Improving care for patients with Clostridioides difficile infection: A clinical practice and healthcare systems perspective.

Introduction: Arriving at a C. difficile infection (CDI) diagnosis, treating patients and dealing with recurrences is not straightforward, but a comprehensive and well-rounded understanding of what is needed to improve patient care is lacking. This manuscript addresses the paucity of multidisciplinary perspectives that consider clinical practice related and healthcare system-related challenges to optimizing care delivery. Methods: We draw on narrative review, consultations with clinical experts and patient representatives, and a survey of 95 clinical and microbiology experts from the UK, France, Italy, Australia and Canada, adding novel multi-method evidence to the knowledge base. Results and discussion: We examine the patient pathway and variations in clinical practice and identify, synthesize insights on and discuss associated challenges. Examples of key challenges include the need to conduct multiple tests for a conclusive diagnosis, treatment side-effects, the cost of some antibiotics and barriers to access of fecal microbiota transplantation, difficulties in distinguishing recurrence from new infection, workforce capacity constraints to effective monitoring of patients on treatment and of recurrence, and ascertaining whether a patient has been cured. We also identify key opportunities and priorities for improving patient care that target both clinical practice and the wider healthcare system. While there is some variety across surveyed countries' healthcare systems, there is also strong agreement on some priorities. Key improvement actions seen as priorities by at least half of survey respondents in at least three of the five surveyed countries include: developing innovative products for both preventing (Canada, Australia, UK, Italy, and France) and treating (Canada, Australia, and Italy) recurrences; facilitating more multidisciplinary patient care (UK, Australia, and France); updating diagnosis and treatment guidelines (Australia, Canada, and UK); and educating and supporting professionals in primary care (Italy, UK, Canada, and Australia) and those in secondary care who are not CDI experts (Italy, Australia, and France) on identifying symptoms and managing patients. Finally, we discuss key evidence gaps for a future research agenda.

Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS).

INTRODUCTION: Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking. METHODS: We conducted a multi-center, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering versus dexamethasone 6 mg daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. PRIMARY OUTCOME: reduction in 28-day mortality. SECONDARY OUTCOMES: mechanical ventilation-free days at 28 days, need for ICU referral, length of hospitalisation, need for tracheostomy, changes in PaO2:FiO2 ratio, C-reactive protein levels and WHO clinical progression scale at days 3, 7, and 14. RESULTS: 677 randomised patients were included. Findings are reported as methylprednisolone (n=337) versus dexamethasone (n=340). By day 28, there were no significant differences in mortality (35[10.4%] versus 41[12.1%]; p=0.49), nor in the median mechanical ventilation-free days (23[14] versus 24[16]; p=0.49). ICU referral was necessary in 41[12.2%] versus 45[13.2%]; p=0.68 and tracheostomy in 8[2.4%] versus 9[2.6%]; p=0.82. Survivors in the methylprednisolone group required a longer median hospitalisation (15[11] versus 14[11] days; p=0.005) and experienced an improvement in C-reactive protein levels, but not in PaO2:FiO2 ratio, at days 7 and 14. There were no differences in disease progression at the prespecified timepoints. CONCLUSION: Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared to conventional dexamethasone in COVID-19 pneumonia.

Invasive cryptococcal disease in COVID-19: systematic review of the literature and analysis

