Persistent Symptoms in Adult Patients 1 Year After Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study.

BACKGROUND: Long COVID is defined as the persistence of symptoms beyond 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To better understand the long-term course and etiology of symptoms we analyzed a cohort of patients with COVID-19 prospectively. METHODS: Patients were included at 5 months after acute COVID-19 in this prospective, noninterventional, follow-up study. Patients followed until 12 months after COVID-19 symptom onset (n = 96; 32.3% hospitalized, 55.2% females) were included in this analysis of symptoms, quality of life (based on an SF-12 survey), laboratory parameters including antinuclear antibodies (ANAs), and SARS-CoV-2 antibody levels. RESULTS: At month 12, only 22.9% of patients were completely free of symptoms and the most frequent symptoms were reduced exercise capacity (56.3%), fatigue (53.1%), dyspnea (37.5%), and problems with concentration (39.6%), finding words (32.3%), and sleeping (26.0%). Females showed significantly more neurocognitive symptoms than males. ANA titers were ≥1:160 in 43.6% of patients at 12 months post-COVID-19 symptom onset, and neurocognitive symptom frequency was significantly higher in the group with an ANA titer ≥1:160 versus <1:160. Compared with patients without symptoms, patients with ≥1 long-COVID symptom at 12 months did not differ significantly with respect to their SARS-CoV-2 antibody levels but had a significantly reduced physical and mental life quality compared with patients without symptoms. CONCLUSIONS: Neurocognitive long-COVID symptoms can persist ≥1 year after COVID-19 symptom onset and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titer elevations. This may indicate autoimmunity as a cofactor in etiology of long COVID.

Severe Dysbiosis and Specific Haemophilus and Neisseria Signatures as Hallmarks of the Oropharyngeal Microbiome in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients.

BACKGROUND: At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict coronavirus disease 2019 (COVID-19) illness. However, the results are not conclusive, as critical illness can drastically alter a patient's microbiome through multiple confounders. METHODS: To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multicenter, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate, and severe COVID-19 (n = 322 participants). RESULTS: In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features. CONCLUSIONS: In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.

[Psychosomatic-psychotherapeutic support for Covid-19 patients in domestic quarantine: a content analysis of supportive telephone calls]. / Psychosomatisch-psychotherapeutische Unterstützung von Covid-19-Patient:innen in häuslicher Quarantäne: Eine Inhaltsanalyse supportiver Telefongespräche.

Objectives: During their domestic quarantine, Covid-19 patients face major physical, psychological and social challenges. The description of support needs and specific topics brought to supportive conversations will be used to add to the body of knowledge about stressors and resources. Methods: A total of 109 telephone conversations with 69 quarantined Corona patients were documented by psychotherapists and physicians at Heidelberg University Hospital from November 2020 to April 2021. Subsequently, clinical documentations were analyzed according to a qualitative content analysis. Results: Most physical complaints related to cardio-respiratory symptoms (29 %), previous illnesses (24 %), and exhaustion or fatigue (16 %). On the psychological level, patients reported mainly anxiety (31 %) and depressive symptoms (16 %). On a social level, patients described stress related to family (56 %), work (20 %), and time in quarantine (16 %). Social support, individual coping strategies, a positive prognosis on the course of the corona disease, psychotherapy, and satisfactory medical care were mentioned as relieving factors. Therapeutic interventions aimed at stabilization and consisted of psychoeducation, relaxation techniques, and general counseling. Conclusions: The study shows that physical complaints, psychological symptoms, and social factors are brought into telephone support conversations. The support offer met a high demand and was well accepted.

Evaluation of two functional CD24 polymorphisms in primary sclerosing cholangitis.

Background: Primary sclerosing cholangitis (PSC) is a progressive liver disease and characterized by chronic inflammation, sclerosis and strictures of bile ducts. Several genetic risk factors might contribute to pathogenesis. Functional single nucleotide polymorphisms (SNPs) in the CD24 gene have been associated with the development of autoimmune and autoinflammatory diseases and might contribute to the susceptibility for inflammatory bowel disease (IBD).Aim: This retrospective study aimed to evaluate the impact of two functional CD24 SNPs on clinical features and disease progression in patients with PSC.Methods: A C to T coding polymorphism (rs8734) and a TG deletion in the 3´- untranslated region (rs3838646) were genotyped. The study cohort comprises of 359 PSC patients for rs3838646 genotype and 335 PSC patients for rs8734 genotype. Clinical and laboratory parameters were collected by chart review.Results: For the rs8734 genotype, 175 patients (52.2%) were found to be homozygous wildtype ('Ala/Ala'), 127 (37.9%) patients were heterozygous ('Ala/Val') and 33 patients (9.9%) were homozygous mutant ('Val/Val'). The rs8734genotype was associated with a decreased risk for dominant strictures at first diagnosis of PSC (p = .04). For the rs3838646 genotype, 322 patients (89.7%) were found to be homozygous wildtype ('TG/TG'); 37 showed the 'TG/del' genotype (10.3%). The 'TG/del'genotype was associated with alower risk of IBD (p = .01).There was no influence of both CD24 SNPs with clinical end points or transplantation-free survival in our PSC cohort.Conclusion: Our results suggest a mild association of the rs8734 CD24 genotype with dominant strictures at first diagnosis of PSC. The rs3838646 CD24 genotype is associated with a lower rate of IBD. Both SNPs seem to modulate the clinical phenotype without major pathogenetic importance for disease progression in PSC.

