-antigen levels. Host immunological markers including interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), interferon-alpha (IFN-α), interferon-gamma (IFN-γ), membrane cofactor protein (MCP), IFN-γ-induced protein 10 (IP-10), and anti-SARS-CoV-2 spike immunoglobulin G (IgG).

Quantitative and real-time reverse transcription PCR targeting SARS-CoV-2 nucleocapsid (N) and envelope (E) genes assessed acute SARS-CoV-2 RNA levels in nasal specimens. Researchers determined SARS-CoV-2 presence by evaluating cytopathic effects (CPE) in Vero cells expressing human angiotensin-converting enzyme 2 (hACE2) and transmembrane serine protease 2 (TMPRSS2). They used logistic regressions and generalized estimating equations (GEE) for analysis. They also performed sensitivity analyses with and without corrections for multiple comparisons.

Results

The median participant age was 36 years; 51% were female, 77% were disease-free, 14% had pulmonary disease, 10% were hypertensive, and 5.0% had diabetes. Among the participants, 93% had pre-SARS-CoV-2 Omicron variant infections, and 65% were not vaccinated against COVID-19 before acute infection. Throughout acute COVID-19, 96 (92%) individuals experienced one or more symptoms (median, nine symptoms); 76% experienced fatigue, 74% developed rhinorrhea, 71% had a cough, 54% had headaches, and 46% developed a sore throat. 

Among 104 individuals infected with SARS-CoV-2 with a follow-up in the post-acute period, 32 (31%) developed PASC. All individuals with PASC experienced 12 symptoms (median) during their acute illness and two symptoms two to six months after acute COVID-19. The most common symptoms of PASC were memory or concentration difficulties (44%), sleep difficulties (28%), rhinorrhea (25%), and fatigue (25%).

Compared to fully recovered individuals, those reporting PASC showed significantly higher maximal nasal viral RNA load and serum N-antigen level. PASC development was related to a higher percentage of nasal SARS-CoV-2 RNA positivity and SARS-CoV-2 shedding during the four weeks after symptom onset and lower anti-spike IgG levels within nine days post-disease onset.

However, these differences attenuated after two weeks, with individuals who developed PASC and those who did not show similar spike IgG titers by four weeks. Anti-SARS-CoV-2 receptor-binding domain (RBD) IgG titers among unvaccinated individuals increased in the four weeks following symptom onset. The differences among host immunological markers were not statistically significant. Sensitivity analyses yielded similar results.

Conclusion

The study demonstrates that early viral dynamics and host immune responses are critical in the pathogenesis of PASC. Viral RNA and N-antigen levels, RNA and infectious virus shedding load, and antibody formation timing may all play a role in PASC pathogenesis.

These early biological indicators might be part of a wider chain of events during the early stages of SARS-CoV-2 infection. Further research on the acute phase of COVID-19 is required to improve the understanding of the underlying causes of PASC and find therapies to prevent or treat the disorder.