Problems with iron regulation in the blood following infection with SARS-CoV-2 may be a key factor leading to long COVID, according to new research published in Nature Immunology by teams at the University of Cambridge and the University of Oxford. The study suggests that disrupted iron levels and ongoing inflammation could help explain persistent symptoms experienced by many after COVID-19, as well as similar issues observed in other post-viral syndromes.
The research followed participants from the start of the pandemic, recruiting individuals who tested positive for SARS-CoV-2 through the National Institute for Health and Care Research (NIHR) BioResource. The cohort included healthcare staff and patients admitted to Cambridge University Hospitals NHS Foundation Trust. Over a year, researchers collected blood samples to track changes post-infection and identify markers linked to long-term symptoms.
Of 214 individuals analyzed, about 45% reported symptoms consistent with long COVID between three and ten months after their initial infection. These symptoms include fatigue, shortness of breath, muscle aches, and cognitive difficulties often referred to as "brain fog." According to the Office of National Statistics, around 1.9 million people in the UK were self-reporting long COVID as of March 2023.
Professor Ken Smith, Director of CITIID at the time of the study and incoming Director of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, commented: "Having recruited a group of people with SARS-CoV-2 early in the pandemic, analysis of several blood samples and clinical information collected over a 12 month period after infection has proved invaluable in giving us important and unexpected insights into why, for some unlucky individuals, initial SARS-CoV-2 infection is followed by months of persistent symptoms."
The team found that low iron levels contributing to anemia appeared as early as two weeks after COVID-19 infection among those who later developed long COVID. This effect was observed regardless of age, sex, or severity of initial illness—suggesting even those not hospitalized could be affected.
Dr Aimee Hanson, formerly at Cambridge and now at Bristol University, explained: "Iron levels, and the way the body regulates iron, were disrupted early on during SARS-CoV-2 infection, and took a very long time to recover, particularly in those people who went on to report long COVID months later.
"Although we saw evidence that the body was trying to rectify low iron availability and the resulting anaemia by producing more red blood cells, it was not doing a particularly good job of it in the face of ongoing inflammation."
Notably, both severe cases requiring hospitalization and milder cases showed similar patterns if they developed long COVID later on. The main link was how quickly inflammation resolved and iron regulation returned to normal; however, symptoms often continued even after blood markers improved.
Co-author Professor Hal Drakesmith from Oxford’s MRC Weatherall Institute described how this process works: "When the body has an infection, it responds by removing iron from the bloodstream. This protects us from potentially lethal bacteria that capture the iron in the bloodstream and grow rapidly. It's an evolutionary response that redistributes iron in the body, and the blood plasma becomes an iron desert.
"However, if this goes on for a long time, there is less iron for red blood cells... The protective mechanism ends up becoming a problem."
The findings indicate possible strategies for preventing or treating long COVID by addressing iron dysregulation early during acute infection. One suggestion is controlling inflammation promptly; another involves remobilizing trapped iron rather than simply supplementing it.
Dr Hanson cautioned: "It isn't necessarily the case that individuals don't have enough iron in their body; it's just that it's trapped in the wrong place... What we need is a way to remobilise the iron and pull it back into the bloodstream..."
Other studies have noted similar effects—for example, preliminary results from trials like IRONMAN suggest patients receiving certain types of iron supplementation had better outcomes during COVID-19 disruptions. Comparable trends are seen among people with beta-thalassemia—a disorder causing excess circulating iron—who may experience different responses during viral infections.
This work received funding support from Wellcome Trust, Medical Research Council (MRC), NIHR (National Institute for Health Research), and European Union Horizon 2020 Programme.
