Brain abscess caused by Actinomyces turicensis in a non-immunocompromised adult patient: a case report and systematic review of the literature.

BACKGROUND: Actinomyces turicensis is rarely responsible of clinically relevant infections in human. Infection is often misdiagnosed as malignancy, tuberculosis, or nocardiosis, therefore delaying the correct identification and treatment. Here we report a case of a 55-year-old immunocompetent adult with brain abscess caused by A. turicensis. A systematic review of A. turicensis infections was performed. METHODS: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases MEDLINE, Embase, Web of Science, CINAHL, Clinicaltrials.gov and Canadian Agency for Drugs and Technology in Health (CADTH) were searched for all relevant literature. RESULTS: Search identified 47 eligible records, for a total of 67 patients. A. turicensis infection was most frequently reported in the anogenital area (n = 21), causing acute bacterial skin and skin structure infections (ABSSSI) including Fournier's gangrene (n = 12), pulmonary infections (n = 8), gynecological infections (n = 6), cervicofacial district infections (n = 5), intrabdominal or breast infections (n = 8), urinary tract infections (n = 3), vertebral column infections (n = 2) central nervous system infections (n = 2), endocarditis (n = 1). Infections were mostly presenting as abscesses (n = 36), with or without concomitant bacteremia (n = 7). Fever and local signs of inflammation were present in over 60% of the cases. Treatment usually involved surgical drainage followed by antibiotic therapy (n = 51). Antimicrobial treatments most frequently included amoxicillin (+clavulanate), ampicillin/sulbactam, metronidazole or cephalosporins. Eighty-nine percent of the patients underwent a full recovery. Two fatal cases were reported. CONCLUSIONS: To the best of our knowledge, we hereby present the first case of a brain abscess caused by A. turicensis and P. mirabilis. Brain involvement by A. turicensis is rare and may result from hematogenous spread or by dissemination of a contiguous infection. The infection might be difficult to diagnose and therefore treatment may be delayed. Nevertheless, the pathogen is often readily treatable. Diagnosis of actinomycosis is challenging and requires prompt microbiological identification. Surgical excision and drainage and antibiotic treatment usually allow for full recovery.

Daptomycin-induced eosinophilic pneumonia: a case report and systematic review.

Introduction Acute eosinophilic pneumonia (AEP) is a rare respiratory condition caused by eosinophil accumulation in the pulmonary tissue that can be related to drug administration. Daptomycin, an antibiotic active against gram-positive bacteria, is one of the leading causes of AEP among drugs. In order to raise awareness of this rare syndrome, in our work we have described a case of an 82 years-old male with Enterococcus faecalis endocarditis treated with daptomycin, who developed a daptomycin-induced AEP. We have performed a systematic review of the literature for all similar reported cases. Methods The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. To conduct the analysis, the terms "daptomycin AND eosinoph* AND pneum*", were entered the databases Medline, Cinahl and Embase on April 13th, 2023. We considered relevant all records documenting AEP after daptomycin use. No restrictions in terms of year or language were made. A formal appraisal of observational studies was performed by Newcastle-Ottawa Scale. All results and data were reported by means of tables. Results Our search identified 93 relevant records, published between 2007 and 2023. A total of 120 patients were considered. Patients who experienced AEP were mostly males (n=88, 73.3%) with a mean age of 68.28 years (SD11.54). Daptomycin was most frequently prescribed for osteoarticular infections (n=75, 62.5%) and to treat gram-positive cocci infections. The most frequently isolated pathogen was Methicillin-resistant Staphylococcus aureus (MRSA). Daptomycin was mostly used with off-label indications (n=89, 74%). Symptoms of AEP were usually reported after a mean of 21.75 days of treatment (range 3-84) and typically included fever, dyspnea, dry cough and acute respiratory failure. Reported treatment strategies invariably included daptomycin withdrawal, respiratory support, and corticosteroid treatment. One hundred and sixteen patients fully recovered. A fatal outcome was described in 4 patients. Suggestive symptoms and imaging raised suspicion for AEP, confirmed with bronchoalveolar lavage in 57.5% of the cases. Discussion and Conclusions Daptomycin-induced AEP is a rare but potentially fatal complication, mostly reported after long treatment with daptomycin. Clinicians should be aware of this syndrome, as it could be initially misdiagnosed for an acute infectious respiratory syndrome, resulting in a delay in its diagnosis and treatment. Furthermore, since the risk of developing AEP is increased by longer drug exposure, caution should be used when discussing the use of daptomycin in longer treatment regimens.

