Donor-derived mold infections in lung transplant recipients: The importance of active surveillance.

Unexpected donor-derived fungal infections represent a rare but potentially fatal complication in lung transplant (Tx) recipients. Timely communication of the results of donor cultures and prompt treatment of recipients are crucial to mitigate the consequences of donor-derived transmissions. In this prospective cohort study, all consecutive patients who underwent lung transplantation from 2015 to 2022 were included. In December 2015, a Local Active Surveillance System has been implemented to provide biovigilance of donor culture results and optimize recipients' management. The aim of this study is to investigate the incidence of unexpected, mold-positive cultures among lung donors and the rate of transmission to recipients. Furthermore, management strategies and outcome of recipients with mold transmission are described. In case of isolation of the same mold in donor and recipient cultures, when possible, transmission was confirmed by dendrogram analysis. During the study period, 82 lung Tx were performed from 80 donors. The prevalence of donors with "unexpected" mold isolation from the respiratory tract was 3.75% (3/80). Isolated molds were Aspergillus niger, Rhizopus oryzae, and Aspergillus flavus. Transmissions occurred in all the three cases (100%) with a mean time of 5 days from lung Tx but none of the recipients developed invasive mold disease. Our Local Active Surveillance System allowed prompt recognition of lung donors unexpected mold colonization. Even though transmission occurred, introduction of early targeted antifungal therapy prevented potential catastrophic consequence of mold donor-derived infection in the immediate post-Tx period.

Donor-derived carbapenem-resistant gram-negative bacterial infections in solid organ transplant recipients: Active surveillance enhances recipient safety.

Donor-derived infections (DDIs) caused by carbapenem-resistant gram-negative bacteria (CR-GNB) in solid organ transplant recipients are potentially life-threatening. In this prospective study, we evaluated the incidence, factors associated with transmission, and the outcome of recipients with unexpected CR-GNB DDIs after the implementation of our local active surveillance system (LASS). LASS provides for early detection of unexpected donor CR-GNB infections, prophylaxis of recipients at high risk, and early diagnosis and treatment of DDIs. Whole genome sequencing confirmed DDI. Among 791 recipients, 38 (4.8%) were at high risk of unexpected CR-GNB DDI: 25 for carbapenem-resistant Enterobacterales (CRE) and 13 for carbapenem-resistant Acinetobacter baumannii (CRAB). Transmission did not occur in 27 (71%) cases, whereas DDIs occurred in 9 of 25 of CRE and 2 of 13 of CRAB cases. Incidence of CR-GNB DDI was 1.4%. Recipients of organs with CR-GNB-positive preservation fluid and liver recipients from a donor with CRE infection were at the highest risk of DDI. There was no difference in length of hospital stay or survival in patients with and without CR-GNB DDI. Our LASS contains transmission and mitigates the negative impacts of CR-GNB DDI. Under well-defined conditions, organs from donors with CR-GNB may be considered after a thorough evaluation of the risk/benefit profile.

Cytokine storm and severe hepatitis in pregnancy due to herpes simplex virus 2.

CASE PRESENTATION: A pregnant woman developed hepatitis due to a herpes simplex virus 2 primary infection with a severe systemic inflammatory response. Treatment with acyclovir and human immunoglobulin was given and both mother and baby survived. PURPOSE: We provide the first description of the inflammatory response associated with herpetic hepatitis in pregnancy.

Phaeohyphomycosis in Solid Organ Transplant Recipients: A Case Series and Narrative Review of the Literature.

Phaeohyphomycosis comprises a variety of infections caused by pigmented fungi. Solid organ transplant (SOT) recipients are particularly at risk of invasive infections due to their prolonged immunosuppression. Here, we describe three cases of phaeohyphomycosis in SOT recipients who were successfully treated with surgical excision and/or antifungal therapy. We additionally carried out a narrative review of the literature on phaeohyphomycosis in 94 SOT recipients from 66 published studies describing 40 different species of fungi. The most reported fungus was Alternaria (21%). The median time from transplant to diagnosis was 18 months (IQR 8.25-48), and kidney transplants were the most reported. Antifungal regimens were not homogeneous, though there was a prevalence of itraconazole- and voriconazole-based treatments. Clinical outcomes included recovery in 81% and death in 5% of infected SOT recipients. Susceptibility testing was done in 26.6% of the cases, with heterogeneous results due to the variety of species isolated. While the wide diversity of dematiaceous fungi and their host range make it difficult to offer a uniform approach for phaeohyphomycosis, an early diagnosis and therapy are critical in preventing the dissemination of disease in the immunocompromised host.

