Efficacy of Remdesivir and Neutralizing Monoclonal Antibodies in Monotherapy or Combination Therapy in Reducing the Risk of Disease Progression in Elderly or Immunocompromised Hosts Hospitalized for COVID-19: A Single Center Retrospective Study.

INTRODUCTION: Remdesivir (REM) and monoclonal antibodies (mAbs) could alleviate severe COVID-19 in at-risk outpatients. However, data on their use in hospitalized patients, particularly in elderly or immunocompromised hosts, are lacking. METHODS: All consecutive patients hospitalized with COVID-19 at our unit from 1 July 2021 to 15 March 2022 were retrospectively enrolled. The primary outcome was the progression to severe COVID-19 (P/F < 200). Descriptive statistics, a Cox univariate-multivariate model, and an inverse probability treatment-weighted (IPTW) analysis were performed. RESULTS: Overall, 331 subjects were included; their median (q1-q3) age was 71 (51-80) years, and they were males in 52% of the cases. Of them, 78 (23%) developed severe COVID-19. All-cause in-hospital mortality was 14%; it was higher in those with disease progression (36% vs. 7%, p < 0.001). REM and mAbs resulted in a 7% (95%CI = 3-11%) and 14% (95%CI = 3-25%) reduction in the risk of severe COVID-19, respectively, after adjusting the analysis with the IPTW. In addition, by evaluating only immunocompromised hosts, the combination of REM and mAbs was associated with a significantly lower incidence of severe COVID-19 (aHR = 0.06, 95%CI = 0.02-0.77) when compared with monotherapy. CONCLUSIONS: REM and mAbs may reduce the risk of COVID-19 progression in hospitalized patients. Importantly, in immunocompromised hosts, the combination of mAbs and REM may be beneficial.

Impact of a Pro-Active Infectious Disease Consultation on the Management of a Multidrug-Resistant Organisms Outbreak in a COVID-19 Hospital: A Three-Months Quasi-Experimental Study.

BACKGROUND: Antimicrobial and diagnostic stewardship (AS/DS) principles are crucial for the management of multidrug-resistant organisms (MDROs) infections. We evaluated the impact of a pro-active Infectious Disease (ID) consultation on the mortality risk of patients during an MDROs outbreak in a COVID-19 hospital. METHODS: A quasi-experimental study was performed in a dedicated COVID-19 hospital, including patients with suspected/confirmed infection and/or colonization by MDROs, which were managed as follows: (i) according to the standard of care during the pre-phase and (ii) in collaboration with a dedicated ID team performing a pro-active bedside evaluation every 48-72 h in the post-phase. RESULTS: Overall, 112 patients were included (pre-phase = 89 and post-phase = 45). The AS interventions included the following: therapy optimization (33%), de-escalation to narrow the spectrum (24%) or to lessen toxic drugs (20%), and discontinuation of antimicrobials (64%). DS included the request of additional microbiologic tests (82%) and instrumental exams (16%). With the Cox model, after adjusting for age, sex, COVID-19 severity, infection source, etiological agents, and post-phase attendance, only age predicted an increased risk of mortality, while attendance in the post-phase resulted in a decreased risk of mortality. CONCLUSIONS: Implementation of AS and DS intervention through a pro-active ID consultation may reduce the risk of 28-day mortality of COVID-19 patients with MDROs infections.

An Epigenetically Driven Mechanism Triggered by Viral and Bacterial RNA Regulates the IL-6 Levels in IGA Nephropathy