The Impact of Viral and Bacterial Co-Infections and Home Antibiotic Treatment in SARS-CoV-2 Hospitalized Patients at the Policlinico Tor Vergata Hospital, Rome, Italy.

Co-infections during COVID-19 may worsen patients' outcomes. This study reports the results of a screening assessing the presence of co-infections among patients hospitalized for SARS-CoV-2 infection in the Infectious Diseases-Ward of the Policlinico Tor Vergata Hospital, Rome, Italy, from 1 January to 31 December 2021. Data on hepatitis B and C virus, urinary antigens for legionella pneumophila and streptococcus pneumoniae, pharyngeal swab for respiratory viruses, QuantiFERON®-TB Gold Plus assay (QFT-P), blood cultures and pre-hospitalization antibiotic prescription were recorded. A total of 482 patients were included, 61% males, median age of 65 years (IQR 52-77), median Charlson comorbidity index of 4 (IQR 2-5). The mortality rate was 12.4%; 366 patients needed oxygen supply. In total, 151 patients (31.3%) received home antibiotics without any association with the outcome. No significant association between mortality and the positivity of viral hepatitis markers was found. Out of 442 patients, 125 had an indeterminate QFT-P, associated with increased mortality. SARS-CoV-2 was the only respiratory virus detected among 389 pharyngeal swabs; 15/428 patients were positive for S. pneumoniae; none for L. pneumophila. In total, 237 blood cultures were drawn within 48 h from hospital admission: 28 were positive and associated with increased mortality. In our cohort, bacterial and viral co-infections in COVID-19 hospitalized patients were rare and not associated with higher mortality.

Frequency of Atypical Mutations in the Spike Glycoprotein in SARS-CoV-2 Circulating from July 2020 to July 2022 in Central Italy: A Refined Analysis by Next Generation Sequencing.

In this study, we provided a retrospective overview in order to better define SARS-CoV-2 variants circulating in Italy during the first two years of the pandemic, by characterizing the spike mutational profiles and their association with viral load (expressed as ct values), N-glycosylation pattern, hospitalization and vaccination. Next-generation sequencing (NGS) data were obtained from 607 individuals (among them, 298 vaccinated and/or 199 hospitalized). Different rates of hospitalization were observed over time and among variants of concern (VOCs), both in the overall population and in vaccinated individuals (Alpha: 40.7% and 31.3%, Beta: 0%, Gamma: 36.5% and 44.4%, Delta: 37.8% and 40.2% and Omicron: 11.2% and 7.1%, respectively, both p-values < 0.001). Approximately 32% of VOC-infected individuals showed at least one atypical major spike mutation (intra-prevalence > 90%), with a distribution differing among the strains (22.9% in Alpha, 14.3% in Beta, 41.8% in Gamma, 46.5% in Delta and 15.4% in Omicron, p-value < 0.001). Overall, significantly less atypical variability was observed in vaccinated individuals than unvaccinated individuals; nevertheless, vaccinated people who needed hospitalization showed an increase in atypical variability compared to vaccinated people that did not need hospitalization. Only 5/607 samples showed a different putative N-glycosylation pattern, four within the Delta VOC and one within the Omicron BA.2.52 sublineage. Interestingly, atypical minor mutations (intra-prevalence < 20%) were associated with higher Ct values and a longer duration of infection. Our study reports updated information on the temporal circulation of SARS-CoV-2 variants circulating in Central Italy and their association with hospitalization and vaccination. The results underline how SARS-CoV-2 has changed over time and how the vaccination strategy has contributed to reducing severity and hospitalization for this infection in Italy.

Remdesivir Influence on SARS-CoV-2 RNA Viral Load Kinetics in Nasopharyngeal Swab Specimens of COVID-19 Hospitalized Patients: A Real-Life Experience.

