ENaC gene variants and their involvement in Covid­19 severity.

Epidemiological studies report the association of diverse cardiovascular conditions with coronavirus disease 2019 (COVID-19), but the causality has remained to be established. Specific genetic factors and the extent to which they can explain variation in susceptibility or severity are largely elusive. The present study aimed to evaluate the link between 32 cardio-metabolic traits and COVID-19. A total of 60 participants were enrolled, who were categorized into the following 4 groups: A control group with no COVID-19 or any other underlying pathologies, a group of patients with a certain form of dyslipidemia and predisposition to atherosclerotic disease, a COVID-19 group with mild or no symptoms and a COVID-19 group with severe symptomatology hospitalized at the Intensive Care Unit of Sotiria Hospital (Athens, Greece). Demographic, clinical and laboratory data were recorded and genetic material was isolated, followed by simultaneous analysis of the genes related to dyslipidemia using a custom-made next-generation sequencing panel. In the COVID-19 group with mild or absent symptoms, the variant c.112C>T:p.P38S was detected in the sodium channel epithelial 1 subunit α (SCNN1A) gene, with a major allele frequency (Maf) of <0.01. In the COVID-19 group with severe symptoms, the variant c.786G>A:p.T262T was detected in the SCNN1B gene, which encodes for the ß-subunit of the epithelial sodium channel ENaC, with a Maf <0.01. None of the two rare variants were detected in the control or dyslipidemia groups. In conclusion, the current study suggests that ENaC variants are likely associated with genetic susceptibility to COVID-19, supporting the rationale for the risk and protective genetic factors for the morbidity and mortality of COVID-19.

Association Between Baseline Driving Pressure and Mortality in Very Old Patients with ARDS.

RATIONALE: Due to effects of aging on the respiratory system, it is conceivable that the association between driving pressure and mortality depends on age. OBJECTIVE: We endeavored to evaluate whether the association between driving pressure and mortality of patients with acute respiratory distress syndrome (ARDS) varies across the adult lifespan, hypothesizing that it is stronger in older, including very old (≥80 years), patients. METHODS: We performed a secondary analysis of individual patient-level data from seven ARDS Network and PETAL Network randomized controlled trials ("ARDSNet cohort"). We tested our hypothesis in a second, independent, national cohort ("Hellenic cohort"). We performed both binary logistic and Cox regression analyses including the interaction term between age (as a continuous variable) and driving pressure at baseline (i.e., the day of trial enrollment) as the predictor, and 90-day mortality as the dependent variable. FINDINGS: Based on data from 4567 patients with ARDS included in the ARDSNet cohort, we found that the effect of driving pressure on mortality depended on age (p=0.01 for the interaction between age as a continuous variable and driving pressure). The difference in driving pressure between survivors and non-survivors significantly changed across the adult lifespan (p<0.01). In both cohorts, a driving pressure threshold of 11 cmH2O was associated with mortality in very old patients. INTERPRETATION: Data from randomized controlled trials with strict inclusion criteria suggest that the effect of driving pressure on mortality of patients with ARDS may depend on age. These results may advocate for a personalized age-dependent mechanical ventilation approach.

The Interaction of Complement and Intrinsic Coagulation System: A Comparative Study between COVID-19 and Bacterial Sepsis Patients.

Background/Objectives: Through the past several years, a constant interaction has been implicated between complement and coagulation cascades. SARS-CoV-2 infection and bacterial sepsis are potent activators of both cascades. This study aims to compare the extent of complement and intrinsic coagulation pathway activation (and the interplay between them) among patients with COVID-19 and bacterial sepsis. Methods: Serum and plasma samples were collected from 25 ICU patients (11 patients with COVID-19 and 14 patients with bacterial sepsis) at two time points (on admission and either on improvement or deterioration). The activities of coagulation factors XI and XII and complement factors C3a and C5a were measured at both time points. Results: The activities of factors XI and XII were increased in both groups of patients and at both time points. However, there were no statistically significant differences between SARS-CoV-2 and bacterial sepsis patients. On the other hand, both C3a and C5a were significantly higher in the COVID-19 group on admission. This correlation was preserved on reassessment. Conclusions: Complement activation seems to be more enhanced in COVID-19 than bacterial sepsis. However, the lack of statistical significance in factors XI and XII indicates t the presence of additional pathways for complement activation in SARS-CoV-2 infection.

