SARS-CoV-2 infection affects multiple immune mechanisms and leads to severe COVID-19 and death, in part related to infection-induced or pre-existing autoantibodies. Here, we describe severe COVID-19 to associate with autoantibodies against interleukin-1 receptor antagonist (IL-1Ra) and progranulin (PGRN), endogenous antagonists of IL-1 and TNF signaling, respectively. These autoantibodies coincide with hyperphosphorylation of IL-1Ra (Thr111) or PGRN (Ser81), form immune complexes independent of phosphorylation, reduce antigen plasma levels, and permit enhanced IL-1 and TNF signaling. Using phage-display selected Fabs specific for hyperphosphorylated isoforms, we track phospho-antigens and autoantibodies in a German national pandemic network cohort. Most seropositive patients show both autoantibodies. Levels peak at baseline and decline over 12 months, with phospho-antigens decreasing before autoantibodies. Seropositivity associates with hyperinflammation and cytokine profiles. Importantly, signaling by key inflammatory cytokines induce IL-1Ra and PGRN hyperphosphorylation in healthy monocytes, but require up to 1000-fold higher doses than in monocytes from previously seropositive severe COVID-19 survivors.

Abstract Acute Respiratory Distress Syndrome (ARDS) represents one of the most severe forms of acute respiratory failure and requires a structured, multidisciplinary therapeutic approach. This review article highlights key aspects of ARDS management as discussed in existing ARDS recommendations given by the American Thoracic Society (ATS) as well as the European Society of Intensive Care Medicine (ESICM). In addition to a detailed discussion of indications and strategies for invasive mechanical ventilation, non-invasive alternatives and adjunctive therapies are discussed. The second part of this article addresses extracorporeal membrane oxygenation for severe ARDS as well as ARDS phenotypes guiding to an individualized treatment approach in future ARDS management. Recent guidelines introduced new aspects to previous ARDS management strategies, including a stronger emphasis on the individualization of ventilation strategies and the consideration of ARDS phenotypes. Ethical considerations and decision-making processes should be systematically integrated into the management of ARDS patients. This article aims to provide a practical, evidence-based, and structured guide for the intensive care clinician managing ARDS patients.

INTRODUCTION Rituximab mediated antibody-dependent cellular cytotoxicity (ADCC) is an essential component of therapy in B-cell malignancies. The efficiency of cellular cytotoxicity depends on many factors including rituximab binding, lytic granule release and perforin/granzyme concentration, or expression of death-inducing ligands. Here we analysed whether selected variants in key effector molecules affect outcomes in B-cell non-Hodgkin lymphoma (B-NHL). METHODS PRF1 A91V (rs35947132) was genotyped in 501 patients enrolled in the RICOVER-60 trial (NCT0052936), comparing 6 versus 8 cycles of CHOP chemotherapy with or without rituximab in untreated elderly patients with aggressive B-NHL (Pfreundschuh et al., Lancet Oncol 2008). We evaluated associations with event-free, progression-free, and overall survival. The NHL-B2 (Pfreunschuh et al. Blood 2004) trial served as validation cohort for the CHOP-only arm and the interim analysis of the OPTIMAL>60 (NCT01478542) (Pfreundschuh et al., J Clin Oncol 2017) trial as validation cohort for the R-CHOP arm of the discovery RICOVER-60-cohort. RESULTS Within the RICOVER-60 trial 63 of 501 patients (13%) were carriers of the PRF1 A91V. Carriers showed significant better outcomes, with a 36-month overall survival of 81% [95% CI: 68%-95%] compared to 64% [95% CI: 57%-71%] in wildtype patients treated with CHOP alone. However, no additional benefit was observed for these carriers of PRF1 A91V by the addition of rituximab: 36-month EFS 61% [95% CI: 44%-77%] with CHOP and 63% [95% CI: 46%-81%] with R-CHOP; 36-month OS 81% [95% CI: 68%-95%] with CHOP and 73% [95% CI: 57%-89%] with R-CHOP, respectively. These results were validated in independent cohorts in aggressive B-NHL. In NHL-B2 trial the positive prognostic impact of PRF1 A91V was confirmed for CHOP-only therapy with a significantly higher 36-month OS of 87% [95% CI: 73%-100%] in PRF1 A91V carriers compared to 60% [95% CI: 54%-66%] (p=0.030) in wildtype carriers. In the interim analysis of OPTIMAL>60, where all patients received rituximab with chemotherapy, there were no significant differences between PRF1 A91V carriers and wildtype carriers in PFS (HR: 0.8 [95% CI: 0.3 - 1.9], p=0.635) or OS (HR: 0.7 [95% CI: 0.2 - 2.2], p=0.526). CONCLUSION Patients with aggressive B-NHL carrying the PRF1 A91V germline variant had a favourable outcome with CHOP only chemotherapy, but no benefit from the addition of rituximab. These results suggest PRF1 A91V as a negative predictive marker for rituximab-mediated cellular cytotoxicity in aggressive B-NHL, and it may have potential implications for other immune effector cell-based therapies.

