Adjunctive immunotherapeutic agents in patients with sepsis and septic shock: a multidisciplinary consensus of 23.

BACKGROUND: In the last decades, several adjunctive treatments have been proposed to reduce mortality in septic shock patients. Unfortunately, mortality due to sepsis and septic shock remains elevated and NO trials evaluating adjunctive therapies were able to demonstrate any clear benefit. In light of the lack of evidence and conflicting results from previous studies, in this multidisciplinary consensus, the authors considered the rational, recent investigations and potential clinical benefits of targeted adjunctive therapies. METHODS: A panel of multidisciplinary experts defined clinical phenotypes, treatments and outcomes of greater interest in the field of adjunctive therapies for sepsis and septic shock. After an extensive systematic literature review, the appropriateness of each treatment for each clinical phenotype was determined using the modified RAND/UCLA appropriateness method. RESULTS: The consensus identified two distinct clinical phenotypes: patients with overwhelming shock and patients with immune paralysis. Six different adjunctive treatments were considered the most frequently used and promising: (i) corticosteroids, (ii) blood purification, (iii) immunoglobulins, (iv) granulocyte/monocyte colony-stimulating factor and (v) specific immune therapy (i.e. interferon-gamma, IL7 and AntiPD1). Agreement was achieved in 70% of the 25 clinical questions. CONCLUSIONS: Although clinical evidence is lacking, adjunctive therapies are often employed in the treatment of sepsis. To address this gap in knowledge, a panel of national experts has provided a structured consensus on the appropriate use of these treatments in clinical practice.

Hemoperfusion with high-affinity polyethylene microbeads (Seraph-100®) for the removal of pathogens in chronic critically ill patients: Clinical experience.

Critically ill septic patients present variable clinical trajectories, with some succumbing to hyperinflammatory responses while others develop a chronic critical illness, characterized by a prolonged low-grade inflammation, muscle atrophy, and mechanical ventilation dependency and often develop secondary infections often caused by from low-virulence microorganisms or reactivated latent viruses. The Seraph-100® hemoperfusion cartridge takes advantage from heparin-coated ultra-high molecular weight polyethylene microbeads mimicking pathogen-binding cell receptors and can adsorb both pathogens and damage-associated molecular patterns released by injured tissues. We describe two chronic critically ill patients who developed secondary viral bloodstream infections successfully treated with this device.

The Role of the Intravenous IgA and IgM-Enriched Immunoglobulin Preparation in the Treatment of Sepsis and Septic Shock.

Polyclonal Intravenous Immunoglobulins (IvIg) are often administered to critically ill patients more as an act of faith than on the basis of relevant clinical studies. This particularly applies to the treatment of sepsis and septic shock because the current guidelines recommend against their use despite many investigations that have demonstrated their beneficial effects in different subsets of patients. The biology, mechanisms of action, and clinical experience related to the administration of IvIg are reviewed, which aim to give a more in-depth understanding of their properties in order to clarify their possible indications in sepsis and septic shock patients.

The Techniques of Blood Purification in the Treatment of Sepsis and Other Hyperinflammatory Conditions.

Even in the absence of strong indications deriving from clinical studies, the removal of mediators is increasingly used in septic shock and in other clinical conditions characterized by a hyperinflammatory response. Despite the different underlying mechanisms of action, they are collectively indicated as blood purification techniques. Their main categories include blood- and plasma processing procedures, which can run in a stand-alone mode or, more commonly, in association with a renal replacement treatment. The different techniques and principles of function, the clinical evidence derived from multiple clinical investigations, and the possible side effects are reviewed and discussed along with the persisting uncertainties about their precise role in the therapeutic armamentarium of these syndromes.

Waterhouse-Friderichsen syndrome following a dog bite in an asplenic patient: case report and review of the literature.

The Waterhouse-Friderichsen syndrome represents a critical condition characterized by a septic shock associated with a disseminated intravascular coagulation causing the plugging of the microvascular network virtually all organs and systems, including the skin, the kidneys, the liver, and adrenal glands; the mortality rate is elevated, and survivors often must undergo multiple limb amputations. Here, we describe the uncommon case of an asplenic patient who developed this syndrome after a superficial wound caused by a dog bite causing an initial infection due to Capnocytophaga canimorsus that is part of the normal oral microbiome of pets. The clinical and pathological findings and the current and future therapeutic options are reviewed and discussed.