BACKGROUND AND AIMS Several models have been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN) and, among them, the multihit model where the gut-microbiota may play an important role. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed that further predisposing factors are present, including immunological, genetic, environmental or nutritional factors. Recently, the role of IL-6 in IgAN pathogenesis is becoming increasingly important. It is essential for the deposition of glomerular immunoglobulin A and the development of renal disease in Cd37-deficient mice, although the pathogenetic mechanisms that determine its increase are not well known. A possible hypothesis emerges from our recent work on genome-wide DNA methylation screening in patients with IgAN, which identified, among other findings, a hypermethylated region comprising Vault 2–1 RNA (VTRNA2-1), a non-RNA coding also known as a precursor of miR-886 (pre-mi-RNA). Consistently, VTRNA2-1 expression was found downregulated in IgAN patients. Here we studied the involvement of the VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN. METHOD Total RNA were isolated from PBMCs of IgAN patients, transplanted IgAN patients (TP-IgAN), non-IgAN transplanted patients (TP) and healthy subjects (HS). VTRNA2-1, CREB and PKR transcripts were evaluated by RT-PCR. Total and phosphorylated PKR, CREB and Il-6 proteins were evaluated by ELISA. Poly (I: C), a synthetic analogue of dsRNA and Pfizer-BioNTech COVID-19 COMIRNATY vaccine were used to transfect patient PBMCs. PKR inhibitor imoxin (C16) 1 µM was used to stimulate patient PBMCs. RESULTS Here we confirm that VTRNA2-1 transcript was down-regulated in native and transplanted IgAN subjects compared to HS and non IgAN transplanted patients, with a decrease of 30- and 100-folds, respectively (P < 0.05, and P < 0.0001). IgAN patients with downregulated VTRNA2-1 showed a PKR overactivation (fold increase of phosphorilation of 2.6- in IgAN and 2-folds in TP-IgAN patients;P < 0.05), coherently with the role played by VTRNA2-1 that binds to PKR and inhibits its phosphorylation. Then, we found that PKR causes the activation of CREB, a classical cAMP-inducible CRE-binding factor (fold increase of phosphorilation of 3- in IgAN and 2.67-folds in TP-IgAN patients;P < 0.01). CREB, interacting with a region of the IL-6 promoter, led to IL-6 production. Indeed, in IgAN patients we showed a IL-6 mean increase to 120 pg/mL compared to the respective controls (P < 0.05). Moreover, the IL-6 levels correlated with CREB and PKR phosphorylation (r = 0.97;P = 0.0006 and r = 0.89;P = 0.0064, respectively, for IgAN and TP-IgAN patients). Since PKR is normally activated by bacterial and viral RNA, we hypothesized that these microorganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production. This may explain both the high levels of IL-6, and infection involvement in the disease, and cases of IgAN associated with COVID-19 infection or with COVID-19 RNA-vaccination, and recent data showing microbiota involvement in IgAN. Effectively, we found that IgAN PMBCs stimulated with RNA poly(I: C) or the COVID-19 RNA-vaccine showed a significant increase in IL-6 levels compared to not-stimulated PBMCs (P < 0.05), supporting the pathogentic role played by viral RNA in IgAN pathogenesis and explaining the cases of IgAN patients developing episodes of macrohematuria after a COVID-19 infection or vaccination. Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin (fold decrease of 5-folds in IgAN and TP-IgAN patients;P < 0.05). CONCLUSION In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide a new pathogenic mechanism in IgAN and may be useful for the development of novel therapeutic approaches, likely by modulating the VTRNA2-1 methylation level in IgAN patients.

A Recombinant BIO-HDL (CER-001) Can Prevent SARS-COV2-Induced Renal Dysfunction by Restoring SR-BI Signalling

BACKGROUND AND AIMS Replication of the enveloped SARS-COV2 virus can alter lipidomic composition and metabolism of infected cells [1]. These alterations commonly result in a decline in HDL, total cholesterol and LDL, and an increase in triglyceride levels in COVID-19 patients. Furthermore, the ‘cytokine storm’ subsequent to release of inflammatory cytokines can severely impair lipid homeostasis. Importantly, decreased HDL-cholesterol correlates with severity of COVID-19 infection and represents a significant prognostic factor in predicting poor clinical outcomes [2]. Similarly, it has been observed that COVID-19 patients’ recovery is accompanied by a rise in serum HDL levels. Pharmacological intervention that aims to restore ApoA-1 or functional HDL particles may have beneficial roles for clinical outcome of COVID-19 patients and has recently been approved for compassionate use [3]. SARS-CoV 2 spike proteins S1 and S2 can bind free cholesterol and HDL-bound cholesterol, facilitating virus entry by binding the ACE2 co-receptor Scavenger Receptor-BI (SR-BI) [4]. When activated at the trans-membrane level, SR-BI signalling culminates in Ser1173-eNOS phosphorylation with both anti-inflammatory and anti-apoptotic effect. We hypothesized that SARS-COV2 binding promoted SR-BI internalization, so that it could not exert its essential protective function. Therefore, the aim of this study is to evaluate the effects of CER-001, a mimetic HDL, in antagonizing this process. METHOD Endothelial and tubular (RPTEC) cells were exposed to S1, S2 and S1 + S2 (50–250 nM) with or without CER-001 (CER-001 50–500 ug/mL) and cholesterol (10–50 uM). Apoptosis tests (MTT and AnnV/PI) were performed. Internalization of SR-BI, ACE2 with S1 and activation of eNOS was evaluated by FACS analysis. SR-BI and ACE2 expression were evaluated on kidney biopsies from COVID-19 patients. RESULTS At concentrations used, the exposition of S1, S2 and S1 + S2 in the presence of CER-001 and cholesterol did not induce apoptosis of endothelial cells and RPTEC. Endothelial and tubular cells stimulated by S1, in presence of cholesterol, showed an increased intracellular level of SR-BI and ACE-2, with significantly reduced eNOS phosphorylation compared to baseline (P < 0.05). The treatment with CER-001 reversed trans-membrane SR-BI levels and eNOS phosphorylation to baseline values. The detection of S1 spike protein by endothelial cells immunohistochemistry revealed an increased level in S1-exposed cells with cholesterol and reduced S1 intracellular positive staining in CER-001-exposed cells (P < 0.05). Interestingly, S1-exposed cells without cholesterol appeared not to be capable of mediating S1 spike protein internalization. Consistent with in vitro results, analysis of renal biopsies from COVID-19 patients with proteinuria showed increased SR-BI and ACE-2 cytoplasmic signals and reduced expression at the apical domain of injured tubules. CONCLUSION Our data confirmed the key role of lipid profile in SARS-COV2 infection, evaluating the molecular signalling involved in HDL metabolism and inflammatory processes, and could offer new therapeutic strategies for COVID-19 patients.