Importance:Limited pharmaceutical options exist for preexposure prophylaxis of COVID-19 beyond vaccination. Azelastine, an antihistamine nasal spray used for decades to treat allergic rhinitis, has in vitro antiviral activity against respiratory viruses, including SARS-CoV-2. Objective:To determine the efficacy and safety of azelastine nasal spray for prevention of SARS-CoV-2 infections in healthy adults. Design, Setting, and Participants:A phase 2, double-blind, placebo-controlled, single-center trial was conducted from March 2023 to July 2024. Healthy adults from the general population were enrolled at the Saarland University Hospital in Germany. Interventions:Participants were randomly assigned 1:1 to receive azelastine, 0.1%, nasal spray or placebo 3 times daily for 56 days. SARS-CoV-2 rapid antigen testing (RAT) was conducted twice weekly, with positive results confirmed by polymerase chain reaction (PCR). Symptomatic participants with negative RAT results underwent multiplex PCR testing for respiratory viruses. Main Outcome:The primary end point was the number of PCR-confirmed SARS-CoV-2 infections during the study. Results:A total of 450 participants were randomized, with 227 assigned to azelastine and 223 to placebo; 299 (66.4%) were female, 151 (33.6%) male, with a mean (SD) age of 33.0 (13.3) years. Most were White (417 [92.7%]), with 4 (0.9%) African, 22 (4.9%) Asian, and 7 (1.6%) of other ethnicity. In the intention-to-treat (ITT) population, the incidence of PCR-confirmed SARS-CoV-2 infection was significantly lower in the azelastine group (n = 5 [2.2%]) compared with the placebo group (n = 15 [6.7%]) (OR, 0.31; 95% CI, 0.11-0.87). As secondary end points, azelastine demonstrated an increase in mean (SD) time to SARS-CoV-2 infection among infected participants (31.2 [9.3] vs 19.5 [14.8] days), a reduction of the overall number of PCR-confirmed symptomatic infections (21 of 227 participants vs 49 of 223 participants), and a lower incidence of PCR-confirmed rhinovirus infections (1.8% vs 6.3%). Adverse events were comparable between the groups. Conclusions and Relevance:In this single-center trial, azelastine nasal spray was associated with reduced risk of SARS-CoV-2 respiratory infections. These findings support the potential of azelastine as a safe prophylactic approach warranting confirmation in larger, multicentric trials. Trial registration:EudraCT number: 2022-003756-13.

Limited pharmaceutical options exist for preexposure prophylaxis of COVID-19 beyond vaccination. Azelastine, an antihistamine nasal spray used for decades to treat allergic rhinitis, has in vitro antiviral activity against respiratory viruses, including SARS-CoV-2. To determine the efficacy and safety of azelastine nasal spray for prevention of SARS-CoV-2 infections in healthy adults. A phase 2, double-blind, placebo-controlled, single-center trial was conducted from March 2023 to July 2024. Healthy adults from the general population were enrolled at the Saarland University Hospital in Germany. Participants were randomly assigned 1:1 to receive azelastine, 0.1%, nasal spray or placebo 3 times daily for 56 days. SARS-CoV-2 rapid antigen testing (RAT) was conducted twice weekly, with positive results confirmed by polymerase chain reaction (PCR). Symptomatic participants with negative RAT results underwent multiplex PCR testing for respiratory viruses. The primary end point was the number of PCR-confirmed SARS-CoV-2 infections during the study. A total of 450 participants were randomized, with 227 assigned to azelastine and 223 to placebo; 299 (66.4%) were female, 151 (33.6%) male, with a mean (SD) age of 33.0 (13.3) years. Most were White (417 [92.7%]), with 4 (0.9%) African, 22 (4.9%) Asian, and 7 (1.6%) of other ethnicity. In the intention-to-treat (ITT) population, the incidence of PCR-confirmed SARS-CoV-2 infection was significantly lower in the azelastine group (n = 5 [2.2%]) compared with the placebo group (n = 15 [6.7%]) (OR, 0.31; 95% CI, 0.11-0.87). As secondary end points, azelastine demonstrated an increase in mean (SD) time to SARS-CoV-2 infection among infected participants (31.2 [9.3] vs 19.5 [14.8] days), a reduction of the overall number of PCR-confirmed symptomatic infections (21 of 227 participants vs 49 of 223 participants), and a lower incidence of PCR-confirmed rhinovirus infections (1.8% vs 6.3%). Adverse events were comparable between the groups. In this single-center trial, azelastine nasal spray was associated with reduced risk of SARS-CoV-2 respiratory infections. These findings support the potential of azelastine as a safe prophylactic approach warranting confirmation in larger, multicentric trials. EudraCT number: 2022-003756-13

