Perceptions on Specialist Palliative Care Involvement During and After Cardiopulmonary Resuscitation: A Qualitative Study.

IMPORTANCE: Cardiopulmonary resuscitation (CPR) is an exceptional physical situation and may lead to significant psychological, spiritual, and social distress in patients and their next of kin. Furthermore, clinicians might experience distress related to a CPR event. Specialist palliative care (sPC) integration could address these aspects but is not part of routine care. OBJECTIVES: This study aimed to explore perspectives on sPC integration during and after CPR. A needs assessment for sPC, possible triggers indicating need, and implementation strategies were addressed. DESIGN SETTING AND PARTICIPANTS: A multiprofessional qualitative semistructured focus group study was conducted in a German urban academic teaching hospital. Participants were clinicians (nursing staff, residents, and consultants) working in the emergency department and ICUs (internal medicine and surgical). ANALYSIS: The focus groups were recorded and subsequently transcribed. Data material was analyzed using the content-structuring content analysis according to Kuckartz. RESULTS: Seven focus groups with 18 participants in total were conducted online from July to November 2022. Six main categories (two to five subcategories) were identified: understanding (of palliative care and death), general CPR conditions (e.g., team, debriefing, and strains), prognosis (e.g., preexisting situation, use of extracorporeal support), next of kin (e.g., communication, presence during CPR), treatment plan (patient will and decision-making), and implementation of sPC (e.g., timing, trigger factors). CONCLUSIONS: Perceptions about the need for sPC to support during and after CPR depend on roles, areas of practice, and individual understanding of sPC. Although some participants perceive CPR itself as a trigger for sPC, others define, for example, pre-CPR-existing multimorbidity or complex family dynamics as possible triggers. Suggestions for implementation are multifaceted, especially communication by sPC is emphasized. Specific challenges of extracorporeal CPR need to be explored further. Overall, the focus groups show that the topic is considered relevant, and studies on outcomes are warranted.

Prevalence and prognostic value of neurological affections in hospitalized patients with moderate to severe COVID-19 based on objective assessments.

Neurological manifestations of coronavirus disease 2019 (COVID-19) have been frequently described. In this prospective study of hospitalized COVID-19 patients without a history of neurological conditions, we aimed to analyze their prevalence and prognostic value based on established, standardized and objective methods. Patients were investigated using a multimodal electrophysiological approach, accompanied by neuropsychological and neurological examinations. Prevalence rates of central (CNS) and peripheral (PNS) nervous system affections were calculated and the relationship between neurological affections and mortality was analyzed using Firth logistic regression models. 184 patients without a history of neurological diseases could be enrolled. High rates of PNS affections were observed (66% of 138 patients receiving electrophysiological PNS examination). CNS affections were less common but still highly prevalent (33% of 139 examined patients). 63% of patients who underwent neuropsychological testing (n = 155) presented cognitive impairment. Logistic regression models revealed pathology in somatosensory evoked potentials as an independent risk factor of mortality (Odds Ratio: 6.10 [1.01-65.13], p = 0.049). We conclude that hospitalized patients with moderate to severe COVID-19 display high rates of PNS and CNS affection, which can be objectively assessed by electrophysiological examination. Electrophysiological assessment may have a prognostic value and could thus be helpful to identify patients at risk for deterioration.

Changes in Therapy and Outcome of Patients Requiring Veno-Venous Extracorporeal Membrane Oxygenation for COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome requiring veno-venous extracorporeal membrane oxygenation (vv-ECMO) is related with poor outcome, especially in Germany. We aimed to analyze whether changes in vv-ECMO therapy during the pandemic were observed and lead to changes in the outcome of vv-ECMO patients. METHODS: All patients undergoing vv-ECMO support for COVID-19 between 2020 and 2021 in a single center (n = 75) were retrospectively analyzed. Weaning from vv-ECMO and in-hospital mortality were defined as primary and peri-interventional adverse events as secondary endpoints of the study. RESULTS: During the study period, four infective waves were observed in Germany. Patients were assigned correspondingly to four study groups: ECMO implantation between March 2020 and September 2020: first wave (n = 11); October 2020 to February 2021: second wave (n = 23); March 2021 to July 2021: third wave (n = 25); and August 2021 to December 2021: fourth wave (n = 20). Preferred cannulation technique changed within the second wave from femoro-femoral to femoro-jugular access (p < 0.01) and awake ECMO was implemented. Mean ECMO run time increased by more than 300% from 10.9 ± 9.6 (first wave) to 44.9 ± 47.0 days (fourth wave). Weaning of patients was achieved in less than 20% in the first wave but increased to approximately 40% since the second one. Furthermore, we observed a continuous numerically decrease of in-hospital mortality from 81.8 to 57.9% (p = 0.61). CONCLUSION: Preference for femoro-jugular cannulation and awake ECMO combined with preexisting expertise and patient selection are considered to be associated with increased duration of ECMO support and numerically improved ECMO weaning and in-hospital mortality.

