The role of obesity and plasma adipocytokines in immune dysregulation in sepsis patients.

INTRODUCTION: The dysregulated immune response in sepsis is highly variable, ranging from hyperinflammation to immunoparalysis. Obesity is associated with the release of inflammatory mediators from adipose tissue, known as adipocytokines, causing a chronic inflammatory state. Perhaps counterintuitively, obesity is also associated with lower mortality in sepsis patients. We investigated the association between obesity, circulating adipocytokine concentrations, immune dysregulation, and outcome in sepsis patients. METHODS: In this secondary analysis of a prospective study, plasma concentrations of the adipocytokines leptin, adiponectin, and resistin were assessed in 167 patients at diagnosis of sepsis due to pneumonia, bacteremia, or acute cholangitis. Adipocytokines were compared between patients with normal weight (BMI: 18.5-24.9 kg/m2; n = 67), overweight (BMI: 25.0-29.9 kg/m2; n = 56), and obesity (BMI ≥30 kg/m2; n = 42), as well as between immunological endotypes: hyperinflammation (n = 40), immunoparalysis (n = 62), and unclassified (n = 55). RESULTS: Higher circulating concentrations of leptin were observed in patients with obesity compared to patients with normal weight (P = 0.008) and overweight (P = 0.02), whereas adiponectin and resistin plasma concentrations were not different (P = 0.08 and P = 0.85, respectively). Resistin concentrations were associated with immunological endotypes, with the highest levels found in hyperinflammatory patients (P < 0.001). Furthermore, resistin concentrations were predictive for 28-day mortality (adjusted OR = 1.03 per 10 ng/mL, P = 0.04). These associations were not found for leptin and adiponectin. CONCLUSIONS: Obesity and BMI-related adipocytokines are not related to the development of a hyperactive or suppressed immune response as defined by ferritin and mHLA-DR expression in sepsis patients. While resistin is related to the immune response and an increased risk of adverse clinical outcomes, these associations are similar in patients with normal weight, overweight, and obesity. This implies that the relationship between resistin and clinical outcome is likely driven by the inflammatory response and not by obesity itself. Taken together, although there exists a strong association between inflammation and sepsis mortality, our results do not point towards a role for obesity and BMI-related adipocytokines in immune dysregulation in sepsis patients.

Study protocol of a randomised, double-blind, placebo-controlled, two-arm parallel-group, multi-centre phase 3 pivotal trial to investigate the efficacy and safety of recombinant human alkaline phosphatase for treatment of patients with sepsis-associated acute kidney injury.

INTRODUCTION: Sepsis, the leading cause of acute kidney injury (AKI), is associated with a high morbidity and mortality. Alkaline phosphatase (ALP) is an endogenous detoxifying enzyme. A recombinant human ALP compound, ilofotase alfa, showed no safety or tolerability concerns in a phase 2 trial. Renal function improvement over 28 days was significantly greater in the ilofotase alfa group. Moreover, a significant relative reduction in 28-day all-cause mortality of >40% was observed. A follow-up trial has been designed to confirm these findings. METHODS AND ANALYSIS: This is a phase 3, global, multi-centre, randomised, double-blind, placebo-controlled, sequential design trial in which patients are randomly assigned to either placebo or 1.6 mg/kg ilofotase alfa. Randomisation is stratified by baseline modified Sequential Organ Failure Assessment (mSOFA) score and trial site. The primary objective is to confirm the survival benefit with ilofotase alfa by demonstrating a reduction in 28-day all-cause mortality in patients with sepsis-associated AKI requiring vasopressors. A maximum of 1400 patients will be enrolled at ∼120 sites in Europe, North America, Japan, Australia and New Zealand. Up to four interim analyses will take place. Based on predefined decision rules, the trial may be stopped early for futility or for effectiveness. In addition, patients with COVID-19 disease and patients with 'moderate to severe' chronic kidney disease are analysed as 2 separate cohorts of 100 patients each. An independent Data Monitoring Committee evaluates safety data at prespecified intervals throughout the trial. ETHICS AND DISSEMINATION: The trial is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will determine the potential of ilofotase alfa to reduce mortality in critically ill patients with sepsis-associated AKI and will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: EudraCT CT Number 2019-0046265-24. US IND Number 117 605 Pre-results. CLINICALTRIALS: gov number: NCT04411472.

