Prognostic Significance of NLR and PLR in COVID-19: A Multi-Cohort Validation Study.

INTRODUCTION: Recent studies have highlighted the prognostic value of easily accessible inflammatory markers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) for predicting severe outcomes in patients affected by Coronavirus disease 2019 (COVID-19). Our study validates NLR and PLR cut-off values from a prior cohort at IRCCS Policlinico San Matteo (OSM) of Pavia, Italy, across two new cohorts from different hospitals. This aims to enhance the generalizability of these prognostic indicators. METHODS: In this retrospective cohort study, conducted at Milan's Ospedale Luigi Sacco (OLS) and IRCCS Ospedale Maggiore Policlinico (OMP) hospitals, we assess the predictive capacity of NLR and PLR for three main outcomes-non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) usage, invasive ventilation (IV), and death-in patients with COVID-19 at admission. For each outcome, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed separately for male and female cohorts. Distinct NLR and PLR cut-off values were used for men (7.00, 7.29, 7.00 for NLR; 239.22, 248.00, 250.39 for PLR) and women (6.36, 7.00, 6.28 for NLR; 233.00, 246.45, 241.54 for PLR), retrieved from the first cohort at OSM. RESULTS: A total of 3599 patients were included in our study, 1842 from OLS and 1757 from OMP. OLS and OMP sensitivity values for both NLR and PLR (NLR: 24-67%, PLR: 40-64%) were inferior to specificity values (NLR: 64-76%, PLR: 55-72%). Additionally, PPVs generally remained lower (< 63%), while NPVs consistently surpassed 68% for PLR and 72% for NLR. Finally, both PLR and NLR exhibited consistently higher NPVs for more severe outcomes (> 82%) compared to NPVs for CPAP/NIV. CONCLUSIONS: Consistent findings across diverse patient populations validate the reliability and applicability of NLR and PLR cut-off values. High NPVs emphasize their role in identifying individuals less likely to experience severe outcomes. These markers not only aid in risk stratification but also guide resource allocation in emergencies or limited-resource situations.

Neuroimmunomodulatory effect of Nitric Oxide on chronic wound healing after photodynamic therapy.

Neuroimmunomodulation is the capacity of the nervous system to regulate immune processes. The existence of neurotransmitter receptors in immune cells enables this phenomenon to take place. Neuronal mediators possess the capacity to direct and control several occurrences during the wound healing process. Nitric oxide (NO) functions as a neuromodulator, playing a crucial role in the regulation of vascular tone and blood pressure with antimicrobial properties. Photodynamic therapy has been shown to augment the function of immune cells involved in the healing process of venous leg ulcers. Nitric oxide can be secreted into the extracellular environment by these cells. In lesions treated with PDT, the synthesis of iNOs (the enzyme that releases NO) increased, as demonstrated by the experimental results. Therefore the significance of PDT in enhancing the clinical condition of the lesion is thus highlighted.

Development and validation of a prediction score for failure to casirivimab/imdevimab in hospitalized patients with COVID-19 pneumonia.

Introduction: Casirivimab and imdevimab (CAS/IMV) are two non-competing, high-affinity human IgG1 anti-SARS-CoV-2 monoclonal antibodies, that showed a survival benefit in seronegative hospitalized patients with COVID-19. This study aimed to estimate the day-28 risk of mechanical ventilation (MV) and death in individuals hospitalized for severe COVID-19 pneumonia and receiving CAS/IMV. Additionally, it aimed to identify variables measured at the time of hospital admission that could predict these outcomes and derive a prediction algorithm. Methods: This is a retrospective, observational cohort study conducted in 12 hospitals in Italy. Adult patients who were consecutively hospitalized from November 2021 to February 2022 receiving CAS/IMV were included. A multivariable logistic regression model was used to identify predictors of MV or death by day 28 from treatment initiation, and ß-coefficients from the model were used to develop a risk score that was derived by means of leave-one-out internal cross-validation (CV), external CV, and calibration. Secondary outcome was mortality. Results: A total of 480 hospitalized patients in the training set and 157 patients in the test set were included. By day 28, 36 participants (8%) underwent MV and 28 died (6%) for a total of 58 participants (12%) experiencing the composite primary endpoint. In multivariable analysis, four factors [age, PaO2/FiO2 ratio, lactate dehydrogenase (LDH), and platelets] were independently associated with the risk of MV/death and were used to generate the proposed risk score. The accuracy of the score in the area under the curve (AUC) was 0.80 and 0.77 in internal validation and test for the composite endpoint and 0.87 and 0.86 for death, respectively. The model also appeared to be well calibrated with the raw data. Conclusion: The mortality risk reported in our study was lower than that previously reported. Although CAS/IMV is no longer used, our score might help in identifying which patients are not likely to benefit from monoclonal antibodies and may require alternative interventions.

