The Impact of Real-Time Whole-Genome Sequencing in Controlling Healthcare-Associated SARS-CoV-2 Outbreaks

Abstract

Nosocomial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have severely affected bed capacity and patient flow. We utilized whole-genome sequencing (WGS) to identify outbreaks and focus infection control resources and intervention during the United Kingdom's second pandemic wave in late 2020. Phylogenetic analysis of WGS and epidemiological data pinpointed an initial transmission event to an admission ward, with immediate prior community infection linkage documented. High incidence of asymptomatic staff infection with genetically identical viral sequences was also observed, which may have contributed to the propagation of the outbreak. WGS allowed timely nosocomial transmission intervention measures, including admissions ward point-of-care testing and introduction of portable HEPA14 filters. Conversely, WGS excluded nosocomial transmission in 2 instances with temporospatial linkage, conserving time and resources. In summary, WGS significantly enhanced understanding of SARS-CoV-2 clusters in a hospital setting, both identifying high-risk areas and conversely validating existing control measures in other units, maintaining clinical service overall.

Keywords: SARS-CoV-2; cluster; genetic epidemiology; infection control; nosocomial transmission; outbreak; virus; whole-genome sequencing: COVID-19.

Figure 1.

Cluster 1 outbreak timeline, showing patients (A to O), ward location, designation and SARS-CoV-2 RT-PCR testing in relation to time in days, with day 0 marking the admission of patients A and B to ward X. The temporospatial window for the putative initial transmission event on ward X, with patients A and B sharing a bay with patient C for 6 hours only on day 1, is highlighted by a red box. Temporal SARS-CoV-2 RT-PCR positivity and healthcare role is also presented for staff (A to L) who were linked by both classical and genomic epidemiology. All staff, with the exception of bank staff L, were based on ward Y. Whole-genome sequencing determined viral sequences in all patients and staff belonged to the same lineage with the exception of staff B and D (Supplementary Table 1). The color scheme key denotes ward location and RT-PCR test results, with broken timelines indicating discharge and subsequent readmission of the patient. Abbreviations: RT-PCR, reverse transcription polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

Snipit plot from the CIVET tool (https://github.com/artic-network/civet) showing 29 SNPs and genomic positions differing from the B.1.177 reference sequence for samples associated with cluster 1. SNPs highlighted in yellow boxes are shared between all samples including those from the community surveillance. The G12052T SNP (highlighted in the red box) is shared between all samples taken from patients and staff within the hospital environment. N indicates positions in samples where no base was called and relative base position in the SARS-CoV-2 genome is indicated at the foot of the figure. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SNP, single-nucleotide polymorphism.

Figure 3.

Phylogenetic relationship by maximum likelihood analysis of all whole-genome SARS-CoV-2 sequences (29574 bases) from described hospital clusters 1 (colored in red, purple, and brown for wards Y, J, and K, respectively), 2 (blue), and 3 (green) and contemporary sequences from Nottingham, UK collected between 1 September 2020 and 30 October 2020 (A) and additional sequences sharing SNP G12052T in the B.1.177.57 lineage. Distinct subgrouping of cluster 2 and 3 sequences is supported by bootstrap values of 99.2 and 100 respectively for basal branches (not shown). B, Focused phylogenetic subtree of cluster 1, colored as per (A). Dashed lines indicate branches for community samples sequenced elsewhere without metadata available for further investigation; numbers above individual branches indicate SH-aLRT (Shimodaira–Hasegawa approximate likelihood ratio test) bootstrap support with values less than 70 not shown, and some values of 100 indicated by an asterisk for clarity. Sequences that did not meet the > 95% genomic coverage criteria were excluded from the analysis. Sequences are identified by their COVID-19 Genomics UK Consortium accession numbers. Branch lengths are drawn to a scale of nucleotide substitutions per site, with scale indicated. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SNP, single-nucleotide polymorphism.

Figure 4.

Snip-it plot from the CIVET tool (https://github.com/artic-network/civet) showing single-nucleotide polymorphisms and genomic positions differing between viral sequences from individuals involved in clusters 2 and 3 and the ancestral Wuhan-Hu-1 lineage B reference sequence (MN908947.3) Relative base position in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome and study sequence lineages are indicated at the foot and right of the plot, respectively.