Blood pH Analysis in Combination with Molecular Medical Tools in Relation to COVID-19 Symptoms.

The global outbreak of SARS-CoV-2/COVID-19 provided the stage to accumulate an enormous biomedical data set and an opportunity as well as a challenge to test new concepts and strategies to combat the pandemic. New research and molecular medical protocols may be deployed in different scientific fields, e.g., glycobiology, nanopharmacology, or nanomedicine. We correlated clinical biomedical data derived from patients in intensive care units with structural biology and biophysical data from NMR and/or CAMM (computer-aided molecular modeling). Consequently, new diagnostic and therapeutic approaches against SARS-CoV-2 were evaluated. Specifically, we tested the suitability of incretin mimetics with one or two pH-sensitive amino acid residues as potential drugs to prevent or cure long-COVID symptoms. Blood pH values in correlation with temperature alterations in patient bodies were of clinical importance. The effects of biophysical parameters such as temperature and pH value variation in relation to physical-chemical membrane properties (e.g., glycosylation state, affinity of certain amino acid sequences to sialic acids as well as other carbohydrate residues and lipid structures) provided helpful hints in identifying a potential Achilles heel against long COVID. In silico CAMM methods and in vitro NMR experiments (including 31P NMR measurements) were applied to analyze the structural behavior of incretin mimetics and SARS-CoV fusion peptides interacting with dodecylphosphocholine (DPC) micelles. These supramolecular complexes were analyzed under physiological conditions by 1H and 31P NMR techniques. We were able to observe characteristic interaction states of incretin mimetics, SARS-CoV fusion peptides and DPC membranes. Novel interaction profiles (indicated, e.g., by 31P NMR signal splitting) were detected. Furthermore, we evaluated GM1 gangliosides and sialic acid-coated silica nanoparticles in complex with DPC micelles in order to create a simple virus host cell membrane model. This is a first step in exploring the structure-function relationship between the SARS-CoV-2 spike protein and incretin mimetics with conserved pH-sensitive histidine residues in their carbohydrate recognition domains as found in galectins. The applied methods were effective in identifying peptide sequences as well as certain carbohydrate moieties with the potential to protect the blood-brain barrier (BBB). These clinically relevant observations on low blood pH values in fatal COVID-19 cases open routes for new therapeutic approaches, especially against long-COVID symptoms.

Secreted Cytokines within the Urine of AKI Patients Modulate TP53 and SIRT1 Levels in a Human Podocyte Cell Model.

Acute kidney injury (AKI) is a major kidney disease with a poor clinical outcome. It is a common complication, with an incidence of 10-15% of patients admitted to hospital. This rate even increases for patients who are admitted to the intensive care unit, with an incidence of >50%. AKI is characterized by a rapid increase in serum creatinine, decrease in urine output, or both. The associated symptoms include feeling sick or being sick, diarrhoea, dehydration, decreased urine output (although occasionally the urine output remains normal), fluid retention causing swelling in the legs or ankles, shortness of breath, fatigue and nausea. However, sometimes acute kidney injury causes no signs or symptoms and is detected by lab tests. Therefore, the identification of cytokines for the early detection and diagnosis of AKI is highly desirable, as their application might enable the prevention of the progression from AKI to chronic kidney disease (CKD). In this study, we analysed the secretome of the urine of an AKI patient cohort by employing a kidney-biomarker cytokine assay. Based on these results, we suggest ADIPOQ, EGF and SERPIN3A as potential cytokines that might be able to detect AKI as early as 24 h post-surgery. For the later stages, as common cytokines for the detection of AKI in both male and female patients, we suggest VEGF, SERPIN3A, TNFSF12, ANPEP, CXCL1, REN, CLU and PLAU. These cytokines in combination might present a robust strategy for identifying the development of AKI as early as 24 h or 72 h post-surgery. Furthermore, we evaluated the effect of patient and healthy urine on human podocyte cells. We conclude that cytokines abundant in the urine of AKI patients trigger processes that are needed to repair the damaged nephron and activate TP53 and SIRT1 to maintain the balance between proliferation, angiogenesis, and cell cycle arrest.

