Francisella novicida infection in a patient with pulmonary infection and pancreatitis in Italy.

Tularemia is a rare but potentially life threatening zoonotic disease caused by Francisella tularensis. F. novicida, previously considered a subspecies of F. tularensis, is currently considered a separate species. Human infections related to F. novicida are exceedingly rare but can cause morbidity and mortality in debilitated or immunocompromised individuals.A 42-year-old male presented at the hospital with vomiting, dehydration, constipation and pain in the right iliac fossa. He was first diagnosed with pancreatitis and admitted for further analysis. Chest computerized tomography scan showed the presence of parenchymal consolidation in the left upper and lower lobes of the lung with pleural effusion. Blood cultures isolated a Gram-negative coccobacillus, that was at first identified by MALDI-TOF as Francisella tularensis. Serological analysis for the detection of total antibodies against F. tularensis and Real-Time PCR targeting the gene coding for 23 kDa, resulting negative. Subsequently, PCR targeting helicases and tul4 genes, and the Regions of Difference RD1 and RD6 were performed allowing the identification of F. novicida. The isolate was further genetically characterized by whole genome sequencing (WGS).This is the first reported case of human infection caused by F. novicida in Italy.Given the rarity of human cases and the lack of specific symptoms, this pathogen is difficult to identify and the diagnosis can be extremely challenging. In this case report, despite the lack of amplification of the gene encoding for 23 kDa protein, the identification of Francisella species was achieved with the amplification of different genes and characterized by WGS.

Real-life comparison of mortality in patients with SARS-CoV-2 infection at risk for clinical progression treated with molnupiravir or nirmatrelvir plus ritonavir during the Omicron era in Italy: a nationwide, cohort study.

Background: Comparative data on mortality in COVID-19 patients treated with molnupiravir or with nirmatrelvir plus ritonavir are inconclusive. We therefore compared all-cause mortality in community-dwelling COVID-19 patients treated with these drugs during the Omicron era. Methods: Data collected in the nationwide, population-based, cohort of patients registered in the database of the Italian Medicines Agency (AIFA) were used. To increase completeness of the recorded deaths and date correctness, a cross-check with the National Death Registry provided by the Ministry of the Interior was performed. We included in this study all patients infected by SARS-CoV-2 treated within 5 days after the test date and symptom onset between February 8 and April 30, 2022. All-cause mortalities by day 28 were compared between the two treatment groups after balancing for baseline characteristics using weights obtained from a gradient boosting machine algorithm. Findings: In the considered timeframe, 17,977 patients treated with molnupiravir and 11,576 patients with nirmatrelvir plus ritonavir were included in the analysis. Most patients (25,617/29,553 = 86.7%) received a full vaccine course including the booster dose. A higher crude incidence rate of all-cause mortality was found among molnupiravir users (51.83 per 100,000 person-days), compared to nirmatrelvir plus ritonavir users (22.29 per 100,000 person-days). However, molnupiravir-treated patients were older than those treated with nirmatrelvir plus ritonavir and differences between the two populations were found as far as types of co-morbidities were concerned. For this reason, we compared the weight-adjusted cumulative incidences using the Aalen estimator and found that the adjusted cumulative incidence rates were 1.23% (95% CI 1.07%-1.38%) for molnupiravir-treated and 0.78% (95% CI 0.58%-0.98%) for nirmatrelvir plus ritonavir-treated patients (adjusted log rank p = 0.0002). Moreover, the weight-adjusted mixed-effect Cox model including Italian regions and NHS centers as random effects and treatment as the only covariate confirmed a significant reduced risk of death in patients treated with nirmatrelvir plus ritonavir. Lastly, a significant reduction in the risk of death associated with nirmatrelvir plus ritonavir was confirmed in patient subgroups, such as in females, fully vaccinated patients, those treated within day 2 since symptom onset and patients without (haemato)-oncological diseases. Interpretation: Early initiation of nirmatrelvir plus ritonavir was associated for the first time with a significantly reduced risk of all-cause mortality by day 28 compared to molnupiravir, both in the overall population and in patient subgroups, including those fully vaccinated with the booster dose. Funding: This study did not receive funding.

