Fighting Post-COVID and ME/CFS - development of curative therapies.

The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation have been identified as potential mechanisms. However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). No curative therapies are available for ME/CFS or PCS. The mechanisms identified so far provide targets for therapeutic interventions. To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping.

The multiple meanings of translational research in (bio)medical research.

Translational research is a buzzword which dominates discussions about the quality, the utilization, and the benefits of (bio)medical research. Yet, although translational research has become a prominent topic, no commonly agreed definition of this terminology exists. Instead, experts from different contexts such as biomedical research, clinical practice or nursing discuss translational research in multiple ways depending on how they define the problem that translational research is supposed to be the solution to. In this paper, we do not seek to find a 'correct' definition of translational research, but instead ask how actors using this terminology for describing their own research make sense of it. To do so, we asked three questions: Which actors are engaged in the debate about translational research? What kind of different meanings of translational research exist? And, which actors refer to which meaning of translational research when using the term? In answering these questions, we highlight the role this terminology plays in defining what medical science is about today.

Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME.

INTRODUCTION: Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2 adrenergic receptors, and muscarinic 3 and 4 acetylcholine receptors in a subset of patients. Immunoadsorption (IA) was shown to be effective in removing autoantibodies and improve outcome in various autoimmune diseases. METHODS: 10 patients with post-infectious CFS/ME and elevated ß2 autoantibodies were treated with IA with an IgG-binding column for 5 days. We assessed severity of symptoms as outcome parameter by disease specific scores. Antibodies were determined by ELISA and B cell phenotype by flow cytometry. RESULTS: IgG levels dropped to median 0.73 g/l (normal 7-16 g/l) after the 4th cycle of IA, while IgA and IgM levels remained unchanged. Similarly, elevated ß2 IgG antibodies rapidly decreased during IA in 9 of 10 patients. Also 6 months later ß2 autoantibodies were significantly lower compared to pretreatment. Frequency of memory B cells significantly decreased and frequency of plasma cells increased after the 4th IA cycle. A rapid improvement of symptoms was reported by 7 patients during the IA. 3 of these patients had long lasting moderate to marked improvement for 6-12+ months, 2 patients had short improvement only and 2 patients improved for several months following initial worsening. CONCLUSIONS: IA can remove autoantibodies against ß2 adrenergic receptor and lead to clinical improvement. B cell phenotyping provides evidence for an effect of IA on memory B cell development. Data from our pilot trial warrants further studies in CFS/ME.

Mild therapeutic hypothermia alters neuron specific enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients.

INTRODUCTION: Neuron specific enolase (NSE) has been proven effective in predicting neurological outcome after cardiac arrest with a current cut off recommendation of 33 microg/l. However, most of the corresponding studies were conducted before the introduction of mild therapeutic hypothermia (MTH). Therefore we conducted a study investigating the association between NSE and neurological outcome in patients treated with MTH. METHODS: In this prospective observational cohort study the data of patients after cardiac arrest receiving MTH (n = 97) were consecutively collected and compared with a retrospective non-hypothermia (NH) group (n = 133). Serum NSE was measured 72 hours after admission to ICU. Neurological outcome was classified according to the Pittsburgh cerebral performance category (CPC 1 to 5) at ICU discharge. RESULTS: NSE serum levels were significantly lower under MTH compared to NH in univariate analysis. However, in a linear regression model NSE was affected significantly by time to return of spontaneous circulation (ROSC) and ventricular fibrillation rhythm but not by MTH. The model for neurological outcome identified NSE, NSE*MTH (interaction) as well as time to ROSC as significant predictors. Receiver Operating Characteristic (ROC) analysis revealed a higher cutoff value for unfavourable outcome (CPC 3 to 5) with a specificity of 100% in the hypothermia group (78.9 microg/l) compared to the NH group (26.9 microg/l). CONCLUSIONS: Recommended cutoff levels for NSE 72 hours after ROSC do not reliably predict poor neurological outcome in cardiac arrest patients treated with MTH. Prospective multicentre trials are required to re-evaluate NSE cutoff values for the prediction of neurological outcome in patients treated with MTH.

2-year survival of patients undergoing mild hypothermia treatment after ventricular fibrillation cardiac arrest is significantly improved compared to historical controls.

