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.

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

INTRODUCTION AND OBJECTIVEPost-COVID syndrome (PCS) is a poorly-known entity. Underlying low-grade inflammation (LGI) has been theorized as one of its pathophysiological mechanisms. We aimed to investigate a possible relationship between PCS and an increase in inflammation markers, in a sex-stratified analysis.PARTICIPANTS AND METHODSMild cases of COVID-19 according to the WHO classification followed-up in a Primary Care Center, were included. We collected epidemiological data (age, sex, body mass index -BMI-, smoking, and comorbidities -Charlson index-), variables of the acute COVID-19 episode, and data at 3 months of follow-up (clinical manifestations and inflammatory markers). Serum C-reactive protein (CRP), neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio (NLR), lactate dehydrogenase (LDH), ferritin, fibrinogen, and D-dimer levels were analyzed. Low-grade inflammation (LGI) was defined as serum CRP between >0.3 and <1.0 mg/dL. Five composite indices were built combining the upper ranges of 4 markers. Bivariate and multivariate analyses (logistic regression and general linear models) were performed, stratified by sex.RESULTSWe analyzed 121 subjects with mild COVID-19 (56.2% women; mean age 46 years). The most common symptom in the acute episode was fever (60.3%), while it was fatigue in PCS (42.8%). Prevalence of PCS was 35.8% in women and 20.8% in men (p = 0.07).In women, after controlling for age, BMI, smoking, and comorbidities, the D1, D3, and D4 indices were consistently associated with PCS, with ORs of 5.14 (95% CI, 1.6-16.4), 4.20 (95% CI, 1.3-13.3), and 4.12 (95% CI, 1.3-13.1), respectively; in patients with post-COVID anosmia and ageusia, neutrophils were significantly elevated (3.43±0.3 vs 2.58±0.1; p = 0.014, and 3.89±0.3 vs 2.59±0.1; p = 0.002,respectively), after adjusting for confounders.In men, the D2 and D5 indices were associated with PCS, with adjusted ORs of 10.1 (95% CI, 1.2-85) and 17.5 (95% CI, 2-153), respectively. Furthermore, serum CRP in the LGI range was associated with PCS [adjusted OR=12.9 (95% CI, 1.3-121)], and in post-COVID persistent fatigue, the neutrophil count was significantly elevated (4.68±0.6 vs 3.37±0.1; p = 0.041), after controlling for confounders.CONCLUSIONSConsistent associations among PCS, anosmia, ageusia, and fatigue, with slight -but significant-elevated levels of inflammatory markers, have been observed. The neutrophil count was the most frequently involved marker. Sex-stratified analyses showed relevant differences between women and men concerning PCS and serum inflammatory markers.

Objective The ABO system modulates the inflammatory response, and it has been involved in SARS-CoV-2 infection. There is increasing evidence of underlying immune-inflammatory mechanisms in post-COVID-19 syndrome (PCS). Blood group O seems to protect against COVID-19 infection, but there is no data on the relationship between blood group O and PCS. This study aimed to assess this potential association. Subjects and methods A case-control study including subjects who had suffered from mild COVID-19 in a community setting was designed. Cases were PCS+ patients, controls were PCS- subjects and the exposure variable was blood group O. Baseline epidemiological data (age, sex, BMI, smoking, comorbidities), and clinical and laboratory parameters (inflammatory markers and IgG anti-N antibodies) 3 months after the acute episode, were obtained. Five composite indices of inflammation were built, combining the upper ranges of the distributions of inflammatory markers. Blood group and Rh factor were obtained from the patient's medical history or capillary blood samples. Bivariate and multivariate analyses were performed. Results One-hundred and twenty-one subjects were analyzed (56.2% women). The mean age was 45.7 (16) years (range, 18-88 years). Blood group frequencies were 43.3% (group A), 7.7% (group B), 5.7% (group AB), and 43.3% (group O). Thirty-six patients were classified as PCS+ (25 women, 11 men; p=0.07). The most frequent symptom was fatigue (42.8%). There were no significant differences between PCS+ and PCS- subjects regarding age, BMI, smoking, or previous comorbidity. The prevalence of PCS was 43.2% (19/44) in the blood group O and 23.7% in non-O subjects (14/60) (p=0.036). The mean number of PCS symptoms was 0.82 (1) in the blood group O and 0.43 (0.9) in the non-O group (p=0.017). There were no significant differences between A, B, and AB groups (PCS+ and PCS-) regarding inflammatory markers. In contrast, blood group O PCS+ patients had significantly higher lymphocyte count, plasma CRP, fibrinogen levels, and higher percentages of C2, C3, and C4 composite indices than PCS- subjects. The blood group O had an increased risk of developing PCS compared to non-O subjects (adjusted OR=4.20 [95%CI, 1.2-14]; p=0.023). The variables that contributed the most to the predictive model were blood group O, lymphocyte count, neutrophil count, and female sex. R-squared was 0.46, and the area under the ROC curve was 0.807 [95% CI, 0.70-0.90] (p=0.0001). Conclusion An increased risk of PCS associated with blood group O has been observed. Slightly, albeit significant, raised levels of fibrinogen, CRP, and neutrophil and lymphocyte counts, not observed in the other ABO blood groups, have been demonstrated in blood group O. Further investigations are needed to confirm these results.