There are still conflicting data on the virological effects of the SARS-CoV-2 direct antivirals used in clinical practice, in spite of the documented clinical efficacy. The aim of this monocentric retrospective study was to compare virologic and laboratory data of patients admitted due to SARS-CoV-2 infection from March to December 2020 treated with either remdesivir (R), a protease inhibitor (lopinavir or darunavir/ritonavir (PI)) or no direct antiviral drugs (NT). Viral load variation was indirectly assessed through PCR cycle threshold (Ct) values on the nasopharyngeal swab, analyzing the results from swabs obtained at ward admission and 7 (±2) days later. Overall, 253 patients were included: patients in the R group were significantly older, more frequently males with a significantly higher percentage of severe COVID-19, requiring more often intensive care admission, compared to the other groups. Ct variation over time did not differ amongst the three treatment groups and did not seem to be influenced by corticosteroid use, even after normalization of the treatment groups for disease severity. Non-survivors had lower Ct on admission and showed a significantly slower viral clearance compared to survivors. CD4 T-lymphocytes absolute count assessed at ward admission correlated with a reduced Ct variation over time. In conclusion, viral clearance appears to be slower in COVID-19 non-survivors, while it seems not to be influenced by the antiviral treatment received.

Validation of the T-Lymphocyte Subset Index (TLSI) as a Score to Predict Mortality in Unvaccinated Hospitalized COVID-19 Patients.

Lymphopenia has been consistently reported as associated with severe coronavirus disease 2019 (COVID-19). Several studies have described a profound decline in all T-cell subtypes in hospitalized patients with severe and critical COVID-19. The aim of this study was to assess the role of T-lymphocyte subset absolute counts measured at ward admission in predicting 30-day mortality in COVID-19 hospitalized patients, validating a new prognostic score, the T-Lymphocyte Subset Index (TLSI, range 0−2), based on the number of T-cell subset (CD4+ and CD8+) absolute counts that are below prespecified cutoffs. These cutoff values derive from a previously published work of our research group at Policlinico Tor Vergata, Rome, Italy: CD3+CD4+ < 369 cells/µL, CD3+CD8+ < 194 cells/µL. In the present single-center retrospective study, T-cell subsets were assessed on admission to the infectious diseases ward. Statistical analysis was performed using JASP (Version 0.16.2. JASP Team, 2022, Amsterdam, The Netherlands) and Prism8 (version 8.2.1. GraphPad Software, San Diego, CA, USA). Clinical and laboratory parameters of 296 adult patients hospitalized because of COVID-19 were analyzed. The overall mortality rate was 22.3% (66/296). Survivors (S) had a statistically significant lower TLSI score compared to non-survivors (NS) (p < 0.001). Patients with increasing TLSI scores had proportionally higher rates of 30-day mortality (p < 0.0001). In the multivariable logistic analysis, the TLSI was an independent predictor of in-hospital 30-day mortality (OR: 1.893, p = 0.003). Survival analysis showed that patients with a TLSI > 0 had an increased risk of death compared to patients with a TLSI = 0 (hazard ratio: 2.83, p < 0.0001). The TLSI was confirmed as an early and independent predictor of COVID-19 in-hospital 30-day mortality.

Hepatitis B-Related Hepatic Flare During Immune Reconstitution Syndrome After Antiretroviral Treatment Initiation in an HBV Surface Antigen-Positive Patient With HIV: Viroimmunological and Histological Characterization.