SUMMARY During the Coronavirus Disease 2019 (COVID-19) pandemic, an increasing number of fungal infections associated with SARS-CoV-2 infection have been reported. Among them, cryptococcosis could be a life-threatening disease. We performed a Systematic Review (PRISMA Statement) of cryptococcosis and COVID-19 co-infection, case report/series were included: a total of 34 cases were found, then we added our case report. We collected patients' data and performed a statistical analysis comparing two groups of patients sorted by outcome: "dead” and "alive”. Three cases were excluded for lack of information. To compare categorical data, we used a Fisher-exact test (α=0.05). To compare quantitative variables a U Mann-Whitney test was used (α=0.05), with a 95% Confidence Interval. A total of 32 co-infected patients were included in the statistical analysis. Mortality rate was 17/32 (53.1%): these patients were included in "dead” group, and 15/32 (46.9%) patients survived and were included in "alive” group. Overall, males were 25/32 (78.1%), the median age was 60 years (IQR 53–70) with non-statistically significant difference between groups (p=0.149 and p=0.911, respectively). Three variables were associated with mortality: ARDS, ICU admission and inadequate treatment. Overall, 21 out of 24 (87.5%) patients were in ARDS with a statistically significant difference among two groups (p=0.028). ICU admission for COVID-19 was observed in 18/26 (69.2%), more frequently among dead group (p=0.034). Finally, 15/32 (46.9%) patients had adequate treatment (amphotericin B + flucytosine for invasive cryptococcosis) mostly among alive patients (p=0.039). In conclusion, mortality due to cryptococcal infection among COVID-19 patients remains high but an early diagnosis and appropriate treatment could reduce mortality.

Neutralizing Antibodies against SARS-CoV-2 Beta and Omicron Variants Inhibition Comparison after BNT162b2 mRNA Booster Doses with a New PETIA sVNT Assay

Background: Monitoring antibody response following SARS-CoV-2 vaccination is strategic, and neutralizing antibodies represent the gold standard. The neutralizing response to Beta and Omicron VOCs was evaluated versus the gold standard by a new commercial automated assay. Methods: Serum samples from 100 healthcare workers from the Fondazione Policlinico Universitario Campus Biomedico and the Pescara Hospital were collected. IgG levels were determined by chemiluminescent immunoassay (Abbott Laboratories, Wiesbaden, Germany) and serum neutralization assay as the gold standard. Moreover, a new commercial immunoassay, the PETIA test Nab (SGM, Rome, Italy), was used for neutralization evaluation. Statistical analysis was performed with R software, version 3.6.0. Results: Anti-SARS-CoV-2 IgG titers decayed during the first ninety days after the vaccine second dose. The following booster dose significantly (p < 0.001) increased IgG levels. A correlation between IgG expression and neutralizing activity modulation was found with a significant increase after the second and the third booster dose (p < 0.05. Compared to the Beta variant of the virus, the Omicron VOC was associated with a significantly larger quantity of IgG antibodies needed to achieve the same degree of neutralization. The best Nab test cutoff for high neutralization titer (≥1:80) was set for both Beta and Omicron variants. Conclusion: This study correlates vaccine-induced IgG expression and neutralizing activity using a new PETIA assay, suggesting its usefulness for SARS-CoV2 infection management.

Invasive cryptococcal disease in COVID-19: systematic review of the literature and analysis.

During the Coronavirus Disease 2019 (COVID-19) pandemic, an increasing number of fungal infections associated with SARS-CoV-2 infection have been reported. Among them, cryptococcosis could be a life-threatening disease. We performed a Systematic Review (PRISMA Statement) of cryptococcosis and COVID-19 co-infection, case report/series were included: a total of 34 cases were found, then we added our case report. We collected patients' data and performed a statistical analysis comparing two groups of patients sorted by outcome: "dead" and "alive". Three cases were excluded for lack of information. To compare categorical data, we used a Fisher-exact test (α=0.05). To compare quantitative variables a U Mann-Whitney test was used (α=0.05), with a 95% Confidence Interval. A total of 32 co-infected patients were included in the statistical analysis. Mortality rate was 17/32 (53.1%): these patients were included in "dead" group, and 15/32 (46.9%) patients survived and were included in "alive" group. Overall, males were 25/32 (78.1%), the median age was 60 years (IQR 53-70) with non-statistically significant difference between groups (p=0.149 and p=0.911, respectively). Three variables were associated with mortality: ARDS, ICU admission and inadequate treatment. Overall, 21 out of 24 (87.5%) patients were in ARDS with a statistically significant difference among two groups (p=0.028). ICU admission for COVID-19 was observed in 18/26 (69.2%), more frequently among dead group (p=0.034). Finally, 15/32 (46.9%) patients had adequate treatment (amphotericin B + flucytosine for invasive cryptococcosis) mostly among alive patients (p=0.039). In conclusion, mortality due to cryptococcal infection among COVID-19 patients remains high but an early diagnosis and appropriate treatment could reduce mortality.