Female gender is associated with long COVID syndrome: a prospective cohort study.

OBJECTIVE: We explored the association between female gender and long COVID syndrome, defined as persistence of physical and/or psychological symptoms for more than 4 weeks after recovery from acute COVID-19 disease. The secondary aim was to identify predictors of long COVID syndrome by multivariable logistic regression analysis. METHODS: This was a single-centre prospective cohort study conducted at San Paolo Hospital in Milan, Italy. We enrolled adult patients who were evaluated at the post-COVID outpatient service of our Infectious Diseases Unit between 15 April 2020 and 15 December 2020. Participants were individuals who had clinically recovered from COVID-19 and in whom virological clearance had occurred. Previous infection by SARS-CoV-2 was microbiologically documented by positivity using a reverse-transcriptase polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab. All enrolled patients underwent blood tests and a comprehensive medical examination at follow-up. Individuals were interviewed about resolved and persisting symptoms and were asked to fill in two questionnaires to allow assessment of the Hospital Anxiety and Depression symptoms (HADS) score and of the Impact of Event Scale-Revised (IES-R) score. RESULTS: A total of 377 patients were enrolled in the study. The median time from symtpom onset to virological clerance was 44 (37-53) days. A diagnosis of long COVID syndrome was made in 260/377 (69%) patients. The most common reported symptoms were fatigue (149/377, 39.5%), exertional dyspnoea (109/377, 28.9%), musculoskeletal pain (80/377, 21.2%) and "brain fog" (76/377, 20.2%). Anxiety symptoms were ascertained in 71/377 (18.8%) individuals, whereas 40/377 (10.6%) patients presented symptoms of depression. Post-traumatic stress disorder (defined by a pathological IES-R score) was diagnosed in one-third of patients (85/275, 31%). Female gender was independently associated with long COVID syndrome at multivariable analysis (AOR 3.3 vs. males, 95% CI 1.8-6.2, p < 0.0001). Advanced age (adjusted (A)OR 1.03 for 10 years older, 95% CI 1.01-1.05, p 0.01) and active smoking (AOR 0.19 for former smokers vs. active smokers, 95% CI 0.06-0.62, p 0.002) were also associated with a higher risk of long COVID, while no association was found between severity of disease and long COVID (AOR 0.67 for continuous positive airway pressure (CPAP)/non-invasive mechanical ventilation (NIMV)/orotracheal intubation (OTI) vs. no 02 therapy, 95% CI 0.29-1.55, p 0.85). DISCUSSION: Factors that were found to be associated with a higher risk of developing "long COVID" syndrome were female gender, older age and active smoking, but not severity of the acute disease. Individuals affected by SARS-CoV-2 infection with the aforementioned features should be early identified and involved in follow-up programmes.

Declining Mortality Rate of Hospitalised Patients in the Second Wave of the COVID-19 Epidemics in Italy: Risk Factors and the Age-Specific Patterns.

BACKGROUND: Mortality rate from COVID-19 in Italy is among the world's highest. We aimed to ascertain whether there was any reduction of in-hospital mortality in patients hospitalised for COVID-19 in the second-wave period (October 2020-January 2021) compared to the first one (February-May 2020); further, we verified whether there were clusters of hospitalised patients who particularly benefitted from reduced mortality rate. METHODS: Data collected related to in-patients' demographics, clinical, laboratory, therapies and outcome. Primary end-point was time to in-hospital death. Factors associated were evaluated by uni- and multivariable analyses. A flow diagram was created to determine the rate of in-hospital death according to individual and disease characteristics. RESULTS: A total of 1561 patients were included. The 14-day cumulative incidence of in-hospital death by competing risk regression was of 24.8% (95% CI: 21.3-28.5) and 15.9% (95% CI: 13.7-18.2) in the first and second wave. We observed that the highest relative reduction of death from first to second wave (more than 47%) occurred mainly in the clusters of patients younger than 70 years. CONCLUSIONS: Progress in care and supporting therapies did affect population over 70 years to a lesser extent. Preventive and vaccination campaigns should focus on individuals whose risk of death from COVID-19 remains high.

Incidence, Risk Factors and Impact on Clinical Outcomes of Bloodstream Infections in Patients Hospitalised with COVID-19: A Prospective Cohort Study.