Preliminary Evidence of Good Safety Profile and Outcomes of Early Treatment with Tixagevimab/Cilgavimab Compared to Previously Employed Monoclonal Antibodies for COVID-19 in Immunocompromised Patients.

OBJECTIVES: Monoclonal antibodies (mAbs) have proven to be a valuable tool against COVID-19, mostly among subjects with risk factors for progression to severe illness. Tixagevimab/cilgavimab (TIX/CIL), a combination of two Fc-modified human monoclonal antibodies, has been recently approved to be employed as early treatment. METHODS: Two groups of immunocompromised patients exposed to different early treatments (i.e., TIX/CIL vs. other mAbs [casirivimab/imdevimab, bamlanivimab/etesevimab, sotrovimab]) were compared in terms of clinical outcomes (hospitalisation and mortality within 14 days from administration) and time to the negativity of nasal swabs. We used either Pearson's chi-square or Fisher's exact test for categorical variables, whereas the Wilcoxon rank-sum test was employed for continuous ones. Kaplan-Meier curves were produced to compare the time to nasopharyngeal swab negativity. RESULTS: Early treatment with TIX/CIL was administered to 19 immunocompromised patients, while 89 patients received other mAbs. Most of them were solid organ transplant recipients or suffering from hematologic or solid malignancies. Overall, no significant difference was observed between the two groups regarding clinical outcomes. In the TIX/CIL group, one patient (1/19, 5.3%), who was admitted to the emergency room within the first 14 days from treatment and was hospitalised due to COVID-19 progression, died. Regarding the time to nasal swab negativity, no significant difference (p = 0.088) emerged. CONCLUSIONS: Early treatment of SARS-CoV-2 infection with TIX/CIL showed favourable outcomes in a small group of immunocompromised patients, reporting no significant difference compared to similar patients treated with other mAbs.

Reply to "successful early use of anti-SARS-CoV-2 monoclonal neutralizing antibodies in SARS-CoV-2 infected hematological patients-A Czech multicenter experience": A case series of SARS-CoV-2 Omicron infection and aggressive lymphoma in the Sotrovimab era.

A prospective multicentre experience of early administration of anti-SARS-CoV-2 spike protein neutralizing monoclonal antibodies (MA) with efficacy among patients with hematological malignancies and early-stage COVID- 19 was reported by Weinbergerová et al. The study validated the safety and efficacy of MA early use among hematological patients with newly diagnosed early-stage COVID-19 in terms of alleviating infection course and decreasing mortality. However no reference to new variant (Delta and Omicron) or other MA (e.g., Sotrovimab) has been reported. We reported our monocentric experience of 8 aggressive lymphoma patients with Omicron infection, 7 of whom treated with this MA in our Institution between December 2021 and February 2022. Among the patients treated with Sotrovimab nobody experienced neither SARS-CoV2 reactivation, nor other infectious events. One patients on active lymphoma treatment was hospitalized for pneumonia and treated with remdesivir. In 4/8 patients negativization of molecular swab occurred concomitantly to symptoms resolution with a median of 5.25 days, while the other 4 patients remained persistently positive with a median of 26.3 days. In this group, in order to maintain the chemo/chemoimmunotherapy (CT/CIT) dose-density, lymphoma treatment was reassumed independently on molecular swab analysis. SARS-CoV-2 negativization occurred with a median of 7.7 days after the resumption of CT/CIT. The one patient treated with remdesivir, although still positive to molecular swab, restarted R-COMP regimen at symptoms resolution too, but experienced an Omicron pneumonia exacerbation. This is the first case series reported in literature of patients affected by Omicron variant in which Sotrovimab seems to provide a resolution of COVID-19 disease, even in patient with molecular swab positive persistence too. Patients with aggressive lymphoma histologies should not be deprived of the best available treatment of their disease after sotrovimab administration, even in the presence of a still positive Omicron swab.