Vincristine-induced peripheral neuropathy (VIPN) is an adverse effect of regimens used for the treatment of aggressive B-cell non-Hodgkin lymphoma (B-NHL). A single-nucleotide polymorphism (SNP) in the promotor region of the CEP72 gene has been identified as risk factor for the development of VIPN in children. To validate these results in adults we aimed to determine the association of the high-risk CEP72 (rs924607 TT genotype) with the occurrence and severity of VIPN. Analysis of SNP rs924607 (TT, CC or CT) was performed in all enrolled patients with available blood samples with a TaqMan genotyping assay. Rates and grades of VIPN were assessed prospectively as part of the RICOVER-60 trial. CEP72 genotype could be assessed in 519 patients. VIPN data was available for 499/519 patients who were included in the final analysis. 286 (57

The acute respiratory failure as well as ARDS (acute respiratory distress syndrome) have challenged clinicians since the initial description over 50 years ago. Various causes can lead to ARDS and therapeutic approaches for ARDS/ARF are limited to the support or replacement of organ functions and the prevention of therapy-induced consequences. In recent years, triggered by the SARS-CoV-2 pathogen, numerous cases of acute lung failure (C-ARDS) have emerged. The pathophysiological processes of classical ARDS and C-ARDS are essentially similar. In their final stages of inflammation, both lead to a disruption of the blood-air barrier. Treatment strategies for C-ARDS, like classical ARDS, focus on supporting or replacing organ functions and preventing consequential damage. This article summarizes the treatment strategies in the intensive care unit.

The acute respiratory failure as well as ARDS (acute respiratory distress syndrome) have challenged clinicians since the initial description over 50 years ago. Various causes can lead to ARDS and therapeutic approaches for ARDS/ARF are limited to the support or replacement of organ functions and the prevention of therapy-induced consequences. In recent years, triggered by the SARS-CoV-2 pathogen, numerous cases of acute lung failure (C-ARDS) have emerged. The pathophysiological processes of classical ARDS and C-ARDS are essentially similar. In their final stages of inflammation, both lead to a disruption of the blood-air barrier. Treatment strategies for C-ARDS, like classical ARDS, focus on supporting or replacing organ functions and preventing consequential damage. This article summarizes the treatment strategies in the intensive care unit.

The acute respiratory failure as well as ARDS (acute respiratory distress syndrome) have challenged clinicians since the initial description over 50 years ago. Various causes can lead to ARDS and therapeutic approaches for ARDS/ARF are limited to the support or replacement of organ functions and the prevention of therapy-induced consequences. In recent years, triggered by the SARS-CoV-2 pathogen, numerous cases of acute lung failure (C-ARDS) have emerged. The pathophysiological processes of classical ARDS and C-ARDS are essentially similar. In their final stages of inflammation, both lead to a disruption of the blood-air barrier. Treatment strategies for C-ARDS, like classical ARDS, focus on supporting or replacing organ functions and preventing consequential damage. This article summarizes the treatment strategies in the intensive care unit.

