Post COVID-19 condition after delta infection and omicron reinfection in children and adolescents.

BACKGROUND: The burden of COVID-19 in children and adolescents has increased during the delta and omicron waves, necessitating studies of long-term symptoms such as fatigue, dyspnoea and cognitive problems. Furthermore, immune responses in relation to persisting symptoms in younger people have not been well characterised. In this cohort study, we investigated the role of antibodies, vaccination and omicron reinfection upon persisting and long-term symptoms up to 8 months post-delta infection. METHODS: SARS-CoV-2 RT-PCR positive participants (n = 276, aged 10-20 years) were prospectively recruited in August 2021. We recorded the major symptoms of post COVID-19 condition and collected serum samples 3- and 8-months post delta infection. Binding antibodies were measured by spike IgG ELISA, and surrogate neutralising antibodies against Wuhan and delta variants by the hemagglutination test (HAT). FINDINGS: After delta infection, persisting symptoms at 3 months were significantly associated with higher delta antibody titres (OR 2.97, 95% CI 1.57-6.04, p = 0.001). Asymptomatic acute infection compared to symptomatic infection lowered the risk of persisting (OR 0.13, 95% CI 0.02-0.55, p = 0.013) and long-term (OR 0.28 95% CI 0.11-0.66, p = 0.005) symptoms at 3 and 8 months, respectively. Adolescents (16-20 years) were more likely to have long-term symptoms compared to children (10-15 years) (OR 2.44, 95% CI 1.37-4.41, p = 0.003). INTERPRETATION: This clinical and serological study compares long-term symptoms after delta infection between children and adolescents. The association between high antibody titres and persisting symptoms suggest the involvement of an immune mechanism. Similarly to adults, the dominant long-term symptoms in children are fatigue, dyspnoea and cognitive problems. FUNDING: This work was funded by the Ministry of Health and Care Services, Norway, the University of Bergen, Norway and Helse Vest, Norway (F-12621).

Durable immune responses after BNT162b2 vaccination in home-dwelling old adults.

Objectives: Elderly are an understudied, high-risk group vulnerable to severe COVID-19. We comprehensively analyzed the durability of humoral and cellular immune responses after BNT162b2 vaccination and SARS-CoV-2 infection in elderly and younger adults. Methods: Home-dwelling old (n = 100, median 86 years) and younger adults (n = 449, median 38 years) were vaccinated with two doses of BNT162b2 vaccine at 3-week intervals and followed for 9-months. Vaccine-induced responses were compared to home-isolated COVID-19 patients (n = 183, median 47 years). Our analysis included neutralizing antibodies, spike-specific IgG, memory B-cells, IFN-γ and IL-2 secreting T-cells and sequencing of the T-cell receptor (TCR) repertoire. Results: Spike-specific breadth and depth of the CD4+ and CD8+ TCR repertoires were significantly lower in the elderly after one and two vaccinations. Both vaccinations boosted IFN-γ and IL-2 secreting spike-specific T-cells responses, with 96 % of the elderly and 100 % of the younger adults responding after the second dose, although responses were not maintained at 9-months. In contrast, T-cell responses persisted up to 12-months in infected patients. Spike-specific memory B-cells were induced after the first dose in 87 % of the younger adults compared to 38 % of the elderly, which increased to 83 % after the second dose. Memory B-cells were maintained at 9-months post-vaccination in both vaccination groups. Neutralizing antibody titers were estimated to last for 1-year in younger adults but only 6-months in the older vaccinees. Interestingly, infected older patients (n = 15, median 75 years) had more durable neutralizing titers estimated to last 14-months, 8-months longer than the older vaccinees. Conclusions: Vaccine-induced spike-specific IgG and neutralizing antibodies were consistently lower in the older than younger vaccinees. Overall, our data provide valuable insights into the kinetics of the humoral and cellular immune response in the elderly after SARS-CoV-2 vaccination or infection, highlighting the need for two doses, which can guide future vaccine design.Clinical trials.gov; NCT04706390.

Symptom Burden and Immune Dynamics 6 to 18 Months Following Mild Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2): A Case-control Study.