Clinical Phenotyping for Prognosis and Immunotherapy Guidance in Bacterial Sepsis and COVID-19.

OBJECTIVES: It is suggested that sepsis may be classified into four clinical phenotypes, using an algorithm employing 29 admission parameters. We applied a simplified phenotyping algorithm among patients with bacterial sepsis and severe COVID-19 and assessed characteristics and outcomes of the derived phenotypes. DESIGN: Retrospective analysis of data from prospective clinical studies. SETTING: Greek ICUs and Internal Medicine departments. PATIENTS AND INTERVENTIONS: We analyzed 1498 patients, 620 with bacterial sepsis and 878 with severe COVID-19. We implemented a six-parameter algorithm (creatinine, lactate, aspartate transaminase, bilirubin, C-reactive protein, and international normalized ratio) to classify patients with bacterial sepsis intro previously defined phenotypes. Patients with severe COVID-19, included in two open-label immunotherapy trials were subsequently classified. Heterogeneity of treatment effect of anakinra was assessed. The primary outcome was 28-day mortality. MEASUREMENTS AND MAIN RESULTS: The algorithm validated the presence of the four phenotypes across the cohort of bacterial sepsis and the individual studies included in this cohort. Phenotype α represented younger patients with low risk of death, ß was associated with high comorbidity burden, and δ with the highest mortality. Phenotype assignment was independently associated with outcome, even after adjustment for Charlson Comorbidity Index. Phenotype distribution and outcomes in severe COVID-19 followed a similar pattern. CONCLUSIONS: A simplified algorithm successfully identified previously derived phenotypes of bacterial sepsis, which were predictive of outcome. This classification may apply to patients with severe COVID-19 with prognostic implications.

Clinical Phenotyping for Prognosis and Immunotherapy Guidance in Bacterial Sepsis and COVID-19.

OBJECTIVES: It is suggested that sepsis may be classified into four clinical phenotypes, using an algorithm employing 29 admission parameters. We applied a simplified phenotyping algorithm among patients with bacterial sepsis and severe COVID-19 and assessed characteristics and outcomes of the derived phenotypes. DESIGN: Retrospective analysis of data from prospective clinical studies. SETTING: Greek ICUs and Internal Medicine departments. PATIENTS AND INTERVENTIONS: We analyzed 1498 patients, 620 with bacterial sepsis and 878 with severe COVID-19. We implemented a six-parameter algorithm (creatinine, lactate, aspartate transaminase, bilirubin, C-reactive protein, and international normalized ratio) to classify patients with bacterial sepsis intro previously defined phenotypes. Patients with severe COVID-19, included in two open-label immunotherapy trials were subsequently classified. Heterogeneity of treatment effect of anakinra was assessed. The primary outcome was 28-day mortality. MEASUREMENTS AND MAIN RESULTS: The algorithm validated the presence of the four phenotypes across the cohort of bacterial sepsis and the individual studies included in this cohort. Phenotype α represented younger patients with low risk of death, ß was associated with high comorbidity burden, and δ with the highest mortality. Phenotype assignment was independently associated with outcome, even after adjustment for Charlson Comorbidity Index. Phenotype distribution and outcomes in severe COVID-19 followed a similar pattern. CONCLUSIONS: A simplified algorithm successfully identified previously derived phenotypes of bacterial sepsis, which were predictive of outcome. This classification may apply to patients with severe COVID-19 with prognostic implications.

Strong ion gap and anion gap corrected for albumin and lactate in patients with sepsis in the intensive care unit.

