Spontaneous cancer remission after COVID-19: insights from the pandemic and their relevance for cancer treatment.

Early in the COVID-19 pandemic, it emerged that the risk of severe outcomes was greater in patients with co-morbidities, including cancer. The huge effort undertaken to fight the pandemic, affects the management of cancer care, influencing their outcome. Despite the high fatality rate of COVID-19 disease in cancer patients, rare cases of temporary or prolonged clinical remission from cancers after SARS-CoV-2 infection have been reported. We have reviewed sixteen case reports of COVID-19 disease with spontaneous cancer reduction of progression. Fourteen cases of remission following viral infections and two after anti-SARS-CoV-2 vaccination. The immune response to COVID-19, may be implicated in both tumor regression, and progression. Specifically, we discuss potential mechanisms which include oncolytic and priming hypotheses, that may have contributed to the cancer regression in these cases and could be useful for future options in cancer treatment.

Targeted genetic analysis unveils novel associations between ACE I/D and APO T158C polymorphisms with D-dimer levels in severe COVID-19 patients with pulmonary embolism.

Only a percentage of COVID-19 patients develop thrombotic complications. We hypothesized that genetic profiles may explain part of the inter-individual differences. Our goal was to evaluate the genotypic distribution of targeted DNA polymorphisms in COVID-19 patients complicated (PE+) or not (PE-) by pulmonary embolism. We designed a retrospective observational study enrolling N = 94 consecutive patients suffering severe COVID-19 with pulmonary embolism (PE+, N = 47) or not (PE-, N = 47) during hospitalization. A panel of N = 13 prothrombotic DNA polymorphisms (FV R506Q and H1299R, FII G20210A, MTHFR C677T and A1298C, CBS 844ins68, PAI-1 4G/5G, GPIIIa HPA-1 a/b, ACE I/D, AGT T9543C, ATR-1 A1166C, FGB - 455G > A, FXIII103G > T) and N = 2 lipid metabolism-related DNA polymorphisms (APOE T 112C and T158C) were investigated using Reverse Dot Blot technique. Then, we investigated possible associations between genotypic subclasses and demographic, clinical, and laboratory parameters including age, obesity, smoking, pro-inflammatory cytokines, drug therapy, and biomarkers of thrombotic risk such as D-dimer (DD). We found that 58.7% of PE+ had homozygous mutant D/D genotype at ACE I/D locus vs. PE- (40.4%) and 87% of PE+ had homozygous mutant C/C genotype at APOE T158C locus vs. PE- (68.1%). In PE+ group, DD levels were significantly higher in D/D and I/D genotypes at ACE I/D locus (P = 0.00066 and P = 0.00023, respectively) and in C/C and T/C genotypes at APOE T158C locus (P = 1.6e-06 and P = 0.0012, respectively) than PE- group. For the first time, we showed significant associations between higher DD levels and ACE I/D and APOE T158C polymorphisms in PE+ vs. PE- patients suggesting potential useful biomarkers of poor clinical outcome.

Beneficial effects of prehospital use of statins in a large United States cohort of hospitalized coronavirus disease 2019 patients.

AIMS: This large cohort study aimed to assess the role of chronic statin use on COVID-19 disease severity. METHODS: An observational retrospective study from electronic medical records of hospitalized patients (n = 43 950) with COVID-19 between January and September 2020 in 185 hospitals in the United States. A total of 38 875 patients met inclusion criteria; 23 066 were included in the propensity-matched sampling with replacement cohort; 11 533 were prehospital statin users. The primary outcome was all-cause death; secondary outcomes were death from COVID-19 and serious complications. Mean, standard deviation, chi-square test, Student's t-test, linear regression, and binary and multinomial logistic regressions were used for statistical analysis. RESULTS: Among 38 875 patients, 30% were chronic statin users [mean age, 70.82 (±12.25); 47.1% women] and 70% were statin nonusers [mean age, 58.44 (±18.27); 48.5% women]. Key propensity-matched outcomes among 11 533 chronic statin users showed 20% lower risk of all-cause mortality (OR 0.80, 95% CI 0.74-0.86, P < 0.001), 23% lower risk of mortality from COVID-19 (OR 0.77, 95% CI 0.71-0.84, P < 0.001), 16% lower risk of ICU admission (OR 0.84, 95% CI 0.79-0.89, P < 0.001), 24% lower risk of critical acute respiratory distress syndrome with COVID-19 (OR 0.76, 95% CI 0.70-0.83, P < 0.001), 23% lower risk of mechanical ventilation (OR 0.77, 95% CI 0.71-0.82, P < 0.001), 20% lower risk of severe sepsis with septic shock (OR 0.80, 95% CI 0.67-0.93, P = 0.004), shorter hospital length of stay [9.87 (±8.94), P < 0.001] and brief duration of mechanical ventilation [8.90 (±8.94), P < 0.001]. CONCLUSION: Chronic use of statins is associated with reduced mortality and improved clinical outcomes in patients hospitalized for COVID-19.