Assessing the prognosis of patients with aggressive non-Hodgkin B cell lymphoma mainly relies on a clinical risk score (IPI). Standard first-line therapies are based on a chemo-immunotherapy with rituximab, which mediates CD16-dependent antibody-dependent cellular cytotoxicity (ADCC). We phenotypically and functionally analyzed blood samples from 46 patients focusing on CD16+ NK cells, CD16+ T cells and CD16+ monocytes. Kaplan-Meier survival curves show a superior progression-free survival (PFS) for patients having more than 1.6 High CD16+ T cell counts have a positive correlation with PFS in aggressive NHL/DLBCL patients (p = 0.02; HR = 0.13, 0.01–0.7). High CD16+ monocyte counts have a negative correlation with PFS in aggressive NHL/DLBCL patients (p = 0.0003; HR = 16.0, 3-292). The combined assessment of CD16+ T cells and CD16+ monocytes accurately predicts PFS in aggressive NHL/DLBCL patients. The strong protective function of CD16+ T cells could be explained by their high antibody-dependent cellular cytotoxicity.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition affecting >10% of intensive care unit (ICU) patients worldwide with a mortality of up to 59% depending on severity. Extracorporeal membrane oxygenation (ECMO) is a potentially life-saving procedure in severe ARDS but is technically and financially challenging. In recent years, various scoring systems have been proposed to select patients most likely to benefit from ECMO, with the PREdiction of Survival on ECMO Therapy (PRESET) score being one of the most used. We collected data from 283 patients with ARDS of various etiology who underwent veno-venous (V-V) ECMO therapy at a German tertiary care ICU from January 2012 to December 2022. Median age in the cohort was 56 years, and 64.31% were males. The in-hospital mortality rate was 50.88% (n = 144). The median (25%; 75% quartile) severity scores were 38 (31; 49) for Simplified Acute Physiology Score (SAPS) II, 12 (10; 13) for Sequential Organ Failure Assessment (SOFA) and 7 (5; 8) for PRESET. Simplified Acute Physiology Score-II displayed the best prognostic value (area under the receiver operating characteristic [AUROC]: 0.665 [confidence interval (CI): 0.574-0.756; p = 0.046]). Prediction performance was weak in all analyzed scores despite good calibration. Simplified Acute Physiology Score-II had the best discrimination after adjustment of our original cohort. The use of scores explored in this study for patient selection for eligibility for V-V ECMO is not recommendable.

Target values for arterial carbon dioxide tension (PaCO2) in extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) are unknown. We hypothesized that lower PaCO2 values on ECMO would be associated with lighter sedation. We used data from two independent patient cohorts with ARDS spending 1,177 days (discovery cohort, 69 patients) and 516 days (validation cohort, 70 patients) on ECMO and evaluated the associations between daily PaCO2, pH, and bicarbonate (HCO3) with sedation. Median PaCO2 was 41 (interquartile range [IQR] = 37–46) mm Hg and 41 (IQR = 37–45) mm Hg in the discovery and the validation cohort, respectively. Lower PaCO2 and higher pH but not bicarbonate (HCO3) served as significant predictors for reaching a Richmond Agitation Sedation Scale (RASS) target range of −2 to +1 (lightly sedated to restless). After multivariable adjustment for mortality, tracheostomy, prone positioning, vasoactive inotropic score, Simplified Acute Physiology Score (SAPS) II or Sequential Organ Failure Assessment (SOFA) Score and day on ECMO, only PaCO2 remained significantly associated with the RASS target range (adjusted odds ratio 1.1 [95% confidence interval (CI) = 1.01–1.21], p = 0.032 and 1.29 [95% CI = 1.1–1.51], p = 0.001 per mm Hg decrease in PaCO2 for the discovery and the validation cohort, respectively). A PaCO2 ≤40 mm Hg, as determined by the concordance probability method, was associated with a significantly increased probability of a sedation level within the RASS target range in both patient cohorts (adjusted odds ratio = 2.92 [95% CI = 1.17–7.24], p = 0.021 and 6.82 [95% CI = 1.50–31.0], p = 0.013 for the discovery and the validation cohort, respectively).

Interhospital transport of acute respiratory distress syndrome (ARDS) patients bears transport-associated risks. It is unknown how interhospital extracorporeal membrane oxygenation (ECMO) transfer of COVID-19 patients by mobile ECMO units affects ARDS mortality. We compared the outcome of 94 COVID-19 patients cannulated in primary care hospitals and retrieved by mobile ECMO-teams to that of 84 patients cannulated at five German ECMO centers. Patients were recruited from March 2020 to November 2021. Twenty-six transports were airborne, 68 were land-based. Age, sex, body-mass-index, Simplified Acute Physiology Score (SAPS) II, days invasively ventilated, and P/F-Ratio before ECMO initiation were similar in both groups. Counting only regional transports (≤250 km), mean transport distance was 139.5 km ± 17.7 km for helicopter (duration 52.5 ± 10.6 minutes) and 69.8 km ± 44.1 km for ambulance or mobile intensive care unit (duration 57.6 ± 29.4 minutes). Overall time of vvECMO support (20.4 ± 15.2 ECMO days for transported patients vs. 21.0 ± 20.5 for control, p = 0.83) and days invasively ventilated (27.9 ± 18.1 days vs. 32.6 ± 25.1 days, p = 0.16) were similar. Overall mortality did not differ between transported patients and controls (57/94 [61%] vs. 51/83 [61%], p = 0.43). COVID-19 patients cannulated and retrieved by mobile ECMO-teams have no excess risk compared with patients receiving vvECMO at experienced ECMO centers. Patients with COVID-19-associated ARDS, limited comorbidities, and no contraindication for ECMO should be referred early to local ECMO centers.