INTRODUCTION: Metabolic acidosis is very common amongst critically ill sepsis patients partly due to the presence of unmeasured ions in serum. These ions can be detected by anion gap (AG) or strong ion gap (SIG) concentration values. The purpose of this study is to assess the correlation and potential agreement of the two methods in critically ill patients with sepsis. MATERIALS AND METHODS: The present is a retrospective study including septic patients admitted to the Intensive Care Unit from December 2014 to July 2016. The [SIG] and the [AG] corrected for albumin and lactate ([AGcl]) were calculated on admission and on sepsis remission or deterioration. The correlation of the two parameters was assessed in all patient groups using the Pearson correlation coefficient and linear regression analysis and the agreement with Bland-Altman plots. ROC survival curves were also generated for the patients in relation to the values of [AGcl], [SIG] and inorganic [SIG] ([SIGi]) on admission. RESULTS: There was a strong correlation linking [AGcl] and [SIG] values (r>0.9, P<0.05) in all patient groups. The results from all three linear regression equations were statistically significant as the models predicted the [AGcl] value from the [SIG] value with high accuracy. The mean difference of the two methods (i.e. [AGcl] - [SIG] in every patient separately) in septic patients on admission was 11.75 mEq/l with 95% limits of agreement [9.7-13.8]; in patients with sepsis deterioration, it was 11.8 mEq/l with 95% limits of agreement [9.8-13.7] and in patients with sepsis remission, it was 11.5 mEq/l with 95% limits of agreement [10.4-12.7]. ROC survival curves demonstrated a small area under the curve (AUC): [SIG] AUC: 0.479, 95% CI [0.351, 0.606], [SIGi] AUC: 0.581, 95% CI [0.457, 0.705], [AGcl] AUC: 0.529, 95% CI [0.401, 0.656]. CONCLUSION: [AGcl] and [SIG] demonstrate excellent correlation in septic patients, with a mean difference of about 12 mEq/l. Both parameters failed to demonstrate any predictive ability regarding patient mortality.

The Real Impact of Age on Mortality in Critically Ill COVID-19 Patients.

OBJECTIVE: The impact of severe infection from COVID-19 and the resulting need for life support in an ICU environment is a fact that caused immense pressure in healthcare systems around the globe. Accordingly, elderly people faced multiple challenges, especially after admission to the ICU. On this basis, we performed this study to assess the impact of age on COVID-19 mortality in critically ill patients. MATERIALS AND METHODS: In this retrospective study, we collected data from 300 patients who were hospitalized in the ICU of a Greek respiratory hospital. We split patients into two age groups using a threshold of 65 years old. The primary objective of the study was the survival of patients in a follow up period of 60 days after their admission to the ICU. Secondary objectives were to determine whether mortality is affected by other factors, including sepsis and clinical and laboratory factors, Charlson Comorbidity Index (CCI), APACHE II and d-dimers, CRP, etc. Results: The survival of all patients in the ICU was 75.7%. Those in the <65 years old age group expressed a survival rate of 89.3%, whereas those in the ≥65 years old age group had a survival rate of 58% (p-value < 0.001). In the multivariate Cox regression, the presence of sepsis and an increased CCI were independent predictors of mortality in 60 days (p-value < 0.001), while the age group did not maintain its statistical significance (p-value = 0.320). CONCLUSIONS: Age alone as a simple number is not capable of predicting mortality in patients with severe COVID-19 in the ICU. We must use more composite clinical markers that may better reflect the biological age of patients, such as CCI. Moreover, the effective control of infections in the ICU is of utmost importance for the survival of patients, since avoiding septic complications can drastically improve the prognosis of all patients, regardless of age.

COVID-19 Outcomes and Diabetes Mellitus: A Comprehensive Multicenter Prospective Cohort Study.

The link between type 2 diabetes (T2D) and the severe outcomes of COVID-19 has raised concerns about the optimal management of patients with T2D. This study aimed to investigate the clinical characteristics and outcomes of T2D patients hospitalized with COVID-19 and explore the potential associations between chronic T2D treatments and adverse outcomes. This was a multicenter prospective cohort study of T2D patients hospitalized with COVID-19 in Greece during the third wave of the pandemic (February-June 2021). Among the 354 T2D patients included in this study, 63 (18.6%) died during hospitalization, and 16.4% required ICU admission. The use of DPP4 inhibitors for the chronic management of T2D was associated with an increased risk of in-hospital death (adjusted odds ratio (adj. OR) 2.639, 95% confidence interval (CI) 1.148-6.068, p = 0.022), ICU admission (adj. OR = 2.524, 95% CI: 1.217-5.232, p = 0.013), and progression to ARDS (adj. OR = 2.507, 95% CI: 1.278-4.916, p = 0.007). Furthermore, the use of DPP4 inhibitors was significantly associated with an increased risk of thromboembolic events (adjusted OR of 2.249, 95% CI: 1.073-4.713, p = 0.032) during hospitalization. These findings highlight the importance of considering the potential impact of chronic T2D treatment regiments on COVID-19 and the need for further studies to elucidate the underlying mechanisms.

