Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: a cross-sectional study

Abstract

Objective

Post-COVID syndrome (PCS) is a poorly known entity. An underlying chronic, low-grade inflammation (LGI) has been theorized as a pathophysiological mechanism. Available data on biomarkers in PCS show conflicting results. Our aim was to know whether subjects with PCS present higher levels of inflammatory markers, after a mild COVID-19.

Methods

Analytical cross-sectional study. Cases of mild COVID-19 in a community setting were included. We collected epidemiological data (age, sex, BMI, smoking, comorbidities), variables of the acute COVID-19 (duration, symptoms), and data at 3 months after the acute phase (symptoms and laboratory test). Serum C-reactive protein (CRP), neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio (NLR), lactate dehydrogenase, ferritin, fibrinogen, and D-dimer levels were analysed. LGI was defined as CRP >0.3 and <1.0 mg/dL. A subject was classified as PCS + if presented signs and symptoms >12 weeks after an infection consistent with COVID-19. Five composite indices (C1–C5) were developed, combining the upper ranges of biomarkers distributions. Multivariate analyses were performed.

Results

We analysed 121 mild COVID-19 cases (mean age = 45.7 years, 56.2% women). Among the acute symptoms, women presented a higher frequency of fatigue (54.4% vs 30.2%; p = .008). PCS affected 35.8% of women and 20.8% of men (p = .07), and the most reported symptoms were fatigue (42.8%), anosmia (40%), ageusia (22.8%), dyspnea (17.1%) and myalgia (11.4%). Neutrophil count, NLR, CRP and fibrinogen showed the best correlations with PCS and were selected to develop the indices. In women PCS+, C1, C3 and C4 indices were more frequently met, while in men PCS+, C2, C5 and CRP were in the range of LGI. Anosmia, ageusia and fatigue were related to higher neutrophil counts, with sex differences. Fibrinogen levels were higher in persistent myalgia (510 ± 82 mg/dL vs 394 ± 87; p = .013). In multivariable analysis, a woman with a neutrophil count above the median, or with fibrinogen level or NLR in the highest tertile, had a 4–5-fold increased risk of prevalent PCS. A man with CRP in the range of LGI, or fibrinogen level or a neutrophil count in the highest tertile, had a 10–17-fold increased risk of prevalent PCS.

Conclusions

The data obtained in the present cross-sectional study seems to demonstrate a consistent association between PCS and upper ranges of the neutrophil count, NLR, fibrinogen, and CRP in the LGI range. Furthermore, composite indices appear useful in detecting relationships between slight elevations of biomarkers and PCS, and our study identifies relevant sex differences in symptoms and markers regarding the PCS.

Keywords:

• Post-COVID syndrome
• low-grade inflammation
• inflammatory markers
• mild COVID-19

Transparency

Declaration of funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of financial/other relationships

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Conception and design of the work: MM, AA, EP; Acquisition of data: YR, SG, MT; Analysis of data: SDS, MT; Interpretation of data: EP, PF, SDS; Drafting the manuscript: CR, EP; Revising the manuscript critically: JMO, JLH; Approval of the final version: MM, AA, EP, PF, YR, SG, MT, SDS, CR, JMO, JLH

Data availability statement

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics statement

The study was approved by the Cantabria Clinical Research Ethics Committee (Internal Code 2021.102). All patients who met the inclusion criteria were informed of the purpose of the study with the delivery of an information sheet and were invited to participate. All of them expressed their verbal consent and there was no refusal to participate.