Safety Profile and Outcomes of Early COVID-19 Treatments in Immunocompromised Patients: A Single-Centre Cohort Study.

BACKGROUND: Early treatment with remdesivir (RMD) or monoclonal antibodies (mAbs) could be a valuable tool in patients at risk of severe COVID-19 with unsatisfactory responses to vaccination. We aim to assess the safety and clinical outcomes of these treatments among immunocompromised subjects. METHODS: We retrospectively reviewed all nonhospitalized patients who received an early treatment with RMD or mAbs for COVID-19, from 25 November 2021 to 25 January 2022, in a large tertiary hospital. Outcomes included frequency of adverse drug reaction (ADR), duration of symptoms and molecular swab positivity, emergency department access, hospital or intensive care unit admission, and mortality in the 14 days following treatment administration. RESULTS: Early treatments were administered to 143 patients, 106/143 (74.1%) immunocompromised, including 41 solid organ and 6 hematopoietic stem cell transplant recipients. Overall, 23/143 (16.1%) subjects reported ADRs. Median time from treatment start to SARS-CoV-2 nasopharyngeal swab negativity and symptom resolution was 10 (IQR 6-16) and 2.5 days (IQR 1.0-6.0), respectively, without differences between immunocompromised and nonimmunocompromised patients. In the 14 days after treatment administration, 5/143 patients (3.5%) were hospitalized and one died as a result of causes related to COVID-19, all of them were immunocompromised. CONCLUSIONS: RMD and mAbs have minimal ADRs and favourable outcomes in immunocompromised patients.

Isolation of a Colistin-Susceptible MDR Pantoea calida Harboring the mcr-9 Gene Suggests the Silent Spread of the Resistance Factor.

Pantoea spp. are bacteria that are often detected in the environment and as symbionts of arthropods. They sporadically cause infections in humans and recently extended spectrum beta-lactamases (ESBL)- and carbapenemase-producing strains have started to emerge. In this study, we report the isolation and the complete genome sequence of a strain of Pantoea calida encoding the colistin-resistance gene mcr-9. The strain was isolated from a preterm newborn in a neonatal pathology ward. On clinical examination, his vital signs were normal and blood culture was negative. Rectal swab screening for ESBL-producing Enterobacterales allowed to isolate the bacterium, and a complete genome was obtained using both short and long read sequencing. The mcr-9 gene was found to be encoded on a IncHI2 superplasmid, which confers resistance to six classes of antibiotics, including beta lactams (ESBL). Despite the presence of mcr-9, the isolate retains susceptibility to colistin, which could be explained by the absence of compatible regulatory genes (qseBC) from the genome. The presence of the resistance gene is undetectable with the routine clinical procedures, that is, phenotypic tests. This suggests that a silent spread might be ongoing in the ward. To our knowledge, this is the first description of an MDR P. calida and of a Pantoea spp. encoding any mobile colistin resistance gene.

Impact of Pneumococcal Urinary Antigen Testing in COVID-19 Patients: Outcomes from the San Matteo COVID-19 Registry (SMACORE).

