Clinical assessment of endothelial function in convalescent COVID-19 patients: a meta-analysis with meta-regressions.

BACKGROUND: Endothelial dysfunction has been proposed to play a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its post-acute sequelae. Flow-mediated dilation (FMD) is recognized as an accurate clinical method to assess endothelial function. Thus, we performed a meta-analysis of the studies evaluating FMD in convalescent COVID-19 patients and controls with no history of COVID-19. METHODS: A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using the random effects method, differences between cases and controls were expressed as mean difference (MD) with 95% confidence intervals (95% CI). The protocol was registered on PROSPERO with reference number CRD42021289684. RESULTS: Twelve studies were included in the final analysis. A total of 644 convalescent COVID-19 patients showed significantly lower FMD values as compared to 662 controls (MD: -2.31%; 95% CI: -3.19, -1.44; p < 0.0001). Similar results were obtained in the sensitivity analysis of the studies that involved participants in either group with no cardiovascular risk factors or history of coronary artery disease (MD: -1.73%; 95% CI: -3.04, -0.41; p = 0.010). Interestingly, when considering studies separately based on enrolment within or after 3 months of symptom onset, results were further confirmed in both short- (MD: -2.20%; 95% CI: -3.35, -1.05; p < 0.0001) and long-term follow-up (MD: -2.53%; 95% CI: -4.19, -0.86; p = 0.003). Meta-regression models showed that an increasing prevalence of post-acute sequelae of COVID-19 was linked to a higher difference in FMD between cases and controls (Z-score: -2.09; p = 0.037). CONCLUSIONS: Impaired endothelial function can be documented in convalescent COVID-19 patients, especially when residual clinical manifestations persist. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.Key messagesThe mechanisms underlying the post-acute sequelae of coronavirus disease 2019 (COVID-19) have not been fully elucidated.Impaired endothelial function can be documented in convalescent COVID-19 patients for up to 1 year after infection, especially when residual clinical manifestations persist.Targeting endothelial dysfunction may represent an attractive therapeutic option in the post-acute phase of COVID-19.

Mechanisms and Clinical Implications of Endothelial Dysfunction in Arterial Hypertension.

The endothelium is composed of a monolayer of endothelial cells, lining the interior surface of blood and lymphatic vessels. Endothelial cells display important homeostatic functions, since they are able to respond to humoral and hemodynamic stimuli. Thus, endothelial dysfunction has been proposed as a key and early pathogenic mechanism in many clinical conditions. Given the relevant repercussions on cardiovascular risk, the complex interplay between endothelial dysfunction and systemic arterial hypertension has been a matter of study in recent years. Numerous articles have been published on this issue, all of which contribute to providing an interesting insight into the molecular mechanisms of endothelial dysfunction in arterial hypertension and its role as a biomarker of inflammation, oxidative stress, and vascular disease. The prognostic and therapeutic implications of endothelial dysfunction have also been analyzed in this clinical setting, with interesting new findings and potential applications in clinical practice and future research. The aim of this review is to summarize the pathophysiology of the relationship between endothelial dysfunction and systemic arterial hypertension, with a focus on the personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction while treating hypertension and cardiovascular comorbidities.

Endothelial Dysfunction in COVID-19: A Unifying Mechanism and a Potential Therapeutic Target.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated a worldwide emergency, until the declaration of the pandemic in March 2020. SARS-CoV-2 could be responsible for coronavirus disease 2019 (COVID-19), which goes from a flu-like illness to a potentially fatal condition that needs intensive care. Furthermore, the persistence of functional disability and long-term cardiovascular sequelae in COVID-19 survivors suggests that convalescent patients may suffer from post-acute COVID-19 syndrome, requiring long-term care and personalized rehabilitation. However, the pathophysiology of acute and post-acute manifestations of COVID-19 is still under study, as a better comprehension of these mechanisms would ensure more effective personalized therapies. To date, mounting evidence suggests a crucial endothelial contribution to the clinical manifestations of COVID-19, as endothelial cells appear to be a direct or indirect preferential target of the virus. Thus, the dysregulation of many of the homeostatic pathways of the endothelium has emerged as a hallmark of severity in COVID-19. The aim of this review is to summarize the pathophysiology of endothelial dysfunction in COVID-19, with a focus on personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction as an attractive therapeutic option in this clinical setting.

Endothelial Dysfunction in COVID-19: A Unifying Mechanism and a Potential Therapeutic Target

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated a worldwide emergency, until the declaration of the pandemic in March 2020. SARS-CoV-2 could be responsible for coronavirus disease 2019 (COVID-19), which goes from a flu-like illness to a potentially fatal condition that needs intensive care. Furthermore, the persistence of functional disability and long-term cardiovascular sequelae in COVID-19 survivors suggests that convalescent patients may suffer from post-acute COVID-19 syndrome, requiring long-term care and personalized rehabilitation. However, the pathophysiology of acute and post-acute manifestations of COVID-19 is still under study, as a better comprehension of these mechanisms would ensure more effective personalized therapies. To date, mounting evidence suggests a crucial endothelial contribution to the clinical manifestations of COVID-19, as endothelial cells appear to be a direct or indirect preferential target of the virus. Thus, the dysregulation of many of the homeostatic pathways of the endothelium has emerged as a hallmark of severity in COVID-19. The aim of this review is to summarize the pathophysiology of endothelial dysfunction in COVID-19, with a focus on personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction as an attractive therapeutic option in this clinical setting.