Kinetics of dried blood spot-measured anti-SARS-CoV2 Spike IgG in mRNA-vaccinated healthcare workers.

Introduction: One of the major criticisms facing the research community during SARS-CoV2 pandemic was the lack of large-scale, longitudinal data on the efficacy of the SARS-CoV2 mRNA vaccines. Currently, even if COVID-19 antiviral treatments have been authorized by European Medicine Agency, prevention through approved specific vaccines is the best approach available in order to contain the ongoing pandemic. Objectives: Here, we studied the antibody kinetic over a one-year period from vaccination with the Pfizer-BioNTech (Pfizer) vaccines and subsequent boosting with either the BioNTech or Moderna (Spikevax) vaccines in a large cohort of 8,071 healthcare workers (HCW). We also described the impact of SARS-CoV2 infection on antibody kinetic over the same period. Methods: We assessed the anti SARS-CoV2 Spike IgG antibody kinetic by the high throughput dried blood spot (DBS) collection method and the GSP®/DELFIA® Anti-SARS-CoV2 IgG assay (PerkinElmer®). Results: Our data support existing models showing that SARS-CoV2 vaccination elicits strong initial antibodies responses that decline with time but are transitorily increased by administering a vaccine booster. We also showed that using heterologous vaccine/booster combinations a stronger antibody response was elicited than utilizing a booster from the same vaccine manufacturer. Furthermore, by considering the impact of SARS-CoV2 infection occurrence in proximity to the scheduled booster administration, we confirmed that booster dose did not contribute significantly to elicit higher antibody responses. Conclusion: DBS sampling in our large population of HCWs was fundamental to collect a large number of specimens and to clarify the effective mRNA vaccine-induced antibody kinetic and the role of both heterologous boosters and SARS-CoV2 infection in modulating antibody responses.

Viral Population Heterogeneity and Fluctuating Mutational Pattern during a Persistent SARS-CoV-2 Infection in an Immunocompromised Patient.

Literature offers plenty of cases of immunocompromised patients, who develop chronic and severe SARS-CoV-2 infections. The aim of this study is to provide further insight into SARS-CoV-2 evolutionary dynamic taking into exam a subject suffering from follicular lymphoma, who developed a persistent infection for over 7 months. Eight nasopharyngeal swabs were obtained, and were analyses by qRT-PCR for diagnostic purposes. All of them were considered eligible (Ct < 30) for NGS sequencing. Sequence analysis showed that all sequences matched the B.1.617.2 AY.122 lineage, but they differed by few mutations identifying three genetically similar subpopulations, which evolved during the course of infection, demonstrating that prolonged replication is paralleled with intra-host virus evolution. These evidences support the hypothesis that SARS-CoV-2 adaptive capacities are able to shape a heterogeneous viral population in the context of immunocompromised patients. Spill-over of viral variants with enhanced transmissibility or immune escape capacities from these subjects is plausible.

Sotrovimab in SARS-COV-2 chronic hemodialysis patients in the Omicron era. Is intradialytic administration feasible? Report of 4 cases.

Chronic hemodialysis patients are at high risk of morbidity and mortality in case of SARS-CoV-2 infection and they may need to be treated with monoclonal antibodies, either because they have not been vaccinated, or because they have a low anti spike antibody titer. Administration of Sotrovimab has recently been proposed for hemodialysis patients, but data are on the results lacking. We report on four cases of chronic dialysis patients who received Sotrovimab during intermittent dialysis sessions. In our series, no adverse reactions were recorded; intradialytic administration resulted safe and allowed an adequate observation time without prolonging hospital stay in chronic hemodialysis outpatients.

Reduction trend of mcr-1 circulation in Emilia-Romagna Region, Italy.

