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Background : Infections frequently occur after orthotopic liver transplantation (OLT) and are associated with increased mortality. In 2018, we introduced perioperative administration of intravenous immunoglobulin enriched in IgM as an optional therapy in recipients at a high risk of infection. This preliminary study evaluated whether this preparation reduced infections in the early post-transplantation period. Methods : Adult patients with a high risk of postoperative infections who underwent OLT between January 2014 and December 2021 in our center were included in the study. The primary outcome was the occurrence of new postoperative bacterial and fungal infections within the first 30 days after OLT. Results : Ninety recipients at a high risk of postoperative infections who underwent OLT were included, of whom 51 (57%) received IgM preparation. Patients treated and not treated with IgM were similar in terms of demographics, model of end-stage liver disease score, and risk factors for postoperative infections. The occurrence of new infections was lower (absolute risk reduction (ARR) 21.2%; p = 0.038) in patients who received IgM than in those who did not. Multivariate analysis adjusted for confounders (OR 0.348; p = 0.033) and propensity score-based matching analysis (ARR 21.2%, p = 0.067) confirmed an association between IgM preparation and lower occurrence of postoperative infections. The 90-day mortality rate was lower (ARR 13.4%, p = 0.018) in patients who received IgM preparation. Conclusions : In OLT recipients at high risk for infections, perioperative administration of an IgM-enriched preparation seems to reduce the development of new infections within the first 30 days after OLT.

Sepsis poses a significant global health challenge due to immune system dysregulation. This narrative review explores the complex relationship between antibiotics and the immune system, aiming to clarify the involved mechanisms and their clinical impacts. From pre-clinical studies, antibiotics exhibit various immunomodulatory effects, including the regulation of pro-inflammatory cytokine production, interaction with Toll-Like Receptors, modulation of the P38/Pmk-1 Pathway, inhibition of Matrix Metalloproteinases, blockade of nitric oxide synthase, and regulation of caspase-induced apoptosis. Additionally, antibiotic-induced alterations to the microbiome are associated with changes in systemic immunity, affecting cellular and humoral responses. The adjunctive use of antibiotics in sepsis patients, particularly macrolides, has attracted attention due to their immune-regulatory effects. However, there are limited data comparing different types of macrolides. More robust evidence comes from studies on community-acquired pneumonia, especially in severe cases with a hyper-inflammatory response. While studies on septic shock have shown mixed results regarding mortality rates and immune response modulation, conflicting findings are also observed with macrolides in acute respiratory distress syndrome. In conclusion, there is a pressing need to tailor antibiotic therapy based on the patient's immune profile to optimize outcomes in sepsis management.

In COVID-19 patients, procalcitonin (PCT) and C-reactive protein (CRP) performance in identifying bacterial infections remains unclear. Our study aimed to evaluate the association of PCT and CRP with secondary infections acquired during ICU stay in critically ill COVID-19 patients. This observational study included adult patients admitted to three COVID-19 intensive care units (ICUs) from February 2020 to May 2022 with respiratory failure caused by SARS-CoV-2 infection and ICU stay ≥ 11 days. The values of PCT and CRP collected on the day of infection diagnosis were compared to those collected on day 11 after ICU admission, the median time for infection occurrence, in patients without secondary infection. The receiver operating characteristic curve (ROC) and multivariate logistic model were used to assess PCT and CRP association with secondary infections. Two hundred and seventy-nine patients were included, of whom 169 (60.6%) developed secondary infection after ICU admission. The PCT and CRP values observed on the day of the infection diagnosis were larger ( p < 0.001) than those observed on day 11 after ICU admission in patients without secondary infections. The ROC analysis calculated an AUC of 0.744 (95%CI 0.685-0.803) and 0.754 (95%CI 0.695-0.812) for PCT and CRP, respectively. Multivariate logistic models showed that PCT ≥ 0.16 ng/mL and CRP ≥ 1.35 mg/dL were associated ( p < 0.001) with infections acquired during ICU stay. Our results indicated that in COVID-19 patients, PCT and CRP values were associated with infections acquired during the ICU stay and can be used to support, together with clinical signs, rather than predict or rule out, the diagnosis of these infections.