A Rapid Antigen Detection Test to Diagnose SARS-CoV-2 Infection Using Exhaled Breath Condensate by A Modified Inflammacheck® Device.

BACKGROUND: The standard test that identifies the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is based on reverse transcriptase-polymerase chain reaction (RT-PCR) from nasopharyngeal (NP) swab specimens. We compared the accuracy of a rapid antigen detection test using exhaled breath condensate by a modified Inflammacheck® device with the standard RT-PCR to diagnose SARS-CoV-2 infection. METHODS: We performed a manufacturer-independent, cross-sectional, diagnostic accuracy study involving two Italian hospitals. Sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), positive (PPV) and negative predictive value (NPV) and diagnostic accuracy with 95% confidence intervals (95% CI) of Inflammacheck® were calculated using the RT-PCR results as the standard. Further RT-PCR tests were conducted on NP specimens from test positive subjects to obtain the Ct (cycle threshold) values as indicative evidence of the viral load. RESULTS: A total of 105 individuals (41 females, 39.0%; 64 males, 61.0%; mean age: 58.4 years) were included in the final analysis, with the RT-PCR being positive in 13 (12.4%) and negative in 92 (87.6%). The agreement between the two methods was 98.1%, with a Cohen's κ score of 0.91 (95% CI: 0.79-1.00). The overall sensitivity and specificity of the Inflammacheck® were 92.3% (95% CI: 64.0%-99.8%) and 98.9% (95% CI: 94.1%-100%), respectively, with a PLR of 84.9 (95% CI: 12.0-600.3) and a NLR of 0.08 (95% CI: 0.01-0.51). Considering a 12.4% disease prevalence in the study cohort, the PPV was 92.3% (95% CI: 62.9%-98.8%) and the NPV was 98.9% (95% CI: 93.3%-99.8%), with an overall accuracy of 98.1% (95% CI: 93.3%-99.8%). The Fagan's nomogram substantially confirmed the clinical applicability of the test in a realistic scenario with a pre-test probability set at 4%. Ct values obtained for the positive test subjects by means of the RT-PCR were normally distributed between 26 and 38 cycles, corresponding to viral loads from light (38 cycles) to high (26 cycles). The single false negative record had a Ct value of 33, which was close to the mean of the cohort (32.5 cycles). CONCLUSIONS: The modified Inflammacheck® device may be a rapid, non-demanding and cost-effective method for SARS-CoV-2 detection. This device may be used for routine practice in different healthcare settings (community, hospital, rehabilitation).

Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study.

BACKGROUND: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients. METHODS: COVID-19 patients referred to a Pulmonary Rehabilitation Unit within 2 months from swab test negativization were consecutively evaluated for inclusion and compared to controls matched for age, gender, and cardiovascular risk factors. RESULTS: A total of 133 convalescent COVID-19 patients (81.2% males, mean age 61.6 years) and 133 matched controls (80.5% males, mean age 60.4 years) were included. A significantly lower FMD was documented in convalescent COVID-19 patients as compared to controls (3.2% ± 2.6 vs. 6.4% ± 4.1 p < 0.001), confirmed when stratifying the study population according to age and major clinical variables. Among cases, females exhibited significantly higher FMD values as compared to males (6.1% ± 2.9 vs. 2.5% ± 1.9, p < 0.001). Thus, no significant difference was observed between cases and controls in the subgroup analysis on females (6.1% ± 2.9 vs. 5.3% ± 3.4, p = 0.362). Among convalescent COVID-19 patients, FMD showed a direct correlation with arterial oxygen tension (rho = 0.247, p = 0.004), forced expiratory volume in 1 s (rho = 0.436, p < 0.001), forced vital capacity (rho = 0.406, p < 0.001), and diffusing capacity for carbon monoxide (rho = 0.280, p = 0.008). Overall, after adjusting for major confounders, a recent COVID-19 was a major and independent predictor of FMD values (ß = -0.427, p < 0.001). CONCLUSIONS: Post-acute COVID-19 syndrome is associated with a persistent and sex-biased endothelial dysfunction, directly correlated with the severity of pulmonary impairment.

Long-term antibody persistence and exceptional vaccination response on previously SARS-CoV-2 infected subjects.