The Effects of Hemoadsorption on the Kinetics of Antibacterial and Antifungal Agents.

The extracorporeal elimination of a pathogen or damage-associated molecular pattern via blood purification techniques is increasingly being used in patients with septic shock and other clinical conditions characterized by a life-threatening inflammatory response. The removal of these substances can be accomoplished by means of ultrafiltration or hemoadsorption. Independently from the blood putification technique used, they could also affect the clearance of antibacterial and antifungal agents with a potentially significant clinical impact. In our review, we describe the basic principles of ultrafiltration and hemoadsorption, the available devices for this latter and the existing experimental and clinical studies; the final paragraph is dedicated to practical considerations that can help clinicians to consider the clearance of antibiotics and antifungals attributable to these techniques to minimize the risk of a iatrogenic underdosage.

Widespread Arterial Thrombosis after ChAdOx1 nCov-19 Vaccination.

Vaccine-induced thrombotic thrombocytopenia is an uncommon complication of COVID-19 vaccines using adenovirus mRNA carriers and has been associated with thrombosis of the cerebral venous sinuses and portal system. We report a case of a 69-year-old woman admitted to the intensive care unit due to stroke caused by thrombosis of the right carotid artery 9 days after receiving the ChAdOx1 nCov-19 vaccine. Further investigations demonstrated multiple thrombi in the arterial tree in the absence of any venous involvement. The clinical course and the treatment are described and discussed.

Effects of the timing and intensity of treatment on septic shock patients treated with CytoSorb®: Clinical experience.

INTRODUCTION: A group of adult septic shock patients treated with hemoperfusion (HA) with the Cytosorb® associated with CVVHD were studied to determine (a) the effects of this technique on different clinical variables; and (b) the impact of the pre CytoSorb® interval and its intensity on the outcome. METHODS: The catecholamine index (CI) and the pressure-catecholamine Index (PCAI) were used to assess the amount of catecholamine administered at baseline and during the procedure, respectively. The pre-treatment time was calculated since the onset of the septic-shock related hypotension and the initiation of the first session and the intensity was assessed considering either the total volume of blood processed and the duration of the HA. RESULTS: Overall, 51 patients with septic shock (30 m, 21 f), age 68 years (IQR 59-76) were retrospectively enrolled in the study; 26 were discharged alive form the ICU (S) and 25 died in ICU (NS); in the S group either CI and PCAI decreased significantly but in NS the CI increased and the PCAI remained stable in NS. In S, the time elapsing from the onset of symptoms and the start of Cytosorb® was shorter than in NS; the duration of the treatment and the volume of blood processed were significantly higher in S than in NS. CONCLUSIONS: In this group of septic shock patients, the earlier initiation of Cytosorb®, its longer duration and the higher volume of blood processed were associated with a better survival.

Effects of tocilizumab versus hemoadsorption combined with tocilizumab in patients with SARS-CoV-2 pneumonia: Preliminary results.

OBJECTIVE: To assess the variations of Interleukin-6 (IL-6) in patients with SARS-CoV-2 infection treated with Tocilizumab (TCZ) alone or in association with hemoadsorption (HA). DESIGN: Retrospective. SETTING: An Intensive Care Unit (ICU) admitting mechanically ventilated patients with SARS-CoV-2 pneumonia. PATIENTS: Four adult patients. INTERVENTIONS: We compared the blood values of IL-6, C-reactive protein (CRP) and of other biochemical variables including the PaO2/FiO2 in two patients who received TCZ alone and in other 2 in whom it was associated with the HA (TCZ-HA) due to the presence of impending or established organ failures other than the lung. All variables were measured before, during and after the treatment. MAIN RESULTS: In all patients, the IL-6 increased during the treatment; after its termination, its values sharply decreased only in those treated also with HA; conversely, the CRP decreased in all patients; the PaO2/FiO2 increased in three patients and remained stable in the remaining one. Both the TCZ and the HA were well tolerated; all patients were weaned from the mechanical ventilation and discharged from the hospital. LIMITATIONS: Although the limited number of patients does not allow to draw firm conclusions, the increase of the IL-6 of can be ascribed to its displacement from cellular and soluble receptors, whereas its decrease is likely due to the scavenging effect exerted by the HA. Although the association TCZ-HA could be valuable in the treatment of the Cytokine Release Storm (CRS) associated with the SARS-CoV-2, the HA could be more effective as it neutralizes a wider panel of inflammatory mediators.