With the aim of describing the burden and epidemiology of community-acquired/healthcare-associated and hospital-acquired bloodstream infections (CA/HCA-BSIs and HA-BSIs) in patients hospitalised with COVID-19, and evaluating the risk factors for BSIs and their relative impact on mortality, an observational cohort study was performed on patients hospitalised with COVID-19 at San Paolo Hospital in Milan, Italy from 24 February to 30 November 2020. Among 1351 consecutive patients hospitalised with COVID-19, 18 (1.3%) had CA/HCA-BSI and 51 (3.8%) HA-BSI for a total of 82 episodes of BSI. The overall incidence of HA-BSI was 3.3/1000 patient-days (95% CI 2.4-4.2). Patients with HA-BSI had a longer hospital stay compared to CA/HCA-BSI and no-BSI groups (27 (IQR 21-35) vs. 12 (7-29) vs. 9 (5-17) median-days, p < 0.001) but a similar in-hospital mortality (31% vs. 33% vs. 25%, p = 0.421). BSI was not associated with an increased risk of mortality (CA/HCA-BSI vs. non-BSI aOR 1.27 95% CI 0.41-3.90, p = 0.681; HA-BSI vs. non-BSI aOR 1.29 95% CI 0.65-2.54, p = 0.463). Upon multivariate analysis, NIMV/CPAP (aOR 2.09, 95% CI 1.06-4.12, p = 0.034), IMV (aOR 5.13, 95% CI 2.08-12.65, p < 0.001) and corticosteroid treatment (aOR 2.11, 95% CI 1.06-4.19, p = 0.032) were confirmed as independent factors associated with HA-BSI. Development of HA-BSI did not significantly affect mortality. Patients treated with corticosteroid therapy had double the risk of developing BSI.

A Quantitative Estimate of the Expected Shortening of the Median Isolation Period of Patients With COVID-19 After the Adoption of a Symptom-Based Strategy.

A long period of isolation was observed in patients hospitalized for COVID-19 in Milan over March-September 2020 (45; IQR: 37-54 days). A significantly shorter period would have been observed by the application of May-WHO (22, IQR: 17-30 days, P < 0.001) and October-Italian (26, IQR: 21-34 days, P < 0.001) Guidelines. The adoption of the new symptom-based criteria is likely to lead to a significant reduction in the length of the isolation period with potential social, economic and psychological benefits, particularly in the younger population with mild/moderate disease and no comorbidities. In our opinion, the release from isolation after 21 days from symptoms onset, even without a PCR diagnostic test, in most cases seems the most adequate strategy that could balance precautions to prevent SARS CoV-2 transmission and unnecessary prolonged isolation or overuse of diagnostic testing.

Long-term positive effect of an educational antimicrobial stewardship program implemented in an Internal Medicine Department: a prospective analysis and a point prevalence survey on long-term effect.

The study aims to evaluate antimicrobial consumption and appropriateness one year after the implementation of an antimicrobial stewardship (AMS) program in an Internal Medicine Department in Milan. AMS program structured in two phases: "AMS phase", 5 months AMS-program based on an "audit-and-feedback model"; the "follow-up phase", 5 months long point prevalence survey conducted one year later. Outcomes of the study: antimicrobial consumption and appropriateness of antimicrobial therapy. Secondary outcomes: in-hospital mortality and length of stay (LOS). During the "AMS phase", we obtained a mean decrease of -11.4% of total antibiotic consumption as compared to the previous year (67.9 defined daily dose (DDD)/100 bed-days (bd) vs. 79.4 DDD/100bd, p = 0.07). Antibiotic consumption remained stable during "follow-up phase" (66.3 DDD/100bd, p = 0.9). Rate of appropriateness during the project increased from 48% to 85% (p < 0.01). No difference in in-hospital mortality and in LOS were observed. The study documents a positive long-term effect of AMS program on consumption and appropriate use of antibiotics.

Impact of daily versus weekly service of infectious diseases consultation on hospital antimicrobial consumption: a retrospective study.