Adipocytokine plasma concentrations reflect influence of inflammation but not body mass index (BMI) on clinical outcomes of COVID-19 patients: A prospective observational study from the Netherlands.

Obesity is recognized as a risk factor for adverse outcome in COVID-19, but the molecular mechanisms underlying this relationship remain unknown. Adipose tissue functions as an endocrine organ by secreting multiple pro-inflammatory and anti-inflammatory factors, known as adipocytokines, which could be involved in COVID-19 severity. We explored the role of adipocytokines in COVID-19 and its association with BMI, clinical outcome, and inflammation. This is an observational study in 195 hospitalized COVID-19 patients. Serial plasma concentrations of the adipocytokines leptin, adiponectin, resistin, and various inflammatory cytokines were assessed. Adipocytokines were compared between patients with normal weight (BMI: 18.5-24.9 kg/m2 ), overweight (BMI: 25.0-29.9 kg/m2 ), and obesity (BMI ≥ 30 kg/m2 ), between patients admitted to the ICU and to non-ICU clinical wards, and between survivors and non-survivors. Patients with overweight and obesity displayed higher leptin concentrations and lower adiponectin concentrations throughout hospital admission (p < .001), whereas resistin concentrations were not different from patients with normal weight (p = .12). Resistin concentrations correlated with inflammatory markers and were persistently higher in ICU patients and non-survivors compared to non-ICU patients and survivors, respectively (both p < .001), whereas no such relationships were found for the other adipocytokines. In conclusion, leptin and adiponectin are associated with BMI, but not with clinical outcomes and inflammation in COVID-19 patients. In contrast, resistin is not associated with BMI, but high concentrations are associated with worse clinical outcomes and more pronounced inflammation. Therefore, it is unlikely that BMI-related adipocytokines or differences in the inflammatory response underlie obesity as a risk factor for severe COVID-19.

Age Moderates the Effect of Obesity on Mortality Risk in Critically Ill Patients With COVID-19: A Nationwide Observational Cohort Study.

OBJECTIVES: A high body mass index (BMI) is associated with an unfavorable disease course in COVID-19, but not among those who require admission to the ICU. This has not been examined across different age groups. We examined whether age modifies the association between BMI and mortality among critically ill COVID-19 patients. DESIGN: An observational cohort study. SETTING: A nationwide registry analysis of critically ill patients with COVID-19 registered in the National Intensive Care Evaluation registry. PATIENTS: We included 15,701 critically ill patients with COVID-19 (10,768 males [68.6%] with median [interquartile range] age 64 yr [55-71 yr]), of whom 1,402 (8.9%) patients were less than 45 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In the total sample and after adjustment for age, gender, Acute Physiology and Chronic Health Evaluation IV, mechanical ventilation, and use of vasoactive drugs, we found that a BMI greater than or equal to 30 kg/m 2 does not affect hospital mortality (adjusted odds ratio [OR adj ] = 0.98; 95% CI, 0.90-1.06; p = 0.62). For patients less than 45 years old, but not for those greater than or equal to 45 years old, a BMI greater than or equal to 30 kg/m 2 was associated with a lower hospital mortality (OR adj = 0.59; 95% CI, 0.36-0.96; p = 0.03). CONCLUSIONS: A higher BMI may be favorably associated with a lower mortality among those less than 45 years old. This is in line with the so-called "obesity paradox" that was established for other groups of critically ill patients in broad age ranges. Further research is needed to understand this favorable association in young critically ill patients with COVID-19.

Circulating dipeptidyl peptidase 3 and bio-adrenomedullin levels are associated with impaired outcomes in critically ill COVID-19 patients: a prospective international multicentre study.