Neutralizing Antibodies against SARS-CoV-2 Beta and Omicron Variants Inhibition Comparison after BNT162b2 mRNA Booster Doses with a New PETIA sVNT Assay.

BACKGROUND: Monitoring antibody response following SARS-CoV-2 vaccination is strategic, and neutralizing antibodies represent the gold standard. The neutralizing response to Beta and Omicron VOCs was evaluated versus the gold standard by a new commercial automated assay. METHODS: Serum samples from 100 healthcare workers from the Fondazione Policlinico Universitario Campus Biomedico and the Pescara Hospital were collected. IgG levels were determined by chemiluminescent immunoassay (Abbott Laboratories, Wiesbaden, Germany) and serum neutralization assay as the gold standard. Moreover, a new commercial immunoassay, the PETIA test Nab (SGM, Rome, Italy), was used for neutralization evaluation. Statistical analysis was performed with R software, version 3.6.0. RESULTS: Anti-SARS-CoV-2 IgG titers decayed during the first ninety days after the vaccine second dose. The following booster dose significantly (p < 0.001) increased IgG levels. A correlation between IgG expression and neutralizing activity modulation was found with a significant increase after the second and the third booster dose (p < 0.05. Compared to the Beta variant of the virus, the Omicron VOC was associated with a significantly larger quantity of IgG antibodies needed to achieve the same degree of neutralization. The best Nab test cutoff for high neutralization titer (≥1:80) was set for both Beta and Omicron variants. CONCLUSION: This study correlates vaccine-induced IgG expression and neutralizing activity using a new PETIA assay, suggesting its usefulness for SARS-CoV2 infection management.

Cardiopulmonary disease as sequelae of long-term COVID-19: Current perspectives and challenges.

COVID-19 infection primarily targets the lungs, which in severe cases progresses to cytokine storm, acute respiratory distress syndrome, multiorgan dysfunction, and shock. Survivors are now presenting evidence of cardiopulmonary sequelae such as persistent right ventricular dysfunction, chronic thrombosis, lung fibrosis, and pulmonary hypertension. This review will summarize the current knowledge on long-term cardiopulmonary sequelae of COVID-19 and provide a framework for approaching the diagnosis and management of these entities. We will also identify research priorities to address areas of uncertainty and improve the quality of care provided to these patients.

Antibiotics Use in COVID-19 Patients: A Systematic Literature Review.

The issue of bacterial infections in COVID-19 patients has received increasing attention among scientists. Antibiotics were widely prescribed during the early phase of the pandemic. We performed a literature review to assess the reasons, evidence and practices on the use of antibiotics in COVID-19 in- and outpatients. Published articles providing data on antibiotics use in COVID-19 patients were identified through computerized literature searches on the MEDLINE and SCOPUS databases. Searching the MEDLINE database, the following search terms were adopted: ((antibiotic) AND (COVID-19)). Searching the SCOPUS database, the following search terms were used: ((antibiotic treatment) AND (COVID-19)). The risk of bias in the included studies was not assessed. Both quantitative and qualitative information were summarized by means of textual descriptions. Five-hundred-ninety-three studies were identified, published from January 2020 to 30 October 2022. Thirty-six studies were included in this systematic review. Of the 36 included studies, 32 studies were on the use of antibiotics in COVID-19 inpatients and 4 on antibiotic use in COVID-19 outpatients. Apart from the studies identified and included in the review, the main recommendations on antibiotic treatment from 5 guidelines for the clinical management of COVID-19 were also summarized in a separate paragraph. Antibiotics should not be prescribed during COVID-19 unless there is a strong clinical suspicion of bacterial coinfection or superinfection.

Association of COVID-19 case fatality rate with disease burden: an ecological analysis in Italy during the first wave.

