[Post-COVID patients with persistent chemosensory symptoms are rare in the general population]. / Post-COVID-Patienten mit persistierenden chemosensorischen Symptomen sind in der Bevölkerung selten.

OBJECTIVE: The prevalence of long-/post-COVID-associated chemosensory symptoms is reported in the literature to be significantly higher than clinical reality reflects. METHODS: 1. N= 4062 adults acutely infected with SARS-CoV-2 and their symptoms transmitted by the Jena health office to the Robert Koch Institute between March 2020 and September 2021 were evaluated. 2. Part of the same cohort (N = 909 of 4062) answered an extensive questionnaire at least 3 months after the start of the infection, including existing chemosensory post-COVID-associated complaints. 3. Fourteen post-COVID Jena patients with chemosensory symptoms who had become acutely infected during the same period were diagnosed, treated and advised in our ENT specialist outpatient clinic. RESULTS: The prevalence of chemosensory symptoms at the onset of infection was 19% (600/3187). About every second written respondent of the formerly acutely infected (441/890) remembered chemosensory symptoms during their COVID-19 infection. Of these, around 38% (167/441) complained of persistent chemosensory post-COVID symptoms after an average of 14.5 months. Only 2.3% (14/600) of the previously acutely infected patients with chemosensory symptoms sought medical help in a special consultation. Quantitative chemosensory damage could only be objectified in half, i.e. 1.2% (7/600) of the total cohort. CONCLUSIONS: Despite a high prevalence of subjective chemosensory symptoms in acutely and formerly SARS-CoV-2 infected people, there is only a low need for specialized treatment, so that, unlike other post-COVID-associated complaints, the healthcare system as a whole appears to be less significantly burdened.

Glucocorticoids regulate lipid mediator networks by reciprocal modulation of 15-lipoxygenase isoforms affecting inflammation resolution.

Glucocorticoids (GC) are potent anti-inflammatory agents, broadly used to treat acute and chronic inflammatory diseases, e.g., critically ill COVID-19 patients or patients with chronic inflammatory bowel diseases. GC not only limit inflammation but also promote its resolution although the underlying mechanisms are obscure. Here, we reveal reciprocal regulation of 15-lipoxygenase (LOX) isoform expression in human monocyte/macrophage lineages by GC with respective consequences for the biosynthesis of specialized proresolving mediators (SPM) and their 15-LOX-derived monohydroxylated precursors (mono-15-OH). Dexamethasone robustly up-regulated pre-mRNA, mRNA, and protein levels of ALOX15B/15-LOX-2 in blood monocyte-derived macrophage (MDM) phenotypes, causing elevated SPM and mono-15-OH production in inflammatory cell types. In sharp contrast, dexamethasone blocked ALOX15/15-LOX-1 expression and impaired SPM formation in proresolving M2-MDM. These dexamethasone actions were mimicked by prednisolone and hydrocortisone but not by progesterone, and they were counteracted by the GC receptor (GR) antagonist RU486. Chromatin immunoprecipitation (ChIP) assays revealed robust GR recruitment to a putative enhancer region within intron 3 of the ALOX15B gene but not to the transcription start site. Knockdown of 15-LOX-2 in M1-MDM abolished GC-induced SPM formation and mono-15-OH production. Finally, ALOX15B/15-LOX-2 upregulation was evident in human monocytes from patients with GC-treated COVID-19 or patients with IBD. Our findings may explain the proresolving GC actions and offer opportunities for optimizing GC pharmacotherapy and proresolving mediator production.

[Outpatient Long/Post-COVID Care: Barriers and Desires of Affected Persons to Medical Care]. / Ambulante Long/Post-COVID-Versorgung: Analyse möglicher Barrieren und Wünsche von Betroffenen an die ärztliche Betreuung.

INTRODUCTION: Persistent and new-onset symptoms after SARS-CoV-2 infection (so-called Long/Post-COVID syndrome) represent a major challenge for our healthcare system. However, there have been limited data on primary outpatient care and care planning, complicating patient flow management and ultimately patient care. Assessing the care reality of patients with Long/Post-COVID-symptoms, as well as their difficulties and desires in receiving medical care, is a necessary first step toward improving outpatient care. METHODS: The JenUP study (Jena study on the population-based incidence of Post-COVID complaints) is a questionnaire-based survey of all adults in the city of Jena who were registered with RT-PCR-confirmed SARS-CoV-2 infection between March 2020 and September 2021. Part of this study focused on the medical care of the affected persons as well as subjective difficulties of the patients in the context of treatment. RESULTS: A total of 1,008 of the 4,209 individuals responded to the questionnaire; 922 (91,5%) experienced at least one Long/Post-COVID-associated symptom. 85,6% of these individuals (790/922) also provided detailed information about contacts with health care facilities. Three out of four persons (590/790) consulted their general practitioner/family doctor in connection with their complaints and 155/790 (19,6%) specialists in addition (most frequently mentioned were specialists in internal medicine - 7,1% (55/790)). Difficulties in obtaining a subjectively required therapy were mentioned by 22,6% (162/718). The main reasons were the patient's apparent feeling of "not being sick enough" (69/162) and a lack of a specialist consultant (65/162). 27% (247/919) of all subjects with Long/Post-COVID complaints expressed a desire for a specific consultant. CONCLUSION: Primary care physicians represent a central element of outpatient care for Long/Post-COVID patients. In addition, nationwide structures for interdisciplinary care should be established according to the national S1 guideline. Analysis of wishes for medical care and perceived barriers to accessing it represent a first step in improving outpatient care for Long/Post-COVID patients.