Prognostic markers for the clinical course in the blood of patients with SARS-CoV-2 infection.

BACKGROUND: The presentation of peptides and the subsequent immune response depend on the MHC characteristics and influence the specificity of the immune response. Several studies have found an association between HLA variants and differential COVID-19 outcomes and have shown that HLA genotypes are associated with differential immune responses against SARS-CoV-2, particularly in severely ill patients. Information, whether HLA haplotypes are associated with the severity or length of the disease in moderately diseased individuals is absent. METHODS: Next-generation sequencing-based HLA typing was performed in 303 female and 231 male non-hospitalized North Rhine Westphalian patients infected with SARS-CoV2 during the first and second wave. For HLA-Class I, we obtained results from 528 patients, and for HLA-Class II from 531. In those patients, who became ill between March 2020 and January 2021, the 22 most common HLA-Class I (HLA-A, -B, -C) or HLA-Class II (HLA -DRB1/3/4, -DQA1, -DQB1) haplotypes were determined. The identified HLA haplotypes as well as the presence of a CCR5Δ32 mutation and number of O and A blood group alleles were associated to disease severity and duration of the disease. RESULTS: The influence of the HLA haplotypes on disease severity and duration was more pronounced than the influence of age, sex, or ABO blood group. These associations were sex dependent. The presence of mutated CCR5 resulted in a longer recovery period in males. CONCLUSION: The existence of certain HLA haplotypes is associated with more severe disease.

Specialist Palliative Care Consultations in COVID-19 Patients in the ICU-A Retrospective Analysis of Patient Characteristics and Symptoms at a German University Hospital.

COVID-19 patients who may require invasive therapeutic procedures such as extracorporeal membrane oxygenation (ECMO) have high symptom burden and in-hospital mortality. In addition, awake patients on ECMO are new in the intensive care unit (ICU) setting. Inpatient specialist palliative care (sPC) provides support such as symptom control on a physical, psychosocial and spiritual level. The field of sPC in COVID-19 patients is still new and important to investigate. We aim to analyze sPC of COVID-19 patients in the ICU with regard to patient characteristics and symptoms from a palliative care perspective. We conducted a retrospective analysis (03/2020-04/2021) and identified 51 ICU patients receiving sPC. The statistical analysis included descriptive statistics and comparisons of symptoms. The first sPC contact of patients (mean age 69.5 years, 62.7% male) was around 14 days after COVID-19 confirmation, and 43% were treated with ECMO therapy. The baseline symptom burden was high with a focus on weakness (100%), tiredness (98%), dyspnea (96%) and family burden (92%). The symptom intensity significantly decreased during the time period of sPC and COVID-19 treatment (t(99) = 3.119, p = 0.003, d = 0.437). These results help intensivists and sPC clinicians to identify symptoms and the need for sPC in COVID-19 patients. However, studies with prospective and controlled designs need to follow.

Palliative Care e-Learning for Physicians Caring for Critically Ill and Dying Patients during the COVID-19 Pandemic: An Outcome Evaluation with Self-Assessed Knowledge and Attitude.

During the COVID-19 pandemic, the care of critically ill and dying patients in isolation wards, intensive care units (ICUs), and regular wards was severely impaired. In order to support physicians in communicative and palliative care skills, an e-learning tool was developed as part of the joint project "Palliative Care in Pandemic Times" (PallPan). This study investigates the feasibility of this e-learning tool. Secondly, we aim to analyze changes in knowledge and attitude upon completion of the e-learning tool. A 38-item questionnaire-based evaluation study with assessment of global and specific outcomes including ICU and non-ICU physicians was performed. In total, 24 questionnaires were included in the anonymous analysis. Feasibility was confirmed by a very high rate of overall satisfaction (94% approval), with relevance reaching 99% approval. Overall, we detected high gains in knowledge and noticeably lower gains on the attitude plane, with the highest gain in naming reasons for incorporating palliative care. The lowest learning gain on the attitude plane was observed when the participants were confronted with their own mortality. This study shows that e-learning is a feasible tool for gaining knowledge and even changing the attitudes of physicians caring for critically ill and dying patients in a self-assessment evaluation.