This study aims to describe trends of mcr-positive Enterobacterales in humans based on laboratory surveillance with a defined catchment population. The data source is the Micro-RER surveillance system, established in Emilia-Romagna region (Italy), to monitor the trend of mcr resistance. Enterobacterales isolates from human clinical samples with minimum inhibitory concentration (MIC) ≥ 2 mg/L for colistin were sent to the study reference laboratory for the detection of mcr genes. Isolates prospectively collected in the period 2018-2020 were considered for the assessment of population rates and trends; further analyses were carried out for the evaluation of clonality and horizontal mcr gene transfer. Previous isolates from local laboratory collection were also described. In the period 2018-2020, 1164 isolates were sent to the reference laboratory, and 51 (4.4%) were confirmed as mcr-positive: 50 mcr-1 (42 Escherichia coli, 6 Klebsiella pneumoniae, 2 Salmonella enterica) and 1 mcr-4 (Enterobacter cloacae). The number of mcr-positive isolates dropped from 24 in the first half of 2018 to 3 in the whole of 2020 (trend p value < 0.001). Genomic analyses showed the predominant role of the horizontal transfer of mcr genes through plasmids or dissemination of transposable elements compared to clonal dissemination of mcr-positive microorganisms. The study results demonstrate a substantial decrease in the circulation of mcr-1 plasmid genes in Emilia-Romagna Region.

Sixty-Day Mortality Among 520 Italian Hospitalized COVID-19 Patients According to the Adopted Ventilatory Strategy in the Context of an Integrated Multidisciplinary Clinical Organization: A Population-Based Cohort Study.

PURPOSE: Although the decision of which ventilation strategy to adopt in COVID-19 patients is crucial, yet the most appropriate means of carrying out this undertaking is not supported by strong evidence. We therefore described the organization of a province-level healthcare system during the occurrence of the COVID-19 epidemic and the 60-day outcomes of the hospitalized COVID-19 patients according to the respiratory strategy adopted given the limited available resources. PATIENTS AND METHODS: All COVID-19 patients (26/02/2020-18/04/2020) in the Rimini Province of Italy were included in this population-based cohort study. The hospitalized patients were classified according to the maximum level of respiratory support: oxygen supplementation (Oxygen group), non-invasive ventilation (NIV-only group), invasive mechanical ventilation (IMV-only group), and IMV after an NIV trial (IMV-after-NIV group). Sixty-day mortality risk was estimated with a Cox proportional hazard analysis adjusted by age, sex, and administration of steroids, canakinumab, and tocilizumab. RESULTS: We identified a total of 1,424 symptomatic patients: 520 (36.5%) were hospitalized, while 904 (63.5%) were treated at home with no 60-day deaths. Based on the respiratory support, 408 (78.5%) were assigned to the Oxygen group, 46 (8.8%) to the NIV-only group, 25 (4.8%) to the IMV-after-NIV group, and 41 (7.9%) to the IMV-only group. There was no significant difference in the PaO2/FiO2 at IMV inception in the IMV-after-NIV and IMV-only groups (p=0.9). Overall 60-day mortality was 24.2% (Oxygen: 23.0%; NIV-only: 19.6%; IMV-after-NIV: 32.0%; IMV-only: 36.6%; p=0.165). Compared with the Oxygen group, the adjusted 60-day mortality risk significantly increased in the IMV-after-NIV (HR 2.776; p=0.024) and IMV-only groups (HR 2.966; p=0.001). CONCLUSION: This study provided a population-based estimate of the impact of the COVID-19 outbreak in a severely affected Italian province. A similar 60-day mortality risk was found for patients undergoing immediate IMV and those intubated after an NIV trial with favorable outcomes after prolonged IMV.

Incomplete IgG response to HIV-1 proteins and low avidity levels in recently converted HIV patients treated with early antiretroviral therapy.

OBJECTIVES: To evaluate the evolution of antibody avidity and Western blot reactivity in recently infected HIV-1 subjects and to study the impact of highly active antiretroviral therapy (HAART) on avidity maturation of HIV-1-specific immunoglobulin G (IgG) in patients with recent HIV-1 infection. METHODS: Thirty-six HIV-1 seroconverters were enrolled in this study and followed longitudinally over 24 months to evaluate if the administration of antiretroviral therapy during primary infection affects Western blot reactivity and the evolution of antibody avidity. The patients were divided into two groups; group A consisted of 19 HIV-1-untreated patients who did not receive any drug treatment during our follow-up period; group B consisted of 17 subjects who were treated early with an association of two nucleoside reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) within 3 months after seroconversion. RESULTS: At diagnosis, Western blot analysis and avidity index (mean value) were exactly matched in untreated and treated patients; subsequently, however, a significantly lower reactivity to HIV-1 pol and gag proteins and a lower avidity index (mean values) were observed in HAART-treated patients up until the end of the follow-up period. CONCLUSIONS: The impaired production and maturation of the humoral immunological response in antiretroviral-treated patients might be related to a rapid suppression of HIV replication, driven by HAART. These results could have important implications in understanding the complex mechanism of the immune response during HIV infection.