Third COVID-19 Vaccine Dose Maximizes Antibody Titer in Kidney Transplant Recipients

BACKGROUND AND AIMS COVID-19 infection in solid organ transplant recipients (SOT) is associated with increased morbidity and mortality due to comorbidities and immunosuppression state (Chaudhry ZS et al, 2020). Although vaccines represent the greatest hope to control COVID-19 pandemic, several studies showed the low immunogenicity of a two-dose mRNA COVID-19 vaccine regimen in SOT as compared with general population (Boyarsky BJ et al, 2021). Based on this evidence, on September 2021, the Italian Medicine Agency (AIFA) authorized a third vaccine administration as additional primary dose to immunocompromised patients. The aim of this study is to evaluate the seroconversion rate after the third dose of BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 mRNA vaccine in kidney transplant recipients (KTRs) and to investigate the baseline factors associated with the absence of the antibody response. METHOD we performed a prospective and observational study on a monocentric cohort of 329 consecutive Caucasian KTRs given three doses of the BNT162b2 COVID-19 vaccine. Key exclusion criteria were a previous history of COVID-19 infection and transplantation or having underwent chemotherapy treatment within the last year. Antibody response against the spike protein was tested on blood sample collected before the administration of vaccine (T0), at 15 and 90 days after the second dose (T2 and T3, respectively) and one month after the third dose (T5). The level of antibodies was assessed using the Roche Elecsys anti–SARS-CoV-2 S enzyme immunoassay (positive cut-off ≥ 0.8 U/mL). A total of 22 patients were excluded from the analysis because categorized as SARS-CoV-2-pre-immunized according to the antibodies’ baseline status (T0) above the positivity cut-off. The Local Ethics Committees approved the study protocol and written informed consent was obtained before enrolment. RESULTS The study population of 307 KTRs was 57.10 ± 13.10 years, with a predominance of male sex (64.2%). Median time from transplantation to vaccine was 10 [IQR 5–17] years. Blood analysis at baseline revealed mean eGFR assessed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to be 56.95 ± 23.04 mL/min/1.73 m2. The standard immunosuppressive regimen consisted of glucocorticoids in all patients, calcineurin inhibitors (88.6% of patients), antimetabolites (73.3% of patients) and mTOR inhibitors (in 15.6% of patients). The first two doses were administered 21 days apart, and the third dose was administrated 172 ± 4 days after the second dose. In our cohort, 43.3% patients (133/307) responded to the vaccine at T2. The proportion of responders increased to 68.4% (186/272) at T3 (median antibody level: 5.2 [0.40–74.07]). One month after the third dose, a positive antibody titer was detected in 251 of 307 patients (81.8%) (median antibody titre: 1137.50 [9.32–4189.75]). The response curve starting at T2 and increasing at T3 makes apparent that there is a distinctive kinetic of humoral response in immunocompromised patients compared to immunocompetent individuals (Walsh EE et al., 2020). A multivariate analysis showed that the negative response to the third primary dose was associated with antimetabolite immunosuppressants (P = .001), lower estimated glomerular filtration rate (P < .001) and female sex (P = .04) (Figure 1). No serious adverse events were reported. Neither denovo DSAs nor change in proteinuria were reported after vaccination.FIGURE 1: Univariate and multivariate analysis of factors associated with vaccine response one month after third dose of SARS-CoV-2 mRNA vaccine. The limitation of this study is the absence of assays for cellular immune response. CONCLUSION Although the exact threshold of antibody titer for protection against SARS-CoV-2 infection remains unclear, the ability of the additional mRNA COVID-19 vaccine dose to increase both immune response (Figure 2A) and the prevalence of seroconversion rate (Figure 2B) associated with the acceptable safety profile s pports its use after an initial 2-dose mRNA COVID-19 primary vaccine series in immunocompromised patients.FIGURE 2: Antibody Response. Panel A shows the anti-SARS-CoV-2 antibody titers at different timepoints T0, T2, T3 and T5. Panel B shows prevalence of responders and noresponders at different timepoints T0, T2, T3 and T5.

