POST-COVID-19 SYNDROME, INFLAMMATORY MARKERS AND SEX DIFFERENCES

Abstract

INTRODUCTION AND OBJECTIVE Post-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 METHODS Mild 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. RESULTS We 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. CONCLUSIONS Consistent 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.