Modified SCOPE (mSCOPE) Score as a Tool to Predict Mortality in COVID-19 Critically Ill Patients.

INTRODUCTION: Efficient clinical scores predicting the outcome of severe COVID-19 pneumonia may play a pivotal role in patients' management. The aim of this study was to assess the modified Severe COvid Prediction Estimate score (mSCOPE) index as a predictor of mortality in patients admitted to the ICU due to severe COVID-19 pneumonia. MATERIALS AND METHODS: In this retrospective observational study, 268 critically ill COVID-19 patients were included. Demographic and laboratory characteristics, comorbidities, disease severity, and outcome were retrieved from the electronical medical files. The mSCOPE was also calculated. RESULTS: An amount of 70 (26.1%) of patients died in the ICU. These patients had higher mSCOPE score compared to patients who survived (p < 0.001). mSCOPE correlated to disease severity (p < 0.001) and to the number and severity of comorbidities (p < 0.001). Furthermore, mSCOPE significantly correlated with days on mechanical ventilation (p < 0.001) and days of ICU stay (p = 0.003). mSCOPE was found to be an independent predictor of mortality (HR:1.219, 95% CI: 1.010-1.471, p = 0.039), with a value ≥ 6 predicting poor outcome with a sensitivity (95%CI) 88.6%, specificity 29.7%, a positive predictive value of 31.5%, and a negative predictive value of 87.7%. CONCLUSION: mSCOPE score could be proved useful in patients' risk stratification, guiding clinical interventions in patients with severe COVID-19.

Tracheal resection in patients post-COVID-19 is associated with high reintervention rate and early restenosis.

Objectives: A remarkable increase in the number of patients presenting with tracheal complications after prolonged endotracheal intubation and mechanical ventilation for the management of the severe COVID-19-associated respiratory failure has been observed. In this study, we assessed the postoperative outcomes of tracheal resection in patients with COVID-19. Methods: We conducted a retrospective study in which all patients with a history of prolonged invasive mechanical ventilation due to COVID-19 infection, who were treated with tracheal resection and reconstruction, were included. The primary objective was in-hospital mortality and postoperative reintervention rate. The secondary objective was the time to tracheal restenosis. Results: During the 16-month study period, 11 patients with COVID-19 with tracheal complications underwent tracheal resection with end-to-end anastomosis. Mean patient age was 51.5 ± 9 years, and the majority were male (9 patients). Eight patients were referred for management of postintubation tracheal stenosis, and 3 patients were referred for tracheoesophageal fistula. Eight patients had a history of tracheostomy during the COVID-19 infection hospitalization. There was 1 in-hospital death (9.1%) due to septicemia in the intensive care unit approximately 2 months after the operation. Postoperatively, 32 reinterventions were required for tracheal restenosis due to granulation tissue formation. The risk for reintervention was higher during the first 3 months after the index operation. Four patients developed tracheal restenosis (36.4%), and 2 of them required endotracheal stent placement during the follow-up period. Conclusions: Tracheal resection and reconstruction after COVID-19 infection are associated with a high reintervention rate postoperatively. Such patients require close follow-up in expert interventional pulmonology units, and physicians should be on high alert for the early diagnosis and optimal management of tracheal restenosis.

Toward personalized immunotherapy in sepsis: The PROVIDE randomized clinical trial.