Clinical Characteristics and Short-Term outcomes of Hemodialysis Patients with SARS-COV-2 Infection: The Experience of a Covid Nephrology Unit

BACKGROUND AND AIMS SARS-CoV-2 pandemic is pressuring healthcare systems worldwide. Disease outcomes in certain subgroups of patients, such as nephropathic patients, are still scarce. Patients with chronic kidney disease (CKD) and on haemodialysis (HD) are at risk of a more severe disease course and worst outcomes. Here, we aimed to describe the characteristics and outcomes of CKD and HD patients with SARS-CoV-2 infection, admitted to the Covid Nephrology Unit in the first three pandemic waves, analysing mortality rate and risk factors for mortality in this subgroup of patients. METHOD A Covid Nephrology Unit was organized in March 2020 to manage the high number of CKD and HD patients with SARS-CoV-2 infection. Several ‘spoke’ units were also set to manage HD asymptomatic patients (Hi Hotel and ‘Villa Luce’ Dialysis Center) or with mild symptoms (‘Miulli Hospital’-Acquaviva delle Fonti and ‘Fallacara Hospital’—Triggiano). Clinical and laboratory data in several timepoints were collected using electronic medical records. Primary outcome was to assess the mortality rate. Moreover, we analysed the trend of inflammatory markers in the first 7 days after hospital admission between survivors and non-survivors;finally, risk factors for mortality were analysed by logistic regression. RESULTS From March 2020 to May 2021, a total of 221 patients were admitted to the Covid Nephrology Unit;among these, 112 patients on chronic haemodialysis, 21 with acute kidney injury (AKI), 58 with CKD, 24 kidney transplant recipients and 6 patients on peritoneal dialysis (PD). Median age was 71 years (IQR 62.5–80), while male gender predominated (61.5%). Main comorbidities were arterial hypertension (81%), diabetes mellitus (41.8%) and cardiovascular disease (CVD, 60.6%). At admission, 13.2% of patients required non-invasive ventilatory (NIV) support (CPAP, BiPAP) and about 60% presented interstitial pneumonia at CT scan. A total of 80 patients (36.1%) died during hospital stay with a medium length of stay of 15.8 days. In the first 7 days, 29 patients presented respiratory failure requiring transfer to ICU. Conversely, 100 patients were discharged at home, while 48 patients were transferred to the spoke units (39 patients at Miulli and Fallacara Hospitals, 9 patients at Hi Hotel). Compared to survivors, patients who died were older (median age 75.5 versus 66 years, P < .001), characterized by more comorbidities (diabetes mellitus 54.5% versus 35.2%, P = .01;CVD 81.1% versus 51.4%, P < .001;chronic obstructive pulmonary disease (COPD, 41.5% versus 19%, P = .01;peripheral vasculopathy 58.4% versus 34.2%, P = .01) and more severe respiratory compromission at hospital admission (patients in NIV, 22.6% versus 8.1%, P = .005). As shown in Table 1, in the first 7 days of hospital stay, a significant increase in WBC (8.29 versus 12.6 × 106P < .001) was described in the non-survivor group;similarly, inflammatory markers such as CRP and IL-6 did not improve in the non-survivors at day 7 (CRP 81.8 versus 85.7 mg/L, P = .62;IL-6 63.1 versus 79.4 pg/mL, P = .84), while they significantly improved in survivors (median CRP 42.5 versus 10.1 mg/L, P < .001;median IL-6 32.3 versus 13.7 pg/mL, P = .01). In a multivariate logistic regression model, age (OR 1.062, 95% CI 1.007–1.119, P = .025), history of CVD (OR 8.308, 95%CI 1.704–40.499, P = .009) and dyspnoea at hospital admission (OR 9.465, 95%CI 1.231–72.79, P = .031) were associated with risk of mortality in this population. CONCLUSION To our knowledge, this is the largest study analyzing characteristics and outcomes of CKD and hemodialysis patients to date. A wide heterogeneity of severity of disease has been documented in our cohort;we documented a higher mortality rate in this cohort of patients compared to general population. The presence of several comorbidities, a more severe disease at hospital admission and the persistence of elevated inflammatory markers during hospital stay are risk factors for mortality.