Mechanistic Considerations and Pharmacokinetic Implications on Concomitant Drug Administration During CytoSorb Therapy.

The CytoSorb hemoadsorption device (CytoSorbents Inc, Monmouth Junction, NJ) is increasingly used in many critical disease states. The potential impact on the pharmacokinetic (PK) of concomitantly administered drugs must be considered in clinical practice. The current review summarizes relevant mechanistic principles, available preclinical and clinical data, and provides general guidance for the management of concomitant drug administration during CytoSorb therapy. DATA SOURCES: Detailed search strategy using the PubMed and OVID MEDLINE databases, as well as presented congress abstracts for studies on drug removal by the CytoSorb device. STUDY SELECTION: Human, animal, and bench-top studies with PK or drug-removal data during CytoSorb therapy were selected for inclusion. Publications reporting on CytoSorb treatments for drug overdose were not considered. DATA EXTRACTION: Relevant PK data were examined and synthesized for narrative review. DATA SYNTHESIS: To date, PK data during CytoSorb hemoadsorption are available for more than 50 drugs, including analgesics, antiarrhythmics, anticonvulsants, antidepressants, antihypertensives, antiinfectives, antithrombotics, anxiolytics, and immunosuppressants. Based on available PK data, drugs were categorized into low (<30%), moderate (30-60%), or high rates of removal (>60%), or, alternatively, according to clearance increase relative to endogenous clearance: negligible (<25%), low (25-100%), moderate (100-400%), or high (>400%). In most reports, additional impact of the extracorporeal platform where CytoSorb was integrated was not available. Based on available data and considering drug, patient, and setup-specific aspects, general dosing guidance for clinical practice was developed. CONCLUSIONS: CytoSorb therapy may increase drug elimination through active removal. However, the extent of removal is heterogeneous, and its clinical significance, if any, depends on the broader clinical context, including a patient's specific endogenous drug clearance and the underlying extracorporeal platform used. The available data, although not definitive, allow for general guidance on dosing adjustments during CytoSorb therapy; however, any treatment decisions should always be complemented by clinical judgment and therapeutic drug monitoring, when available.

Intravenous IgM-enriched immunoglobulins in critical COVID-19: a multicentre propensity-weighted cohort study.

BACKGROUND: A profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications of critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable of mitigating the inflicted inflammatory harm. However, the efficacy of intravenous IgM-enriched preparations in critically ill patients with COVID-19 is largely unclear. METHODS: In this retrospective multicentric cohort study, 316 patients with laboratory-confirmed critical COVID-19 were treated in ten German and Austrian ICUs between May 2020 and April 2021. The primary outcome was 30-day mortality. Analysis was performed by Cox regression models. Covariate adjustment was performed by propensity score weighting using machine learning-based SuperLearner to overcome the selection bias due to missing randomization. In addition, a subgroup analysis focusing on different treatment regimens and patient characteristics was performed. RESULTS: Of the 316 ICU patients, 146 received IgM-enriched immunoglobulins and 170 cases did not, which served as controls. There was no survival difference between the two groups in terms of mortality at 30 days in the overall cohort (HRadj: 0.83; 95% CI: 0.55 to 1.25; p = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance (HRadj: 0.23; 95% CI: 0.05 to 1.08; p = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of ≥ 15 g and a duration of ≥ 3 days of IgM-enriched immunoglobulins were applied (HRadj: 0.65; 95% CI: 0.41 to 1.03; p = 0.068). CONCLUSIONS: Although we cannot prove a statistically reliable effect of intravenous IgM-enriched immunoglobulins, the confidence intervals may suggest a clinically relevant effect in certain subgroups. Here, an early administration (i.e. in critically ill but not yet mechanically ventilated COVID-19 patients) and a dose of ≥ 15 g for at least 3 days may confer beneficial effects without concerning safety issues. However, these findings need to be validated in upcoming randomized clinical trials. Trial registration DRKS00025794 , German Clinical Trials Register, https://www.drks.de . Registered 6 July 2021.