The state of immune activation may guide targeted immunotherapy in sepsis. In a double-blind, double-dummy randomized clinical study, 240 patients with sepsis due to lung infection, bacteremia, or acute cholangitis were subjected to measurements of serum ferritin and HLA-DR/CD14. Patients with macrophage activation-like syndrome (MALS) or immunoparalysis were randomized to treatment with anakinra or recombinant interferon-gamma or placebo. Twenty-eight-day mortality was the primary endpoint; sepsis immune classification was the secondary endpoint. Using ferritin >4,420 ng/mL and <5,000 HLA-DR receptors/monocytes as biomarkers, patients were classified into MALS (20.0%), immunoparalysis (42.9%), and intermediate (37.1%). Mortality was 79.1%, 66.9%, and 41.6%, respectively. Survival after 7 days with SOFA score decrease was achieved in 42.9% of patients of the immunotherapy arm and 10.0% of the placebo arm (p = 0.042). Three independent immune classification strata are recognized in sepsis. MALS and immunoparalysis are proposed as stratification for personalized adjuvant immunotherapy. Clinicaltrials.gov registration NCT03332225.

Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections.

Background: Rising antimicrobial resistance has led to a revived interest in inhaled colistin treatment in the critically ill patient with ventilator-associated respiratory infection (VARI). Nebulization via vibrating mesh nebulizers (VMNs) is considered the current standard-of-care, yet the use of generic jet nebulizers (JNs) is more widespread. Few data exist on the intrapulmonary pharmacokinetics of colistin when administered through VMNs, while there is a complete paucity regarding the use of JNs. Methods: In this study, 18 VARI patients who received 2 million international units of inhaled colistimethate sodium (CMS) through a VMN were pharmacokinetically compared with six VARI patients who received the same drug dose through a JN, in the absence of systemic CMS administration. Results: Surprisingly, VMN and JN led to comparable formed colistin exposures in the epithelial lining fluid (ELF) (median (IQR) AUC0-24: 86.2 (46.0-185.9) mg/L∙h with VMN and 91.5 (78.1-110.3) mg/L∙h with JN). The maximum ELF concentration was 10.4 (4.7-22.6) mg/L and 7.4 (6.2-10.3) mg/L, respectively. Conclusions: Based on our results, JN might be considered a viable alternative to the theoretically superior VMN. Therapeutic drug monitoring in the ELF can be advised due to the observed low exposure, high variability, and appreciable systemic absorption.

Thromboinflammation in Sepsis and Heparin: A Review of Literature and Pathophysiology.

BACKGROUND/AIM: Thromboinflammation is the pathophysiologic mechanism in which coagulation and inflammation interact and complement each other. It is observed in a number of degenerative diseases, one of them being sepsis. Quiescent endothelial cells exert antithrombotic and anti-inflammatory actions that are reduced during sepsis. The concomitant effect of the subsequent dysregulation of coagulation and complement actuation is platelet activation and aggregation, and leukocyte recruitment, with detrimental effects on the vascular endothelium. Tissue factor and α-thrombin are major sentinels in the pathogenesis of this process. This literature review aimed to cover the basic principles of the mechanisms implicated in thromboinflammation occurring during sepsis and also investigates the role of heparin as a possible therapeutic agent, since it exhibits both anticoagulant and anti-inflammatory functions. MATERIALS AND METHODS: PubMed, SCOPUS and ScienceDirect databases were used for search of literature from inception to April 2022. To be included in our review, studies had to refer to the pathophysiologic mechanisms leading to coincident coagulation and inflammation, or to the administration of heparin either for treatment or prophylaxis, both in the context of sepsis. RESULTS: A total of 276 articles were drawn from the initial literature search. 124 were duplicated and out of the remaining 152 articles, 29 met our inclusion criteria and were reviewed. CONCLUSION: Clinical trials among sepsis patients have indicated that the thromboinflammatory process is more complex than believed, as adverse bleeding events continue to occur despite the use of anticoagulants with different pharmacodynamics. However, heparin has a pleiotropic effect that might provide protection against sepsis and related complications and merits further research.

Daily Physical Activity in Asthma and the Effect of Mepolizumab Therapy.