GLP-1 receptor agonists and renal outcomes in patients with diabetes mellitus type 2 and diabetic kidney disease: state of the art.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are highly effective in improving glycaemic control either as monotherapy or in combination with other hypoglycaemic drugs, and have low incidence of side effects, such as hypoglycaemia, nausea and weight gain, thus increasing patients' adherence to therapy. Methods: In this review we report the most recent studies demonstrating the beneficial effects of GLP-1RAs on renal outcomes, and also discuss the direct and indirect mechanisms through which they confer kidney protection. Finally, we discuss the metabolic and anti-inflammatory effects of GLP-1RAs in diabetic patients with COVID-19 disease. Results: GLP-1RAs have a nephroprotective action, which is expressed through both indirect (improvement of blood pressure and glycaemic control, weight loss) and direct (restoration of normal intrarenal haemodynamics, prevention of ischaemic and oxidative damage) effects. They have shown also metabolic and anti-inflammation beneficial effects in patients with COVID-19 disease. Conclusions: GLP-1RAs prevent albuminuria and slow the decline of renal function towards end stage renal disease in patients with diabetic kidney disease. They might be an opportunity to break the typical inflammation processes of COVID-19 disease.

Effect of single session receptive music therapy on anxiety and vital parameters in hospitalized Covid-19 patients: a randomized controlled trial.

Hospitalized COVID-19 patients are vulnerable to different degrees of stress disorders as well as depression, anxiety and fear. The aim of this study was to evaluate the feasibility of introducing Music therapy on site with Covid-19 patients and investigating the immediate effects a single session has on anxiety, heart rate (HR), oxygen saturation (O2Sat) and satisfaction compared to standard care. A randomized controlled trial of 40 patients was conducted. Participants were assigned to control group (CG) or the treatment group (MG). MG received an individual single session of music therapy in presence. CG received standard care. MG and CG were subjected to identical measurements (pre-during-post) of the parameters STAI-Y, HR and O2Sat. Participants in MG were asked to fill in an optional open-ended question concerning their experience with music therapy. Significant difference in anxiety levels between scores in MG and CG (34.50 (23.25-40.00) vs 45.00(38, 25-54.00); p = 0.000) was observed. MG compared to CG had statistically significantly higher values of O2Sat (97.50 (96.25-99.00) versus 96.00 (96.00-98.00); p = 0.026). Results show the feasibility of introducing music therapy as a supporting complementary/non-pharmacological intervention on site in Covid-19 patients. A single session of music therapy improves O2Sat and can significantly reduce anxiety.Trial registration: 14/10/2021 No. NCT05077306. https://www.clinicaltrials.cov .

mTOR inhibitors improve both humoral and cellular response to SARS-CoV-2 messenger RNA BNT16b2 vaccine in kidney transplant recipients.

Kidney transplant recipients (KTRs) have been considered as patients at higher risk of SARS-CoV-2-related disease severity, thus COVID-19 vaccination was highly recommended. However, possible interferences of different immunosuppression with development of both humoral and T cell-mediated immune response to COVID-19 vaccination have not been determined. Here we evaluated the association between mTOR-inhibitors (mTOR-I) and immune response to mRNA BNT162b2 (Pfizer-BioNTech) vaccine in KTR. To this aim 132 consecutive KTR vaccinated against COVID-19 in the early 2021 were enrolled, and humoral and T cell-mediated immune response were assessed after 4-5 weeks. Patients treated with mTOR-I showed significantly higher anti-SARS-CoV-2 IgG titer (p = .003) and higher percentages of anti-SARS-CoV-2 S1/RBD Ig (p = .024), than those without. Moreover, SARS-CoV-2-specific T cell-derived IFNγ release was significantly increased in patients treated with mTOR-I (p < .001), than in those without. Multivariate analysis confirmed that therapy with mTOR-I gained better humoral (p = .005) and T cell-mediated immune response (p = .005) in KTR. The presence of mTOR-I is associated with a better immune response to COVID-19 vaccine in KTR compared to therapy without mTOR-I, not only by increasing vaccine-induced antibodies but also by stimulating anti-SARS-CoV-2 T cell response. These finding are consistent with a potential beneficial role of mTOR-I as modulators of immune response to COVID-19 vaccine in KTR.

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.

BACKGROUND: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. METHODS: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry. RESULTS: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10-8) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86×10-9). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. CONCLUSIONS: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.

Association between Long COVID and Overweight/Obesity.