[Venovenous extracorporeal membrane oxygenation for COVID-19]. / Venovenöse extrakorporale Membranoxygenierung bei COVID-19: Erkenntnisse eines Zentrums aus 96 konsekutiven Fällen.

Background: Since the beginning of the COVID-19 pandemic global health systems are confronted with a large number of unknown problems. Venovenous (vv) extracorporeal membrane oxygenation (ECMO) in cases of therapy refractive ARDS often represents a last resort treatment. To improve the health care it is necessary to identify possible influencing factors. Objective: This analysis presents the findings of an ECMO centre and aims to identify potential factors with an impact on vv-ECMO therapy in cases of COVID-19. Material and methods: Between 03/2020 and 01/2022 n = 96 patients were treated with vv-ECMO in cases of a COVID-19 infection in our center. A retrospective analysis of demographic and health-specific data took place. The patients with fatal treatment outcome (L-group, n = 62) were compared to the surviving patients (Ü-group, n = 34). Results: Overall n = 34 (35%) of the patients survived the hospital stay. The patients with a fatal treatment outcome had an average age of 56.7 ± 9.5 years compared to the average age of the surviving patients of 47.9 ± 12.9 years. There were n = 72 (75%) males and n = 24 (25%) females among the treated patients, n = 51 (82.3%) of the deceased patients were male and n = 11 (17.7%) were female. The prevalence of pre-existing illnesses like COPD, diabetes mellitus, cardiovascular diseases and chronic renal insufficiency had shown no significant difference between both groups. Also, in relation to the presence of arterial hypertension and obesity we could not prove a negative influence on the treatment outcome. A nicotine abuse in the patient history showed a negative tendency. The most common reasons for the death of patients were respiratory failure, neurological injury, multiorgan failure and sepsis. Conclusion: The use of vv-ECMO in cases of therapy resistant ARDS in COVID-19 still correlates with a high mortality and as such should only be considered as a last resort of intensive care treatment.According to our expectations we could notice better therapy results for younger patients as well as for women in our patient database. In addition, for most comorbidities we could not prove any negative influence on the therapy outcome. This knowledge could help to identify future high-risk patients.

Core body temperatures during final stages of life-an evaluation of data from in-hospital decedents.

Temperature-based methods are widely accepted as the gold standard for death time estimation. In the absence of any other information, the nomogram method generally assumes that a person died with a core body temperature of approximately 37.2 °C. Nevertheless, several external and internal factors may alter the body temperature during agony. A retrospective medical record analysis was carried out on in-hospital death cases from two consecutive years of surgical intensive care units to determine the effects of factors influencing the core body temperature at the point of death. Data from 103 case files were included in the statistical data evaluation. The body temperature fluctuated between and within individuals over time. No clear correlation to certain death groups was observed. Even primary cardiac deaths showed broad intervals of temperatures at the point of death. Men seem to die with higher body temperatures than women. The presented data highlight potential biases for death time estimations when generally assuming a core body temperature of 37.2 °C. In conclusion, the estimation of the time of death should include various methods, including a non-temperature-dependent method. Any uncertainties regarding the body temperature at point of death need to be resolved (e.g. by identifying fever constellations) and elucidated if elimination is not possible.

[ECMO cannulation for COVID-19]. / ECMO-Kanülierung bei COVID-19: Venovenöse extrakorporale Membranoxygenierung bei COVID-19: Einfluss der Kanülierungsstrategie auf das Therapieergebnis.