Despite low rates of bacterial co-infections, most COVID-19 patients receive antibiotic therapy. We hypothesized that patients with positive pneumococcal urinary antigens (PUAs) would benefit from antibiotic therapy in terms of clinical outcomes (death, ICU admission, and length of stay). The San Matteo COVID-19 Registry (SMACORE) prospectively enrolls patients admitted for COVID-19 pneumonia at IRCCS Policlinico San Matteo, Pavia. We retrospectively extracted the data of patients tested for PUA from October to December 2020. Demographic, clinical, and laboratory data were recorded. Of 469 patients, 42 tested positive for PUA (8.95%), while 427 (91.05%) tested negative. A positive PUA result had no significant impact on death (HR 0.53 CI [0.22-1.28] p-value 0.16) or ICU admission (HR 0.8; CI [0.25-2.54] p-value 0.70) in the Cox regression model, nor on length of stay in linear regression (estimate 1.71; SE 2.37; p-value 0.47). After adjusting for age, we found no significant correlation between urinary antigen positivity and variations in the WHO ordinal scale and laboratory markers at admission and after 14 days. We found that a positive PUA result was not frequent and had no impact on clinical outcomes or clinical improvement. Our results did not support the routine use of PUA tests to select COVID-19 patients who will benefit from antibiotic therapy.

A challenging case of SARS-CoV-2- AIDS and Nocardiosis coinfection from the SMatteo COvid19 REgistry (SMACORE).

The COVID-19 pandemic is posing an unprecedented threat worldwide. One issue that has faltered, though, concerns the underestimated risk to trade all for COVID-19, misdiagnosing other potentially life-threatening diseases. Further still, the presence of respiratory symptoms in AIDS patients should stimulate more vigilant efforts to uncover other or additional infections. This case report highlights the pitfalls of diagnosing a rare pulmonary infection during the COVID-19 pandemic.

An eight-year experience of Nocardia infection in Italy: does immunosuppression matter?

Nocardia has always been considered a pathogen of the immunocompromised host, but recent evidence has also highlighted its role as a pathogen in the immunocompetent. We aim to assess the role of immunosuppression in the disease. We reviewed all the cases of infections due to Nocardia spp. in our center that occurred from 1 January 2012 to 30 September 2019. Patients were divided into three groups: typical immunocompromised (PLWHIV, solid organ or hematopoietic cell transplant recipients, individuals under immunosuppressive drugs), atypical immunocompromised (ongoing chronic diseases involving the lung, kidney, liver and diabetes) and immunocompetent. We identified 53 patients with an infection by Nocardia spp. Thirty-four (60.4%) of them were immunocompromised, 22 (64.7%) typical and 12 (35.3%) atypical immunocompromised. Nineteen (35.8%) were immunocompetent. The two conditions most frequently associated with infection were chronic lung disease (41.5%) and ongoing treatment with immunosuppressive drugs (33.9%). In our cohort a remarkable prevalence of nocardiosis in immunocompetent and atypical immunosuppressed patients was observed.

A case of Corynebacterium striatum endocarditis successfully treated with an early switch to oral antimicrobial therapy.

Patients with Corynebacterium striatum endocarditis are usually managed with long-term intravenous antibiotic therapy and hospitalization. Here we describe a case of a 76-year-old woman with hepatitis C virus (HCV) related cirrhosis who developed endocarditis due to Corynebacterium striatum associated with severe aortic regurgitation. To our knowledge, this is the first case to be successfully treated with an early switch to oral linezolid after three weeks of vancomycin. We performed a literature review using the PubMed database and found 27 cases which showed the enhanced virulence of this pathogen especially for long-term hospitalized patients with a frequent need of surgical treatment (44.4%) and long course of parenteral antimicrobial therapy, with vancomycin as drug of choice. There are no studies confirming the possibility of using oral treatment in non-diphtheritic Corynebacteria infective endocarditis. This case report provides us with the evidence that once the patient is in a stable condition, the efficacy and safety of linezolid might be similar to vancomycin administration. New trials and prospective studies are needed to confirm the opportunity of an early switch to oral therapy in this specific setting.

Epidemiological Characterization of Listeria monocytogenes Infections in Pavia Province in 2017 Reveals the Presence of Multiple Concurrently Circulating Strains.

Consumption of raw food, especially smoked fish, meat, soft cheeses, and vegetables, contaminated with Listeria monocytogenes can cause listeriosis, which can be invasive in pregnant women, elderly, and immunocompromised and diabetic patients. Through June to November of 2017, 11 patients developed invasive listeriosis in a small area of northern Italy. In the same period, 15 food samples (ready-to-eat seafood, raw vegetables, cheese samples, and salami) collected during the routine screening programs in the same area were found to be contaminated with L. monocytogenes. We characterized the isolates to determine the relatedness of L. monocytogenes strains isolated from patients and isolates from food samples and food-processing plants. Whole genome sequencing analysis showed that multiple L. monocytogenes strains were circulating in the area and no association was found between clinical and food isolates.