Glycaemic control is associated with SARS-CoV-2 breakthrough infections in vaccinated patients with type 2 diabetes.

Patients with type 2 diabetes (T2D) are characterized by blunted immune responses, which are affected by glycaemic control. Whether glycaemic control influences the response to COVID-19 vaccines and the incidence of SARS-CoV-2 breakthrough infections is unknown. Here we show that poor glycaemic control, assessed as mean HbA1c in the post-vaccination period, is associated with lower immune responses and an increased incidence of SARS-CoV-2 breakthrough infections in T2D patients vaccinated with mRNA-BNT162b2. We report data from a prospective observational study enroling healthcare and educator workers with T2D receiving the mRNA-BNT162b2 vaccine in Campania (Italy) and followed for one year (5 visits, follow-up 346 ± 49 days) after one full vaccination cycle. Considering the 494 subjects completing the study, patients with good glycaemic control (HbA1c one-year mean < 7%) show a higher virus-neutralizing antibody capacity and a better CD4 + T/cytokine response, compared with those with poor control (HbA1c one-year mean ≥ 7%). The one-year mean of HbA1c is linearly associated with the incidence of breakthrough infections (Beta = 0.068; 95% confidence interval [CI], 0.032-0.103; p < 0.001). The comparison of patients with poor and good glycaemic control through Cox regression also show an increased risk for patients with poor control (adjusted hazard ratio [HR], 0.261; 95% CI, 0.097-0.700; p = 0.008). Among other factors, only smoking (HR = 0.290, CI 0.146-0.576 for non-smokers; p < 0.001) and sex (HR = 0.105, CI 0.035-0.317 for females; p < 0.001) are significantly associated with the incidence of breakthrough infections.

Evaluation of circulating leucocyte populations both in subjects with previous SARS-COV-2 infection and in healthy subjects after vaccination.

Innate immune mechanisms are central players in response to the binding of pathogens to pattern-recognition receptors providing a crucial initial block on viral replication. Moreover, innate immune response mobilizes cells of the cellular-mediated immune system, which develop into effector cells that promote viral clearance. Here, we observed circulating leukocyte T cell response in healthy subjects, COVID-19 infected, and in healthy vaccinated subjects. We found a significant CD8+ T cells (p < 0,05) decrease and an augmented CD4+/CD8+ ratio (p < 0,05) in COVID-19 infected group compared with vaccinated subjects. In addition, healthy vaccinated subjects have a significant increased expression of CD8+ T cells, and a reduction of CD4+/CD8+ ratio with respect to subjects previously COVID-19 infected. Central Memory and Terminal Effector Memory cells (TEMRA) increased after vaccine but not among groups.

Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte.

