Severe, primary, and incidental COVID-19 in hospitalised children, South Africa: 2020–2023

Background: Knowledge gaps persist regarding paediatric COVID-19 clinical presentation, treatment and outcomes in high HIV prevalence settings, with low COVID-19 vaccine coverage. Methods: An ambi-directional cohort study was conducted in 13 South African public sector hospitals. Hospitalised children with SARS-CoV-2 infection or post-infection syndrome were included. Main outcomes measures included severe disease and primary COVID-19 (hospitalisation for SARS-CoV-2 infection). Results: There were 2363 SARS-CoV-2 positive children included (March 2020 through May 2023); median age 23.6 months (interquartile range (IQR) = 4.3-98.2 months). Excluding missing values, 1618 (68.9%) children had primary COVID-19; 1121 (69.3%) of these had severe primary COVID-19. In the primary COVID-19 group with data, 318 / 1588 (20.0%) received intensive or high care, 121/1285 (9.4%) received a blood transfusion and 48/1616 (3.0%) died. Multivariable analyses demonstrated that severe primary COVID-19 was 32% higher in children aged 29-365 days (adjusted Risk Ratio (aRR) = 1.32 (95% confidence interval (CI) = 1.13-1.55); reference: 0-28 days), 13% higher with one or more comorbidities (aRR = 1.13; CI = 1.05-1.22)), and 14-22% lower during the Beta, Delta and Omicron periods (reference: ancestral period). Amongst all hospitalised children with a positive SARS-CoV-2 test, severe disease was commoner in underweight children (aRR 1.09; CI = 1.02-1.17, P = 0.013)). Severe signs were commoner in children living with HIV (CLHIV), 88/121 (72.7%), vs. HIV uninfected 1320 / 2104 (62.7%), P = 0.026, and in antiretroviral therapy-naïve CLHIV, (37 / 41 (90.2%), vs. CLHIV on therapy 51 / 80 (63.8%), P = 0.002). Conclusions: In a high HIV prevalence country, approximately 70% of children with a positive SARS-CoV-2 test were hospitalised for COVID-19 treatment; almost 70% of these children were severely ill. Controlling for other factors, disease severity was highest in the hypothesised pre-immunity Ancestral period. HIV infection and delayed ART initiation were associated with severe signs. In such settings, strengthening general child health programmes to reduce underweight and prevent or treat paediatric HIV may reduce the severity of new diseases of pandemic proportion.