Rare cases of Pseudomonas aeruginosa community-acquired pneumonia (PA-CAP) were reported in non-immunocompromised patients. We describe a case of Pseudomonas aeruginosa (PA) necrotizing cavitary CAP with a fatal outcome in a 53-year-old man previously infected with SARS-CoV-2, who was admitted for dyspnea, fever, cough, hemoptysis, acute respiratory failure and a right upper lobe opacification. Six hours after admission, despite effective antibiotic therapy, he experienced multi-organ failure and died. Autopsy confirmed necrotizing pneumonia with alveolar hemorrhage. Blood and bronchoalveolar lavage cultures were positive for PA serotype O:9 belonging to ST1184. The strain shares the same virulence factor profile with reference genome PA01. With the aim to better investigate the clinical and molecular characteristics of PA-CAP, we considered the literature of the last 13 years concerning this topic. The prevalence of hospitalized PA-CAP is about 4% and has a mortality rate of 33-66%. Smoking, alcohol abuse and contaminated fluid exposure were the recognized risk factors; most cases presented the same symptoms described above and needed intensive care. Co-infection of PA-influenza A is described, which is possibly caused by influenza-inducing respiratory epithelial cell dysfunction: the same pathophysiological mechanism could be assumed with SARS-CoV-2 infection. Considering the high rate of fatal outcomes, additional studies are needed to identify sources of infections and new risk factors, along with genetic and immunological features. Current CAP guidelines should be revised in light of these results.

The aim of our study was to evaluate whether the introduction of SDD in a structured protocol for VAP prevention was effective in reducing the occurrence of ventilator-associated pneumonia (VAP) in COVID-19 patients without changes in the microbiological pattern of antibiotic resistance. This observational pre-post study included adult patients requiring invasive mechanical ventilation (IMV) for severe respiratory failure related to SARS-CoV-2 admitted in three COVID-19 intensive care units (ICUs) in an Italian hospital from 22 February 2020 to 8 March 2022. Selective digestive decontamination (SDD) was introduced from the end of April 2021 in the structured protocol for VAP prevention. The SDD consisted of a tobramycin sulfate, colistin sulfate, and amphotericin B suspension applied in the patient's oropharynx and the stomach via a nasogastric tube. Three-hundred-and-forty-eight patients were included in the study. In the 86 patients (32.9%) who received SDD, the occurrence of VAP decreased by 7.7% ( p = 0.192) compared to the patients who did not receive SDD. The onset time of VAP, the occurrence of multidrug-resistant microorganisms AP, the length of invasive mechanical ventilation, and hospital mortality were similar in the patients who received and who did not receive SDD. The multivariate analysis adjusted for confounders showed that the use of SDD reduces the occurrence of VAP (HR 0.536, CI 0.338-0.851; p = 0.017). Our pre-post observational study indicates that the use of SDD in a structured protocol for VAP prevention seems to reduce the occurrence of VAP without changes in the incidence of multidrug-resistant bacteria in COVID-19 patients.

Background: Investigating the health-related quality of life (HRQoL) after intensive care unit (ICU) discharge is necessary to identify possible modifiable risk factors. The primary aim of this study was to investigate the HRQoL in COVID-19 critically ill patients one year after ICU discharge., Methods: In this multicenter prospective observational study, COVID-19 patients admitted to nine ICUs from 1 March 2020 to 28 February 2021 in Italy were enrolled. One year after ICU discharge, patients were required to fill in short-form health survey 36 (SF-36) and impact of event-revised (IES-R) questionnaire. A multivariate linear or logistic regression analysis to search for factors associated with a lower HRQoL and post-traumatic stress disorded (PTSD) were carried out, respectively., Results: Among 1003 patients screened, 343 (median age 63 years [57-70]) were enrolled. Mechanical ventilation lasted for a median of 10 days [2-20]. Physical functioning (PF 85 [60-95]), physical role (PR 75 [0-100]), emotional role (RE 100 [33-100]), bodily pain (BP 77.5 [45-100]), social functioning (SF 75 [50-100]), general health (GH 55 [35-72]), vitality (VT 55 [40-70]), mental health (MH 68 [52-84]) and health change (HC 50 [25-75]) describe the SF-36 items. A median physical component summary (PCS) and mental component summary (MCS) scores were 45.9 (36.5-53.5) and 51.7 (48.8-54.3), respectively, considering 50 as the normal value of the healthy general population. In all, 109 patients (31.8%) tested positive for post-traumatic stress disorder, also reporting a significantly worse HRQoL in all SF-36 domains. The female gender, history of cardiovascular disease, liver disease and length of hospital stay negatively affected the HRQoL. Weight at follow-up was a risk factor for PTSD (OR 1.02, p = 0.03)., Conclusions: The HRQoL in COVID-19 ARDS (C-ARDS) patients was reduced regarding the PCS, while the median MCS value was slightly above normal. Some risk factors for a lower HRQoL have been identified, the presence of PTSD is one of them. Further research is warranted to better identify the possible factors affecting the HRQoL in C-ARDS.