Effect of scheduled endoscopic dilatation of dominant strictures on outcome in patients with primary sclerosing cholangitis.

OBJECTIVE: Scheduled endoscopic dilatation of dominant strictures (DS) in primary sclerosing cholangitis (PSC) might improve outcome relative to endoscopic treatment on demand, but evidence is limited. Since randomisation is difficult in clinical practice, we present a large retrospective study comparing scheduled versus on-demand endoscopic retrograde cholangiopancreatography (ERCP) based on patient preferences. DESIGN: Between 1987 and 2017, all new patients with PSC had been offered scheduled ERCP with dilatation of a DS if diagnosed; the latter was repeated at defined intervals until morphological resolution, independent of clinical symptoms (treatment group). Patients who refused participation were clinically evaluated annually and received endoscopic treatment only on demand (control group). The primary clinical endpoint was transplantation-free survival. Secondary outcomes were overall survival, bacterial cholangitis episodes, hepatic decompensation of liver cirrhosis and endoscopy-related adverse events. RESULTS: The final study included 286 patients, 133 (46.5%) receiving scheduled ERCP and 153 (53.5%) receiving on-demand ERCP. After a mean follow-up of 9.9 years, the rate of transplantation-free survival was higher in patients receiving scheduled ERCP (51% vs 29.3%; p<0.001), as was transplantation-free survival time (median: 17.9 vs 15.2 years; log-rank: p=0.008). However, the benefit of scheduled ERCP was significant only in patients with the initial (17.1%) or later (45.5%) diagnosis of a DS (17.8 vs 11.1 years; log-rank: p<0.001). IBD (p=0.03), DS (p=0.006), higher Mayo Risk Score (p=0.02) and non-adherence to scheduled endoscopy (p=0.005) were independently associated with transplantation-free survival. CONCLUSION: In our large retrospective study, regular ERCP with endoscopic balloon dilatation significantly benefits patients with PSC with DS, diagnosed both at initial presentation and during surveillance, even if asymptomatic. Further studies have to find out how to best identify stricture patients non-invasively.

Association between serum IgG level and clinical course in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a chronic cholestatic liver disease. The pathomechanism is still not fully understood, but there is evidence that immune-mediated processes may contribute to disease progression. METHODS: We studied the prognostic relevance of serum immunoglobulin G (IgG) elevated above the upper limit of normal as a marker for immune activation at initial diagnosis and its influence on transplantation-free survival in a well-defined cohort of PSC patients. RESULTS: The final study cohort comprises of 148 PSC patients. Elevated IgG levels were found in 66 patients (44.6%). Apart from their younger age at first diagnosis, there was no significant difference between patients with or without elevated IgG levels. The presence of a concomitant inflammatory bowel disease, an autoimmune hepatitis or immunosuppressive medication was equally distributed between both groups. Patients with elevated IgG levels reached the combined endpoint (34 (59.6%) vs. 23 (40.4%); p = 0.004) significantly more often and had reduced transplantation-free survival (Log-rank: 24.0 (10.2-37.9) vs. 14.0 (8.5-19.5); p < 0.05). Cox regression analysis including age, gender, presence of IBD, presence of dominant stricture (DS), Mayo Risk Score (MRS), immunosuppression, biochemical response to UDCA and elevated IgG-levels confirmed MRS (p = 0.03), DS (p = 0.04), biochemical response (p = 0.04) and elevated IgG level (p = 0.04) as independent risk factors for reduced transplantation-free survival. CONCLUSION: We identified elevated serum IgG levels at first diagnosis as an independent risk factor for reduced transplant free-survival in patients with PSC.