Radiological-pathological signatures of patients with COVID-19-related pneumomediastinum: is there a role for the Sonic hedgehog and Wnt5a pathways?

Pneumomediastinum is a rare complication of ARDS but is more common during #COVID19. The fibrous hyaline degeneration of the tracheal rings seen in this autoptic series is an original observation that has not been previously described in COVID-19 patients. https://bit.ly/3vxTQde.

Rationale for Polyclonal Intravenous Immunoglobulin Adjunctive Therapy in COVID-19 Patients: Report of a Structured Multidisciplinary Consensus.

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.

Multimodal Long-Term Predictors of Outcome in Out of Hospital Cardiac Arrest Patients Treated with Targeted Temperature Management at 36 °C.

Introduction: Early prediction of long-term outcomes in patients resuscitated after cardiac arrest (CA) is still challenging. Guidelines suggested a multimodal approach combining multiple predictors. We evaluated whether the combination of the electroencephalography (EEG) reactivity, somatosensory evoked potentials (SSEPs) cortical complex and Gray to White matter ratio (GWR) on brain computed tomography (CT) at different temperatures could predict survival and good outcome at hospital discharge and six months after the event. Methods: We performed a retrospective cohort study including consecutive adult, non-traumatic patients resuscitated from out-of-hospital CA who remained comatose on admission to our intensive care unit from 2013 to 2017. We acquired SSEPs and EEGs during the treatment at 36 °C and after rewarming at 37 °C, Gray to white matter ratio (GWR) was calculated on the brain computed tomography scan performed within six hours of the hospital admission. We primarily hypothesized that SSEP was associated with favor-able functional outcome at distance and secondarily that SSEP provides independent information from EEG and CT. Outcomes were evaluated using the Cerebral Performance Category (CPC) scale at six months from discharge. Results: Of 171 resuscitated patients, 75 were excluded due to missing data or uninterpretable neurophysiological findings. EEG reactivity at 37 °C has been shown the best single predictor of good out-come (AUC 0.803) while N20P25 was the best single predictor for survival at each time point. (AUC 0.775 at discharge and AUC 0.747 at six months follow up). The predictive value of a model including EEG reactivity, average GWR, and SSEP N20P25 amplitude was superior (AUC 0.841 for survival and 0.920 for good out-come) to any combination of two tests or any single test. Conclusions: Our study, in which life-sustaining treatments were never suspended, suggests SSEP cortical complex N20P25, after normothermia and off sedation, is a reliable predictor for survival at any time. When SSEP cortical complex N20P25 is added into a model with GWR average and EEG reactivity, the predictivity for good outcome and survival at distance is superior than each single test alone.

Kinetics of Immunoglobulins in Septic Shock Patients Treated With an IgM- and IgA-Enriched Intravenous Preparation: An Observational Study.

Objective: To assess the variations of the blood levels of immunoglobulins (Ig) in septic shock patients treated with an Ig preparation enriched in IgM and IgA (eIg). Design: The blood levels of Ig in survivors (S) and non-survivors (NS) of a group of septic shock patients were measured before the initial administration (D0) and 1 (D1), 4 (D4), and 7 (D7) days thereafter. The SAPS II score, the capillary permeability, the primary site of infection, the antibiotic appropriateness, and the outcome at 28 days were also assessed. Results: In the interval D0-D7, the IgM increased significantly only in the S while remained stable in NS; the IgA significantly increased in both groups; the IgG did not vary significantly in both groups. At D4, the capillary permeability significantly decreased in S but not in NS. Conclusions: The kinetics of the different classes of Ig after eIg were different between S and NS. This could be related either to (a) different capillary permeability in the two groups or to (b) higher Ig consumption in NS. Further studies to confirm the benefits of eIg in the treatment of sepsis syndrome and to define the specific target population and the correct eIg dose are warranted.

Adjunctive IgM-enriched immunoglobulin therapy with a personalised dose based on serum IgM-titres versus standard dose in the treatment of septic shock: a randomised controlled trial (IgM-fat trial).