BACKGROUND: Long COVID is a syndrome characterized by the persistence of SARS-CoV-2 infection symptoms. Among HCWs, prolonged COVID symptoms could lead to the inability to perform work tasks. The aim of this study is to investigate 35-day long-COVID (35-LC) characteristics and risk factors in a one-year period. METHODS: We carried out a retrospective cohort study during the COVID-19 pandemic at University Hospital of Bari. A total of 5750 HCWs were tested for close contact with a confirmed case, in the absence of personal protective equipment, or for symptom development. RESULTS: Each positive HCW was investigated for cardiovascular risk factors or respiratory diseases. An amount of 352 HCWs (6.1%) were infected by SARS-CoV-2, and 168 cases evolved to long COVID. The 35-LC group showed mean BMI values higher than the non-35-LC group (25.9 kg/m2 vs. 24.8 kg/m2, respectively), and this difference was significant (p-value: 0.020). Moreover, HCWs who suffered from pulmonary disease (OR = 3.7, CL 95%: 1.35-10.53; p-value = 0.007) or overweight (OR = 1.6 CL 95%: 1.05-2.56; p-value = 0.029) had an increased risk of developing 35-LC. CONCLUSIONS: Long COVID is an emerging problem for hospital managers as it may reduce the number of HCWs deployed in the fight against COVID-19. High BMI and previous pulmonary disease could be risk factors for 35-LC development in exposed HCWs.

The Vitamin D, IL-6 and the eGFR Markers a Possible Way to Elucidate the Lung-Heart-Kidney Cross-Talk in COVID-19 Disease: A Foregone Conclusion.

BACKGROUND: Based on recent findings, we speculated the existence of the lung, heart, and kidney axis as the main pathway for the COVID-19 disease progression. METHODS: This paper reports on an observational study conducted by a team of researchers and doctors of the 118-Pre-Hospital and Emergency Department of SG Moscati of Taranto City in Italy. The study was conducted on a totality of 185 participants that were divided into three groups. The study group included COVID-19 affected patients (PP n = 80), the first control group included patients with different pathologies (non-COVID-19 NNp n = 62) of the SG Moscati Hospital, and the second control group included healthy individuals (NNh n = 43). The core of the current trial was focused on assessing the level of the vitamin D (serum 25(OH) D concentration), IL-6, and the renal glomerular filtrate (eGFR) in COVID-19 disease and non-COVID-19 patients in both groups. RESULTS: It was observed that the majority of COVID-19-infected patients showed a progressive multi-organ involvement, especially in regard to the lung, kidney, and heart. The majority of the COVID-19 patients exhibited preexisting comorbidities which include cardiovascular, respiratory, and renal disorders accompanied by a severely low level of vitamin D, extremely high level of IL-6, and low glomerular filtration rate (eGFR). The significant overall damages exerted by the immune-mediated responses under the hyper-expression of proinflammatory cytokines and interleukins, such as IL-6, may be facilitated by either a decreased level of vitamin D or the ageing process. The reduced presence of vitamin D was often found together with a reduced functionality of renal activity, as revealed by the low eGFR, and both were seen to be concomitant with an increased mortality risk in patients with lung disorders and heart failure (HF), whether it is showed at baseline or it develops during manifestation of COVID-19. Therefore, the documentation of the modifiable risk factors related to SARS-CoV-2 and lung impairment in older patients with kidney and heart disease may help the clinician to better manage the situation. CONCLUSIONS: This paper addresses how a low level of vitamin D and older age may be indicative of systemic worsening in patients with COVID-19, with a goal of providing a broader context in which to view a better therapeutic approach.

Severe COVID-19 by SARS-CoV-2 Lineage B.1.1.7 in Vaccinated Solid-Organ Transplant Recipients: New Preventive Strategies Needed to Protect Immunocompromised Patients.

BACKGROUND: Solid-organ transplant (SOT) recipients are at a high risk of severe COVID-19, and are priority for vaccination. Here, we describe three cases of severe COVID-19 caused by SARS-CoV-2 B.1.1.7 lineage in vaccinated SOT recipients. METHODS: Three SOT patients were hospitalized in the Policlinico Hospital of Bari (southern Italy) and underwent nasopharyngeal swabs for molecular detection of SARS-CoV-2 genes and spike protein mutations by real-time PCR. One sample was subjected to whole-genome sequencing. RESULTS: One patient was a heart transplant recipient and two were kidney transplant recipients. All were hospitalized with severe COVID-19 between March and May 2021. Two patients were fully vaccinated and one had received only one dose of the BNT162b2 mRNA vaccine. All the patients showed a high viral load at diagnosis, and molecular typing revealed the presence of B.1.1.7 lineage SARS-CoV-2. In all three cases, prolonged viral shedding was reported. CONCLUSIONS: The three cases pose concern about the role of the B.1.1.7 lineage in severe COVID-19 and about the efficacy of COVID-19 vaccination in immunocompromised patients. Protecting immunocompromised patients from COVID-19 is a challenge. SOT recipients show a suboptimal response to standard vaccination, and thus, an additive booster or a combined vaccination strategy with mRNA, protein/subunit, and vector-based vaccines may be necessary. This population should continue to practice strict COVID-19 precautions post-vaccination, until new strategies for protection are available.