BACKGROUND: Therapeutic hypothermia has been proven to be effective in improving neurological outcome in patients after cardiac arrest due to ventricular fibrillation (VF). Data concerning the effect of hypothermia treatment on long-term survival however is limited. MATERIALS AND METHODS: Clinical and outcome data of 107 consecutive patients undergoing therapeutic hypothermia after cardiac arrest due to VF were compared with 98 historical controls. Neurological outcome was assessed at ICU discharge according to the Pittsburgh cerebral performance category (CPC). A Kaplan-Meier analysis of follow-up data concerning mortality after 24 months as well as a Cox-regression to adjust for confounders were calculated. RESULTS: Neurological outcome significantly improved after mild hypothermia treatment (hypothermia group CPC 1-2 59.8%, control group CPC 1-2 24.5%; p < 0.01). In Kaplan-Meier survival analysis hypothermia treatment was also associated with significantly improved 2-year probability for survival (hypothermia 55% vs. control 34%; p = 0.029). Cox-regression analysis revealed hypothermia treatment (p = 0.031) and age (p = 0.013) as independent predictors of 24-month survival. CONCLUSIONS: Our study demonstrates that the early survival benefit seen with therapeutic hypothermia persists after two years. This strongly supports adherence to current recommendations regarding postresuscitation care for all patients after cardiac arrest due to VF and maybe other rhythms as well.

Mild therapeutic hypothermia shortens intensive care unit stay of survivors after out-of-hospital cardiac arrest compared to historical controls.

INTRODUCTION: Persistent coma is a common finding after cardiac arrest and has profound ethical and economic implications. Evidence suggests that therapeutic hypothermia improves neurological outcome in these patients. In this analysis, we investigate whether therapeutic hypothermia influences the length of intensive care unit (ICU) stay and ventilator time in patients surviving out-of-hospital cardiac arrest. METHODS: A prospective observational study with historical controls was conducted at our medical ICU. Fifty-two consecutive patients (median age 62.6 years, 43 males, 34 ventricular fibrillation) submitted to therapeutic hypothermia after out-of-hospital cardiac arrest were included. They were compared with a historical cohort (n = 74, median age 63.8 years, 53 males, 43 ventricular fibrillation) treated in the era prior to hypothermia treatment. All patients received the same standard of care. Neurological outcome was assessed using the Pittsburgh cerebral performance category (CPC) score. Univariate analyses and multiple regression models were used. RESULTS: In survivors, therapeutic hypothermia and baseline disease severity (Acute Physiology and Chronic Health Evaluation II [APACHE II] score) were both found to significantly influence ICU stay and ventilator time (all P < 0.01). ICU stay was shorter in survivors receiving therapeutic hypothermia (median 14 days [interquartile range (IQR) 8 to 26] versus 21 days [IQR 15 to 30] in the control group; P = 0.017). ICU length of stay and time on ventilator were prolonged in patients with CPC 3 or 4 compared with patients with CPC 1 or 2 (P = 0.003 and P = 0.034, respectively). Kaplan-Meier analysis showed improved probability for 1-year survival in the hypothermia group compared with the controls (log-rank test P = 0.013). CONCLUSION: Therapeutic hypothermia was found to significantly shorten ICU stay and time of mechanical ventilation in survivors after out-of-hospital cardiac arrest. Moreover, profound improvements in both neurological outcome and 1-year survival were observed.

Prehospital cooling with hypothermia caps (PreCoCa): a feasibility study.

BACKGROUND: Animal studies suggest that the induction of therapeutic hypothermia in patients after cardiac arrest should be initiated as soon as possible after ROSC to achieve optimal neuroprotective benefit. A "gold standard" for the method of inducing hypothermia quickly and safely has not yet been established. In order to evaluate the feasibility of a hypothermia cap we conducted a study for the prehospital setting. METHODS AND RESULTS: The hypothermia cap was applied to 20 patients after out-of-hospital cardiac arrest with a median of 10 min after ROSC (25/75 IQR 8-15 min). The median time interval between initiation of cooling and hospital admission was 28 min (19-40 min). The median tympanic temperature before application of the hypothermia cap was 35.5 degrees C (34.8-36.3). Until hospital admission we observed a drop of tympanic temperature to a median of 34.4 degrees C (33.6-35.4). This difference was statistically significant (P < 0.001). We could not observe any side effects related to the hypothermia cap. 25 patients who had not received prehospital cooling procedures served as a control group. Temperature at hospital admission was 35.9 degrees C (35.3-36.4). This was statistically significant different compared to patients treated with the hypothermia cap (P < 0.001). CONCLUSIONS: In summary we demonstrated that the prehospital use of hypothermia caps is a safe and effective procedure to start therapeutic hypothermia after cardiac arrest. This approach is rapidly available, inexpensive, non-invasive, easy to learn and applicable in almost any situation.