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Background: Healthcare-associated SARS-CoV-2 infections need to be explored further. Our study is an analysis of hospital-acquired infections (HAIs) and ambulatory healthcare workers (aHCWs) with SARS-CoV-2 across the pandemic in a Belgian university hospital. Methods: We compared HAIs with community-associated infections (CAIs) to identify the factors associated with having an HAI. We then performed a genomic cluster analysis of HAIs and aHCWs. We used this alongside the European Centre for Disease Control (ECDC) case source classifications of an HAI. Results: Between March 2020 and March 2022, 269 patients had an HAI. A lower BMI, a worse frailty index, lower C-reactive protein (CRP), and a higher thrombocyte count as well as death and length of stay were significantly associated with having an HAI. Using those variables to predict HAIs versus CAIs, we obtained a positive predictive value (PPV) of 83.6% and a negative predictive value (NPV) of 82.2%; the area under the ROC was 0.89. Genomic cluster analyses and representations on epicurves and minimal spanning trees delivered further insights into HAI dynamics across different pandemic waves. The genomic data were also compared with the clinical ECDC definitions for HAIs; we found that 90.0% of the ‘definite’, 87.8% of the ‘probable’, and 70.3% of the ‘indeterminate’ HAIs belonged to one of the twenty-two COVID-19 genomic clusters we identified. Conclusions: We propose a novel prediction model for HAIs. In addition, we show that the management of nosocomial outbreaks will benefit from genome sequencing analyses.

This case report describes a 60-year-old female patient suffering from systemic sclerosis, for which she received immunomodulatory drugs. Her first SARS-CoV-2-positive nasopharyngeal sample was obtained in the emergency department, on 31 January 2022. Whole genome sequencing confirmed infection with Omicron BA.1.1. Her hospital stay was long and punctuated by many complications, including admission to the intensive care unit. At the beginning of April 2022, she started complaining of increased coughing, for which another SARS-CoV-2 RT-qPCR test was performed. The latter nasopharyngeal swab showed a strongly positive result. To support the theory of healthcare-associated reinfection, whole genome sequencing was performed and confirmed reinfection with Omicron BA.2. Since this patient was one of ten positive cases in this particular ward, a hospital outbreak investigation was performed. Whole genome sequencing data were available for five of these ten patients and showed a cluster of four patients with ≤2 small nucleotide polymorphisms difference.