Multifaced Roles of HDL in Sepsis and SARS-CoV-2 Infection: Renal Implications.

High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.

Large-scale IgM and IgG SARS-CoV-2 serological screening among healthcare workers with a low infection prevalence based on nasopharyngeal swab tests in an Italian university hospital: Perspectives for public health.

BACKGROUND: Healthcare workers (HCWs) are highly exposed to SARS-CoV-2 infection given their specific tasks. The IgG-IgM serological assay has demonstrated good accuracy in early detection in symptomatic patients, but its role in the diagnosis of asymptomatic patients is uncertain. The aim of our study was to assess IgM and IgG prevalence in sera in a large cohort of HCWs previously subjected to Nasopharyngeal swab test (NST) after accurate risk assessment due to positive COVID-19 patient exposure during an observation period of 90 days. METHODS: 2407 asymptomatic HCWs that had close contact with COVID-19 patients in the period between April 8th and June 7th were screened with NST based on the RT-PCR method. In parallel, they underwent large-scale chemiluminescence immunoassays involving IgM-IgG serological screening to determine actual viral spread in the same cohort. RESULTS: During the 90-day observation period, 18 workers (0.75%) resulted positive for SARS-CoV-2 infection at the NST, whereas the positivity rates for IgM and IgG were 11.51% and 2.37%, respectively (277 workers). Despite high specificity, serological tests were inadequate for detecting SARS-CoV-2 infection in patients with previous positive NST results (IgM and IgG sensitivities of 27.78% and 50.00%, respectively). CONCLUSIONS: These findings indicate a widespread low viral load of SARS-CoV-2 among hospital workers. However, serological screening showed very low sensitivity with respect to NST in identifying infected workers, and negative IgG and IgM results should not exclude the diagnosis of COVID-19. IgG-IgM chemiluminescence immunoassays could increase the diagnosis of COVID-19 only in association with NST, and this association is considered helpful for decision-making regarding returning to work.

Focus on renal blood flow in mechanically ventilated patients with SARS-CoV-2: a prospective pilot study.

Mechanically ventilated patients with ARDS due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seem particularly susceptible to AKI. Our hypothesis was that the renal blood flow could be more compromised in SARS-CoV-2 patients than in patients with "classical" ARDS. We compared the renal resistivity index (RRI) and the renal venous flow (RVF) in ARDS patients with SARS-CoV-2 and in ARDS patients due to other etiologies. Prospective, observational pilot study performed on 30 mechanically ventilated patients (15 with SARS-COV-2 ARDS and 15 with ARDS). Mechanical ventilation settings included constant-flow controlled ventilation, a tidal volume of 6 ml/kg of ideal body weight and the PEEP level titrated to the lowest driving pressure. Ultrasound Doppler measurements of RRI and RVF pattern were performed in each patient. Patients with SARS-COV-2 ARDS had higher RRI than patients with ARDS (0.71[0.67-0.78] vs 0.64[0.60-0.74], p = 0.04). RVF was not-continuous in 9/15 patients (71%) in the SARS-COV-2 ARDS group and in and 5/15 (33%) in the ARDS group (p = 0.27). A linear correlation was found between PEEP and RRI in patients with SARS-COV-2 ARDS (r2 = 0.31; p = 0.03) but not in patients with ARDS. Occurrence of AKI was 53% in patients with SARS-COV-2 ARDS and 33% in patients with ARDS (p = 0.46). We found a more pronounced impairment in renal blood flow in mechanically ventilated patients with SARS-COV-2 ARDS, compared with patients with "classical" ARDS.

SARS-CoV-2 and Viral Sepsis: Immune Dysfunction and Implications in Kidney Failure.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), first emerged in Wuhan, China. The clinical manifestations of patients infected with COVID-19 include fever, cough, and dyspnea, up to acute respiratory distress syndrome (ARDS) and acute cardiac injury. Thus, a lot of severe patients had to be admitted to intensive care units (ICU). The pathogenic mechanisms of SARS-CoV-2 infection are mediated by the binding of SARS-CoV-2 spikes to the human angiotensin-converting enzyme 2 (ACE-2) receptor. The overexpression of human ACE-2 is associated with the disease severity in SARS-CoV-2 infection, demonstrating that viral entry into cells is a pivotal step. Although the lung is the organ that is most commonly affected by SARS-CoV-2 infection, acute kidney injury (AKI), heart dysfunction and abdominal pain are the most commonly reported co-morbidities of COVID-19. The occurrence of AKI in COVID-19 patients might be explained by several mechanisms that include viral cytopathic effects in renal cells and the host hyperinflammatory response. In addition, kidney dysfunction could exacerbate the inflammatory response started in the lungs and might cause further renal impairment and multi-organ failure. Mounting recent evidence supports the involvement of cardiovascular complications and endothelial dysfunction in COVID-19 syndrome, in addition to respiratory disease. To date, there is no vaccine, and no specific antiviral medicine has been shown to be effective in preventing or treating COVID-19. The removal of pro-inflammatory cytokines and the shutdown of the cytokine storm could ameliorate the clinical outcome in severe COVID-19 cases. Therefore, several interventions that inhibit viral replication and the systemic inflammatory response could modulate the severity of the renal dysfunction and increase the probability of a favorable outcome.