For the various asthma-specific beneficial effects of physical activity, daily physical activity (DPA) and the potential of asthma therapies on DPA require better characterization. Hence, we aimed to determine (a) the DPA of asthma patients, and (b) the effect of add-on mepolizumab on the DPA of severe asthma patients. Methods: Adult outpatients with mild-to-moderate or severe asthma had accelerometer assessment of DPA. Severe asthma patients who were commenced on mepolizumab had their DPA reassessed after 12 months. Results: For the total cohort (n = 36), daily step count, time in moderate-to-vigorous physical activity (MVPA), MVPA volume and Movement Intensity (MI) were 7806 ± 3823 steps, 123 (interquartile range, 63) min, 657 ± 255 MET·min and 1.96 (0.45) m/s2, respectively. All patients met at least one recommendation for DPA but less than half met recommendations for vigorous DPA. Patients on mepolizumab therapy increased daily step count (646 steps; 9%), time in MVPA (20 min; 21%), MVPA volume (87 MET·min; 17%) and MI (0.11 m/s2; 6%) for the same amount of moving time; lung function, asthma control and health-related quality of life also improved. Conclusions: Analysis of the first national data on DPA in asthma and novel comparison against current applicable guidelines and identified beneficial thresholds showed borderline levels of DPA with room for improvement especially for severe asthma patients. In a non-sedentary cohort of severe asthma patients, mepolizumab conferred significant and meaningful improvements in DPA.

A Novel Non-invasive Index of Cardiopulmonary Reserve for the Prediction of Failure of Weaning From Mechanical Ventilation.

PURPOSE: To develop an easy-to-implement prediction index of weaning failure for ICU patients. Materials and methods: We developed a prediction index modifying respiratory exchange ratio (RER), Mod-RER, a parameter measured during the cardiopulmonary exercise test (CPET) based on respiratory quotient. The Mod-RER index is the ratio of partial pressure of CO2 in central venous blood over the difference of partial pressure of O2 in arterial and central venous blood (Mod-RER=PcvCO2/PaO2-PcvO2, where PcvCO2 = partial pressure of CO2 in central venous blood, PaO2 = partial pressure of O2 in arterial blood, and PcvO2 = partial pressure of O2 in central venous blood). We prospectively tested its predictive value, compared to other indices of weaning outcome, in an observational study of difficult-to-wean ICU patients. RESULTS: Mod-RER index increased significantly only in failed trials and receiver operating characteristic (ROC) analysis for prediction of outcome based on Mod-RER index change had an area under the curve (AUC) 0.80 (p<0.001). Mod-RER change exhibited the highest sensitivity (84.6%) and specificity (78.1%) among the tested indices, with the optimal cut-off of 19.3%. Comparison of AUCs did not reach statistical significance (p=0.106). CONCLUSIONS: We conclude that Mod-RER index is an accurate, easy-to-use prediction tool of weaning failure, useful in decision making of timely extubation of ICU patients, especially in the demanding era of the coronavirus disease 2019 (COVID-19) pandemic.

Fungal Infections in the ICU during the COVID-19 Era: Descriptive and Comparative Analysis of 178 Patients.

BACKGROUND: COVID-19-associated fungal infections seem to be a concerning issue. The aim of this study was to assess the incidence of fungal infections, the possible risk factors, and their effect on outcomes of critically ill patients with COVID-19. METHODS: A retrospective observational study was conducted in the COVID-19 ICU of the First Respiratory Department of National and Kapodistrian University of Athens in Sotiria Chest Diseases Hospital between 27 August 2020 and 10 November 2021. RESULTS: Here, 178 patients were included in the study. Nineteen patients (10.7%) developed fungal infection, of which five had COVID-19 associated candidemia, thirteen had COVID-19 associated pulmonary aspergillosis, and one had both. Patients with fungal infection were younger, had a lower Charlson Comorbidity Index, and had a lower PaO2/FiO2 ratio upon admission. Regarding health-care factors, patients with fungal infections were treated more frequently with Tocilizumab, a high regimen of dexamethasone, continuous renal replacement treatment, and were supported more with ECMO. They also had more complications, especially infections, and subsequently developed septic shock more frequently. Finally, patients with fungal infections had a longer length of ICU stay, as well as length of mechanical ventilation, although no statistically significant difference was reported on 28-day and 90-day mortality. CONCLUSIONS: Fungal infections seem to have a high incidence in COVID-19 critically ill patients and specific risk factors are identified. However, fungal infections do not seem to burden on mortality.

Fungal Infections in Critically Ill COVID-19 Patients: Inevitabile Malum.