Abdominal pain as first manifestation of lyme neuroborreliosis in children, case report and review of literature.

BACKGROUND: Lyme neuroborreliosis can cause a variety of neurological manifestations. European children usually present facial nerve palsy, other cranial nerve palsies and aseptic meningitis. CASE PRESENTATION: We hereby report a case of Lyme neuroborreliosis in a 9-year-old boy with abdominal pain as first symptom and subsequent onset of attention deficit and ataxia. Diagnosis was made by detection of specific antibody in both serum and cerebrospinal fluid with neuro-radiological images suggestive for this infectious disease. A 12-months follow-up was performed during which no relevant neurological sequelae were revealed. CONCLUSION: This case report shows that abdominal radiculitis, although extremely rare, could be the first manifestation of early Lyme neuroborreliosis in pediatric patients. Pediatricians must consider Lyme disease in the differential diagnosis of abdominal pain of unknown origin in children, especially in countries where the infection is endemic.

The roles of triiodothyronine and irisin in improving the lipid profile and directing the browning of human adipose subcutaneous cells.

Triiodothyronine (T3) and irisin (I) can modulate metabolic status, increase heat production, and promote differentiation of white adipose tissue (WAT) into brown adipose tissue (BAT). Herein, human subcutaneous white adipocytes were treated with 10 nM T3 or 20 nM I for 24 h to evaluate intracellular lipid accumulation, triglyceride, and glycerol levels, oxidative stress, DNA damage, and protein levels of uncoupling protein 1 (UCP1), adiponectin, leptin, peroxisome proliferator-activated receptor gamma (PPARγ), and fibronectin type III domain-containing protein 5 (FNDC5). T3 and irisin improved UCP1 production, lipid profile, oxidative stress, and DNA damage. T3 elevated adiponectin and leptin levels with a concomitant decrease in PPARy and FNDC5 levels. However, irisin did not alter adipokine, PPARy, and FNDC5 levels. The results indicate that T3 may be used to increase leptin and adiponectin levels to improve insulin sensitivity, and irisin may be used to prevent obesity or maintain weight due to its impact on the lipid profile without altering adipokine levels.

Bloodstream infections caused by Escherichia coli carrying mcr-1 gene in hospitalized patients in northern Italy from 2012 to 2018.

PURPOSE: The recurrence of multi-drug resistant (MDR) pathogens to the latest antibiotics and the limited development of new antibacterial agents have reduced the options for the treatment of severe infections. The reintroduction of old antibiotics, such as colistin, represents an effective strategy, since the latest antibiotics are over-consumed and ineffective against MDR pathogens. In 2015, Liu (Lancet Infect Dis 16:161-168, 2016) reported Escherichia coli (E. coli) isolates carrying plasmid-mediated colistin resistance gene mcr-1. The first of mcr-1 positive colistin-resistant (col-R) E. coli from a human blood culture was observed in 2012 in Latin America, while in Italy was reported for the first time by our center in 2016. The present study aimed to describe the prevalence of mcr-1 positive col-R strains in E. coli-related bloodstream infection among patients hospitalized in Fondazione IRCCS Policlinico San Matteo in Pavia, Italy, from 2012 to 2018, including the three cases already published. METHODS: All col-R E. coli strains isolated from blood cultures collected during the study period were analyzed. The minimal inhibitory concentration of colistin was determined using broth microdilution and detection of mcr-1 and mcr-2 genes was performed by PCR. The sequence type of E. coli mcr-1 positive was determined according to Multilocus sequence typing. RESULTS: Out of 1557 samples, 14 strains (0.90%) were col-R. and positive for the presence of the mcr-1 gene, with no mcr-2 detected. The most common ST was ST10 (n = 3), followed by ST410 (n = 2). The remaining strains exhibited different MLST profiles, indicating that they were genetically unrelated. CONCLUSIONS: Proper reporting of the presence of mcr-1 genes is an essential component to anticipate the spread of colistin resistance. This public health issue is particularly alarming in Italy due to the consistent circulation of MDR bacteria.