HIV and hepatitis B virus (HBV) coinfection is relatively common. Initiation of antiretroviral therapy (ART) in people with HIV (PWH) causes a progressive restoration of cell-mediated immune functions. In the presence of overt or occult coinfections, immune restoration might lead to immune reconstitution inflammatory syndrome (IRIS). Here, we describe the clinical, immunological, virological, and histological characterization of a case of HBV-related IRIS hepatitis in a PWH after ART initiation. A liver biopsy was performed during HBV-related IRIS hepatic flare, and liver samples were analyzed through immunohistochemistry and molecular techniques, with the assessment of intrahepatic HBV-DNA, covalently closed circular DNA, and HBV pregenomic RNA through a droplet digital polymerase chain reaction system. Immune activation and senescence were also longitudinally assessed. In this clinical case, the hepatic flare occurred 6 weeks after ART initiation with a therapeutic regimen including tenofovir alafenamide (TAF) and emtricitabine (FTC). The episode was self-limiting, characterized by hyperactivation of peripheral blood CD4+ and CD8+ T-lymphocytes, and resolved without ART discontinuation, leading to the achievement of HBsAg seroconversion (HBsAg-/HBsAb+) and HBV-DNA plasma undetectability. Notably, hyperactivation of the immune system plays a pivotal role in promoting the control of HBV replication, thus triggering the achievement of HBsAg seroconversion during treatment with TAF/FTC.

In Patients with Severe COVID-19, the Profound Decrease in the Peripheral Blood T-Cell Subsets Is Correlated with an Increase of QuantiFERON-TB Gold Plus Indeterminate Rates and Reflecting a Reduced Interferon-Gamma Production.

Increased rates of indeterminate QuantiFERON-TB Gold Plus Assay (QFT-Plus) were demonstrated in patients hospitalized with Coronavirus Disease (COVID)-19. We aimed to define the prevalence and characteristics of hospitalized COVID-19 patients with indeterminate QFT-Plus. A retrospective study was performed including hospitalized COVID-19 patients, stratified in survivors and non-survivors, non-severe and severe according to the maximal oxygen supply required. Statistical analysis was performed using JASP ver0.14.1 and GraphPad Prism ver8.2.1. A total of 420 patients were included, median age: 65 years, males: 66.4%. The QFT-Plus was indeterminate in 22.1% of patients. Increased rate of indeterminate QFT-Plus was found in non-survivors (p = 0.013) and in severe COVID-19 patients (p < 0.001). Considering the Mitogen-Nil condition of the QFT-Plus, an impaired production of interferon-gamma (IFN-γ) was found in non-survivors (p < 0.001) and in severe COVID-19 patients (p < 0.001). A positive correlation between IFN-γ levels in the Mitogen-Nil condition and the absolute counts of CD3+ (p < 0.001), CD4+ (p < 0.001), and CD8+ (p < 0.001) T-lymphocytes was found. At the multivariable analysis, CD3+ T-cell absolute counts and CD4/CD8 ratio were confirmed as independent predictors of indeterminate results at the QFT-Plus. Our study confirmed the increased rate of indeterminate QFT-Plus in COVID-19 patients, mainly depending on the peripheral blood T-lymphocyte depletion found in the most severe cases.

Lactoferrin as Antiviral Treatment in COVID-19 Management: Preliminary Evidence.

Lactoferrin (Lf), a multifunctional cationic glycoprotein synthesized by exocrine glands and neutrophils, possesses an in vitro antiviral activity against SARS-CoV-2. Thus, we conducted an in vivo preliminary study to investigate the antiviral effect of oral and intranasal liposomal bovine Lf (bLf) in asymptomatic and mild-to-moderate COVID-19 patients. From April 2020 to June 2020, a total of 92 mild-to-moderate (67/92) and asymptomatic (25/92) COVID-19 patients were recruited and divided into three groups. Thirty-two patients (14 hospitalized and 18 in home-based isolation) received only oral and intranasal liposomal bLf; 32 hospitalized patients were treated only with standard of care (SOC) treatment; and 28, in home-based isolation, did not take any medication. Furthermore, 32 COVID-19 negative, untreated, healthy subjects were added for ancillary analysis. Liposomal bLf-treated COVID-19 patients obtained an earlier and significant (p < 0.0001) SARS-CoV-2 RNA negative conversion compared to the SOC-treated and untreated COVID-19 patients (14.25 vs. 27.13 vs. 32.61 days, respectively). Liposomal bLf-treated COVID-19 patients showed fast clinical symptoms recovery compared to the SOC-treated COVID-19 patients. In bLf-treated patients, a significant decrease in serum ferritin, IL-6, and D-dimers levels was observed. No adverse events were reported. These observations led us to speculate a potential role of bLf in the management of mild-to-moderate and asymptomatic COVID-19 patients.

