HLI StoriesHow Long COVID Affects the Immune System and Metabolism in Non-Hospitalized Healthcare Workers

This work was supported by the Canadian Institutes of Health Research (CIHR Grant No. 177747) and Mitacs Inc. (IT44473 / UBC No. F22-01762). It was published in Frontiers in Cellular and Infection Microbiology, and can be accessed here.

Long COVID continues to affect millions of people worldwide, yet the biological changes underlying the persistent symptoms that people experience are still not well understood. One major challenge is the lack of reliable biomarkers—biological signs or molecules, measured in the body—that could help improve diagnosis and guide care. Most biomarker studies have focused on hospitalized patients with severe disease, leaving non-hospitalized populations, particularly healthcare workers, who are at high occupational risk, underrepresented. These workers are an important group to study as they have high exposure risk and frequent reports of long-lasting symptoms.

Recent work suggests that long COVID occurs because of persistent viral reservoirs (sites where viruses persist, evading the immune system) and immune dysregulation, leading to chronic inflammation and blood vessel injury.

_{“My name is Estefanía Espín, and I am a PhD student in the Tebbutt Lab at the Centre for Heart Lung Innovation. Our lab, in collaboration with the PROOF Centre of Excellence, focuses on the analysis of genes, proteins, and metabolites to develop biomarkers for a range of health conditions.“}

_{“My PhD research focuses on identifying biomarkers for long COVID. As part of this work, I conducted and published a scoping review of long COVID biomarkers, followed by a qualitative study exploring the experiences of patients and clinicians and their expectations regarding biomarker research (currently under review). I also led the pilot multi-omics study that we have recently published, and I am now validating these findings in a larger independent cohort.”}

To investigate this further, we coincidentally had the opportunity to collaborate with Dr. Brian Grunau and Dr. David Goldfarb, researchers leading the COVID-19 Occupational Risks, Seroprevalence, and Immunity among Paramedics in Canada (CORSIP) study, a prospective longitudinal cohort of adult paramedics. The CORSIP team had collected blood samples and health questionnaire data from study participants, allowing us to access samples and data from the British Columbia cohort.

Among the 1,706 participants, we identified 17 healthcare workers with long COVID, defined according to World Health Organization guidelines. Of these, 12 had available blood samples, and all happened to have experienced non-hospitalized COVID-19. We then conducted a small exploratory study comparing biological changes in participants with long COVID to those in individuals who had recovered from COVID-19 without persistent symptoms.

We analyzed two complementary biological measures: gene expression in blood cells and circulating small molecules (metabolites). For the metabolomic analysis, we also examined how these changes evolved over time using samples collected both before and after SARS-CoV-2 infection.

We found evidence of persistent activation of immune-related pathways, particularly those linked to early inflammatory responses. Several of the affected genes we found are involved in neutrophil activity, a key component of the body’s first-line immune defense. These findings suggest that in some individuals, immune activation may persist long after their initial SARS-CoV-2 infection has resolved.

At the same time, we observed changes in molecules involved in energy production, metabolism, and brain-related biochemical pathways. One metabolite in particular, oxoglutarate, showed opposite patterns over time in people with long COVID compared to those who recovered fully, suggesting differences in how the body adapts after infection.

When we integrated these immune and metabolic findings, we saw that they were connected rather than independent. The affected pathways pointed toward ongoing inflammation, cellular stress, and changes in signaling systems that may be relevant to long COVID symptoms, such as fatigue, brain fog, and reduced cognitive function. These were the symptoms reported by the healthcare workers in this study, as seen in other non-hospitalized long COVID populations.

Overall, our exploratory work suggests that long COVID may involve coordinated changes across both the immune system and metabolism. Although larger studies should be carried out to confirm our findings, understanding these interconnected biological changes may help guide future efforts to develop better diagnostic tools and more targeted approaches to care.