Quality of life and intrinsic capacity in patients with post-acute COVID-19 syndrome is in relation to frailty and resilience phenotypes.

The objective of this study was to characterize frailty and resilience in people evaluated for Post-Acute COVID-19 Syndrome (PACS), in relation to quality of life (QoL) and Intrinsic Capacity (IC). This cross-sectional, observational, study included consecutive people previously hospitalized for severe COVID-19 pneumonia attending Modena (Italy) PACS Clinic from July 2020 to April 2021. Four frailty-resilience phenotypes were built: "fit/resilient", "fit/non-resilient", "frail/resilient" and "frail/non-resilient". Frailty and resilience were defined according to frailty phenotype and Connor Davidson resilience scale (CD-RISC-25) respectively. Study outcomes were: QoL assessed by means of Symptoms Short form health survey (SF-36) and health-related quality of life (EQ-5D-5L) and IC by means of a dedicated questionnaire. Their predictors including frailty-resilience phenotypes were explored in logistic regressions. 232 patients were evaluated, median age was 58.0 years. PACS was diagnosed in 173 (74.6%) patients. Scarce resilience was documented in 114 (49.1%) and frailty in 72 (31.0%) individuals. Predictors for SF-36 score < 61.60 were the phenotypes "frail/non-resilient" (OR = 4.69, CI 2.08-10.55), "fit/non-resilient" (OR = 2.79, CI 1.00-7.73). Predictors for EQ-5D-5L < 89.7% were the phenotypes "frail/non-resilient" (OR = 5.93, CI 2.64-13.33) and "frail/resilient" (OR = 5.66, CI 1.93-16.54). Predictors of impaired IC (below the mean score value) were "frail/non-resilient" (OR = 7.39, CI 3.20-17.07), and "fit/non-resilient" (OR = 4.34, CI 2.16-8.71) phenotypes. Resilience and frailty phenotypes may have a different impact on wellness and QoL and may be evaluated in people with PACS to identify vulnerable individuals that require suitable interventions.

A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients.

Little is known about SARS-CoV-2 evolution under Molnupiravir and Paxlovid, the only antivirals approved for COVID-19 treatment. By investigating SARS-CoV-2 variability in 8 Molnupiravir-treated, 7 Paxlovid-treated and 5 drug-naïve individuals at 4 time-points (Days 0-2-5-7), a higher genetic distance is found under Molnupiravir pressure compared to Paxlovid and no-drug pressure (nucleotide-substitutions/site mean±Standard error: 18.7 × 10-4 ± 2.1 × 10-4 vs. 3.3 × 10-4 ± 0.8 × 10-4 vs. 3.1 × 10-4 ± 0.8 × 10-4, P = 0.0003), peaking between Day 2 and 5. Molnupiravir drives the emergence of more G-A and C-T transitions than other mutations (P = 0.031). SARS-CoV-2 selective evolution under Molnupiravir pressure does not differ from that under Paxlovid or no-drug pressure, except for orf8 (dN > dS, P = 0.001); few amino acid mutations are enriched at specific sites. No RNA-dependent RNA polymerase (RdRp) or main proteases (Mpro) mutations conferring resistance to Molnupiravir or Paxlovid are found. This proof-of-concept study defines the SARS-CoV-2 within-host evolution during antiviral treatment, confirming higher in vivo variability induced by Molnupiravir compared to Paxlovid and drug-naive, albeit not resulting in apparent mutation selection.

Do All Critically Ill Patients with COVID-19 Disease Benefit from Adding Tocilizumab to Glucocorticoids? A Retrospective Cohort Study.