The coronavirus disease 2019 (COVID-19)-pandemic-related overload of health systems has compromised the application of antimicrobial stewardship (AS) models and infection prevention and control (IPC) programs. We aimed to evaluate the impact of COVID-19 on antimicrobial consumption (AC) and antimicrobial resistance (AMR) in the University Hospital of Modena. A time series analysis with an autoregressive integrated moving average model was conducted from January 2015 to October 2021 to evaluate the AC in the whole hospital and the intensive care unit (ICU), the incidence density (ID) of bloodstream infections (BSIs) due to the main multidrug-resistant organisms, and of C. difficile infections (CDIs). After an initial peak during the COVID-19 period, a decrease in the trend of AC was observed, both at the hospital (CT: -1.104, p = 0.025) and ICU levels (CT: -4.47, p = 0.047), with no significant difference in the single classes. Among the Gram-negative isolates, we observed a significant increase only in the level of BSIs due to carbapenem-susceptible Pseudomonas aeruginosa (CL: 1.477, 95% CI 0.130 to 2.824, p = 0.032). Considering Gram-positive bacteria, an increase in the level of BSIs due to methicillin-resistant Staphylococcus aureus and in the trend of CDIs were observed, though they did not reach statistical significance (CL: 0.72, 95% CI -0.039 to 1.48, p = 0.062; CT: 1.43, 95% CI -0.002 to 2.863, p = 0.051; respectively). Our findings demonstrated that the increases in AMR and AC that appeared in the first COVID-19 wave may be later controlled by restoring IPC and AS programs to pre-epidemic levels. A coordinated healthcare effort is necessary to address the longer-term impact of COVID-19 on AC to avoid irreversible consequences on AMR.

The synergic combination of D-dimer (as proxy of thrombotic/vascular injury) and static compliance (as proxy of parenchymal injury) in predicting mortality in COVID-19-ARDS has not been systematically evaluated. The objective is to determine whether the combination of elevated D-dimer and low static compliance can predict mortality in patients with COVID-19-ARDS. A "training sample" (March-June 2020) and a "testing sample" (September 2020-January 2021) of adult patients invasively ventilated for COVID-19-ARDS were collected in nine hospitals. D-dimer and compliance in the first 24 h were recorded. Study outcome was all-cause mortality at 28-days. Cut-offs for D-dimer and compliance were identified by receiver operating characteristic curve analysis. Mutually exclusive groups were selected using classification tree analysis with chi-square automatic interaction detection. Time to death in the resulting groups was estimated with Cox regression adjusted for SOFA, sex, age, PaO 2 /FiO 2 ratio, and sample (training/testing). "Training" and "testing" samples amounted to 347 and 296 patients, respectively. Three groups were identified: D-dimer ≤ 1880 ng/mL (LD); D-dimer > 1880 ng/mL and compliance > 41 mL/cmH 2 O (LD-HC); D-dimer > 1880 ng/mL and compliance ≤ 41 mL/cmH 2 O (HD-LC). 28-days mortality progressively increased in the three groups (from 24% to 35% and 57% (training) and from 27% to 39% and 60% (testing), respectively; p < 0.01). Adjusted mortality was significantly higher in HD-LC group compared with LD (HR = 0.479, p < 0.001) and HD-HC (HR = 0.542, p < 0.01); no difference was found between LD and HD-HC. In conclusion, combination of high D-dimer and low static compliance identifies a clinical phenotype with high mortality in COVID-19-ARDS.