Introduction: Dipeptidyl peptidase-3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. Adrenomedullin (bio-ADM) is a peptide essential for regulation of endothelial barrier function. In different shock-pathologies, both biomarkers are associated with disease severity, organ dysfunction and mortality. Associations with outcome in critically ill COVID-19 patients are unknown. The objectives of the present study were to investigate associations of bio-ADM and "circulating DPP3" (cDPP3) with short-term outcome in critically ill COVID-19 patients (n=80). Methods: A multicentre prospective cohort study was performed. The primary end-point was 28-day mortality. Secondary end-points included different severities of acute kidney injury (AKI). Results: cDPP3 levels were mainly associated with 28-day mortality; Area under the receiver operating characteristics (AUROCs) of 0.69 (0.56-0.82, p=0.023), 0.77 (0.64-0.90, p<0.001) and 0.81 (0.65-0.96, p<0.001) at admission, day 3 and day 7, respectively. In contrast, bio-ADM levels were mainly associated with AKI, with AUROCs of 0.64 (0.51-0.77, p=0.048), 0.75 (0.64-0.86, p<0.001) and 0.83 (0.74-0.93, p<0.001) for day 1, 3 and 7, respectively. Interestingly, patients with high levels of both cDPP3 and bio-ADM at day 7 had an additionally increased risk of 28-day mortality (hazard ratio 11.8; 95% CI 2.5-55.3, p<0.001). Conclusions: cDPP3 and bio-ADM responses were associated with short-term mortality and AKI in critically ill COVID-19 patients, respectively. These findings suggest that treatment with specific antibodies modulating cDPP3 or bio-ADM-related pathways may improve outcome of COVID-19.

ImmunoSep (Personalised Immunotherapy in Sepsis) international double-blind, double-dummy, placebo-controlled randomised clinical trial: study protocol.

INTRODUCTION: Sepsis is a major cause of death among hospitalised patients. Accumulating evidence suggests that immune response during sepsis cascade lies within a spectrum of dysregulated host responses. On the one side of the spectrum there are patients whose response is characterised by fulminant hyperinflammation or macrophage activation-like syndrome (MALS), and on the other side patients whose immune response is characterised by immunoparalysis. A sizeable group of patients are situated between the two extremes. Recognising immune endotype is very important in order to choose the appropriate immunotherapeutic approach for each patient resulting in the best chance to improve the outcome. METHODS AND ANALYSIS: ImmunoSep is a randomised placebo-controlled phase 2 clinical trial with a double-dummy design in which the effect of precision immunotherapy on sepsis phenotypes with MALS and immunoparalysis is studied. Patients are stratified using biomarkers. Specifically, 280 patients will be 1:1 randomly assigned to placebo or active immunotherapy as adjunct to standard-of-care treatment. In the active immunotherapy arm, patients with MALS will receive anakinra (recombinant interleukin-1 receptor antagonist) intravenously, and patients with immunoparalysis will receive subcutaneous recombinant human interferon-gamma. Τhe primary endpoint is the comparative decrease of the mean total Sequential Organ Failure Assessment score by at least 1.4 points by day 9 from randomisation. ETHICS AND DISSEMINATION: The protocol is approved by the German Federal Institute for Drugs and Medical Devices; the National Ethics Committee of Greece and by the National Organization for Medicines of Greece; the Central Committee on Research Involving Human Subjects and METC Oost Netherland for the Netherlands; the National Agency for Medicine and Medical Products of Romania; and the Commission Cantonale d'éthique de la recherche sur l'être human of Switzerland. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04990232.

Targeted proteomics identifies circulating biomarkers associated with active COVID-19 and post-COVID-19.

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic is caused by the highly infectious Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). There is an urgent need for biomarkers that will help in better stratification of patients and contribute to personalized treatments. We performed targeted proteomics using the Olink platform and systematically investigated protein concentrations in 350 hospitalized COVID-19 patients, 186 post-COVID-19 individuals, and 61 healthy individuals from 3 independent cohorts. Results revealed a signature of acute SARS-CoV-2 infection, which is represented by inflammatory biomarkers, chemokines and complement-related factors. Furthermore, the circulating proteome is still significantly affected in post-COVID-19 samples several weeks after infection. Post-COVID-19 individuals are characterized by upregulation of mediators of the tumor necrosis (TNF)-α signaling pathways and proteins related to transforming growth factor (TGF)-ß. In addition, the circulating proteome is able to differentiate between patients with different COVID-19 disease severities, and is associated with the time after infection. These results provide important insights into changes induced by SARS-CoV-2 infection at the proteomic level by integrating several cohorts to obtain a large disease spectrum, including variation in disease severity and time after infection. These findings could guide the development of host-directed therapy in COVID-19.