BACKGROUND: The burden and duration of persistent symptoms after nonsevere coronavirus disease 2019 (COVID-19) remains uncertain. This study aimed to assess postinfection symptom trajectories in home-isolated COVID-19 cases compared with age- and time- matched seronegative controls, and investigate immunological correlates of long COVID. METHODS: A prospective case-control study included home-isolated COVID-19 cases between February 28 and April 4, 2020, and followed for 12 (n = 233) to 18 (n = 149) months, and 189 age-matched severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive controls. We collected clinical data at baseline, 6, 12, and 18 months postinfection, and blood samples at 2, 4, 6, and 12 months for analysis of SARS-CoV-2-specific humoral and cellular responses. RESULTS: Overall, 46% (108/233) had persisting symptoms 12 months after COVID-19. Compared with controls, adult cases had a high risk of fatigue (27% excess risk, sex, and comorbidity adjusted odds ratio [aOR] 5.86; 95% confidence interval [CI], 3.27-10.5), memory problems (21% excess risk; aOR 7.42; CI, 3.51-15.67), concentration problems (20% excess risk; aOR 8.88; 95% CI, 3.88-20.35), and dyspnea (10% excess risk; aOR 2.66; 95% CI, 1.22-5.79). The prevalence of memory problems increased overall from 6 to 18 months (excess risk 11.5%; 95% CI, 1.5-21.5; P = .024) and among women (excess risk 18.7%; 95% CI, 4.4-32.9; P = .010). Longitudinal spike immunoglobulin G was significantly associated with dyspnea at 12 months. The spike-specific clonal CD4+ T-cell receptor ß depth was significantly associated with both dyspnea and number of symptoms at 12 months. CONCLUSIONS: This study documents a high burden of persisting symptoms after mild COVID-19 and suggests that infection induced SARS-CoV-2-specific immune responses may influence long-term symptoms.

A rapid antibody screening haemagglutination test for predicting immunity to SARS-CoV-2 variants of concern.

Background: Evaluation of susceptibility to emerging SARS-CoV-2 variants of concern (VOC) requires rapid screening tests for neutralising antibodies which provide protection. Methods: Firstly, we developed a receptor-binding domain-specific haemagglutination test (HAT) to Wuhan and VOC (alpha, beta, gamma and delta) and compared to pseudotype, microneutralisation and virus neutralisation assays in 835 convalescent sera. Secondly, we investigated the antibody response using the HAT after two doses of mRNA (BNT162b2) vaccination. Sera were collected at baseline, three weeks after the first and second vaccinations from older (80-99 years, n = 89) and younger adults (23-77 years, n = 310) and compared to convalescent sera from naturally infected individuals (1-89 years, n = 307). Results: Here we show that HAT antibodies highly correlated with neutralising antibodies (R = 0.72-0.88) in convalescent sera. Home-dwelling older individuals have significantly lower antibodies to the Wuhan strain after one and two doses of BNT162b2 vaccine than younger adult vaccinees and naturally infected individuals. Moverover, a second vaccine dose boosts and broadens the antibody repertoire to VOC in naïve, not previously infected older and younger adults. Most (72-76%) older adults respond after two vaccinations to alpha and delta, but only 58-62% to beta and gamma, compared to 96-97% of younger vaccinees and 68-76% of infected individuals. Previously infected older individuals have, similarly to younger adults, high antibody titres after one vaccination. Conclusions: Overall, HAT provides a surrogate marker for neutralising antibodies, which can be used as a simple inexpensive, rapid test. HAT can be rapidly adaptable to emerging VOC for large-scale evaluation of potentially decreasing vaccine effectiveness.

Durable T-cellular and humoral responses in SARS-CoV-2 hospitalized and community patients.