BACKGROUND: Treatment guidelines recommend the tocilizumab use in patients with a CRP of >7.5 mg/dL. We aimed to estimate the causal effect of glucocorticoids + tocilizumab on mortality overall and after stratification for PaO2/FiO2 ratio and CRP levels. METHODS: This was an observational cohort study of patients with severe COVID-19 pneumonia. The primary endpoint was day 28 mortality. Survival analysis was conducted to estimate the conditional and average causal effect of glucocorticoids + tocilizumab vs. glucocorticoids alone using Kaplan-Meier curves and Cox regression models with a time-varying variable for the intervention. The hypothesis of the existence of effect measure modification by CRP and PaO2/FiO2 ratio was tested by including an interaction term in the model. RESULTS: In total, 992 patients, median age 69 years, 72.9% males, 597 (60.2%) treated with monotherapy, and 395 (31.8%), adding tocilizumab upon respiratory deterioration, were included. At BL, the two groups differed for median values of CRP (6 vs. 7 mg/dL; p < 0.001) and PaO2/FiO2 ratio (276 vs. 235 mmHg; p < 0.001). In the unadjusted analysis, the mortality was similar in the two groups, but after adjustment for key confounders, a significant effect of glucocorticoids + tocilizumab was observed (adjusted hazard ratio (aHR) = 0.59, 95% CI: 0.38-0.90). Although the study was not powered to detect interactions (p = 0.41), there was a signal for glucocorticoids + tocilizumab to have a larger effect in subsets, especially participants with high levels of CRP at intensification. CONCLUSIONS: Our data confirm that glucocorticoids + tocilizumab vs. glucocorticoids alone confers a survival benefit only in patients with a CRP > 7.5 mg/dL prior to treatment initiation and the largest effect for a CRP > 15 mg/dL. Large randomized studies are needed to establish an exact cut-off for clinical use.

Is It Possible to Eradicate Carbapenem-Resistant Acinetobacter baumannii (CRAB) from Endemic Hospitals?

BACKGROUND: Despite the global efforts to antagonize carbapenem-resistant Acinetobacter baumannii (CRAB) spreading, it remains an emerging threat with a related mortality exceeding 40% among critically ill patients. The purpose of this review is to provide evidence concerning the best infection prevention and control (IPC) strategies to fight CRAB spreading in endemic hospitals. METHODS: The study was a critical review of the literature aiming to evaluate all available studies reporting IPC measures to control CRAB in ICU and outside ICU in both epidemic and endemic settings in the past 10 years. RESULTS: Among the 12 included studies, the majority consisted of research reports of outbreaks mostly occurred in ICUs. The reported mortality reached 50%. Wide variability was observed related to the frequency of application of recommended CRAB IPC measures among the studies: environmental disinfection (100%); contact precautions (83%); cohorting staff and patients (75%); genotyping (66%); daily chlorhexidine baths (58%); active rectal screening (50%); closing or stopping admissions to the ward (33%). CONCLUSIONS: Despite effective control of CRAB spreading during the outbreaks, the IPC measures reported were heterogeneous and highly dependent on the different setting as well as on the structural characteristics of the wards. Reinforced 'search and destroy' strategies both on the environment and on the patient, proved to be the most effective measures for permanently eliminating CRAB spreading.

Resilience and Frailty in People Living With HIV During the COVID Era: Two Complementary Constructs Associated With Health-Related Quality of Life.

BACKGROUND: Resilience is defined as an individual's positive adaptation to stressors. The COVID-19 pandemic represents a generalized stressor which may affect differently people living with HIV (PLWH). The objective of this study was to characterize resilience in PLWH with particular regarding the identification of frailty-resilience phenotypes, which may differently affect health-related quality of life (HR-QoL). METHODS: This was an observational study of PLWH attending Modena HIV Metabolic Clinic. Frailty was assessed in 2019, before the onset of the COVID-19 pandemic by using 37-Item frailty index ranging from 0 to 1. The frailty index score was categorized as fit (<0.25) or frail (>0.25). In January 2021, PLWH were offered to complete a set of electronic questionnaires including the CD-RISC-25 for resilience and EQ-5D5L and SF-36 for HR-QoL. Resilience was defined as CD-RISC-25 score >75.7 (ranging from 0 to 100). RESULTS: Of 800 PLWH reached by mail, 575 (72%) completed the questionnaires. The median age and HIV duration were 54.5 and 24.3 years, respectively. Impaired resilience was associated with loneliness [odds ratio (OR = 2.39; 1.20 to 4.76, P < 0.001)]. Predictors for EQ-5D5L <89.7% were the phenotypes "frail/nonresilient" [OR = 5.21, 95% confidence interval (CI): 2.62 to 10.33] and "fit/nonresilient" (OR = 5.48, 95% CI: 2.8 to 10.74). Predictors for SF-36 <64.40 were the phenotypes "frail/nonresilient" (OR = 7.43, 95% CI: 2.57 to 21.22) and "fit/nonresilient" (OR = 6.27, 95% CI: 2.17 to 18.16). Both models were corrected for age, sex, HIV duration, and nadir CD4. CONCLUSIONS: Resilience characterizes the well-being of PLWH during the COVID-19 crisis. This construct is complementary to frailty in the identification of clinical phenotypes with different impacts on HR-QoL.