Circulating dipeptidyl peptidase 3 and bio-adrenomedullin levels are associated with impaired outcomes in critically ill COVID-19 patients: a prospective international multicentre study

Introduction Dipeptidyl-peptidase-3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. Adrenomedullin (bio-ADM) is a peptide essential for regulation of endothelial barrier function. In different shock-pathologies, both biomarkers are associated with disease-severity, organ dysfunction and mortality. Associations with outcome in critically ill COVID-19 patients are unknown. Objectives To investigate associations of bio-ADM and cDPP3 with short-term outcome in critically ill COVID-19 patients (n=80). Methods Multicenter prospective cohort study. Primary endpoint was 28-day mortality. Secondary endpoints included different severities of acute kidney injury (AKI). Results cDPP3 levels were mainly associated with 28-day mortality;AUROC's of 0.69 (0.56–0.82, p=0.023), 0.77 (0.64–0.90, p<0.001) and 0.81 (0.65–0.96, p<0.001) at admission, day 3 and day 7, respectively. In contrast, bio-ADM levels were mainly associated with AKI: AUROC's of 0.64 (0.51–0.77, p=0.048), 0.75 (0.64–0.86, p<0.001) and 0.83 (0.74–0.93, p<0.001) for day 1, 3 and 7, respectively. Interestingly, patients with high levels of both cDPP3 and bio-ADM at day 7 had an additionally increased risk of 28-day-mortality;HR 11.8 (2.5–55.3, p<0.001). Conclusions cDPP3 and bio-ADM responses were associated with short-term mortality and AKI in critically ill COVID-19 patients, respectively. These findings suggest that treatment with specific antibodies modulating cDPP3 or bio-ADM related pathways may improve outcome of COVID-19.

Long-term cognitive performance and its relation to anti-inflammatory therapy in a cohort of survivors of severe COVID-19.

Background and objectives: Long-term cognitive performance data in former critically ill COVID-19 patients are sparse. Current evidence suggests that cognitive decline is related to neuroinflammation, which might be attenuated by COVID-19 related anti-inflammatory therapies. The objective of this prospective cohort study was to study long term cognitive outcomes following severe COVID-19 and the relation to anti-inflammatory therapies. Methods: Prospective observational cohort of patients that survived an intensive care unit (ICU) admission due to severe COVID-19. Six months after hospital discharge, we extensively assessed both objective cognitive functioning and subjective cognitive complaints. Furthermore, patients were stratified in cohorts according to their anti-inflammatory treatment (i.e. no immunomodulatory therapy, dexamethasone, or both dexamethasone and interleukin-6 receptor antagonist tocilizumab). Results: 96 patients were included (March 2020-June 2021, median [IQR] age 61 [55-69] years). 91% received invasive mechanical ventilation, and mean ± SD severity-of-disease APACHE-II-score at admission was 15.8 ± 4.1. After 6.5 ± 1.3 months, 27% of patients scored cognitively impaired. Patients that did or did not develop cognitive impairments were similar in ICU-admission parameters, clinical course and delirium incidence. Patients with subjective cognitive complaints (20%) were more likely women (61% vs 26%), and had a shorter ICU stay (median [IQR] 8 [5-15] vs 18 [9-31], p = 0.002). Objective cognitive dysfunction did not correlate with subjective cognitive dysfunction. 27% of the participants received dexamethasone during intensive care admission, 44% received additional tocilizumab and 29% received neither. Overall occurrence and severity of cognitive dysfunction were not affected by anti-inflammatory therapy, although patients treated with both dexamethasone and tocilizumab had worse executive functioning scores (Trail Making Test interference) than patients without anti-inflammatory treatment (T-score 40.3 ± 13.5 vs 49.1 ± 9.3, p = 0.007). Discussion: A relevant proportion of critically ill COVID-19 patients shows deficits in long-term cognitive functioning. Apart from more pronounced executive dysfunction, overall, anti-inflammatory therapy appeared not to affect long-term cognitive performance. Our findings provide insight in long-term cognitive outcomes in patients who survived COVID-19, that may facilitate health-care providers counseling patients and their caregivers.

