Nationwide study finds no convincing biomarkers for long COVID, with lower INR the only standout finding

A nationwide population-based study accepted for publication in Scientific Reports has found no convincing clinical, neurological, or blood biomarkers for long COVID (搜索)搜索该疾病, despite testing dozens of potential clues. The only finding that stood out — a lower international normalized ratio (INR) among those with persistent symptoms — remained within the normal range and therefore carried no clinical significance.

The study, conducted among residents of the Faroe Islands who contracted COVID-19 (搜索)搜索该疾病 during the early phase of the pandemic, combined clinical examinations, neurological testing, and routine blood markers in an effort to identify a measurable biological signature for the condition.

Study Design and Cohort

In March 2020, the Faroe Islands' Ministry of Health established a dedicated task force to monitor all polymerase chain reaction (PCR)-confirmed COVID-19 (搜索)搜索该疾病 cases and their contacts every 48 hours for symptoms and hospitalization needs. A total of 324 individuals infected in either spring (March–April) or autumn (August–October) 2020 were eligible and invited to participate, each having been monitored for at least 3 months.

Of the 324 eligible individuals, 273 participated in the clinical follow-up, and 218 were included in the final analysis. Participants completed baseline and symptom questionnaires via telephone interviews conducted up to 6 times over an 8-month period, retrospectively reporting symptoms experienced during acute infection and whether they persisted. The follow-up phase ran from September 2020 to March 2021.

A 21-item symptom questionnaire rated symptoms on a 0–3 scale. Clinical examinations measured vital signs and assessed the heart and lungs. Neurological evaluations covered cranial nerves, muscle strength, sensation, reflexes, tactile and vibration sensitivity, and neuromotor control, with additional tests for smell, taste, vision, and hearing. Paraclinical assessments included electrocardiograms (ECGs), lung function tests (spirometry), and blood tests for hematological, renal, liver, and endocrine markers.

Key Findings

After an average follow-up period of 192 days, 41% of participants reported moderate or severe symptoms and were classified as having long COVID (搜索)搜索该疾病 for the study's statistical analyses. The most commonly assessed symptoms were fatigue and loss of smell or taste, while many participants also reported cognitive issues not included in the symptom questionnaire. The authors cautioned that the relatively high proportion classified as having long COVID probably did not reflect its true prevalence in the population.

The group with long COVID (搜索)搜索该疾病 had more symptoms, a higher body mass index (BMI), more hospital admissions during acute illness, and more smokers compared to those without long COVID. No reinfections were reported, and only three participants were vaccinated.

No prespecified baseline predictors were significantly associated with long COVID (搜索)搜索该疾病 in the multivariable analysis, except that having more acute-phase symptoms was borderline significant. Clinical and neurological assessments showed no significant associations with long COVID in univariable analyses. Participants in the first wave had higher odds of long COVID than those in the second wave, although the researchers said the reason for this difference was unclear.

In blood biomarker analysis, higher neutrophil counts were associated with long COVID (搜索)搜索该疾病 in univariable analysis, but this was not confirmed in the adjusted (penalized) model.

Lower mean INR values were observed in participants with long COVID (搜索)搜索该疾病 (0.9) compared to those without (1.0). INR is a standardized measure of how quickly blood clots and is commonly used to assess coagulation, particularly in people taking anticoagulant medication. Although lower INR was statistically associated with long COVID, all INR values were within the normal range, so no clinical significance was observed. The finding, therefore, should not be interpreted as evidence of abnormal blood clotting.

The association between lower INR and long COVID (搜索)搜索该疾病 remained consistent across different analyses, including alternative symptom-severity groupings, inclusion of more participants, and separate analyses by COVID-19 (搜索)搜索该疾病 wave. The link between INR and long COVID was observed in both waves, though it was not always statistically significant in smaller subgroups.

Context and Limitations

Current estimates suggest that approximately 6% of those who contract COVID-19 (搜索)搜索该疾病 develop long COVID (搜索)搜索该疾病, though this figure varies by population and setting. The risk appears to have declined over time, likely due to vaccination, prior immunity, and changes in circulating viral variants. More than 200 symptoms have been associated with long COVID, with severe fatigue, cognitive dysfunction, and dysautonomia among the most debilitating. The underlying causes are not yet fully understood but may involve viral persistence, immune system disruption, autoimmunity, and multi-organ effects.

Previous studies have identified several risk factors for developing long COVID (搜索)搜索该疾病, including female sex, older age, pre-existing chronic conditions, severe acute illness, and recurrent infections. In contrast, vaccination and antiviral treatments appear to reduce the risk. However, efforts to identify reliable biomarkers have been hindered by inconsistencies in study design and varying definitions of the condition.

The authors underscored several limitations that constrained interpretation of the findings: the relatively small sample size, reliance on self-reported symptom severity, absence of an uninfected control group, multiple exploratory analyses, and lack of internal or external validation. They concluded that validation in larger, rigorously designed studies is needed to determine whether any of these findings have clinical relevance, reinforcing the ongoing challenge of identifying reliable biomarkers for long COVID (搜索)搜索该疾病.