OBJECTIVES: In Italy, the case fatality rate (CFR) of coronavirus disease 2019 (COVID-19) during the first wave of the pandemic showed significant geographic heterogeneity. The aim of this study was to explore the possible association between the CFR and measures of disease burden in the Italian regions using an ecological approach. METHODS: Cumulated regional data for the period February 24 to May 11, 2020 were analysed to assess the association of the CFR with the cumulative incidence of COVID-19 and the ratio between the maximum number of COVID-19 patients in intensive care units (ICU) and ICU beds available before the pandemic (ICU load), adjusting for median age of the patients at disease onset, number of nasopharyngeal swabs performed per confirmed case, and prevalence of chronic diseases . RESULTS: During the study period, the COVID-19 CFR in the Italian regions ranged between 5.0% and 18.4%. On multivariable regression analysis, the CFR was found to be significantly associated with the cumulative incidence (relative rate (RR) 1.02 per 100 cases/1 million increase), median patient age (RR 1.07 per 1 year increase), and ICU load (RR 1.72, 2.18, and 2.57, for >40-70% vs ≤40%, 70-140% vs ≤40%, and ≥140 vs ≤40%, respectively). CONCLUSIONS: A high burden of COVID-19 may contribute to increased disease fatality, possibly as a result of the increasing demand for care of critically ill patients beyond health system capability.

Clostridioides difficile Infection: A Never-Ending Challenge.

The most common worldwide cause of antibiotic-associated diarrhea/colitis is the toxin-producing bacterium Clostridioides difficile [...].

The Monkeypox Pandemic as a Worldwide Emergence: Much Ado?

The dramatic emergence of SARS-CoV-2 infection worldwide opened the Pandora's box of fears and frights for new emerging infections [...].

Double-Blind, Randomized, Placebo-Controlled Study on hzVSF-v13, a Novel Anti-Vimentin Monoclonal Antibody Drug as Add-on Standard of Care in the Management of Patients with Moderate to Severe COVID-19.

Humanized Virus Suppressing Factor-variant 13 (hzVSF-v13), a monoclonal IgG4 antibody against vimentin, was investigated in moderate to severe COVID-19 pneumonia through a Phase II study. Patients were randomized to two different IV doses of the test drug or saline with standard of care. Overall, 64 patients were recruited, and 62 entered the efficacy assessment in the full analysis set. Primary endpoint: The clinical failure rate at day 28 was 15.8% for placebo, 9.1% for low-dose hzVSF-v13 and 9.5% for high-dose hzVSF-v13 (not significant). A trend toward better efficacy was shown in several secondary endpoints, with statistical significance between low-dose hzVSF-v13 and placebo in terms of the rate of improved patients on the ordinal scale for clinical improvement (OSCI): 90.0% vs. 52.63% (p = 0.0116). In the severe stratum, the results of low-dose hzVSF-v13 vs. placebo were 90.0% and 22.2% for OSCI (p = 0.0092), 9 days and 14 days for time to discontinuation of oxygen therapy (p = 0.0308), 10 days and 15 days for both time to clinical improvement (TTCI) and time to recovery (TTR) and p = 0.0446 for both TTCI and TTR. Change from baseline of NEWS2 score at day 28 was -3.4 vs. + 0.4 (p = 0.0441). The results propose hzVSF-v13 as a candidate in the treatment of severe COVID-19.

The burden of Clostridioides difficile infection in COVID-19 patients: A systematic review and meta-analysis.

OBJECTIVES: The main aim of this systematic review and meta-analysis was to assess the proportion of confirmed COVID-19 patients with Clostridioides difficile infection (CDI) and to describe risk factors and outcome of these patients. METHODS: MEDLINE and Cochrane Central Register of Controlled Trials databases were searched up to July 15, 2021. We included studies reporting data on CDI occurring in patients with a confirmed diagnosis of COVID-19. We pooled proportion of CDI patients using a random effects model (DerSimonian-Laird method) stabilising the variances using the Freeman-Tukey double arcsine transformation. RESULTS: Thirteen studies were included in the systematic review. All the studies retrospectively collected data between February 2020 and February 2021. The reported CDI incidence rates ranged from 1.4 to 4.4 CDI cases per 10,000 patient-days. Seven studies reported data on the number of COVID-19 patients who developed CDI and the total number of COVID-19 patients in the study period and were included in the meta-analysis, comprising 23,697 COVID-19 patients. The overall pooled proportion of COVID-19 patients who had CDI was 1% [95% confidence interval: 1-2]. Among studies reporting CDI occurrence in patients with and without COVID-19, the majority of them reported reduced or unchanged CDI rates compared to pre-COVID period. CONCLUSIONS: CDI is a relevant issue for COVID-19 patients. Adherence to infection prevention and control measures and to the antimicrobial stewardship principles is crucial even during the COVID-19 pandemic.