Clinical sepsis phenotypes in critically ill COVID-19 patients.

BACKGROUND: A greater understanding of disease heterogeneity may facilitate precision medicine for coronavirus disease 2019 (COVID-19). Previous work identified four distinct clinical phenotypes associated with outcome and treatment responses in non-COVID-19 sepsis patients, but it is unknown if and how these phenotypes are recapitulated in COVID-19 sepsis patients. METHODS: We applied the four non-COVID-19 sepsis phenotypes to a total of 52,274 critically ill patients, comprising two cohorts of COVID-19 sepsis patients (admitted before and after the introduction of dexamethasone as standard treatment) and three non-COVID-19 sepsis cohorts (non-COVID-19 viral pneumonia sepsis, bacterial pneumonia sepsis, and bacterial sepsis of non-pulmonary origin). Differences in proportions of phenotypes and their associated mortality were determined across these cohorts. RESULTS: Phenotype distribution was highly similar between COVID-19 and non-COVID-19 viral pneumonia sepsis cohorts, whereas the proportion of patients with the δ-phenotype was greater in both bacterial sepsis cohorts compared to the viral sepsis cohorts. The introduction of dexamethasone treatment was associated with an increased proportion of patients with the δ-phenotype (6% vs. 11% in the pre- and post-dexamethasone COVID-19 cohorts, respectively, p < 0.001). Across the cohorts, the α-phenotype was associated with the most favorable outcome, while the δ-phenotype was associated with the highest mortality. Survival of the δ-phenotype was markedly higher following the introduction of dexamethasone (60% vs 41%, p < 0.001), whereas no relevant differences in survival were observed for the other phenotypes among COVID-19 patients. CONCLUSIONS: Classification of critically ill COVID-19 patients into clinical phenotypes may aid prognostication, prediction of treatment efficacy, and facilitation of personalized medicine.

Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19.

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.

Mature neutrophils and a NF-κB-to-IFN transition determine the unifying disease recovery dynamics in COVID-19.

Disease recovery dynamics are often difficult to assess, as patients display heterogeneous recovery courses. To model recovery dynamics, exemplified by severe COVID-19, we apply a computational scheme on longitudinally sampled blood transcriptomes, generating recovery states, which we then link to cellular and molecular mechanisms, presenting a framework for studying the kinetics of recovery compared with non-recovery over time and long-term effects of the disease. Specifically, a decrease in mature neutrophils is the strongest cellular effect during recovery, with direct implications on disease outcome. Furthermore, we present strong indications for global regulatory changes in gene programs, decoupled from cell compositional changes, including an early rise in T cell activation and differentiation, resulting in immune rebalancing between interferon and NF-κB activity and restoration of cell homeostasis. Overall, we present a clinically relevant computational framework for modeling disease recovery, paving the way for future studies of the recovery dynamics in other diseases and tissues.

Dexamethasone and tocilizumab treatment considerably reduces the value of C-reactive protein and procalcitonin to detect secondary bacterial infections in COVID-19 patients.