Immunoadsorption to treat patients with severe post-COVID syndrome.

INTRODUCTION: Following SARS-CoV-2-infection up to 21% of patients will develop post-COVID-syndrome. Autoantibodies (AAbs) targeting neuronal-ß-adrenergic and muscarinic receptors may provide crucial contributions to the pathophysiology of this condition. Immunoadsorption (IA) has been identified as an effective means of removing AAbs and has resulted in clinical improvements of other autoantibody-associated diseases. METHODS: We determined AAb-levels (anti-ß1/ß2 and anti-M3/M4 receptor) in 178 patients diagnosed with post-COVID-syndrome and described the clinical courses of two patients with elevated AAb-levels that underwent IA-treatment. RESULTS: AAbs were detected in 57% (101/178) of patients diagnosed with post-COVID-syndrome. Substantial reductions in AAb-levels and clinical remission were achieved in one of two patients who was treated with IA. However, this patient relapsed within 6 weeks with a concomitant increase in AAb-levels. CONCLUSION: Collectively, AAbs may play a pathophysiologic role in post-COVID and their removal provide transient benefits in some patients. However, these findings should be further investigated in randomized-controlled-trials.

Post-COVID-19 condition is not only a question of persistent symptoms: structured screening including health-related quality of life reveals two separate clusters of post-COVID.

PURPOSE: Some patients experience long-term sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, despite a present post-COVID condition, defined as "any symptom lasting longer than 12 weeks," only a subset of patients search for medical help and therapy. METHOD: We invited all adults with a positive real-time polymerase chain reaction (RT-PCR) for SARS-CoV-2 between March 2020 and September 2021 (n = 4091) in the city of Jena to answer a standardized questionnaire including demographic information, the course of the acute infection and current health status. K-means-clustering of quality of life (QoL) was used to explore post-COVID subgroups. RESULTS: A total of 909 participants at a median interval of 367 (IQR 291/403) days after acute infection were included in the analysis. Of those, 643 (70.7%) complained of having experienced persistent symptoms at the time of the survey. Cluster analysis based on QoL revealed two subgroups of people with persistent post-COVID symptoms. Whereas 189/643 participants (29.4%) showed markedly diminished QoL, normal QoL was detected in 454/643 individuals (70.6%). CONCLUSION: Despite persistent symptoms being reported by nearly three quarters of participants, only one-third of these described a significant reduction in QoL (cluster 1), whereas the other two-thirds reported a near-normal QoL (cluster 2), thus indicating a differentiation between "post-COVID disease" and "post-COVID condition". The prevalence of clinically relevant post-COVID disease was at least 20.7%. Health policies should focus on this subset.

Mobile primary healthcare for post-COVID patients in rural areas: a proof-of-concept study.

INTRODUCTION: Post-COVID syndrome is increasingly recognized as a new clinical entity after SARS-CoV-2 infection. Patients living in rural areas may have to travel long with subjectively great effort to be examined using all necessary interdisciplinary tools. This problem could be addressed with mobile outpatient clinics. METHODS: In this prospective observational study, we investigated physical fitness, fatigue, depression, cognitive dysfunction, and dyspnea in patients with post-COVID syndrome in a mobile interdisciplinary post-COVID outpatient clinic. Upon referral from their primary care physician, patients were offered an appointment at a mobile post-COVID outpatient clinic close to their home. RESULTS: We studied 125 patients (female, n = 79; 63.2%) in our mobile unit. All patients reported symptoms lasting for more than 12 weeks after acute infection. 88.3% and 64.1% of patients reported significant impairment in physical and mental quality of life. Patients reported a median of three symptoms. The most frequently reported symptoms were fatigue (86.4%), cognitive dysfunction (85.6%), and dyspnea (37.6%). 56.0% of patients performed at < 2.5th percentile at the 1 min sit-to-stand test compared to age- and sex-matched healthy controls, and 25 patients (20.0%) exhibited a drop in oxygen saturation. A questionnaire given to each patient regarding the mobile unit revealed a very high level of patient satisfaction. CONCLUSION: There is an increasing need for high-quality and locally available care for patients with post-COVID syndrome. A mobile post-COVID outpatient clinic is a new concept that may be particularly suitable for use in rural regions. Patients' satisfaction following visits in such units is very high.

Recurrent Disseminated Intravascular Coagulation in Metastatic Castration-Resistant Prostate Cancer: A Case Report.