RATIONALE: About 50% of hospitalized coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM) developed myocardial damage. The mechanisms of direct SARS-CoV-2 cardiomyocyte infection include viral invasion via ACE2-Spike glycoprotein-binding. In DM patients, the impact of glycation of ACE2 on cardiomyocyte invasion by SARS-CoV-2 can be of high importance. OBJECTIVE: To evaluate the presence of SARS-CoV-2 in cardiomyocytes from heart autopsy of DM cases compared to Non-DM; to investigate the role of DM in SARS-COV-2 entry in cardiomyocytes. METHODS AND RESULTS: We evaluated consecutive autopsy cases, deceased for COVID-19, from Italy between Apr 30, 2020 and Jan 18, 2021. We evaluated SARS-CoV-2 in cardiomyocytes, expression of ACE2 (total and glycosylated form), and transmembrane protease serine protease-2 (TMPRSS2) protein. In order to study the role of diabetes on cardiomyocyte alterations, independently of COVID-19, we investigated ACE2, glycosylated ACE2, and TMPRSS2 proteins in cardiomyocytes from DM and Non-DM explanted-hearts. Finally, to investigate the effects of DM on ACE2 protein modification, an in vitro glycation study of recombinant human ACE2 (hACE2) was performed to evaluate the effects on binding to SARS-CoV-2 Spike protein. The authors included cardiac tissue from 97 autopsies. DM was diagnosed in 37 patients (38%). Fourth-seven out of 97 autopsies (48%) had SARS-CoV-2 RNA in cardiomyocytes. Thirty out of 37 DM autopsy cases (81%) and 17 out of 60 Non-DM autopsy cases (28%) had SARS-CoV-2 RNA in cardiomyocytes. Total ACE2, glycosylated ACE2, and TMPRSS2 protein expressions were higher in cardiomyocytes from autopsied and explanted hearts of DM than Non-DM. In vitro exposure of monomeric hACE2 to 120 mM glucose for 12 days led to non-enzymatic glycation of four lysine residues in the neck domain affecting the protein oligomerization. CONCLUSIONS: The upregulation of ACE2 expression (total and glycosylated forms) in DM cardiomyocytes, along with non-enzymatic glycation, could increase the susceptibility to COVID-19 infection in DM patients by favouring the cellular entry of SARS-CoV2.

Immune reactivity during COVID-19: Implications for treatment.

Clinical symptoms of COVID-19 include fever, cough, and fatigue which may progress to acute respiratory distress syndrome (ARDS). The main hematological laboratory findings associated with the severe form of disease are represented by lymphopenia and eosinopenia which mostly occur in the elderly population characterized by cardiovascular comorbidities and immunosenescence. Besides, increased levels of D-dimer, procalcitonin, and C reactive protein (CRP) seem to be powerful prognostic biomarkers helping to predict the onset of coagulopathy. The host immune response to SARS-CoV-2 can lead to an aberrant inflammatory response or "cytokine storm" which contributes to the severity of illness. At immunological level, patients affected by a severe form of COVID-19 show poor clinical trajectories characterized by differential "immunotypes" for which T cell response seems to play a critical role in understanding pathogenic mechanisms of disease. Also, patients with mild to severe COVID-19 displayed macrophage activation syndrome (MAS), very low human leukocyte antigen D related (HLA-DR) expression with a parallel reduction of CD04+ lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Corticosteroids resulted the best therapy for the immune dysregulation whereas repurposing of tocilizumab (IL-6 receptor antagonist) appears to have mixed results in patients with COVID-19. Besides, anticoagulative therapy was associated with reduced in-hospital mortality and need of intubation among COVID-19 patients. Furthermore, the beneficial use of intravenous immunoglobulin (IVIG) and passive immunotherapy with convalescent plasma needs to be validated in large controlled clinical trials. In this review, we summarize the main hematological parameters with a prognostic value in COVID-19 and the basis of immunological reactivity during COVID-19, with a focus on ongoing clinical trials evaluating immune targets as possible therapeutic strategies.

Epigenetic susceptibility to severe respiratory viral infections and its therapeutic implications: a narrative review.

The emergence of highly pathogenic strains of influenza virus and coronavirus (CoV) has been responsible for large epidemic and pandemic outbreaks characterised by severe pulmonary illness associated with high morbidity and mortality. One major challenge for critical care is to stratify and minimise the risk of multi-organ failure during the stay in the intensive care unit (ICU). Epigenetic-sensitive mechanisms, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) methylation, histone modifications, and non-coding RNAs may lead to perturbations of the host immune-related transcriptional programmes by regulating chromatin structure and gene expression patterns. Viruses causing severe pulmonary illness can use epigenetic-regulated mechanisms during host-pathogen interaction to interfere with innate and adaptive immunity, adequacy of inflammatory response, and overall outcome of viral infections. For example, Middle East respiratory syndrome-CoV and H5N1 can affect host antigen presentation through DNA methylation and histone modifications. The same mechanisms would presumably occur in patients with coronavirus disease 2019, in which tocilizumab may epigenetically reduce microvascular damage. Targeting epigenetic pathways by immune modulators (e.g. tocilizumab) or repurposed drugs (e.g. statins) may provide novel therapeutic opportunities to control viral-host interaction during critical illness. In this review, we provide an update on epigenetic-sensitive mechanisms and repurposed drugs interfering with epigenetic pathways which may be clinically suitable for risk stratification and beneficial for treatment of patients affected by severe viral respiratory infections.