First and second waves among hospitalised patients with COVID-19 with severe pneumonia: a comparison of 28-day mortality over the 1-year pandemic in a tertiary university hospital in Italy.

OBJECTIVE: The first COVID-19-19 epidemic wave was over the period of February-May 2020. Since 1 October 2020, Italy, as many other European countries, faced a second wave. The aim of this analysis was to compare the 28-day mortality between the two waves among COVID-19 hospitalised patients. DESIGN: Observational cohort study. Standard survival analysis was performed to compare all-cause mortality within 28 days after hospital admission in the two waves. Kaplan-Meier curves as well as Cox regression model analysis were used. The effect of wave on risk of death was shown by means of HRs with 95% CIs. A sensitivity analysis around the impact of the circulating variant as a potential unmeasured confounder was performed. SETTING: University Hospital of Modena, Italy. Patients admitted to the hospital for severe COVID-19 pneumonia during the first (22 February-31 May 2020) and second (1 October-31 December 2020) waves were included. RESULTS: During the two study periods, a total of 1472 patients with severe COVID-19 pneumonia were admitted to our hospital, 449 during the first wave and 1023 during the second. Median age was 70 years (IQR 56-80), 37% women, 49% with PaO2/FiO2 <250 mm Hg, 82% with ≥1 comorbidity, median duration of symptoms was 6 days. 28-day mortality rate was 20.0% (95% CI 16.3 to 23.7) during the first wave vs 14.2% (95% CI 12.0 to 16.3) in the second (log-rank test p value=0.03). After including key predictors of death in the multivariable Cox regression model, the data still strongly suggested a lower 28-day mortality rate in the second wave (aHR=0.64, 95% CI 0.45 to 0.90, p value=0.01). CONCLUSIONS: In our hospitalised patients with COVID-19 with severe pneumonia, the 28-day mortality appeared to be reduced by 36% during the second as compared with the first wave. Further studies are needed to identify factors that may have contributed to this improved survival.

Real-life experience with compassionate use of cefiderocol for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections.

OBJECTIVES: To describe our real-life experience with cefiderocol in XDR and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections without any other available treatment options. METHODS: We included patients with a proven infection due to an XDR/DTR-P, who had failed on previous regimens, and were treated with cefiderocol, following them prospectively to day 90 or until hospital discharge or death. RESULTS: Seventeen patients treated for >72 h with cefiderocol were included: 14 receiving combination regimens (82.4%) and 3 receiving monotherapy (17.6%). Fourteen patients were males (82%) with a median age of 64 years (IQR 58-73). Fifteen patients (88.2%) were admitted to the ICU and five had septic shock (29%). Seven cases (41.2%) were ventilator-associated pneumonia, of which 71% (5/7) occurred in COVID-19 patients. Four were complicated intrabdominal infections, one ecthyma gangrenosum, one nosocomial pneumonia and one empyema, one osteomyelitis, one primary bacteraemia, and one nosocomial external ventricular drainage meningitis. Clinical cure and microbiological cure rates were 70.6% and 76.5%, respectively. There were six deaths (35.3%) after a median of 8 days (IQR 3-10) from the end of treatment, but only two of them (11.7%) were associated with P. aeruginosa infection progression. CONCLUSIONS: Our experience collecting this large case series of DTR-P treated with cefiderocol may help clinicians consider this new option in this hard-to-manage setting. Our results are even more relevant in the current scenario of ceftolozane/tazobactam shortage. Importantly, this is the first study providing real-life data indicating adequate cefiderocol concentrations in CSF.