Patients with severe COVID-19 belong to a population at high risk of invasive fungal infections (IFIs), with a reported incidence of IFIs in critically ill COVID-19 patients ranging between 5% and 26.7%. Common factors in these patients, such as multiple organ failure, immunomodulating/immunocompromising treatments, the longer time on mechanical ventilation, renal replacement therapy or extracorporeal membrane oxygenation, make them vulnerable candidates for fungal infections. In addition to that, SARS-CoV2 itself is associated with significant dysfunction in the patient's immune system involving both innate and acquired immunity, with reduction in both CD4+ T and CD8+ T lymphocyte counts and cytokine storm. The emerging question is whether SARS-CoV-2 inherently predisposes critically ill patients to fungal infections or the immunosuppressive therapy constitutes the igniting factor for invasive mycoses. To approach the dilemma, one must consider the unique pathogenicity of SARS-CoV-2 with the deranged immune response it provokes, review the well-known effects of immunosuppressants and finally refer to current literature to probe possible causal relationships, synergistic effects or independent risk factors. In this review, we aimed to identify the prevalence, risk factors and mortality associated with IFIs in mechanically ventilated patients with COVID-19.

Immunostimulation and Coagulopathy in COVID-19 Compared to Patients With H1N1 Pneumonia or Bacterial Sepsis.

BACKGROUND/AIM: Multiple reports from all over the world link COVID-19 with endothelial/coagulation disorders as well as a dysregulated immune response. This study tested the hypothesis that immunostimulation will be greater in COVID-19 patients than in patients with H1N1 infection or bacterial sepsis. Also, whether an increase in immune stimulation will be accompanied by a more severely affected endothelium/coagulation system was examined. PATIENTS AND METHODS: Twenty-three septic patients, admitted in the Intensive Care Unit (ICU), were enrolled (9 with SARS-CoV-2, 5 with H1N1 pneumonia, 9 with bacterial sepsis). Myeloperoxidase (MPO) activity along with certain endothelial/coagulation factors were assessed on admission (time point 1) and at either improvement or deterioration (time point 2). RESULTS: MPO levels were significantly higher in COVID-19 patients compared to both other groups. Furthermore, in patients with COVID-19, vWF levels did not differ significantly, fVIII levels were lower while ADAMTS-13 activity was higher compared to patients with H1N1 pneumonia and bacterial sepsis (a trend in the latter). CONCLUSION: Increased immunostimulation was noted in COVID-19 patients compared to other septic patients; however, this was not accompanied by greater disturbance of the clotting system and/or more severe endothelial injury.

COVID-19 Patients Presenting with Post-Intubation Upper Airway Complications: A Parallel Epidemic?

During the current pandemic, we witnessed a rise of post-intubation tracheal stenosis (PITS) in patients intubated due to COVID-19. We prospectively analyzed data from patients referred to our institution during the last 18 months for severe symptomatic post-intubation upper airway complications. Interdisciplinary bronchoscopic and/or surgical management was offered. Twenty-three patients with PITS and/or tracheoesophageal fistulae were included. They had undergone 31.85 (±22.7) days of ICU hospitalization and 17.35 (±7.4) days of intubation. Tracheal stenoses were mostly complex, located in the subglottic or mid-tracheal area. A total of 83% of patients had fracture and distortion of the tracheal wall. Fifteen patients were initially treated with rigid bronchoscopic modalities and/or stent placement and eight patients with tracheal resection-anastomosis. Post-treatment relapse in two of the bronchoscopically treated patients required surgery, while two of the surgically treated patients required rigid bronchoscopy and stent placement. Transient, non-life-threatening post-treatment complications developed in 60% of patients and were all managed successfully. The histopathology of the resected tracheal specimens didn't reveal specific alterations in comparison to pre-COVID-era PITS cases. Prolonged intubation, pronation maneuvers, oversized tubes or cuffs, and patient- or disease-specific factors may be pathogenically implicated. An increase of post-COVID PITS is anticipated. Careful prevention, early detection and effective management of these iatrogenic complications are warranted.

ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically lll COVID-19 Patients.

BACKGROUND: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19. METHODS: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints. RESULTS: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment. CONCLUSION: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.