HIV-1 subtype C transmission network: the phylogenetic reconstruction strongly supports the epidemiological data.

The sequence and times of the transmission events was reported after a hospital accident by a phylodynamic reconstruction of transmission network among four subjects. The dated tree allowed to date the transmission events with good approximation, the time point and direction of each transmission, estimated on the basis of the phylogeny, and agreed with the presumptive time of infection on the basis of clinical history-taking.

HIV-1 infection of a nurse from a newborn with an unknown HIV infection: a case report.

BACKGROUND: HIV infection of healthcare workers by injury is an important issue in the management and prophylaxis of HIV-related disease. OBJECTIVES: To describe a case where a nurse has been HIV-1 infected by needle-stick whilst taking blood from a newborn with an unknown HIV infection. STUDY DESIGN: Virological, immunological and clinical analysis of a peculiar case of HIV transmission from newborn to nurse has been reported. RESULTS: The nurse has been infected by needle-stick injury whilst taking blood from a newborn with an unknown HIV infection. The delayed declaration of accident by nurse and the inaccurate medical management of pregnant woman determined the subsequent absence of correct prophylaxis measures and then the impossibility to tackle the HIV transmission. CONCLUSION: This case indicates that HIV serological screening of pregnant women and prompt accident notification by health-care workers represent basic preventive measures that should effectively tackle the spread of HIV infection.

Prevalence of antiretroviral drug resistance in untreated persons newly diagnosed with HIV-1 infection.

Current knowledge of HIV-primary resistance indicates that the prevalence of transmitted resistant strains has increased to substantial levels over the past few years, with a wide variation depending upon a number of factors. New infections with a virus strain already resistant to antiretroviral drugs, namely non-nucleoside reverse transcriptase inhibitor (NNRTI), have a negative impact on initial treatment response and also shorten the time to first virologic failure. The aim of this study was to determine the prevalence of antiretroviral drug resistance by a genotypic test in a population with newly diagnosed HIV-1 infection at a clinical centre in Bologna between June 2006 and September 2007.

Paradoxical immune reconstitution inflammatory syndrome associated with previous Cryptococcus neoformans infection in an HIV-positive patient requiring neurosurgical intervention.

Immune reconstitution inflammatory syndrome (IRIS) in HIV-1-infected patients is associated with an exaggerated inflammatory response against an opportunistic infection during highly active antiretroviral therapy. The only review on IRIS associated with Criptococcus neoformans reported 21 episodes including lymphadenitis, necrotizing pneumonitis, breast and cutaneous abscess, and cryptococcomas. To our knowledge this is the first report of IRIS associated with previous meningeal criptococcal infection which required neurosurgical intervention with placement of a ventriculo-peritoneal shunt to drain a CSF cyst formed by exclusion of the temporal horn of the right lateral ventricle. We demonstrate that this procedure is possible without complications such as cryptococcal dissemination into the peritoneum.

Low avidity antibody: a reliable method to diagnose a recent HIV-1 infection.

Standard serological tests (both EIA and Immunoblotting) have reached high levels of sensitivity and reproducibility, but do not indicate whether infection is recent or longstanding. Since many patients with HIV-1 infection are not usually diagnosed until symptom presentation, the possibility to distinguish between acute and chronic infection has become increasingly important for the purposes of therapeutic decision-making, partner notification and epidemiological surveillance. We evaluated a guanidine-based-antibody-avidity assay in a selected group of recent (within six months from seroconversion) and chronic (more than forty eight months) HIV-1 infections in an attempt to shed more light on the significance of the avidity index in establishing the time of infection. Sera from newly infected individuals showed a low mean avidity index (ranging from 0.35 to 0.60 with a standard deviation 0.09) at baseline and a clear increasing value at the following times of observation. Our data showed that an avidity index <0.70 might be presumptive of infection occurring within 9 months. Avidity index levels might distinguish between acute and chronic infection. The method is semi-automated, inexpensive and easy to perform, and estimates the time elapsed from seroconversion, thereby identifying a recent infection.