New endemic and pandemic pathologies with interhuman airborne transmission through ear, nose and throat anatomical sites Nuove patologie endemiche e pandemiche con trasmissione aerea interumana attraverso siti anatomici di orecchio, naso e gola

SUMMARY The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has once again stigmatised the importance of airborne pathogens and their clinical, social and public health impact. Respiratory viruses are transmitted between individuals when the pathogen is released from the upper airways or from the lower respiratory tract of an infected individual. Airborne transmission is defined as the inhalation of the infectious aerosol, named droplet nuclei which size is smaller than 5 mm and that can be inhaled at a distance up to 2 metres. This route of transmission is relevant for viral respiratory pathogens, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS)-CoV, influenza virus, human rhinovirus, respiratory syncytial virus (RSV) and other respiratory virus families that differ in viral and genomic structures, susceptibility of a population to the infection, severity, transmissibility, ways of transmission and seasonal recurrence. Human respiratory viruses generally infect cells of the upper respiratory tract, eliciting respiratory signs and symptoms, sometimes without the possibility to differentiate them clinically. As seen by the current Coronavirus Disease 2019 (COVID-19) pandemic, human respiratory viruses can substantially contribute to increased morbidity and mortality, economic losses and, eventually, social disruption. In this article, we describe the structural, clinical and transmission aspects of the main respiratory viruses responsible for endemic, epidemic and pandemic infections.

Double-Blind, Randomized, Placebo-Controlled Study on hzVSF-v13, a Novel Anti-Vimentin Monoclonal Antibody Drug as Add-on Standard of Care in the Management of Patients with Moderate to Severe COVID-19

Humanized Virus Suppressing Factor-variant 13 (hzVSF-v13), a monoclonal IgG4 antibody against vimentin, was investigated in moderate to severe COVID-19 pneumonia through a Phase II study. Patients were randomized to two different IV doses of the test drug or saline with standard of care. Overall, 64 patients were recruited, and 62 entered the efficacy assessment in the full analysis set. Primary endpoint: The clinical failure rate at day 28 was 15.8% for placebo, 9.1% for low-dose hzVSF-v13 and 9.5% for high-dose hzVSF-v13 (not significant). A trend toward better efficacy was shown in several secondary endpoints, with statistical significance between low-dose hzVSF-v13 and placebo in terms of the rate of improved patients on the ordinal scale for clinical improvement (OSCI): 90.0% vs. 52.63% (p = 0.0116). In the severe stratum, the results of low-dose hzVSF-v13 vs. placebo were 90.0% and 22.2% for OSCI (p = 0.0092), 9 days and 14 days for time to discontinuation of oxygen therapy (p = 0.0308), 10 days and 15 days for both time to clinical improvement (TTCI) and time to recovery (TTR) and p = 0.0446 for both TTCI and TTR. Change from baseline of NEWS2 score at day 28 was −3.4 vs. + 0.4 (p = 0.0441). The results propose hzVSF-v13 as a candidate in the treatment of severe COVID-19.

How Does COVID-19 Pandemic Impact on Incidence of Clostridioides difficile Infection and Exacerbation of Its Gastrointestinal Symptoms?