BACKGROUND: Neutralizing antibodies are important for protection against the pandemic SARS-CoV-2 virus, and long-term memory responses determine the risk of re-infection or boosting after vaccination. T-cellular responses are considered important for partial protection against novel variants of concern. METHODS: A prospective cohort of hospitalized (n = 14) and community (n = 38) patients with rt-PCR confirmed SARS-CoV-2 infection were recruited. Blood samples and clinical data were collected when diagnosed and at 6 months. Serum samples were analyzed for SARS-CoV-2-spike specific antibodies using ELISA (IgG, IgA, IgM), pseudotype neutralization and microneutralization assays. Peripheral blood mononuclear cells were investigated for virus-specific T-cell responses in the interferon-γ and interleukin-2 fluorescent-linked immunosorbent spot (FluroSpot) assay. RESULTS: We found durable SARS-CoV-2 spike- and internal protein specific T-cellular responses in patients with persistent antibodies at 6 months. Significantly higher IL-2 and IFN-γ secreting T-cell responses as well as SARS-CoV-2 specific IgG and neutralizing antibodies were detected in hospitalized compared to community patients. The immune response was impacted by age, gender, comorbidity and severity of illness, reflecting clinical observations. CONCLUSIONS: SARS-CoV-2 specific T-cellular and antibody responses persisted for 6 months post confirmed infection. In previously infected patients, re-exposure or vaccination will boost long-term immunity, possibly providing protection against re-infection with variant viruses.

Lower antibiotic prescription rates in hospitalized COVID-19 patients than influenza patients, a prospective study.

BACKGROUND: COVID-19 patients are extensively treated with antibiotics despite few bacterial complications. We aimed to study antibiotic use in hospitalized COVID-19 patients compared to influenza patients in two consecutive years. Furthermore, we investigated changes in antibiotic use from the first to second pandemic wave. METHODS: This prospective study included both patients from two referral hospitals in Bergen, Norway, admitted with influenza (n = 215) during the 2018/2019 epidemic and with COVID-19 (n = 82) during spring/summer 2020, and national data on registered Norwegian COVID-19 hospital admissions from March 2020 to January 2021 (n = 2300). Patient characteristics were compared, and logistic regression analysis was used to identify risk factors for antibiotic use. RESULTS: National and local COVID-19 patients received significantly less antibiotics (53% and 49%) than influenza patients (69%, p < .001). Early antibiotics contributed to >90% of antibiotic prescriptions in the two local hospitals, and >70% of prescriptions nationally. When adjusted for age, comorbidities, symptom duration, chest X-ray infiltrates and oxygen treatment, local COVID-19 patients still had significantly lower odds of antibiotic prescription than influenza patients (aOR 0.21, 95%CI 0.09-0.50). At the national level, we observed a significant reduction in antibiotic prescription rates in the second pandemic wave compared to the first (aOR 0.35, 95% CI 0.29-0.43). CONCLUSION: Fewer COVID-19 patients received antibiotics compared to influenza patients admitted to the two local hospitals one year earlier. The antibiotic prescription rate was lower during the second pandemic wave, possibly due to increased clinical experience and published evidence refuting the efficacy of antibiotics in treating COVID-19 pneumonia.

Point-of-Care Influenza Testing Impacts Clinical Decision, Patient Flow, and Length of Stay in Hospitalized Adults.

BACKGROUND: Influenza is difficult to distinguish clinically from other acute respiratory infections. Rapid laboratory diagnosis can help initiate early effective antiviral treatment and isolation. Implementing a novel point-of-care test (POCT) for influenza in the emergency department (ED) could improve treatment and isolation strategies and reduce the length of stay (LOS). METHODS: In a prospective, controlled observational cohort study, we enrolled patients admitted due to acute respiratory illness to 2 public hospitals in Bergen, Norway, one using a rapid POCT for influenza (n = 400), the other (n = 167) using conventional rapid laboratory-based assay. RESULTS: Prevalence of influenza was similar in the 2 hospitals (154/400, 38% vs 38%, 63/167; P = .863). Most patients in both hospitals received antiviral (83% vs 81%; P = .703) and antibiotic treatment (72% vs 62%; P = .149). Isolation was more often initiated in ED in the hospital using POCT (91% vs 80%; P = .025). Diagnosis by POCT was associated with shorter hospital stay; old age, diabetes, cancer, and use of antibiotics, particularly broad-spectrum antibiotics, were associated with prolonged stay. CONCLUSIONS: POCT implementation in ED resulted in improved targeted isolation and shorter LOS. Regardless of POCT use, most influenza patients received antivirals (>80%) and antibiotics (>69%).