ABSTRACT
Background: Human SARS-CoV-2 infection can induce a wide spectrum of organ dysfunctions, including microvascular impairment [1]. S1 subunit of viral receptor-binding domain binds to the angiotensin-converting enzyme 2 receptor on endothelium and S2 subunit allows the virus to enter endothelial cells. The resulting breakdown of barrier integrity drives a cascade of infammatory and thrombotic events, that aggravate the course of COVID-19 together with other risk factors [2-4]. Up to date, a lower capillary density has been reported in several distinct body districts, using sublingual video microscopy, ocular optical coherence tomography angiography, skin functional laser Doppler perfusion imaging and nailfold videocapillaroscopy (NVC) [5-8]. NVC examination has been performed in adult COVID-19 patients, however, without a control group [8]. Objectives: To confrm the statistical signifcance of the reduction in capillary density per linear millimeter evaluated by NVC in comparison with primary Ray-naud's phenomenon (PRP) patients and control subjects (CNT) and to evaluate the impact of an aggressive therapy against COVID-19 on the sparing in the number of capillaries. Methods: Sixty-one COVID-19 survivors, thirty-one PRP patients and thirty CNT age and sex-matched underwent NVC analysis. Demographic and clinical data of COVID-19 survivors were collected with special regard to concomitant therapies, that included antivirals, antibiotics, anticoagulants and anti-infamma-tory/immunomodulant drugs (glucocorticoids, hydroxychloroquine, IL-6 receptor antagonist). COVID-19 survivors were divided in two subgroups according to the severity of the active infection: thirty-four survivors with past mild-moderate disease (either unneedy for oxygen supplementation or need for Venturi mask) and twenty-seven survivors with past severe disease (need for Continuous Positive Airways Pressure and/or mechanical ventilation). The same Rheumatologist performed NVC evaluations in all patients and controls, using an optical probe, equipped with a 200x magnifcation lens and connected to a picture analysis software (Videocap, DS Medica, Milan, Italy). Absolute capillary number per linear millimeter was counted. Results: COVID-19 survivors underwent NVC examination after a mean period of 126±53 days from the disease onset. Multivariate analysis showed differences in absolute capillary number per linear millimeter (p<0.001) after adjusting for age, sex, body mass index, comorbidities and concomitant drugs. The mean (± standard deviation) absolute nailfold capillary number per linear millimeter was signifcantly lower in severe (8.2±1.15) and mild-moderate (8.4±0.75) COVID-19 survivors than in both PRP (8.7±0.68) and CNT subjects (9.3±0.53) (p<0.001). The analysis of the impact of treatments on capillary density in the severe COVID-19 patients showed a positive trend (preservation of the capillary number) with antivirals (no: 7.8±1.53;yes: 8.5±0.64;p=0.35) and anti-IL-6 receptor antagonist administration (no: 7.8±1.36;yes: 8.6±0.74;p=0.16), while none of the other drugs was shown to be effective (glucocorticoids p = 0.46;antibiotics = 0.52;anticoagulants not evaluable as they were used in all COVID-19 patients). Conclusion: SARS-CoV-2 infection seems associated to a signifcant capillary loss as distinctive NVC feature and data concerning the comparison of capillary density pre COVID-19 and post COVID-19 are desirable to reinforce this observation. The positive trend in saving the number of capillaries induced by aggressive anti-infammatory therapies in COVID-19 survivors needs larger cohorts of patients.
ABSTRACT
Background: COVID-19 is a multifaceted condition with a wide range of clinical manifestations, including microvascular/endothelial dysfunction, that starts in the early phase of the disease and may become dramatically harmful in the late stage, causing a massive pro-thrombotic state. Nailfold videocapillaroscopy (NVC) is the most used tool to identify microvascular status in a large spectrum in a cohort of COVID-19 patients (no controls used) [2]. Objectives: To assess microvascular damage in recovered COVID-19 patients (range of 40-270 days from recovery) by considering the previous severity of the disease, and, as mandatory, the comparison with matched individuals suffering from primary Raynaud's phenomenon (PRP) and healthy volunteers (HV). Methods: NVC investigations were performed during standard clinical assessments in forty-four recovered COVID-19 patients (mean age 58±14 years, mean days from disease onset 129±54, mean days from disease recovery 106±52), twenty-two patients with PRP (mean age 60±15 years, mean years from disease onset 11±10) and twenty-two HV (mean age 60±14 years). COVID-19 patients were divided into two subgroups, according to the need of oxygen supplementation: twenty-two patients with severe lung involvement (need of Continuous Positive Airways Pressure and/or mechanical ventilation, mean age 57±12 years) vs twenty-two patients with mild-moderate lung involvement (need of Venturi mask or no need of oxygen supplementation, mean age 59±15 years). Clinical and demographic data of all the enrolled subjects were collected, during NVC examination. The following capillaroscopic parameters were evaluated: capillary number, dilated capillaries, giant capillaries, microhemorrhages, angiogenesis, disorganization of the microvascular array. A validated semiquantitative scoring (0-3) was adopted for NVC abnormalities [3-5]. Statistical analysis was carried out by non-parametric tests. Results: After COVID-19 recovery, no statistically significant difference was observed between COVID-19 patients and control groups of subjects concerning the score for the following NVC parameters: dilated capillaries, giant capillaries, disorganization of the microvascular array, angiogenesis. However, the capillary number per linear millimeter was significantly lower in COVID-19 patients (8.3±0.9) than in PRP (8.8±0.7, p=0.05) and HV (9.3±0.6, p<0.0001). Surprisingly, recovered COVID-19 patients showed significantly less microhemorrhages (score 0.4±0.3) than subjects of the other groups (PRP 0.6±0.5, p=0.01;HV 0.6±0.6, p=0.05). In particular, recovered patients who had more severe COVID-19 showed less microhemorrhages than patients with mild/moderate disease (score 0.18±0.4 vs 0.36±0.5), but this didn't reach the statistical significance (p=0.18). On the other hand, patients recovered from severe SARS-CoV-2 infection also showed higher rate of angiogenesis (0.18±0.4) than patients with mild/ moderate disease (no case, p=0.04). Conclusion: COVID-19 doesn't seem to significantly induce, in short-term, specific alterations in peripheral microvascular array as evaluated by NVC, despite the severity of the disease, except for a significant reduction of the absolute number of nailfold capillaries. The topic needs longer time of evaluation and larger number of COVID-19 recovered cases to also assess the role of concomitant therapies.