Background: The novel coronavirus disease 2019 (COVID-19) can cause a severe and therapy-refractory acute respiratory distress syndrome. Temporary mechanical assistance by veno-venous extracorporeal membrane oxygenation (v.v.-EMCO) is a well-established supportive therapy, but is still associated with a high mortality. Objective: This work aimed to identify potential effects of the ECMO cannulation strategy on the outcome in COVID-19 patients. Material and methods: All patients who were treated in a single center between March 2020 and November 2021 for COVID-19-related ARDS (n = 75) were prospectively entered into an institutional database. The patients were assigned into two groups with respect to the ECMO cannulation (femorofemoral: n = 20, femorojugular: n = 55) and the outcome was retrospectively analyzed. Results: We observed severe therapy-related adverse events in both groups in more than 70% of patients with sepsis being the most common (> 50% each). The outcome (successful ECMO weaning, in-hospital death, 6­month survival) was comparable in both groups. In-hospital mortality was about 70% each; however, the duration of event-free ECMO support seemed to be prolonged in the femorojugular group. Conclusion: Regardless of the support duration, v.v.-ECMO therapy for COVID-19 is associated with high mortality rates. The cannulation strategy did not impact on the outcome; however, femorojugular cannulation might prolong the event-free support duration and facilitate the mobilization of the patients during ECMO support.

Association of chronic heart failure with mortality in old intensive care patients suffering from Covid-19.

AIMS: Chronic heart failure (CHF) is a major risk factor for mortality in coronavirus disease 2019 (COVID-19). This prospective international multicentre study investigates the role of pre-existing CHF on clinical outcomes of critically ill old (≥70 years) intensive care patients with COVID-19. METHODS AND RESULTS: Patients with pre-existing CHF were subclassified as having ischaemic or non-ischaemic cardiac disease; patients with a documented ejection fraction (EF) were subclassified according to heart failure EF: reduced (HFrEF, n = 132), mild (HFmrEF, n = 91), or preserved (HFpEF, n = 103). Associations of heart failure characteristics with the 30 day mortality were analysed in univariate and multivariate logistic regression analyses. Pre-existing CHF was reported in 566 of 3917 patients (14%). Patients with CHF were older, frailer, and had significantly higher SOFA scores on admission. CHF patients showed significantly higher crude 30 day mortality [60% vs. 48%, P < 0.001; odds ratio 1.87, 95% confidence interval (CI) 1.5-2.3] and 3 month mortality (69% vs. 56%, P < 0.001). After multivariate adjustment for confounders (SOFA, age, sex, and frailty), no independent association of CHF with mortality remained [adjusted odds ratio (aOR) 1.2, 95% CI 0.5-1.5; P = 0.137]. More patients suffered from pre-existing ischaemic than from non-ischaemic disease [233 vs. 328 patients (n = 5 unknown aetiology)]. There were no differences in baseline characteristics between ischaemic and non-ischaemic disease or between HFrEF, HFmrEF, and HFpEF. Crude 30 day mortality was significantly higher in HFrEF compared with HFpEF (64% vs. 48%, P = 0.042). EF as a continuous variable was not independently associated with 30 day mortality (aOR 0.98, 95% CI 0.9-1.0; P = 0.128). CONCLUSIONS: In critically ill older COVID-19 patients, pre-existing CHF was not independently associated with 30 day mortality. TRIAL REGISTRATION NUMBER: NCT04321265.

[Present practise patterns of renal replacement therapy in German intensive care medicine]. / Aktueller Stand der Durchführung von Nierenersatztherapien auf deutschen Intensivstationen.

About 50% of all critically ill patients develop acute kidney injury (AKI) and approximately 15% receive renal replacement therapy (RRT). Although RRT is frequently used in intensive care units in Germany, it is currently unknown which RRT procedures are available, which qualification the involved staff has, which anticoagulation strategies are used and how RRT doses are prescribed. To investigate quality and structural characteristics of the performance of RRT in intensive care units throughout Germany, the German Interdisciplinary Society of Intensivists (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin [DIVI]) performed an inquiry among their members. A total of 897 members participated in the survey in which practical aspects were queried. In 69.1% of the cases, RRT was performed in hospitals with more than 400 beds and in 74.5% in university hospitals or other primary care hospitals. Furthermore, 93.3% of clinics are equipped with continuous and 75.8% with intermittent renal replacement devices. In 91.9%, indication for initiation of RRT was performed by trained physicians specialized in intensive care medicine or nephrologists. Intermittent as well as continuous modalities are both present in three-quarters of cases, which allows for individualized therapy. However, the documentation of dialysis dose needs to be improved.

Association of HLA genotypes, AB0 blood type and chemokine receptor 5 mutant CD195 with the clinical course of COVID-19.

BACKGROUND: COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5). PATIENT AND METHODS: An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation. RESULTS: Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing. CONCLUSION: The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.