BACKGROUND: To verify whether a daily service of Infectious Diseases consultation (ID-cons) is more effective than a weekly service in reducing antibiotic (ATB) consumption without worsening of clinical outcomes. METHODS: Two-year observational analysis of the ID-cons provided in a hospital setting in Milan, Italy. ID-cons resulted in: start-of-ATB; no-ATB; confirmation; modification-of-ATB. The impact of a weekly (September 1, 2016 - August 31, 2017 versus a daily (September 1, 2017 - September 30, 2018) service of ID-cons was evaluated in terms of: time-from-admission-to-first-ID-cons, type of ATB-intervention and number-of-ID-cons per 100 bed-days (bd). Primary outcomes: reduction of hospital ATB consumption overall and by department and classes expressed as Defined Daily Dose (DDD)/100bd (by Wilcoxon test for paired data). SECONDARY OUTCOMES: overall and sepsis-related in-hospital annual mortality rates (as death/patient's admissions). RESULTS: Overall 2552 ID-cons in 1111 patients (mean, 2.3 ID-cons per patient) were performed (18.6% weekly vs 81.4% daily). No differences in patient characteristics were observed. In the daily-service, compared to the weekly-service, patients were seen by the ID-consultant earlier (time-from-admission-to-ID-cons: 6 days (IQR 2-13) vs 10 days (IQR 6-19), p < 0.001) and ATB was more often started by the ID-consultant (Start-of-ATB: 11.6% vs 8%, p = 0.02), rather than treating physicians. After switching to daily-service, the number-of-ID-cons increased from 0.4/100bd to 1.5/100bd (p = 0.01), with the greatest increase in the emergency department (1.5/100bd vs 6.7/100bd, p < 0.001). Total ATB consumption decreased from 64 to 60 DDD/100bd. As for the number-of-cons, the consumption of ATB decreased mainly in the emergency area. According to ATB classes, glycopeptides consumption was reduced from 3.1 to 2.1 DDD/100bd (p = 0.02) while carbapenem use decreased from 3.7 to 3.1 DDD/100bd (p = 0.07). No changes in overall mortality (5.2% vs 5.2%) and sepsis-related mortality (19.3% vs 20.9%; p = 0.7) were observed among the two time-period. CONCLUSIONS: Daily-ID-cons resulted in a more comprehensive management of the infected patient by the ID-consultant, especially in the emergency area where we also observed the highest rate of reduction of ATB-usage. No change in mortality was observed.

The importance of patients' case-mix for the correct interpretation of the hospital fatality rate in COVID-19 disease.

OBJECTIVE: We aimed to document data on the epidemiology and factors associated with clinical course leading to death of patients hospitalised with COVID-19. METHODS: Prospective observational cohort study on patients hospitalised with COVID-19 disease in February-24th/May-17th 2020 in Milan, Italy. Uni-multivariable Cox regression analyses were performed. Death's percentage by two-weeks' intervals according to age and disease severity was analysed. RESULTS: A total of 174/539 (32.3%) patients died in hospital over 8228 person-day follow-up; the 14-day Kaplan-Meier probability of death was 29.5% (95%CI: 25.5-34.0). Older age, burden of comorbidities, COVID-19 disease severity, inflammatory markers at admission were independent predictors of increased risk, while several drug-combinations were predictors of reduced risk of in-hospital death. The highest fatality rate, 36.5%, occurred during the 2nd-3rd week of March, when 55.4% of patients presented with severe disease, while a second peak, by the end of April, was related to the admission of older patients (55% ≥80 years) with less severe disease, 30% coming from long-term care facilities. CONCLUSIONS: The unusual fatality rate in our setting is likely to be related to age and the clinical conditions of our patients. These findings may be useful to better allocate resources of the national healthcare system, in case of re-intensification of COVID-19 epidemics.

Variation of effect estimates in the analysis of mortality and length of hospital stay in patients with infections caused by bacteria-producing extended-spectrum beta-lactamases: a systematic review and meta-analysis.