The impact of tocilizumab on respiratory support states transition and clinical outcomes in COVID-19 patients. A Markov model multi-state study.

BACKGROUND: The benefit of tocilizumab on mortality and time to recovery in people with severe COVID pneumonia may depend on appropriate timing. The objective was to estimate the impact of tocilizumab administration on switching respiratory support states, mortality and time to recovery. METHODS: In an observational study, a continuous-time Markov multi-state model was used to describe the sequence of respiratory support states including: no respiratory support (NRS), oxygen therapy (OT), non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), OT in recovery, NRS in recovery. RESULTS: Two hundred seventy-one consecutive adult patients were included in the analyses contributing to 695 transitions across states. The prevalence of patients in each respiratory support state was estimated with stack probability plots, comparing people treated with and without tocilizumab since the beginning of the OT state. A positive effect of tocilizumab on the probability of moving from the invasive and non-invasive mechanical NIV/IMV state to the OT in recovery state (HR = 2.6, 95% CI = 1.2-5.2) was observed. Furthermore, a reduced risk of death was observed in patients in NIV/IMV (HR = 0.3, 95% CI = 0.1-0.7) or in OT (HR = 0.1, 95% CI = 0.0-0.8) treated with tocilizumab. CONCLUSION: To conclude, we were able to show the positive impact of tocilizumab used in different disease stages depicted by respiratory support states. The use of the multi-state Markov model allowed to harmonize the heterogeneous mortality and recovery endpoints and summarize results with stack probability plots. This approach could inform randomized clinical trials regarding tocilizumab, support disease management and hospital decision making.

Darunavir/Cobicistat Is Associated with Negative Outcomes in HIV-Negative Patients with Severe COVID-19 Pneumonia.

The aim of this study was to evaluate both positive outcomes, including reduction of respiratory support aid and duration of hospital stay, and negative ones, including mortality and a composite of invasive mechanical ventilation or death, in patients with coronavirus disease 2019 (COVID-19) pneumonia treated with or without oral darunavir/cobicistat (DRV/c, 800/150 mg/day) used in different treatment durations. The secondary objective was to evaluate the percentage of patients treated with DRV/c who were exposed to potentially severe drug-drug interactions (DDIs) and died during hospitalization. This observational retrospective study was conducted in consecutive patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare patients receiving standard of care with or without DRV/c. Adjustment for key confounders was applied. Two hundred seventy-three patients (115 on DRV/c) were included, 75.8% males, mean age was 64.6 (±13.2) years. Clinical improvement was similar between the groups, depicted by respiratory aid switch (p > .05). The same was observed for duration of hospital stay [13.2 (±8.9) for DRV/c vs. 13.4 (±7.2) days for no-DRV/c, p = .9]. Patients on DRV/c had higher rates of mortality (25.2% vs. 10.1%, p < .0001. The rate of composite outcome of mechanical ventilation and death was higher in the DRV/c group (37.4% vs. 25.3%, p = .03). Multiple serious DDI associated with DRV/c were observed in the 19 patients who died. DRV/c should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials.

Hypokalemia in Patients with COVID-19.

BACKGROUND: Patients with COVID-19 experience multiple clinical conditions that may cause electrolyte imbalances. Hypokalemia is a concerning electrolyte disorder closely associated with severe complications. This study aimed to estimate prevalence, risk factors and outcome of hypokalemia in a cohort of patients with confirmed COVID-19. METHODS: A retrospective analysis was conducted on 290 non-ICU admitted patients with COVID-19 at the tertiary teaching hospital of Modena, Italy, from February 16 to April 14, 2020. RESULTS: Hypokalemia was detected in 119 out of 290 patients (41%) during hospitalization. Mean serum potassium was 3.1 ± 0.1 meq/L. The majority of patients (90.7%) patients experienced only a mild decrease in serum potassium level (3-3.4 mEq/L). Hypokalemia was associated with hypocalcemia, which was detected in 50% of subjects. Urine potassium-to-creatinine ratio, measured in a small number of patients (n = 45; 36.1%), revealed an increase of urinary potassium excretion in most cases (95.5%). Risk factors for hypokalemia were female sex (odds ratio (OR) 2.44; 95% CI 1.36-4.37; P 0.003) and diuretic therapy (OR 1.94, 95% CI 1.08-3.48; P 0.027). Hypokalemia, adjusted for sex, age and SOFA score, was not associated with ICU transfer (OR 0.52; 95% CI 0.228-1.212; P = 0.131), in-hospital mortality (OR, 0.47; 95% CI 0.170-1.324; P = 0.154) and composite outcome of ICU transfer or in-hospital mortality (OR 0.48; 95% CI 0.222-1.047; P = 0.065) in our cohort of patients. CONCLUSIONS: Hypokalemia was a frequent disorder in subjects with COVID-19. Female sex and diuretic therapy were identified as risk factors for low serum potassium levels. Hypokalemia was unrelated to ICU transfer and death in this cohort of patients.