Lactoferrin Against SARS-CoV-2: In Vitro and In Silico Evidences.

Lactoferrin (Lf) is a cationic glycoprotein synthetized by exocrine glands and is present in all human secretions. It is also secreted by neutrophils in infection and inflammation sites. This glycoprotein possesses antimicrobial activity due to its capability to chelate two ferric ions per molecule, as well as to interact with bacterial and viral anionic surface components. The cationic features of Lf bind to cells, protecting the host from bacterial and viral injuries. Its anti-inflammatory activity is mediated by the ability to enter inside the nucleus of host cells, thus inhibiting the synthesis of proinflammatory cytokine genes. In particular, Lf down-regulates the synthesis of IL-6, which is involved in iron homeostasis disorders and leads to intracellular iron overload, favoring viral replication and infection. The well-known antiviral activity of Lf has been demonstrated against DNA, RNA, and enveloped and naked viruses and, therefore, Lf could be efficient in counteracting also SARS-CoV-2 infection. For this purpose, we performed in vitro assays, proving that Lf exerts an antiviral activity against SARS-COV-2 through direct attachment to both SARS-CoV-2 and cell surface components. This activity varied according to concentration (100/500 µg/ml), multiplicity of infection (0.1/0.01), and cell type (Vero E6/Caco-2 cells). Interestingly, the in silico results strongly supported the hypothesis of a direct recognition between Lf and the spike S glycoprotein, which can thus hinder viral entry into the cells. These in vitro observations led us to speculate a potential supplementary role of Lf in the management of COVID-19 patients.

Baseline T-lymphocyte subset absolute counts can predict both outcome and severity in SARS-CoV-2 infected patients: a single center study.

The aim of this study was to evaluate the role of baseline lymphocyte subset counts in predicting the outcome and severity of COVID-19 patients. Hospitalized patients confirmed to be infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were included and classified according to in-hospital mortality (survivors/nonsurvivors) and the maximal oxygen support/ventilation supply required (nonsevere/severe). Demographics, clinical and laboratory data, and peripheral blood lymphocyte subsets were retrospectively analyzed. Overall, 160 patients were retrospectively included in the study. T-lymphocyte subset (total CD3+, CD3+ CD4+, CD3+ CD8+, CD3+ CD4+ CD8+ double positive [DP] and CD3+ CD4- CD8- double negative [DN]) absolute counts were decreased in nonsurvivors and in patients with severe disease compared to survivors and nonsevere patients (p < 0.001). Multivariable logistic regression analysis showed that absolute counts of CD3+ T-lymphocytes < 524 cells/µl, CD3+ CD4+ < 369 cells/µl, and the number of T-lymphocyte subsets below the cutoff (T-lymphocyte subset index [TLSI]) were independent predictors of in-hospital mortality. Baseline T-lymphocyte subset counts and TLSI were also predictive of disease severity (CD3+ < 733 cells/µl; CD3+ CD4+ < 426 cells/µl; CD3+ CD8+ < 262 cells/µl; CD3+ DP < 4.5 cells/µl; CD3+ DN < 18.5 cells/µl). The evaluation of peripheral T-lymphocyte absolute counts in the early stages of COVID-19 might represent a useful tool for identifying patients at increased risk of unfavorable outcomes.

B- and T-Cell Responses After SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis Receiving Disease Modifying Therapies: Immunological Patterns and Clinical Implications.

