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

Abstract

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).

Keywords: Antibody; Children and adolescents; Delta variant; Omicron variant; Post COVID-19 condition; SARS-CoV-2 infection.

Fig. 1

Risk factors for long-term symptoms 8 months post delta infection. Forest plots show odds ratios (OR) with 95% confidence intervals (CIs) and p-values calculated by univariable binary logistic regression models using relevant symptoms. The outcomes are a fatigue, b dyspnoea and c cognitive symptoms at 8 months and relevant risk factors are age (<16 or ≥16 years), sex, symptoms at baseline and omicron reinfection status. The number and percentage (n/N, %) of individuals in each risk factor are shown with the relevant outcomes in the table and forest plot.

Fig. 2

Dynamics of long-term symptoms after delta infection by age group and omicron reinfection status. Symptoms were recorded 0- (acute), 3- and 8-months post-infection. The percentage of symptoms after delta infection are shown by continuous lines for participants 10–15 (orange) and 16–20 (light blue) years, a any symptom, b fatigue, c dyspnoea, d headache, e taste/smell distortion and f cognitive impairment. The dashed line indicates the percentage of symptoms reported at 8 months by omicron reinfected individuals. Crude risk differences were calculated between age groups after delta infection.

Fig. 3

The relationship between SARS-CoV-2 antibodies and persisting symptoms. Hemagglutination test (HAT)-specific and binding (spike IgG) antibodies and persisting symptoms 3 months post-infection. The geometric mean antibody titres (GMT) with 95% confidence intervals are shown in black. a Delta (turquoise) and Wuhan (orange) antibodies and b Wuhan spike specific IgG antibody titres (orange) in individuals with persisting (grey background) and no persisting symptoms (white background). Vaccination status is shown by circles (unvaccinated) and triangles (vaccinated). Each symbol represents one individual. The dotted line indicates a positive test (HAT titre of ≥40), associated with neutralising antibodies. Negative values were assigned a value of 5. The differences between antibody titres in groups with persisting and no persisting symptoms were compared by the Mann Whitney U test.

Fig. 4

Antibody titres in vaccinated and unvaccinated individuals. Hemagglutination test (HAT)-specific antibodies to the delta, Wuhan and omicron SARS-CoV-2 receptor binding domain (RBD), HAT titres (a,c) and percentage (%) with titres ≥40 (b,d). Sera were collected at 3 (a,b) and 8 months (c,d) post delta infection. At 3 months, individuals were divided based on pre delta infection vaccination status: vaccinated (blue, n = 35, sampled mean 76.1 days) and unvaccinated (red, n = 53, sampled mean 87.9 days). At 8 months, individuals who had never been previously COVID vaccinated were defined as unvaccinated (red, n = 39, sampled mean 147.0 days), and individuals with any previous vaccination, n = 48 (blue, n = 48, sampled mean 95.4 days). At 8 months, the percentage of reinfected individuals was comparable (54.5% in vaccinated and 66.7% in unvaccinated). Each individual is indicated by a circle. The dotted line indicates a positive test (HAT titre of ≥40), and negative values were assigned a value of 5. The geometric mean titres (GMT) with 95% confidence intervals are shown in black by horizontal lines. Vaccinated individuals were compared to unvaccinated by a Mann Whitney U test for each variant. Significant differences were maintained after adjusting for days since infection or vaccination at both time points.