To the Editor: We thank Wieruszewski et al.1 for their critical evaluation of our manuscript2 demonstrating increased extracorporeal membrane oxygenator (ECMO) half-life through administration of recombinant tissue plasminogen activator (rtPA) and would like to address several points made by the authors: In their letter,1 they advise against a systemic bolus application of rtPA for oxygenator thrombolysis since its application through a local catheter directed to the site of the thrombus will provide a superior risk-benefit ratio. In contrast to localized deep vein thrombosis or occlusive pulmonary embolism (PE), thrombi in an ECMO oxygenator will be concentrated to the basal sites of the inflow part,3 making it difficult to place a catheter in proximity. To our knowledge, no ECMO consumable provider currently offers such a system. If an integrated ECMO thrombolysis catheter were to be engineered, attention to avoid air embolism when the catheter is advanced in the draining circuit will be crucial. A thrombolysis catheter launched from the arterial site to the oxygenator may not reach most thrombi,3 plus it will be useless if clots are sucked into the oxygenator from the patient’s central veins. Therefore, a step-back to an intravenous or intracircuitry injection of thrombolytic agents will be inevitable. Despite thorough literature research, we were not able to identify sufficient data to assess whether a bolus injection or continuous application of rtPA into the ECMO circuit should be chosen for oxygenator lysis. We suggest investigating the optimal administration route for rtPA or different thrombolytic agents through controlled trials. Wieruszewski et al. advice against bolus administrations of rtPA, potentially causing ‘devastating’ bleeding complications. It is recommended for hemodynamically unstable patients with pulmonary embolism to inject similar doses of rtPA intravenously, followed by a continuous perfusion.4 In contrast to acute PE with hemodynamic compromise; we chose not to administer rtPA by continuous infusion to avoid excess bleeding risk. The expectable mortality of complete ECMO oxygenator thrombosis in case of full ECMO dependence is presumably close to 100% with no reserve oxygenator available. Another of Wieruszewski et al.1 concerns is that lowering ECMO blood flow in between multiple rtPA injections might have obscured pressure drops in one particular patient. We chose to define pump head efficiency ƞ (ml of conveyed blood per pump head revolution) exactly to avoid such clouding. Thrombolysis increased ƞ in that patient (0.88 ± 0.04 ml/revolution vs. 0.93 ± 0.03 ml/revolution, p = 0.04), before and after rates per minute were lowered. Optimal target activated thromboplastin time (aPTT) to prevent ECMO circuitry component thrombosis is under debate. While they criticize our selected aPTT target of 45–55 s as being too low, no suggestions as to what the ideal range should be are made. They cite Extracorporeal Life Support Organization 2020 interim guidelines5 to support their claim, however, said guidelines merely acknowledge weak evidence that aPTT should be titrated to the ‘higher end of normal’4 for coronavirus disease 2019. A recent report revealed no correlation between aPTT of heparin-treated patients on ECMO and clot load or distribution in their explanted ECMO oxygenator.3 Due to complex alterations of hemostasis and diffuse intravascular coagulation, COVID-19 Acute respiratory distress syndrome patients are prone to both thromboembolism and bleeding complications. The work referenced by Wieruszewski et al. suggesting higher targets of anticoagulation is based on a publication that included eight patients treated in a single ECMO center.6 This can hardly be regarded as satisfactory evidence to support such a suggestion—especially since Guihaire et al.6 report that 4 of 24 patients suffered life-threatening lung bleeding, in one case requiring bronchial artery embolization and one patient suffered hemorrhagic stroke under stricter anticoagulation.

This case reports on a patient with antineutrophil cytoplasmatic antibody–associated vasculitis and severe pulmonary and cutaneous involvement who received conventional therapy that failed and who was rescued by daratumumab therapy.