An Outpatient Management Strategy Using a Coronataxi Digital Early Warning System Reduces Coronavirus Disease 2019 Mortality.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused sudden, severe strain to healthcare systems. Better outpatient management is required to save lives, manage resources effectively, and prepare for future pandemics. Methods: The Coronataxi digital early warning (CDEW) system deployed in Rhein-Neckar County and Heidelberg, Germany is an outpatient care system consisting of remote digital monitoring via a mobile application, a medical doctor dashboard, and medical care delivery to COVID-19 patients in home quarantine when indicated. Patients reported their symptoms, temperature, breathing rate, oxygen saturation, and pulse via the app. This single-center cohort study compared outcomes of the population with and without using the CDEW system. The primary outcome was mortality; the secondary outcomes were hospitalization, duration of hospitalization, intensive care therapy, and mechanical ventilation. Results: Mortality rate was 3- to 4-fold lower and hospitalization rate was higher in the CDEW cohort (459 patients) compared with the cohort without CDEW in the same test area and other regions (Mannheim, Karlsruhe town, Karlsruhe district, and Germany), (mortality rate: 0.65% [95% confidence interval {CI}, .13%-1.90%] versus 2.16%, 2.32%, 2.48%, 2.82% and 2.76%, respectively, P < .05 for all; hospitalization rate: 14.81% [95% CI, 11.69%-18.40%] versus 6.89%, 6.93%, 6.59%, 6.15%, and 7.22%, respectively, P < .001 for all). The median duration of hospitalization in the CDEW cohort was significantly lower compared with a national sentinel cohort (6 days [interquartile range {IQR}, 4-9.75 days] versus 10 days [IQR, 5-19 days]; Z = -3.156; P = .002). A total of 1.96% patients needed intensive care and 1.09% were mechanically ventilated. Conclusions: The CDEW system significantly reduced COVID-19 mortality and duration of hospitalization and can be applied to the management of future pandemics.

High rate of HSV-1 reactivation in invasively ventilated COVID-19 patients: Immunological findings.

SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome with the need of invasive ventilation. Pulmonary herpes simplex-1 (HSV-1) reactivation in invasively ventilated patients is a known phenomenon. To date very little is known about the frequency and the predisposing factors of HSV-1 reactivation in COVID-19. Therefore, we evaluated our cohort of invasively ventilated COVID-19 patients with severe pneumonia for HSV-1 in respiratory specimens and combined these results with functional immunomonitoring of the peripheral blood. Tracheal secretions and bronchial lavages were screened by PCR for HSV-1 positivity. Comprehensive immunophenotyping and quantitative gene expression analysis of Interferon-stimulated genes (IFI44L, MX1, RSAD2, ISIG15 and IFIT1) and IL-1 beta were performed in whole blood. Time course of infection beginning at symptom onset was grouped into three phases ("early" phase 1: day 1-10, "middle" phase 2: day 11-30 and "late" phase 3: day 31-40). Pulmonary HSV-1 reactivation was exclusively observed in the later phases 2 and 3 in 15 of 18 analyzed patients. By FACS analysis a significant increase in activated CD8 T cells (CD38+HLADR+) in phase 2 was found when compared with phase 1 (p<0.05). Expression of Interferon-stimulated genes (IFI44L, RSAD2 ISIG15, MX1, IFIT1) was significantly lower after HSV-1 detection than before. Taken together, reactivation of HSV-1 in the later phase of SARS-CoV-2- infection occurs in parallel with a drop of antiviral innate responsiveness as shown by decreased expression of Interferon-stimulated genes and a concurrent increase of highly activated CD38+HLADR+ CD8 T cells.

From Multiplex Serology to Serolomics-A Novel Approach to the Antibody Response against the SARS-CoV-2 Proteome.

The emerging SARS-CoV-2 pandemic entails an urgent need for specific and sensitive high-throughput serological assays to assess SARS-CoV-2 epidemiology. We, therefore, aimed at developing a fluorescent-bead based SARS-CoV-2 multiplex serology assay for detection of antibody responses to the SARS-CoV-2 proteome. Proteins of the SARS-CoV-2 proteome and protein N of SARS-CoV-1 and common cold Coronaviruses (ccCoVs) were recombinantly expressed in E. coli or HEK293 cells. Assay performance was assessed in a COVID-19 case cohort (n = 48 hospitalized patients from Heidelberg) as well as n = 85 age- and sex-matched pre-pandemic controls from the ESTHER study. Assay validation included comparison with home-made immunofluorescence and commercial enzyme-linked immunosorbent (ELISA) assays. A sensitivity of 100% (95% CI: 86-100%) was achieved in COVID-19 patients 14 days post symptom onset with dual sero-positivity to SARS-CoV-2 N and the receptor-binding domain of the spike protein. The specificity obtained with this algorithm was 100% (95% CI: 96-100%). Antibody responses to ccCoVs N were abundantly high and did not correlate with those to SARS-CoV-2 N. Inclusion of additional SARS-CoV-2 proteins as well as separate assessment of immunoglobulin (Ig) classes M, A, and G allowed for explorative analyses regarding disease progression and course of antibody response. This newly developed SARS-CoV-2 multiplex serology assay achieved high sensitivity and specificity to determine SARS-CoV-2 sero-positivity. Its high throughput ability allows epidemiologic SARS-CoV-2 research in large population-based studies. Inclusion of additional pathogens into the panel as well as separate assessment of Ig isotypes will furthermore allow addressing research questions beyond SARS-CoV-2 sero-prevalence.