A clinical case of sepsis due to Staphylococcus pettenkoferi.

Coagulase-negative staphylococci are part of the human skin flora but are frequently responsible for bloodstream infection, especially in the presence of intravascular devices or immunosuppressive conditions. Antibiotic resistance in such bacteria is common, with more than 80% of isolates resistant to methicillin. Among this genus Staphylococcus pettenkoferi is a recently identified organism, reported to be responsible for a growing number of infections. Here we describe a case of sepsis due to methicillin-resistant S. pettenkoferi.

Necrotizing Fasciitis by Two Anaerobic Bacteria in an Immunocompetent Patient after Minor Trauma: A Case Report.

Necrotizing fasciitis (NF) is a soft tissue infection affecting subcutaneous tissue and the muscular fascia without involvement of the muscle and can be either monomicrobial or polymicrobial. Monomicrobial infections are usually caused by group A streptococci, while infections caused by anaerobic germs usually affect immunodepressed patients. We report a rare case of NF caused by two anaerobic bacteria in an immunocompetent patient.

Characterization of an Outbreak of Extended-Spectrum ß-Lactamase-Producing Klebsiella pneumoniae in a Neonatal Intensive Care Unit in Italy.

Here we report an outbreak of extended spectrum ß-lactamase-producing Klebsiella pneumoniae that occurred in a neonatal intensive care unit in Northern Italy and involved 97 patients. Progressively tightened sets of containment measures were implemented but the epidemic event was stopped only 9 months later. The final, effective, containment strategy consisted of the application of strict geographic cohorting of colonized infants and their nursing staff, the suspension of any new admission and a rigorous daily sterilization protocol for all surfaces and fomites in the ward. A posteriori characterization of the outbreak strain was performed using both traditional microbiology and molecular biology techniques, and whole genome sequencing, allowing to compare outbreak isolates with other strains collected in the previous two years. The results allowed to determine that the outbreak strain had been circulating inside the ward since the year before. Genomic characterization revealed that the strain carried a wide array of virulence and antibiotic resistance determinants, including gene blaTEM-206, which had never been reported in a clinical isolate of K. pneumoniae before. The presence of such a high number of determinants for antibiotic resistance imposes significant therapeutic limitations on the treatment of infections, thus, further epidemiological investigations are needed to evaluate the prevalence of the newly described variant.

Genomic Characterization Helps Dissecting an Outbreak of Listeriosis in Northern Italy.

INTRODUCTION: Listeria monocytogenes (Lm) is a bacterium widely distributed in nature and able to contaminate food processing environments, including those of dairy products. Lm is a primary public health issue, due to the very low infectious dose and the ability to produce severe outcomes, in particular in elderly, newborns, pregnant women and immunocompromised patients. METHODS: In the period between April and July 2015, an increased number of cases of listeriosis was observed in the area of Pavia, Northern Italy. An epidemiological investigation identified a cheesemaking small organic farm as the possible origin of the outbreak. In this work we present the results of the retrospective epidemiological study that we performed using molecular biology and genomic epidemiology methods. The strains sampled from patients and those from the target farm's cheese were analyzed using PFGE and whole genome sequencing (WGS) based methods. The performed WGS based analyses included: a) in-silico MLST typing; b) SNPs calling and genetic distance evaluation; c) determination of the resistance and virulence genes profiles; d) SNPs based phylogenetic reconstruction. RESULTS: Three of the patient strains and all the cheese strains resulted to belong to the same phylogenetic cluster, in Sequence Type 29. A further accurate SNPs analysis revealed that two of the three patient strains and all the cheese strains were highly similar (0.8 SNPs of average distance) and exhibited a higer distance from the third patient isolate (9.4 SNPs of average distance). DISCUSSION: Despite the global agreement among the results of the PFGE and WGS epidemiological studies, the latter approach agree with epidemiological data in indicating that one the patient strains could have originated from a different source. This result highlights that WGS methods can allow to better.