Adult cardiovascular surgery and the coronavirus disease 2019 (COVID-19) pandemic: the Italian experience.

The coronavirus disease 2019 (COVID-19) pandemic has profoundly affected all health care professionals. The outbreak required a thorough reorganization of the Italian regional local health care system to preserve resources such as ventilators, beds in intensive care units and surgical and anaesthesiological staff. Levels of priority were created, together with a rigorous triage procedure for patients with COVID-19, which led to postponement of all elective procedures. Urgent cases were discussed with the local heart team and percutaneous approaches were selected as the first treatment option to reduce hospital stay. COVID-19 and COVID-19-free pathways were created, including adequate preparation of the operating room, management of anaesthesiological procedures, transportation of patients and disinfection. It was determined that patients with chronic diseases were at increased risk of adverse outcomes. Systemic inflammation, cytokine storm and hypercoagulability associated with COVID-19 increased the risk of heart failure and cardiac death. In this regard, the early use of extracorporeal membrane oxygenation could be life-saving in patients with severe forms of acute respiratory distress syndrome or refractory heart failure. The goal of this paper was to report the Italian experience during the COVID-19 pandemic in the setting of cardiovascular surgery.

Cardiovascular involvement during COVID-19 and clinical implications in elderly patients. A review.

SARS-CoV-2 betacoronavirus is responsible for the Corona Virus Disease 2019 (COVID-19) which has relevant pathogenic implications for the cardiovascular system. Incidence and severity of COVID-19 are higher in the elderly population (65 years and older). This may be due to higher frequency of comorbidities, but increased frailty and immunosenescence linked with aging may also contribute. Moreover, in elderly individuals, SARS-CoV-2 may adopt different molecular strategies to strongly impact on cardiac aging that culminate in exacerbating a pro-inflammatory state (cytokine storm activation), which, in turn, may lead to pulmonary vascular endothelialitis, microangiopathy, diffuse thrombosis, myocarditis, heart failure, cardiac arrhythmias, and acute coronary syndromes. All these events are particularly relevant in elderly patients, and deserve targeted cardiovascular treatments and specific management of repurposed drugs against COVID-19. We discuss current evidence about the cardiovascular involvement during COVID-19, and elaborate on clinical implications in elderly patients.

Can COVID 2019 induce a specific cardiovascular damage or it exacerbates pre-existing cardiovascular diseases?

A novel coronavirus SARS-CoV-2 causes acute respiratory distress syndrome (ARDS) with cardiovascular and multiple organ failure till death. The main mechanisms of virus internalization and interaction with the host are down-regulation or upregulation of the ACE2 receptor, the surface glycoprotein competition mechanism for the binding of porphyrin to iron in heme formation as well as interference with the immune system. The interference on renin-angiotensin-aldosterone system (RAAS) activation, heme formation, and the immune response is responsible for infection diffusion, endothelial dysfunction, vasoconstriction, oxidative damage and releasing of inflammatory mediators. The main pathological findings are bilateral interstitial pneumonia with diffuse alveolar damage (DAD). Because ACE receptor is also present in the endothelium of other districts as well as in different cell types, and as porphyrins are transporters in the blood and other biological liquids of iron forming heme, which is important in the assembly of the hemoglobin, myoglobin and the cytochromes, multiorgan damage occurs both primitive and secondary to lung damage. More relevantly, myocarditis, acute myocardial infarction, thromboembolism, and disseminated intravasal coagulation (DIC) are described as complications in patients with poor outcome. Here, we investigated the role of SARSCoV-2 on the cardiovascular system and in patients with cardiovascular comorbidities, and possible drug interference on the heart.