COVID-19 hospital outbreaks: Protecting healthcare workers to protect frail patients. An Italian observational cohort study.

OBJECTIVES: To determine the prevalence of SARS-CoV-2 infection among exposed healthcare workers (HCWs) after preventive protocol implementation. METHODS: A total of 5750 HCWs were included in the study. Those in contact with COVID-19 patients were allocated into a high-risk or a low-risk group based on contact type (PPE- or non-PPE-protected); high-risk workers underwent nasopharyngeal swab tests, while among low-risk workers, swab tests were carried out only for symptomatic workers (active surveillance). The prevalence was determined by real-time reverse transcriptase-polymerase chain reaction on nasopharyngeal samples. RESULTS: 3570 HCWs had contact with 1065 COVID-19 patients. Among them, 3494 were subjected to active surveillance (low-risk group); 2886 (82.60%) were subjected to a swab test; and 15 were positive (0.52%). Seventy-six HCWs (2.13% of exposed) were included in the high-risk group, and a swab test was mandatory for each participant. Overall, 66 (86.84% of high-risk) were negative, and 10 were positive (13.16%), resulting in a higher risk of infection than in the low-risk group [OR = 29.00; 95% CI:12.56-66.94; p < 0.0001]. CONCLUSION: To date, the SARS-CoV-2 infection prevalence is 0.70% among exposed HCWs and 0.435% among all HCWs working at the examined university hospital. The correct use of PPE and the early identification of symptomatic workers are essential factors to avoiding nosocomial clusters.

Impact of lockdown on the microbiological status of the hospital water network during COVID-19 pandemic.

The COVID-19 pandemic started in China in early December 2019, and quickly spread around the world. The epidemic gradually started in Italy at the end of February 2020, and by May 31, 2020, 232,664 cases and 33,340 deaths were confirmed. As a result of this pandemic, the Italian Ministerial Decree issued on March 11, 2020, enforced lockdown; therefore, many social, recreational, and cultural centers remained closed for months. In Apulia (southern Italy), all non-urgent hospital activities were suspended, and some wards were closed, with a consequent reduction in the use of the water network and the formation of stagnant water. This situation could enhance the risk of exposure of people to waterborne diseases, including legionellosis. The purpose of this study was to monitor the microbiological quality of the water network (coliforms, E. coli, Enterococci, P. aeruginosa, and Legionella) in three wards (A, B and C) of a large COVID-19 regional hospital, closed for three months due to the COVID-19 emergency. Our study revealed that all three wards' water network showed higher contamination by Legionella pneumophila sg 1 and sg 6 at T1 (after lockdown) compared to the period before the lockdown (T0). In particular, ward A at T1 showed a median value = 5600 CFU/L (range 0-91,000 CFU/L) vs T0, median value = 75 CFU/L (range 0-5000 CFU/L) (p-value = 0.014); ward B at T1 showed a median value = 200 CFU/L (range 0-4200 CFU/L) vs T0, median value = 0 CFU/L (range 0-300 CFU/L) (p-value = 0.016) and ward C at T1 showed a median value = 175 CFU/L (range 0-22,000 CFU/L) vs T0, median value = 0 CFU/L (range 0-340 CFU/L) (p-value < 0.001). In addition, a statistically significant difference was detected in ward B between the number of positive water samples at T0 vs T1 for L. pneumophila sg 1 and sg 6 (24% vs 80% p-value < 0.001) and for coliforms (0% vs 64% p-value < 0.001). Moreover, a median value of coliform load resulted 3 CFU/100 ml (range 0-14 CFU/100 ml) at T1, showing a statistically significant increase versus T0 (0 CFU/100 ml) (p-value < 0.001). Our results highlight the need to implement a water safety plan that includes staff training and a more rigorous environmental microbiological surveillance in all hospitals before occupying a closed ward for a longer than one week, according to national and international guidelines.