Better prognosis in females with severe COVID-19 pneumonia: possible role of inflammation as potential mediator.

OBJECTIVES: Sex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference. METHODS: This was a retrospective, observational cohort study among patients with severe COVID-19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death according to sex. Interaction was formally tested to compare the risk difference by sex in sub-populations. Mediation analysis with a binary endpoint IMV or death (yes/no) by day 28 of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted. RESULTS: Among 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54-77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO2/FiO2 (254 mmHg vs. 191 mmHg; p 0.023). By 28 days from admission, 49.2% (95% CI 39.6-58.9%) of males vs. 31.7% (17.9-45.4%) of females underwent IMV or death (log-rank p < 0.0001) and this amounted to a difference in terms of HR of 0.40 (0.26-0.63, p 0.0001). The area under the curve in C-reactive protein (CRP) over the study period appeared to explain 85% of this difference in risk by sex. DISCUSSION: Our analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. Specifically, CRP showed a predominant role to mediate the difference in risk by sex.

Machine learning in predicting respiratory failure in patients with COVID-19 pneumonia-Challenges, strengths, and opportunities in a global health emergency.

AIMS: The aim of this study was to estimate a 48 hour prediction of moderate to severe respiratory failure, requiring mechanical ventilation, in hospitalized patients with COVID-19 pneumonia. METHODS: This was an observational prospective study that comprised consecutive patients with COVID-19 pneumonia admitted to hospital from 21 February to 6 April 2020. The patients' medical history, demographic, epidemiologic and clinical data were collected in an electronic patient chart. The dataset was used to train predictive models using an established machine learning framework leveraging a hybrid approach where clinical expertise is applied alongside a data-driven analysis. The study outcome was the onset of moderate to severe respiratory failure defined as PaO2/FiO2 ratio <150 mmHg in at least one of two consecutive arterial blood gas analyses in the following 48 hours. Shapley Additive exPlanations values were used to quantify the positive or negative impact of each variable included in each model on the predicted outcome. RESULTS: A total of 198 patients contributed to generate 1068 usable observations which allowed to build 3 predictive models based respectively on 31-variables signs and symptoms, 39-variables laboratory biomarkers and 91-variables as a composition of the two. A fourth "boosted mixed model" included 20 variables was selected from the model 3, achieved the best predictive performance (AUC = 0.84) without worsening the FN rate. Its clinical performance was applied in a narrative case report as an example. CONCLUSION: This study developed a machine model with 84% prediction accuracy, which is able to assist clinicians in decision making process and contribute to develop new analytics to improve care at high technology readiness levels.

Pneumomediastinum in COVID-19 patients: a case series of a rare complication.

Pneumomediastinum is a rare clinical finding, but one which can be the source of significant concern for clinicians. By presenting 3 such cases, we highlight that pneumomediastinum can complicate the course of a severe coronavirus disease 2019 infection but emphasize that conservative management is the first-line method of treatment, with gradual resorption of the air from the tissues. It is important to be alert to the development of pneumothorax, which will require drainage.

Expansion of plasmablasts and loss of memory B cells in peripheral blood from COVID-19 patients with pneumonia.

Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naïve B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM+ and IgM- plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies.