The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to present a major healthcare burden globally, with over 170,000,000 confirmed cases and 3,500,000 deaths worldwide [
1]. Coronavirus Disease 2019 (COVID-19) has a spectrum of severity, and while the vast majority of cases result in a minor self-limiting illness, approximately 5% of patients will become critically unwell with severe respiratory failure which can progress to sepsis and multiple organ failure [
2,
3]. Despite recent advances in treatment strategies, the mortality rate for COVID-19 patients admitted to the intensive care unit (ICU) in Scotland remains high at around 35% [
4,
5].
The incidence of secondary infections in hospitalised patients with COVID-19 appears relatively low with rates between 6 and 15% [
6‐
8]. However the rates are significantly higher in critically ill patients and carry a mortality rate of around 50% [
8‐
10]. The clinical features of COVID-19 such as pyrexia, cough and dyspnoea are non-specific and are also observed in bacterial pneumonia [
11]. It can therefore be difficult to make a diagnosis of secondary infection by clinical means [
12]. Biomarkers such as lactate, C-reactive protein (CRP) and procalcitonin have a well-established role in identifying septic patients who are at risk of further deterioration, but as of yet a specific biomarker to detect the presence of a secondary infection remains elusive [
13‐
15]. As such, liberal use of broad spectrum antibiotics has been observed in critically ill COVID-19 patients [
2]. The World Health Organisation (WHO) and the Surviving Sepsis Campaign both recommend initiating empirical antibiotics for all severe cases of COVID-19 [
12,
16], whereas the National Institutes of Health (NIH) and the National Institute for Health and Care Excellence (NICE) suggest only starting antibiotics when there is a clear clinical suspicion of a secondary infection [
17,
18]. Early initiation of antibiotic therapy has been shown to reduce mortality in bacterial sepsis [
19], however unnecessary use of broad spectrum antibiotics increases the risk of side effects and promotes antimicrobial resistance [
20]. Prompt diagnosis of a secondary infection and identification of the causative pathogen is therefore important in optimal management. Microbiological cultures can guide antimicrobial therapy, but these are time-consuming, and have a low sensitivity [
21]. Alternative diagnostic strategies to improve sensitivity and provide rapid specificity would therefore be valuable.
All infections have the potential to cause major disruption to physiological processes, potentially leading to a degree of metabolic dysfunction [
22,
23]. This can lead to alteration of the normal serum metabolome (all low molecular weight metabolites less than 1 kDa circulating in the bloodstream at a given point in time) [
24]. The physiological response to an infection can result in depletion of certain important nutrients, while simultaneously causing accumulation of other toxic by-products [
23]. As such, variation in the composition of the metabolome can be indicative of pathological processes occurring further upstream [
24].