Severe acute respiratory syndrome coronavirus 2 infection might induce a significant and sustained lymphopenia, increasing the risk of developing opportunistic infections. Mucormycosis is a rare but severe invasive fungal infection, mainly described in immunocompromised patients. The first case of a patient diagnosed with coronavirus disease (COVID-19) who developed a pulmonary mucormycosis with extensive cavitary lesions is here reported. This case highlights how this new coronavirus might impair the immune response, exposing patients to higher risk of developing opportunistic infections and leading to worse outcomes.

Introduction. It is known that bacterial infections represent a common complication during viral respiratory tract infections such as influenza, with a concomitant increase in morbidity and mortality. Nevertheless, the prevalence of bacterial co-infections and secondary infections in critically ill patients affected by coronavirus disease 2019 (COVID-19) is not well understood yet. We performed a review of the literature currently available to examine the incidence of bacterial secondary infections acquired during hospital stay and the risk factors associated with multidrug resistance. Most of the studies, mainly retrospective and single-centered, highlighted that the incidence of co-infections is low, affecting about 3.5% of hospitalized patients, while the majority are hospital acquired infections, developed later, generally 10–15 days after ICU admission. The prolonged ICU hospitalization and the extensive use of broad-spectrum antimicrobial drugs during the COVID-19 outbreak might have contributed to the selection of pathogens with different profiles of resistance. Consequently, the reported incidence of MDR bacterial infections in critically ill COVID-19 patients is high, ranging between 32% to 50%. MDR infections are linked to a higher length of stay in ICU but not to a higher risk of death. The only risk factor independently associated with MDR secondary infections reported was invasive mechanical ventilation (OR 1.062; 95% CI 1.012–1.114), but also steroid therapy and prolonged length of ICU stay may play a pivotal role. The empiric antimicrobial therapy for a ventilated patient with suspected or proven bacterial co-infection at ICU admission should be prescribed judiciously and managed according to a stewardship program in order to interrupt or adjust it on the basis of culture results.

Healthcare-associated infections (HAIs) result in significant patient morbidity and can prolong the duration of the hospital stay, causing high supplementary costs in addition to those already sustained due to the patient’s underlying disease. Moreover, bacteria are becoming increasingly resistant to antibiotics, making HAI prevention even more important nowadays. The public health consequences of antimicrobial resistance should be constrained by prevention and control actions, which must be a priority for all health systems of the world at all levels of care. As many HAIs are preventable, they may be considered an important indicator of the quality of patient care and represent an important patient safety issue in healthcare. To share implementation strategies for preventing HAIs in the surgical setting and in all healthcare facilities, an Italian multi-society document was published online in November 2022. This article represents an evidence-based summary of the document.

Objectives: To assess the hypothesis that an adjunctive therapy with methylprednisolone and unfractionated heparin (UFH) or with methylprednisolone and low molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill ventilated patients with pneumonia from SARS-CoV-2 infection compared to LMWH alone. Trial design: The study is designed as a multi-centre, interventional, parallel group, superiority, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the three treatment groups in a ratio 1:1:1. Participants: Inpatients will be recruited from 8 Italian Academic and non-Academic Intensive Care Units Inclusion Criteria (all required): 1. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 2. Positive pressure ventilation (either non-invasive or invasive) from > 24 hours 3. Invasive mechanical ventilation from < 96 hours 4. PaO₂/FiO₂ ratio lower than 150 mmHg 5. D-dimer level > 6 times the upper limit of normal reference range 6. C-reactive Protein > 6-fold upper the limit of normal reference range Exclusion Criteria: 1. Age < 18 years 2. On-going treatment with anticoagulant drugs 3. Platelet count < 100.000/mm³ 4. History of heparin-induced thrombocytopenia 5. Allergy to sodium enoxaparin or other LMWH, UFH or methylprednisolone 6. Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment 7. Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery 8. Chronic assumption or oral corticosteroids 9. Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available 10. Clinical decision to withhold life-sustaining treatment or “too sick to benefit” 11. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 12. Lack or withdrawal of informed consent Intervention and comparator: • LMWH group: patients in this group will be administered enoxaparin at standard prophylactic dosage. • LMWH + steroid group: patients in this group will receive enoxaparin at standard prophylactic dosage and methylprednisolone. • UFH + steroid group: patients in this group will receive UFH at therapeutic dosages and methylprednisolone. UFH will be administered intravenously in UFH + steroid group at therapeutic doses. The infusion will be started at an infusion rate of 18 UI/kg/hour and then modified to obtain aPTT Ratio in between the range of 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with UFH will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician. Enoxaparin will be administered in both LMWH group and LMWH + steroid group at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered subcutaneously once a day up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered in both LMWH + steroid group and UHF + steroid group intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14. Main Outcomes: Primary Efficacy Endpoint: All-cause mortality at day 28 Secondary Efficacy Endpoints: - Ventilation free days (VFDs) at day 28, defined as the total number of days that patient is alive and free of ventilation (either invasive or non-invasive) between randomization and day 28 (censored at hospital discharge). - Need of rescue administration of high-dose steroids or immune-modulatory drugs; - Occurrence of switch from non-invasive to invasive mechanical ventilation during ICU stay; - Delay from start of non-invasive ventilation to switch to invasive ventilation; - All-cause mortality at ICU discharge and hospital discharge; - ICU free days (IFDs) at day 28, defined as the total number of days between ICU discharge and day 28. - Occurrence of new infections from randomization to day 28; including infections by Candida, Aspergillus, Adenovirus, Herpes Virus e Cytomegalovirus - Occurrence of new organ dysfunction and grade of dysfunction during ICU stay. - Objectively confirmed venous thromboembolism, stroke or myocardial infarction; Safety endpoints: - Occurrence of major bleeding, defined as transfusion of 2 or more units of packed red blood cells in a day, bleeding that occurs in at least one of the following critical sites [intracranial, intra-spinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal], bleeding that necessitates surgical intervention and bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death); - Occurrence of clinically relevant non-major bleeding, defined ad acute clinically overt bleeding that does not meet the criteria for major and consists of any bleeding compromising hemodynamic; spontaneous hematoma larger than 25 cm², intramuscular hematoma documented by ultrasonography, haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures; haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention or any other bleeding requiring temporary cessation of a study drug. Randomization: A block randomisation will be used with variable block sizes (block size 4-6-8), stratified by 3 factors: Centre, BMI (<30/≥30) and Age (<75/≥75). Central randomisation will be performed using a secure, web-based, randomisation system with an allocation ratio of 1:1:1. The allocation sequence will be generated by the study statistician using computer generated random numbers. Blinding (masking): Participants to the study will be blinded to group assignment. Numbers to be randomised (sample size): The target sample size is based on the hypothesis that the combined use of UHF and steroid versus the LMWH group will significantly reduce the risk of death at day 28. The overall sample size in this study is expected to be 210 with a randomization 1:1:1 and seventy patients in each group. Assuming an alpha of 2.5% (two tailed) and mortality rate in LMWH group of 50%, as indicated from initial studies of ICU patients, the study will have an 80% power to detect at least a 25 % absolute reduction in the risk of death between: a) LMHW + steroid group and LMWH group or b) UHF + steroid group and LMWH group. The study has not been sized to assess the difference between LMHW + steroid group and UHF + steroid group, therefore the results obtained from this comparison will need to be interpreted with caution and will need further adequately sized studies confirm the effect. On the basis of a conservative estimation, that 8 participating sites admit an average of 3 eligible patients per month per centre (24 patients/month). Assuming that 80 % of eligible patients are enrolled, recruitment of 210 participants will be completed in approximately 10 months. Trial Status: Protocol version 1.1 of April 26^th, 2020. Recruitment start (expected): September 1^st, 2020 Recruitment finish (expected): June 30^th, 2021 Trial registration: EudraCT number 2020-001921-30, registered on April 15^th, 2020 AIFA approval on May 4^th, 2020 Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Purpose: Vasoplegia often complicates on-pump cardiac surgery. Systemic inflammatory response induced by extracorporeal circulation represents the major determinant, but adrenal insufficiency and postoperative vasopressin deficiency may have a role. Pathophysiological meaning of perioperative changes in endocrine markers of hydro-electrolyte balance has not still fully elucidated. Objectives of the present research study were to estimate the incidence of vasoplegia in a homogeneous cohort of not severe cardiopathic patients, to define the role of presurgical adrenal insufficiency, to evaluate copeptin and NT-proBNP trends in the perioperative. Methods: We conducted a prospective cohort study in the cardiac intensive care unit of a tertiary referral center. We evaluated 350 consecutive patients scheduled for cardiac surgery; 55 subjects completed the study. Both standard and low-dose corticotropin stimulation tests were performed in the preoperative; copeptin and NT-proBNP were evaluated in the preoperative (T0), on day 1 (T1) and day 7 (T2) after surgery. Results: Nine subjects (16.3%) developed vasoplegic syndrome with longer bypass and clamping time (p < 0.001). Reduced response to low-dose ACTH test was not associated to vasoplegia. Preoperative copeptin > 16.9 pmol/L accurately predicted the syndrome (AUC 0.86, 95% CI 0.73–0.94; OR 1.17, 95% CI 1.04–1.32). An evident correlation was observed at 7 days postoperative between NT-proBNP and copeptin (r 0.88, 95% CI 0.8–0.93; p < 0.001). Conclusion: Preoperative impaired response to low-dose ACTH stimulation test is not a risk factor for post-cardiotomic vasoplegia; conversely, higher preoperative copeptin predicts the complication. On-pump cardiac surgery could be an interesting model of rapid heart failure progression.

Background: Preliminary studies suggest that moderate ARDS and acute renal failure might benefit from extracorporeal CO₂ removal (ECCO₂R) coupled with CRRT. However, evidence is limited and potential for this coupled treatment may need to be explored. The aim of the present study was to evaluate whether a protective driving pressure was obtained applying low-flow ECCO_2-R plus CRRT in patients affected by moderate ARDS with COVID-19 compared to an historical group without COVID-19. Methods: A case-control study has been conducted comparing a group of consecutive moderate ARDS patients presenting AKI and affected by COVID-19, who needed low-flow ECCO_2-R plus CRRT to achieve an ultra-protective ventilatory strategy, with historical group without COVID-19 that matched for clinical presentation and underwent the same ultra-protective treatment. V_T was set at 6 mL/kg predicted body weight then ECCO₂R was assessed to facilitate ultra-protective low V_T ventilation to preserve safe Pplat and low driving pressure. Results: ECCO₂R+CRRT reduced the driving pressure from 17 (14-18) to 11.5 (10-15) cmH₂O (p<0.0004) in the fourteen ARDS patients by decreasing V_T from 6.7 ml/kg PBW (6.1-6.9) to 5.1 (4.2-5.6) after 1 hour (p <0.0001). In the ARDS patients with COVID-19, the driving pressure reduction was more effective from baseline 18 (14-24) cmH₂O to 11 (10-15) cmH₂O (p<0.004), compared to the control group from 15 (13-17) to 12(10-16) cmH₂O (p< 0.03), after one hour. ECCO₂R+CRRT did not affected 28 days mortality in the two groups, while we observed a shorter duration of mechanical ventilation (19 {7-29} vs 24 {22-38} days; p=0.24) and ICU length of stay (19 {7-29} vs 24 {22-78} days; p=0.25) in moderate ARDS patients with COVID-19 compared to control group. Conclusions: In moderate ARDS patients with or without COVID-19 disease, ECCO₂R+CRRT may be and effective supportive treatment to reach protective values of driving pressure unless severe oxygenation defects arise requiring ECMO therapy initiation.