BACKGROUND: The first COVID-19 vaccines are being distributed to the general population. However, the shortage of doses is slowing down the goal of reaching herd immunity. The aim of the study was to verify whether previously SARS-CoV-2 infected subjects, a considerable portion of the population, should receive the same vaccination treatment of seronegative individuals. METHODS: Health-professionals either recovered from COVID-19 or never infected by SARS-CoV-2 were serologically tested at different time-points right before, and several days after, vaccination. RESULTS: Previously infected individuals showed humoral immune responses, 21 days after the first dose, that was approximately 10-folds higher than the seronegative group 21 days after the second dose. Seropositivity persists for at least 11 months. CONCLUSION: During a shortage of COVID-19 vaccine doses, previously SARS-CoV-2 infected individuals should be dispensed from the vaccination campaign. When dose availability returns to normality, injection of a single dose for seropositive individuals should be considered.

Clinical Assessment of Endothelial Function in Convalescent COVID-19 Patients Undergoing Multidisciplinary Pulmonary Rehabilitation.

BACKGROUND: Growing evidence points to a key role of endothelial dysfunction in the pathogenesis of COVID-19. In this study, we evaluated changes in endothelium-dependent flow-mediated dilation (FMD) in a cohort of convalescent COVID-19 patients undergoing pulmonary rehabilitation (PR). METHODS: After swab test negativization, convalescent COVID-19 patients referring to a post-acute care facility for PR were consecutively screened for inclusion. Study procedures were performed at the time of hospitalization and discharge. RESULTS: We enrolled 82 convalescent COVID-19 patients (85.4% males, mean age 60.4 years). After PR, a significant improvement in most pulmonary function tests and exercise capacity was documented. FMD changed from 2.48% ± 2.01 to 4.24% ± 2.81 (p < 0.001), corresponding to a 70.9% increase. Significantly higher changes in FMD were found in patients without a history of vascular events as compared to those with (+2.04% ± 2.30 vs. +0.61% ± 1.83, p = 0.013). Values of forced expiratory volume in 1 s (FEV1%), forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLCO%) significantly and directly correlated with FMD both at baseline and after PR. Patients with normal FEV1% (≥80% predicted) during the overall study period or those normalizing FEV1% after PR showed a more significant FMD change as compared to patients with persistently impaired FEV1% (<80% predicted) (p for trend = 0.029). This finding was confirmed in a multivariate analysis. CONCLUSIONS: Clinically evaluated endothelial function improves after PR in convalescent COVID-19 patients. A direct and persistent association between the severity of pulmonary and vascular disease can be hypothesized. Endothelial function testing may be useful in the follow-up of convalescent COVID-19 patients.

Routine blood analysis greatly reduces the false-negative rate of RT-PCR testing for Covid-19.

BACKGROUND: The COVID-19 outbreak is now a pandemic disease reaching as much as 210 countries worldwide with more than 2.5 million infected people and nearly 200.000 deaths. Amplification of viral RNA by RT-PCR represents the gold standard for confirmation of infection, yet it showed false-negative rates as large as 15-20% which may jeopardize the effect of the restrictive measures taken by governments. We previously showed that several hematological parameters were significantly different between COVID-19 positive and negative patients. Among them aspartate aminotransferase and lactate dehydrogenase had predictive values as large as 90%. Thus a combination of RT-PCR and blood tests could reduce the false-negative rate of the genetic test. METHODS: We retrospectively analyzed 24 patients showing multiple and inconsistent RT-PCR, test during their first hospitalization period, and compared the genetic tests results with their AST and LDH levels. RESULTS: We showed that when considering the hematological parameters, the RT-PCR false-negative rates were reduced by almost 4-fold. CONCLUSIONS: The study represents a preliminary work aiming at the development of strategies that, by combining RT-PCR tests with routine blood tests, will lower or even abolish the rate of RT-PCR false-negative results and thus will identify, with high accuracy, patients infected by COVID-19.

Routine blood tests as a potential diagnostic tool for COVID-19.

Objectives The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to date, the epidemic has gradually spread to 209 countries worldwide with more than 1.5 million infected people and 100,000 deaths. Amplification of viral RNA by rRT-PCR serves as the gold standard for confirmation of infection, yet it needs a long turnaround time (3-4 h to generate results) and shows false-negative rates as large as 15%-20%. In addition, the need of certified laboratories, expensive equipment and trained personnel led many countries to limit the rRT-PCR tests only to individuals with pronounced respiratory syndrome symptoms. Thus, there is a need for alternative, less expensive and more accessible tests. Methods We analyzed the plasma levels of white blood cells (WBCs), platelets, C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT), alkaline phosphatase and lactate dehydrogenase (LDH) of 207 patients who, after being admitted to the emergency room of the San Raffaele Hospital (Milan, Italy) with COVID-19 symptoms, were rRT-PCR tested. Of them, 105 tested positive, whereas 102 tested negative. Results Statistically significant differences were observed for WBC, CRP, AST, ALT and LDH. Empirical thresholds for AST and LDH allowed the identification of 70% of either COVID-19-positive or -negative patients on the basis of routine blood test results. Conclusions Combining appropriate cutoffs for certain hematological parameters could help in identifying false-positive/negative rRT-PCR tests. Blood test analysis might be used as an alternative to rRT-PCR for identifying COVID-19-positive patients in those countries which suffer from a large shortage of rRT-PCR reagents and/or specialized laboratory.