Background: Vaccination campaign to contrast the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has raised the issue of vaccine immunogenicity in special populations such as people with multiple sclerosis (PwMS) on highly effective disease modifying treatments (DMTs). While humoral responses to SARS-CoV-2 mRNA vaccines have been well characterized in the general population and in PwMS, very little is known about cell-mediated responses in conferring protection from SARS-CoV-2 infection and severe coronavirus disease-2019 (COVID-19). Methods: PwMS on ocrelizumab, fingolimod or natalizumab, vaccinated with two doses of mRNABNT162b2 (Comirnaty®) vaccine were enrolled. Anti-Spike (S) and anti-Nucleoprotein (N) antibody titers, IFN-gamma production upon S and N peptide libraries stimulation, peripheral blood lymphocyte absolute counts were assessed after at least 1 month and within 4 months from vaccine second dose administration. A group of age and sex matched healthy donors (HD) were included as reference group. Statistical analysis was performed using GraphPad Prism 8.2.1. Results: Thirty PwMS and 9 HDs were enrolled. All the patients were negative for anti-N antibody detection, nor reported previous symptoms of COVID-19. Peripheral blood lymphocyte counts were assessed in PwMS showing: (i) reduction of circulating B-lymphocytes in PwMS on ocrelizumab; (ii) reduction of peripheral blood B- and T-lymphocyte absolute counts in PwMS on fingolimod and (iii) normal B- and T-lymphocyte absolute counts with an increase in circulating CD16+CD56+ NK-cells in PwMS on natalizumab. Three patterns of immunological responses were identified in PwMS. In patients on ocrelizumab, anti-S antibody were lacking or reduced, while T-cell responses were normal. In patients on fingolimod both anti-S titers and T-cell mediated responses were impaired. In patients on natalizumab both anti-S titers and T-cell responses were present and comparable to those observed in HD. Conclusions: The evaluation of T-cell responses, anti-S titers and peripheral blood lymphocyte absolute count in PwMS on DMTs can help to better characterize the immunological response after SARS-CoV-2 vaccination. The evaluation of T-cell responses in longitudinal cohorts of PwMS will help to clarify their protective role in preventing SARS-CoV-2 infection and severe COVID-19. The correlation between DMT treatment and immunological responses to SARS-CoV-2 vaccines could help to better evaluate vaccination strategies in PwMS.

Expression profiles of the SARS-CoV-2 host invasion genes in nasopharyngeal and oropharyngeal swabs of COVID-19 patients.

We collect the nasopharyngeal and oropharyngeal swabs of 63 subjects with severe symptoms or contacts with COVID-19 confirmed cases to perform a pilot-study aimed to verify the "in situ" expression of SARS-CoV-2 host invasion genes (ACE2, TMPRSS2, PCSK3, EMILIN1, EMILIN2, MMRN1, MMRN2, DPP4). ACE2 (FC = +1.88, p ≤ 0.05) and DPP4 (FC = +3, p < 0.01) genes showed a significant overexpression in COVID-19 patients. ACE2 and DPP4 expression levels had a good performance (AUC = 0.75; p < 0.001) in distinguishing COVID-19 patients from negative subjects. Interestingly, we found a significant positive association of ACE2 mRNA and PCSK3, EMILIN1, MMRN1 and MMRN2 expression and of DPP4 mRNA and EMILIN2 expression only in COVID-19 patients. Noteworthy, a subgroup of severe COVID-19 (n = 7) patients, showed significant high level of ACE2 mRNA and another subgroup of less severe COVID-19 patients (n = 6) significant raised DPP4 levels. These results indicate that a group of SARS-CoV-2 host invasion genes are functionally related in COVID-19 patients and suggests that ACE2 and DPP4 expression level could act as genomic biomarkers. Moreover, at the best of our knowledge, this is the first study that shows an elevated DPP4 expression in naso- and oropharyngeal swabs of COVID-19 patient thus suggesting a functional role of DPP4 in SARS-CoV-2 infections.

Mild clinical manifestations of SARS-CoV-2 related pneumonia in two patients with multiple sclerosis under treatment with ocrelizumab.

BACKGROUND: Recently SARS-CoV-2 has spread worldwide causing a pandemic. Little is known about disease severity in immunocompromised hosts and people receiving disease modifying therapies (DMTs). In the last decades DMTs have been widely employed, and ocrelizumab represents one of the newest therapies for the relapsing remitting and progressive forms of multiple sclerosis (MS). OBJECTIVES: to describe SARS-CoV-2 related pneumonia in two MS patients under ocrelizumab treatment. METHODS: Case series. RESULTS: Patients showed a mild clinical course of SARS-CoV-2 related pneumonia without complications or sequelae. CONCLUSION: Ocrelizumab treatment is not necessarily associated to increased severity in MS patients with SARS-CoV-2 infection.