Post-COVID-19 syndrome and insulin resistance 20 months after a mild COVID-19 (preprint)

Objective SARS-CoV-2 infection is associated with impaired glucose metabolism. Although the mechanisms are not fully understood, insulin resistance (IR) appears to be a central factor. Patients who had a severe acute phase, but even asymptomatic or with mild COVID-19, have an increased risk of T2DM. After the acute phase, post-COVID-19 syndrome (PCS) also seems to be related to this metabolic disturbance, but there is a paucity of studies. This study aims to evaluate a possible relationship between PCS and IR after mild COVID-19 and, if confirmed, whether there are differences by sex. Subjects and methods Retrospective observational cohort study including subjects who had mild COVID-19 between April and September 2020 in a community setting. None had been vaccinated against SARS-CoV-2 at inclusion, and previous T2DM and liver disease were exclusion criteria. Patients who met NICE criteria were classified as PCS+. Epidemiological and laboratory data were analysed. Three assessments were performed: 1E (pre-COVID-19, considered baseline and reference for comparisons), 2E (approximately 3 months after the acute phase), and 3E (approximately 20 months after the acute phase). A triglyceride-to-glucose (TyG) index [≥]8.74 was considered IR. Albumin-to-globulin ratio (AGR) and lactate dehydrogenase (LDH) were assessed as inflammatory markers. Bivariate analyses were performed, using nonparametric and repeated measures tests. A subsample without metabolic disorder or CVD (age< median, BMI<25 kg/m^2, elevated AGR, TyG index=7.80 [0.5]) was generated to reasonably rule out prior baseline IR that could bias the results. The relationships between PCS and TyG in 3E (TyG3) were modeled in 8 multiple regressions, stratifying by sex and BMI combinations. Results A total of 112 subjects (median [IQR] of age= 44 [20] years; 65 women) were analysed. Up to 14.3% was obese and 17% was hypertensive. Significant increases between 1E and 3E were registered regarding (i) basal glycemia (BG), 87 [14] mg/dL vs. 89 [14]; p=0.014, (ii) TyG index (8.25 [0.8] vs. 8.32 [0.7]; p=0.002), and (iii) LDH in 3rd tertile (16.1% vs 32.1%; p=0.007). A total of 8 previously normoglycemic subjects, showed BG2 or BG3 >126 mg/dL. The subgroups with IR highest prevalence at 3E were those of BMI [≥]25 kg/m^2 and PCS+. The subgroup without CVD presented a significant increase in the TyG index (TyG1=7.80 [0.1] vs. TyG3= 8.28 [0.1]; p=0.017). LDH1 was significantly correlated with TyG3 in both sexes (rho=0.214 in women, rho=0.298 in men); in contrast, LDH2 and LDH3 did not present such an association. In multivariable analysis, PCS has shown to be an independent and predictive variable of TyG index in women with BMI<25 kg/m^2, after adjustment for age, hypertension, BMI, Charlson comorbidity index, AGR1, AGR2, LDH1, number of symptoms of acute COVID-19, and number of days of the acute episode (beta coefficient=0.350; p=0.039). Conclusions PCS has played a secondary role in predicting IR, showing a modest effect compared to BMI or prior hypertension. A significant increase in IR has been noted 20 months after mild COVID-19, both in cases of previous baseline IR and in those without previous IR. Basal serum LDH has shown to be predictive of current TyG, regardless of elevated LDH after SARS-CoV-2 infection. There were profound differences between women and men, confirming the need for a sex-stratified analysis when addressing the relation between PCS and glycemic alterations.

Blood group O and post-COVID-19 syndrome (preprint)

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.

POST-COVID-19 SYNDROME, INFLAMMATORY MARKERS AND SEX DIFFERENCES (preprint)

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.

Acutely Altered Mental Status as the Main Clinical Presentation of Multiple Strokes in Critically Ill Patients With COVID-19. (preprint)

Background and aims:Cerebral infarction in COVID-19 patients might be associated with a hypercoagulable state related to a systemic inflammatory response. Its diagnosis might be challenging. We present two critically ill patients with COVID-19 who presented acutely altered mental status as the main manifestation of multiple strokes.Methods:Clinical presentation and diagnostic work-up of the patients.Results:Two patients in their sixties were hospitalized with a bilateral pneumonia COVID-19. They developed respiratory failure and were admitted to ICU for mechanical ventilation and intense medical treatment. They were started on low-molecular-weight heparin since admission. Their laboratory results showed lymphopenia and increased levels of C-reactive protein and D-dimer. Case 1 developed hypofibrinogenemia and presented several cutaneous lesions with biopsy features of thrombotic vasculopathy. Case 2 was performed a CT pulmonary angiogram at ICU showing a bilateral pulmonary embolism. When waking up, both patients were conscious but with a remarkable global altered mental status without focal neurological deficits. A brain MRI revealed multiple acute bilateral ischemic lesions with areas of hemorrhagic transformation in both patients (Case 1: affecting the left frontal and temporal lobes and both occipital lobes; Case 2: affecting both frontal and left occipital lobes). Cardioembolic source and acquired antiphospholipid syndrome were ruled out. COVID-19-associated coagulopathy was suspected as the possible main etiology of the strokes.Conclusion:Acutely altered mental status might be the main manifestation of multiple brain infarctions in critically ill COVID-19 patients. It should be specially considered in those with suspected COVID-19-associated coagulopathy. Full-dose anticoagulation and clinical-radiological monitoring might reduce their neurological consequences.