OBJECTIVE: To assess the variation of effect estimates in the analysis of mortality and length of stay (LOS) in patients with infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. DESIGN: Systematic review and meta-analysis METHODS: Literature search for clinical studies from 1 January 1960 to 1 October 2018 was conducted in PubMed. Primary outcomes were risk ratios (RRs) of all-cause and attributable mortality and weighted mean differences (WMDs) in LOS in patients with bloodstream infections (BSIs) and non-invasive infections. Any change in the effect estimates was assessed by grouping studies according to design, setting, economy-based country classification, reporting period, microbiological aetiology, infection type and adjustment for appropriateness of empirical treatment. The impact of ESBL production was calculated using random-effect meta-analysis and heterogeneity was evaluated by I2 statistics and metaregression. RESULTS: Eighty-four studies including 22 030 patients and 149 outcome measures were included in the meta-analysis. Most studies were retrospective cohorts from high-income countries, providing unadjusted estimates. ESBL production in patients with BSIs (56 studies) increased the RR for all-cause mortality by a factor of 1.70 (95% CI 1.52 to 1.90; p<0.001), attributable mortality (16 studies) by 1.75 (95% CI 1.448 to 2.108; p<0.001) and WMD in the intensive care unit by 3.07 days (95% CI 1.61 to 4.54; p<0.001). WMD in hospital LOS was significantly higher in BSIs (4.41 days; 95% CI 3.37 to 5.46; p<0.001) and non-invasive (2.19 days; 95% CI 1.56 to 2.81; p<0.001). Subgroup analyses showed variation of estimates by study design, population, strain and assessment of appropriateness of empiric treatment. High heterogeneity was observed in all analyses. CONCLUSIONS: Current evidence of the clinical burden of infections caused by ESBL-producing bacteria is highly heterogeneous and based mainly on unadjusted estimates derived from retrospective studies. Despite these limitations, ESBL production in strains causing BSIs seems associated with higher all-cause and attributable mortality and longer hospitalisation.

Disseminated cytomegalovirus disease after bendamustine: a case report and analysis of circulating B- and T-cell subsets.

BACKGROUND: Bendamustine, used for the treatment of indolent B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia, is known to cause prolonged myelosuppression and lymphocytopenia and has been associated with the risk of developing serious and fatal infections. While reports of localized CMV infections in asymptomatic patients exist, disseminated CMV disease has not been described. CASE PRESENTATION: We report the first case of disseminated CMV infection in a 75-year-old male diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with massive bone marrow infiltration. Despite 6-cycle R-bendamustine chemotherapy resulted in a good partial response, the patient developed persistent fever and severe weight loss. Analysis of cerebrospinal fluid and peripheral blood revealed the presence of CMV-DNA, while the fundus oculi examination revealed bilateral CMV retinitis. Treatment with induction and maintenance drugs was complicated by neutropenia and deterioration of renal function with electrolyte imbalance. From an immunological standpoint, we observed a profound imbalances in phenotype and function of B- and T-cell subsets, with a high proportion of circulating total, activated CD69+ and CD80+ B-cells, a low γ/δ T-cell frequency with a high proportion of CD69- and CD38-expressing cells, and hyperactivated/exhausted CD4+ and CD8+ T-cell phenotypes unable to face CMV challenge. CONCLUSIONS: We hereby describe a severe form of disseminated CMV disease after R-bendamustine treatment. Our observations strongly support the careful clinical monitoring of CMV reactivation/infection in oncologic patients undergoing this therapeutic regimen.

Antimicrobial resistance rates in gram-positive bacteria do not drive glycopeptides use.

Surveillance data are considered essential to appropriate empiric antibiotic therapy and stewardship. The objective of this study was to determine if a change in the rates of antibiotic resistance impacts antibiotic use in European hospitals. Glycopeptides use was selected to study the correlation between resistance rates and antibiotic use because of the restricted spectrum against resistant gram positive bacteria. PubMed, ECDC databases and national/regional surveillance systems were searched to identify glycopeptides´ consumption in defined daily dose per 1000 inhabitant-days (DID) and rate of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase negative staphylococci (MRCoNS), and vancomycin-resistant enterococci (VRE) in bloodstream infections (BSIs) in European countries between 1997 and 2015. Time trends were studied and associations between DID and BSI resistance rates were tested using multi-level mixed effect models. To account for the gap in the publication and dissemination of the yearly resistance data, a 2-year lag in the resistance rates was applied. Data on glycopeptides´ DID and resistance rates of target microorganisms in blood cultures were identified among 31 countries over a 19-year period. Glycopeptides use significantly increased (p<0·0001) while rates of MRSA BSIs decreased in majority of the countries (p<0·0001) and MRCoNS and VRE BSIs remained stable. Variation in glycopeptides' DID was not associated with variation in BSIs due to MRSA (p = 0·136) and VRE (p = 0·613). After adjusting for MRCoNS and VRE resistance rates, among 21 countries, 11 (52%) had a concordant and 10 (48%) a discordant trend in yearly glycopeptides´ DID and MRSA BSI rates. No correlation was found between resistance rates and DID data even among 8 countries with more than 5% decrease in MRSA rates over time. (RC -0·009, p = 0·059). Resistance rate of MRSA, MRCoNS, and VRE BSIs does not impact DID of glycopeptides in European hospitals. This finding is key to redefining the role and structure of antimicrobial surveillance and stewardship programmes.