Coronavirus disease 2019 (COVID-19) has rapidly spread all over the world with a very high rate of mortality. Different symptoms developed by COVID-19 infection and its impacts on various organs of the human body have highlighted the importance of both coinfections and superinfections with other pathogens. The gastrointestinal (GI) tract is vulnerable to infection with COVID-19 and can be exploited as an alternative transmission route and target for virus entry and pathogenesis. The GI manifestations of COVID-19 disease are associated with severe disease outcomes and death in all age groups, in particular, elderly patients. Empiric antibiotic treatments for microbial infections in hospitalized patients with COVID-19 in addition to experimental antiviral and immunomodulatory drugs may increase the risk of antibiotic-associated diarrhea (AAD) and Clostridioides difficile infection (CDI). Alterations of gut microbiota are associated with depletion of beneficial commensals and enrichment of opportunistic pathogens such as C. difficile. Hence, the main purpose of this review is to explain the likely risk factors contributing to higher incidence of CDI in patients with COVID-19. In addition to lung involvement, common symptoms observed in COVID-19 and CDI such as diarrhea, highlight the significance of bacterial infections in COVID-19 patients. In particular, hospitalized elderly patients who are receiving antibiotics might be more prone to CDI. Indeed, widespread use of broad-spectrum antibiotics such as clindamycin, cephalosporins, penicillin, and fluoroquinolones can affect the composition and function of the gut microbiota of patients with COVID-19, leading to reduced colonization resistance capacity against opportunistic pathogens such as C. difficile, and subsequently develop CDI. Moreover, patients with CDI possibly may have facilitated the persistence of SARS-CoV-2 viral particles in their feces for approximately one month, even though the nasopharyngeal test turned negative. This coinfection may increase the potential transmissibility of both SARS-CoV-2 and C. difficile by fecal materials. Also, CDI can complicate the outcome of COVID-19 patients, especially in the presence of comorbidities or for those patients with prior exposure to the healthcare setting. Finally, physicians should remain vigilant for possible SARS-CoV-2 and CDI coinfection during the ongoing COVID-19 pandemic and the excessive use of antimicrobials and biocides.

From Syndemic Lesson after COVID-19 Pandemic to a "Systemic Clinical Risk Management" Proposal in the Perspective of the Ethics of Job Well Done.

The syndemic framework proposed by the 2021-2030 World Health Organization (WHO) action plan for patient safety and the introduction of enabling technologies in health services involve a more effective interpretation of the data to understand causation. Based on the Systemic Theory, this communication proposes the "Systemic Clinical Risk Management" (SCRM) to improve the Quality of Care and Patient Safety. This is a new Clinical Risk Management model capable of developing the ability to observe and synthesize different elements in ways that lead to in-depth interventions to achieve solutions aligned with the sustainable development of health services. In order to avoid uncontrolled decision-making related to the use of enabling technologies, we devised an internal Learning Algorithm Risk Management (LARM) level based on a Bayesian approach. Moreover, according to the ethics of Job Well Done, the SCRM, instead of giving an opinion on events that have already occurred, proposes a bioethical co-working because it suggests the best way to act from a scientific point of view.

SARS-CoV-2 Infection in Patients on Dialysis: Incidence and Outcomes in the Lazio Region, Italy.

Patients with end-stage kidney disease represent a frail population and might be at higher risk of SARS-CoV-2 infection. The Lazio Regional Dialysis and Transplant Registry collected information on dialysis patients with a positive swab. The study investigated incidence of SARS-CoV-2 infection, mortality and their potential associated factors in patients undergoing maintenance hemodialysis (MHD) in the Lazio region. Method: The occurrence of infection was assessed among MHD patients included in the RRDTL from 1 March to 30 November 2020. The adjusted cumulative incidence of infection and mortality risk within 30 days of infection onset were estimated. Logistic and Cox regression models were applied to identify factors associated with infection and mortality, respectively. Results: The MHD cohort counted 4942 patients; 256 (5.2%) had COVID-19. The adjusted cumulative incidence was 5.1%. Factors associated with infection included: being born abroad, educational level, cystic renal disease/familial nephropathy, vascular disease and being treated in a dialysis center located in Local Health Authority (LHA) Rome 2. Among infected patients, 59 (23.0%) died within 30 days; the adjusted mortality risk was 21.0%. Factors associated with 30-day mortality included: age, malnutrition and fever at the time of swab. Conclusions: Factors associated with infection seem to reflect socioeconomic conditions. Factors associated with mortality, in addition to age, are related to clinical characteristics and symptoms at the time of swab.