Antiretroviral Therapy in the Real World : Population-Based Pharmacoeconomic Analysis of Administration of Anti-HIV Regimens to 990 Patients.

OBJECTIVE AND METHODS: The aim of our study was to analyse retrospectively the nature and frequency of antiretroviral prescriptions for 990 HIV-infected patients followed at our outpatient centre in Bologna, Italy, from January 2003 to March 2004. The main focus of the study was to identify the most commonly prescribed combinations and their related expenses, in order to identify the most competitive treatment regimens with regard to costs. Prescriptions were given directly to patients at monthly intervals, and drug treatment adherence data was stored in an electronic database. Antiretroviral regimens administered for the longest period to each patient during the 15 months of the study were selected for the study. All patients treated for <9 consecutive months and/or with treatment adherence levels <90% were excluded. Physicians assessed antiretroviral therapy at least quarterly according to efficacy and safety criteria, but not in terms of pharmacoeconomic considerations. Direct pharmacy expenses were obtained for the 24 most commonly used therapeutic regimens, covering 80.1% of patients. RESULTS: The zidovudine-lamivudine-efavirenz combination proved to be the most prescribed combination (7.3%), followed by zidovudine-lamivudine- nevirapine (7.1%), lamivudine-stavudine (6.2%), zidovudine-lamivudine- lopinavir-ritonavir (5.2%), didanosine-stavudine-lopinavir-ritonavir (4.8%), and lamivudine-stavudine-nevirapine (4.7%). Anti-HIV combinations varied from a minimum yearly cost of euro3895.6 for lamivudine-stavudine to euro9422.8 for the zidovudine-lamivudine-lopinavir-ritonavir combination (+241.9%) [year of costing 2003]. There was a significant difference between the two first-line regimens for antiretroviral-naive subjects, with lopinavir-ritonavir-based combinations costing more than euro9000 per patient/year compared with efavirenz-containing combinations, which were 28% less expensive. Mean daily costs varied substantially, from a minimum of euro10.7 per day for lamivudine-stavudine to a maximum of euro25.8 per day (+241.1%) for zidovudine-lamivudine-lopinavir-ritonavir. Regimens based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) were less costly than most of those including protease inhibitors (PIs). The increased expense of each combination was compared with the cheapest therapeutic selection (lamivudine-stavudine), and costs of all triple combinations were also compared. Regimens based on NNRTIs accounted for 29.3% of our cohort (nevirapine-containing therapies 15.1%, and efavirenz-based ones 14.2%), while PIs were used in the majority of cases (37.3%), with lopinavir-ritonavir as the leading combination (13.6% of patients), followed by nelfinavir (9.9%) and indinavir (9.2%). When drug-related costs were examined, dual nucleoside analogues showed the lowest expense (euro10.7-euro11.6 per day), while triple nucleoside/nucleotide analogue combinations cost nearly twice as much (euro18.5-euro20.4 per day). Among the NNRTIs, there were comparable costs for nevirapine-based combinations (euro18.3-euro18.7 per day), while efavirenz-including regimens were 10% more costly (euro19.2-euro20.l per day). A very broad range of combinations and related costs were found with PIs, but apart from indinavir and saquinavir combinations (euro15.7-euro21.7 per day), all other regimens had a higher daily cost (from euro22.0 per day for ritonavir-based regimens to euro23.4-euro24.3 per day for nelfinavir combinations, and up to euro24.9-euro25.8 per day with lopinavir-ritonavir). When considering nelfinavir- and lopinavir-containing combinations, the difference compared with NNRTI-based regimens varied from 41% when nevirapine- and lopinavir-ritonavir were compared, to 11.6% when efavirenz and nelfinavir were compared. CONCLUSIONS: Investigations that link prescribing patterns and related costs in the setting of HIV disease therapy are needed to improve patient management and help with the planning of healthcare resource allocation.