INTRODUCTION: In patients with septic shock, low levels of circulating immunoglobulins are common and their kinetics appear to be related to clinical outcome. The pivotal role of immunoglobulins in the host immune response to infection suggests that additional therapy with polyclonal intravenous immunoglobulins may be a promising option in patients with septic shock. Immunoglobulin preparations enriched with the IgM component have largely been used in sepsis, mostly at standard dosages (250 mg/kg per day), regardless of clinical severity and without any dose adjustment based on immunoglobulin serum titres or other biomarkers. We hypothesised that a personalised dose of IgM enriched preparation based on patient IgM titres and aimed to achieve a specific threshold of IgM titre is more effective in decreasing mortality than a standard dose. METHODS AND ANALYSIS: The study is designed as a multicentre, interventional, randomised, single-blinded, prospective, investigator sponsored, two-armed study. Patients with septic shock and IgM titres <60 mg/dL will be randomly assigned to an IgM titre-based treatment or a standard treatment group in a ratio of 1:1. The study will involve 12 Italian intensive care units and 356 patients will be enrolled. Patients assigned to the IgM titre-based treatment will receive a personalised daily dose based on an IgM serum titre aimed at achieving serum titres above 100 mg/dL up to discontinuation of vasoactive drugs or day 7 after enrolment. Patients assigned to the IgM standard treatment group will receive IgM enriched preparation daily for three consecutive days at the standard dose of 250 mg/kg. The primary endpoint will be all-cause mortality at 28 days. ETHICS AND DISSEMINATION: The study protocol was approved by the ethics committees of the coordinating centre (Comitato Etico dell'Area Vasta Emilia Nord) and collaborating centres. The results of the trial will be published within 12 months from the end of the study and the steering committee has the right to present them at public symposia and conferences. TRIAL REGISTRATION DETAILS: The trial protocol and information documents have received a favourable opinion from the Area Vasta Emilia Nord Ethical Committee on 12 September 2019. The trial protocol has been registered on EudraCT (2018-001613-33) on 18 April 2018 and on ClinicalTrials.gov (NCT04182737) on 2 December 2019.

Neck circumference as reliable predictor of mechanical ventilation support in adult inpatients with COVID-19: A multicentric prospective evaluation.

AIMS: COVID-19 is especially severe for elderly subjects with cardiometabolic and respiratory comorbidities. Neck circumference (NC) has been shown to be strongly related to cardiometabolic and respiratory illnesses even after adjustment for body mass index (BMI). We performed a prospective study to investigate the potential of NC to predict the need for invasive mechanical ventilation (IMV) in adult COVID-19 inpatients. MATERIALS AND METHODS: We prospectively and consecutively enrolled COVID-19 adult patients admitted to dedicated medical wards of two Italian hospitals from 25 March to 7 April 2020. On admission, clinical, biochemical and anthropometric data, including BMI and NC were collected. As primary outcome measure, the maximum respiratory support received was evaluated. Follow-up time was 30 days from hospital admission. RESULTS: We enrolled 132 subjects (55.0-75.8 years, 32% female). During the study period, 26 (19.7%) patients underwent IMV. In multivariable logistic regression analyses, after adjusting for age, sex, diabetes, hypertension and COPD, NC resulted independently and significantly associated with IMV risk (adjusted OR 1.260-per 1 cm increase 95% CI:1.120-1.417; P < .001), with a stronger association in the subgroup with BMI ≤30 Kg/m2 (adjusted OR 1.526; 95% CI:1.243-1.874; P < .001). NC showed a good discrimination power in predicting patients requiring IMV (AUC 0.783; 95% CI:0.684-0.882; P < .001). In particular, NC > 40.5 cm (>37.5 for females and >42.5 for males) showed a higher and earlier IMV risk compared to subjects with lower NC (Log-rank test: P < .001). CONCLUSIONS: NC is an easy to measure parameter able to predict the need for IMV in adult COVID-19 inpatients.

Dexamethasone and postoperative analgesia in minimally invasive thoracic surgery: a retrospective cohort study.

BACKGROUND: Dexamethasone is commonly used for the prevention of postoperative nausea and vomiting (PONV), and recent reviews suggest a role for dexamethasone in postoperative analgesia. The aim of this study is to evaluate the efficacy of dexamethasone as an analgesic adjuvant in minimally invasive thoracic surgery. Primary outcome was morphine consumption 24 h after surgery; secondary outcomes were pain control, measured as numeric rating scale (NRS), glycemic changes, PONV, and surgical wound infection. RESULTS: We performed a retrospective cohort study considering 70 patients who underwent elective lobectomy, segmentectomy, or wedge resection surgery with a mini-thoracotomy approach or video-assisted thoracoscopic surgery (VATS). All patients received the same locoregional techniques and short-acting opioids during surgery; 46 patients received dexamethasone at induction. There were no significant differences in morphine consumption at 24 h (p = 0.09) and in postoperative pain scores. Nevertheless, a higher frequency of rescue therapy (p = 0.01) and a tendency for a higher attempted-PCA pushes count were observed in patients who did not receive dexamethasone. No cases of surgical wound infections were detected, and the incidence of PONV was similar in the two groups. Postoperative glycemia was transiently higher in the dexamethasone group (p = 0.004), but the need of hypoglycemic therapy was not significantly different. CONCLUSIONS: Preoperative administration of dexamethasone did not cause a significant reduction in morphine consumption, but appears to be safe and plays a role in a multimodal anesthesia approach for patients undergoing elective minimally invasive thoracic surgery.

Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology.

BACKGROUND: COVID-19 is a deadly pulmonary disease with peculiar characteristics, which include variable clinical course and thrombophilia. A thorough understanding of the pathological correlates of the disease is still missing. METHODS: Here we report the systematic analysis of 41 consecutive post-mortem samples from individuals who died of COVID-19. Histological analysis is complemented by immunohistochemistry for cellular and viral antigens and the detection of viral genomes by in situ RNA hybridization. FINDINGS: COVID-19 is characterized by extensive alveolar damage (41/41 of patients) and thrombosis of the lung micro- and macro-vasculature (29/41, 71%). Thrombi were in different stages of organization, consistent with their local origin. Pneumocytes and endothelial cells contained viral RNA even at the later stages of the disease. An additional feature was the common presence of a large number of dysmorphic pneumocytes, often forming syncytial elements (36/41, 87%). Despite occasional detection of virus-positive cells, no overt signs of viral infection were detected in other organs, which showed non-specific alterations. INTERPRETATION: COVID-19 is a unique disease characterized by extensive lung thrombosis, long-term persistence of viral RNA in pneumocytes and endothelial cells, along with the presence of infected cell syncytia. Several of COVID-19 features might be consequent to the persistence of virus-infected cells for the duration of the disease. FUNDING: This work was supported by a King's Together Rapid COVID-19 Call grant from King's College London. MG is supported by the European Research Council (ERC) Advanced Grant 787971 "CuRE" and by Programme Grant RG/19/11/34633 from the British Heart Foundation.

Best-practice IgM- and IgA-enriched immunoglobulin use in patients with sepsis.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Despite treatment being in line with current guidelines, mortality remains high in those with septic shock. Intravenous immunoglobulins represent a promising therapy to modulate both the pro- and anti-inflammatory processes and can contribute to the elimination of pathogens. In this context, there is evidence of the benefits of immunoglobulin M (IgM)- and immunoglobulin A (IgA)-enriched immunoglobulin therapy for sepsis. This manuscript aims to summarize current relevant data to provide expert opinions on best practice for the use of an IgM- and IgA-enriched immunoglobulin (Pentaglobin) in adult patients with sepsis. MAIN TEXT: Sepsis patients with hyperinflammation and patients with immunosuppression may benefit most from treatment with IgM- and IgA-enriched immunoglobulin (Pentaglobin). Patients with hyperinflammation present with phenotypes that manifest throughout the body, whilst the clinical characteristics of immunosuppression are less clear. Potential biomarkers for hyperinflammation include elevated procalcitonin, interleukin-6, endotoxin activity and C-reactive protein, although thresholds for these are not well-defined. Convenient biomarkers for identifying patients in a stage of immune-paralysis are still matter of debate, though human leukocyte antigen-antigen D related expression on monocytes, lymphocyte count and viral reactivation have been proposed. The timing of treatment is potentially more critical for treatment efficacy in patients with hyperinflammation compared with patients who are in an immunosuppressed stage. Due to the lack of evidence, definitive dosage recommendations for either population cannot be made, though we suggest that patients with hyperinflammation should receive an initial bolus at a rate of up to 0.6 mL (30 mg)/kg/h for 6 h followed by a continuous maintenance rate of 0.2 mL (10 mg)/kg/hour for ≥ 72 h (total dose ≥ 0.9 g/kg). For immunosuppressed patients, dosage is more conservative (0.2 mL [10 mg]/kg/h) for ≥ 72 h, without an initial bolus (total dose ≥ 0.72 g/kg). CONCLUSIONS: Two distinct populations that may benefit most from Pentaglobin therapy are described in this review. However, further clinical evidence is required to strengthen support for the recommendations given here regarding timing, duration and dosage of treatment.