Disseminated intravascular coagulation (DIC) is a systemic disease characterized by simultaneous thrombosis, bleeding, and partially excessive fibrinolysis. Systemic shock, trauma, bacterial toxins, and procoagulants-expressing solid and hematologic malignancies are common causes of this life-threatening hemorrhagic complication and often require treatment in intensive care units. We describe a case of an elderly man with recurrent severe bleeding events in the cause of DIC, including epistaxis, hemoptysis, hematuria, and gastrointestinal bleeding. Laboratory investigations revealed elevated prostate-specific antigen (PSA), suggesting an underlying prostate cancer. Despite intensified coagulatory therapy, the coagulation disorder could not be stabilized. A single injection of degarelix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, led to rapid stabilization of the coagulation and decreased PSA within days. One year after initiating androgen-deprivation therapy, there were recurrent transfusion-requiring bleeding events, and a concomitant PSA increase occurred, suggesting metastatic castration-resistant disease associated with DIC. This case emphasizes DIC as a possible primary phenomenon and indicator for the progression of the underlying malignancy, as well as the importance of etiological therapies in the management of DIC.

Recurrent Upper Gastrointestinal Bleeding from Isolated Gastric Varices as Primary Symptom of Myelofibrosis: A Case Report on Combining Interventional and Pharmacologic Treatment Options.

Portal hypertension leads to pronounced venous collateralization and development of varices. Besides manifest liver cirrhosis, primarily left-sided portal hypertension is causal for the development of gastric varices. We present a case of a 36-year-old female patient with splenomegaly, underlying primary myelofibrosis, and detection of somatic Janus-kinase-2 driver-mutation JAK2V617F. Following first upper gastrointestinal bleeding, isolated gastric varices could be detected as a result of underlying left-sided portal hypertension. Within a few months, repeated life-threatening bleedings with transfusion requirements and frequent hospitalizations occurred. Despite multiple injections of cyanoacrylates, the proven therapy of choice, varices could not be stabilized. Combination of targeted JAK-inhibitor therapy in conjunction with the use of EUS-guided application of coils with subsequent cyanoacrylate injection resulted in acute and long-term bleeding control.

Corrigendum: Monocyte-induced recovery of inflammation-associated hepatocellular dysfunction in a biochip-based human liver model.

This corrects the article DOI: 10.1038/srep21868.

Acid Sphingomyelinase Inhibition Prevents Development of Sepsis Sequelae in the Murine Liver.

The molecular mechanisms of maladaptive response in liver tissue with respect to the acute and post-acute phase of sepsis are not yet fully understood. Long-term sepsis survivors might develop hepatocellular/hepatobiliary injury and fibrosis. Here, we demonstrate that acid sphingomyelinase, an important regulator of hepatocyte apoptosis and hepatic stellate cell (HSC) activation, is linked to the promotion of liver dysfunction in the acute phase of sepsis as well as to fibrogenesis in the long-term. In both phases, we observed a beneficial effect of partial genetic sphingomyelinase deficiency in heterozygous animals (smpd1+/-) on oxidative stress levels, hepatobiliary function, macrophage infiltration and on HSC activation. Strikingly, similar to heterozygote expression of SMPD1, either preventative (p-smpd1+/+) or therapeutic (t-smpd1+/+) pharmacological treatment strategies with desipramine - a functional inhibitor of acid sphingomyelinase (FIASMA) - significantly improved liver function and survival. The inhibition of sphingomyelinase exhibited a protective effect on liver function in the acute-phase, and the reduction of HSC activation diminished development of sepsis-associated liver fibrosis in the post-acute phase of sepsis. In summary, targeting sphingomyelinase with FDA-approved drugs is a novel promising strategy to overcome sepsis-induced liver dysfunction.

Monocyte-induced recovery of inflammation-associated hepatocellular dysfunction in a biochip-based human liver model.

Liver dysfunction is an early event in sepsis-related multi-organ failure. We here report the establishment and characterization of a microfluidically supported in vitro organoid model of the human liver sinusoid. The liver organoid is composed of vascular and hepatocyte cell layers integrating non-parenchymal cells closely reflecting tissue architecture and enables physiological cross-communication in a bio-inspired fashion. Inflammation-associated liver dysfunction was mimicked by stimulation with various agonists of toll-like receptors. TLR-stimulation induced the release of pro- and anti-inflammatory cytokines and diminished expression of endothelial VE-cadherin, hepatic MRP-2 transporter and apolipoprotein B (ApoB), resulting in an inflammation-related endothelial barrier disruption and hepatocellular dysfunction in the liver organoid. However, interaction of the liver organoid with human monocytes attenuated inflammation-related cell responses and restored MRP-2 transporter activity, ApoB expression and albumin/urea production. The cellular events observed in the liver organoid closely resembled pathophysiological responses in the well-established sepsis model of peritoneal contamination and infection (PCI) in mice and clinical observations in human sepsis. We therefore conclude that this human liver organoid model is a valuable tool to investigate sepsis-related liver dysfunction and subsequent immune cell-related tissue repair/remodeling processes.