Background: Herpes simplex 1 co-infections in patients with COVID-19 are considered relatively uncommon; some reports on re-activations in patients in intensive-care units were published. The aim of the study was to analyze herpetic re-activations and their clinical manifestations in hospitalized COVID-19 patients, performing HSV-1 PCR on plasma twice a week., Methods: we conducted a prospective, observational, single-center study involving 70 consecutive patients with severe/critical SARS-CoV-2 pneumonia tested for HSV-1 hospitalized at Azienda Ospedaliero-Universitaria of Modena., Results: of these 70 patients, 21 (30.0%) showed detectable viremia and 13 (62%) had clinically relevant manifestations of HSV-1 infection corresponding to 15 events (4 pneumonia, 5 herpes labialis, 3 gingivostomatitis, one encephalitis and two hepatitis). HSV-1 positive patients were more frequently treated with steroids than HSV-1 negative patients (76.2% vs. 49.0%, p = 0.036) and more often underwent mechanical ventilation (IMV) (57.1% vs. 22.4%, p = 0.005). In the unadjusted logistic regression analysis, steroid treatment, IMV, and higher LDH were significantly associated with an increased risk of HSV1 re-activation (odds ratio 3.33, 4.61, and 16.9, respectively). The association with the use of steroids was even stronger after controlling for previous use of both tocilizumab and IMV (OR = 5.13, 95% CI:1.36-19.32, p = 0.016). The effect size was larger when restricting to participants who were treated with high doses of steroids while there was no evidence to support an association with the use of tocilizumab Conclusions: our study shows a high incidence of HSV-1 re-activation both virologically and clinically in patients with SARS-CoV-2 severe pneumonia, especially in those treated with steroids.

Introduction: Adjunctive therapy with polyclonal intravenous immunoglobins (IVIg) is currently used for preventing or managing infections and sepsis, especially in immunocompromised patients. The pathobiology of COVID-19 and the mechanisms of action of Ig led to the consideration of this adjunctive therapy, including in patients with respiratory failure due to the SARS-CoV-2 infection. This manuscript reports the rationale, the available data and the results of a structured consensus on intravenous Ig therapy in patients with severe COVID-19., Methods: A panel of multidisciplinary experts defined the clinical phenotypes of COVID-19 patients with severe respiratory failure and, after literature review, voted for the agreement on the rationale and the potential role of IVIg therapy for each phenotype. Due to the scarce evidence available, a modified RAND/UCLA appropriateness method was used., Results: Three different phenotypes of COVID-19 patients with severe respiratory failure were identified: patients with an abrupt and dysregulated hyperinflammatory response (early phase), patients with suspected immune paralysis (late phase) and patients with sepsis due to a hospital-acquired superinfection (sepsis by bacterial superinfection). The rationale for intravenous Ig therapy in the early phase was considered uncertain whereas the panelists considered its use in the late phase and patients with sepsis/septic shock by bacterial superinfection appropriate., Conclusion: As with other immunotherapies, IVIg adjunctive therapy may have a potential role in the management of COVID-19 patients. The ongoing trials will clarify the appropriate target population and the true effectiveness.

The primary objective of this multicenter, observational, retrospective study was to assess the incidence rate of ventilator-associated pneumonia (VAP) in coronavirus disease 2019 (COVID-19) patients in intensive care units (ICU). The secondary objective was to assess predictors of 30-day case-fatality of VAP. From 15 February to 15 May 2020, 586 COVID-19 patients were admitted to the participating ICU. Of them, 171 developed VAP (29%) and were included in the study. The incidence rate of VAP was of 18 events per 1000 ventilator days (95% confidence intervals [CI] 16-21). Deep respiratory cultures were available and positive in 77/171 patients (45%). The most frequent organisms were Pseudomonas aeruginosa (27/77, 35%) and Staphylococcus aureus (18/77, 23%). The 30-day case-fatality of VAP was 46% (78/171). In multivariable analysis, septic shock at VAP onset (odds ratio [OR] 3.30, 95% CI 1.43-7.61, p = 0.005) and acute respiratory distress syndrome at VAP onset (OR 13.21, 95% CI 3.05-57.26, p < 0.001) were associated with fatality. In conclusion, VAP is frequent in critically ill COVID-19 patients. The related high fatality is likely the sum of the unfavorable prognostic impacts of the underlying viral and the superimposed bacterial diseases.