BACKGROUND: Procalcitonin (PCT) and C-reactive protein (CRP) were previously shown to have value for the detection of secondary infections in critically ill COVID-19 patients. However, since the introduction of immunomodulatory therapy, the value of these biomarkers is unclear. We investigated PCT and CRP kinetics in critically ill COVID-19 patients treated with dexamethasone with or without tocilizumab, and assessed the value of these biomarkers to detect secondary bacterial infections. METHODS: In this prospective study, 190 critically ill COVID-19 patients were divided into three treatment groups: no dexamethasone, no tocilizumab (D-T-), dexamethasone, no tocilizumab (D+T-), and dexamethasone and tocilizumab (D+T+). Serial data of PCT and CRP were aligned on the last day of dexamethasone treatment, and kinetics of these biomarkers were analyzed between 6 days prior to cessation of dexamethasone and 10 days afterwards. Furthermore, the D+T- and D+T+ groups were subdivided into secondary infection and no-secondary infection groups to analyze differences in PCT and CRP kinetics and calculate detection accuracy of these biomarkers for the occurrence of a secondary infection. RESULTS: Following cessation of dexamethasone, there was a rebound in PCT and CRP levels, most pronounced in the D+T- group. Upon occurrence of a secondary infection, no significant increase in PCT and CRP levels was observed in the D+T- group (p = 0.052 and p = 0.08, respectively). Although PCT levels increased significantly in patients of the D+T+ group who developed a secondary infection (p = 0.0003), this rise was only apparent from day 2 post-infection onwards. CRP levels remained suppressed in the D+T+ group. Receiver operating curve analysis of PCT and CRP levels yielded area under the curves of 0.52 and 0.55, respectively, which are both markedly lower than those found in the group of COVID-19 patients not treated with immunomodulatory drugs (0.80 and 0.76, respectively, with p values for differences between groups of 0.001 and 0.02, respectively). CONCLUSIONS: Cessation of dexamethasone in critically ill COVID-19 patients results in a rebound increase in PCT and CRP levels unrelated to the occurrence of secondary bacterial infections. Furthermore, immunomodulatory treatment with dexamethasone and tocilizumab considerably reduces the value of PCT and CRP for detection of secondary infections in COVID-19 patients.

A guide to immunotherapy for COVID-19.

Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.

Effects of dalteparin on anti-Xa activities cannot be predicted in critically ill COVID-19 patients.

Critically ill COVID-19 patients are at high risk of thromboembolic events despite routine-dosed low-molecular-weight heparin thromboprophylaxis. However, in recent randomized trials increased-intensity thromboprophylaxis seemed futile and possibly even harmful. In this explorative pharmacokinetic (PK) study we measured anti-Xa activities on frequent timepoints in 15 critically ill COVID-19 patients receiving dalteparin and performed PK analysis by nonlinear mixed-effect modelling. A linear one-compartment model with first-order kinetics provided a good fit. However, wide interindividual variation in dalteparin absorption (variance 78%) and clearance (variance 34%) was observed, unexplained by routine clinical covariates. Using the final PK model for Monte Carlo simulations, we predicted increased-intensity dalteparin to result in anti-Xa activities well over prophylactic targets (0.2-0.4 IU/mL) in the majority of patients. Therapeutic-intensity dalteparin results in supratherapeutic anti-Xa levels (target 0.6-1.0 IU/mL) in 19% of patients and subtherapeutic levels in 22%. Therefore, anti-Xa measurements should guide high-intensity dalteparin in critically ill COVID-19 patients.

Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.

BACKGROUND: Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19. METHODS: For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491). FINDINGS: 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO2/FiO2), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20-0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO2/FiO2. In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17-0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12-0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37-1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59-3·10]). INTERPRETATION: Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L. FUNDING: Sobi.

Interferon gamma immunotherapy in five critically ill COVID-19 patients with impaired cellular immunity: A case series.

BACKGROUND: Prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding has been described in immunocompromised coronavirus disease 2019 (COVID-19) patients, resulting in protracted disease and poor outcome. Specific therapy to improve viral clearance and outcome for this group of patients is currently unavailable. METHODS: Five critically ill COVID-19 patients with severe defects in cellular immune responses, high SARS-CoV-2 viral RNA loads, and no respiratory improvement were treated with interferon gamma, 100 µg subcutaneously, thrice weekly. Bronchial secretion was collected every 48 h for routine diagnostic SARS-CoV-2 RT-PCR and viral culture. FINDINGS: Interferon gamma administration was followed by a rapid decline in SARS-CoV-2 load and a positive-to-negative viral culture conversion. Four patients recovered, and no signs of hyperinflammation were observed. CONCLUSIONS: Interferon gamma may be considered as adjuvant immunotherapy in a subset of immunocompromised COVID-19 patients. FUNDING: A.v.L. and R.v.C. are supported by National Institutes of Health (R01AI145781). G.J.O. and R.P.v.R. are supported by a VICI grant (016.VICI.170.090) from the Dutch Research Council (NWO). W.F.A. is supported by a clinical fellowship grant (9071561) of Netherlands Organization for Health Research and Development. M.G.N. is supported by an ERC advanced grant (833247) and a Spinoza grant of the Netherlands Organization for Scientific Research.