Description and analysis of representative COVID-19 cases-A retrospective cohort study.

BACKGROUND: Most data on COVID-19 was collected in hospitalized cases. Much less is known about the spectrum of disease in entire populations. In this study, we examine a representative cohort of primarily symptomatic cases in an administrative district in Southern Germany. METHODS: We contacted all confirmed SARS-CoV-2 cases in the administrative district. Consenting participants answered a retrospective survey either via a telephone, electronically or via mail. Clinical and sociodemographic features were compared between hospitalized and non-hospitalized patients. Additionally, we assessed potential risk factors for hospitalization and time to hospitalization in a series of regression models. RESULTS: We included 897 participants in our study, 69% out of 1,305 total cases in the district with a mean age of 47 years (range 2-97), 51% of which were female and 47% had a pre-existing illness. The percentage of asymptomatic, mild, moderate (leading to hospital admission) and critical illness (requiring mechanical ventilation) was 54 patients (6%), 713 (79%), 97 (11%) and 16 (2%), respectively. Seventeen patients (2%) died. The most prevalent symptoms were fatigue (65%), cough (62%) and dysgeusia (60%). The risk factors for hospitalization included older age (OR 1.05 per year increase; 95% CI 1.04-1.07) preexisting lung conditions (OR 3.09; 95% CI 1.62-5.88). Female sex was a protective factor (OR 0.51; 95% CI 0.33-0.77). CONCLUSION: This representative analysis of primarily symptomatic COVID-19 cases confirms age, male sex and preexisting lung conditions but not cardiovascular disease as risk factors for severe illness. Almost 80% of infection take a mild course, whereas 13% of patients suffer moderate to severe illness. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00022926. URL: https://www.drks.de/drks_web/setLocale_EN.do.

Hypoferremia is Associated With Increased Hospitalization and Oxygen Demand in COVID-19 Patients.

Iron metabolism might play a crucial role in cytokine release syndrome in COVID-19 patients. Therefore, we assessed iron metabolism markers in COVID-19 patients for their ability to predict disease severity. COVID-19 patients referred to the Heidelberg University Hospital were retrospectively analyzed. Patients were divided into outpatients (cohort A, n = 204), inpatients (cohort B, n = 81), and outpatients later admitted to hospital because of health deterioration (cohort C, n = 23). Iron metabolism parameters were severely altered in patients of cohort B and C compared to cohort A. In multivariate regression analysis including age, gender, CRP and iron-related parameters only serum iron and ferritin were significantly associated with hospitalization. ROC analysis revealed an AUC for serum iron of 0.894 and an iron concentration <6 µmol/l as the best cutoff-point predicting hospitalization with a sensitivity of 94.7% and a specificity of 67.9%. When stratifying inpatients in a low- and high oxygen demand group serum iron levels differed significantly between these two groups and showed a high negative correlation with the inflammatory parameters IL-6, procalcitonin, and CRP. Unexpectedly, serum iron levels poorly correlate with hepcidin. We conclude that measurement of serum iron can help predicting the severity of COVID-19. The differences in serum iron availability observed between the low and high oxygen demand group suggest that disturbed iron metabolism likely plays a causal role in the pathophysiology leading to lung injury.

Vitamin D Deficiency and Outcome of COVID-19 Patients.

Infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses an enormous challenge to health care systems throughout the world. Without causal treatment, identification of modifiable prognostic factors may help to improve outcomes. To explore possible associations of vitamin D (VitD) status with disease severity and survival, we studied 185 patients diagnosed with coronavirus disease 2019 (COVID-19) and treated at our center. VitD status at first presentation was assessed retrospectively using accredited laboratory methods. VitD deficiency was defined as serum total 25-hydroxyvitamin D level < 12 ng/mL (<30 nM). Primary endpoint was severe course of disease (i.e., need for invasive mechanical ventilation and/or death, IMV/D). Within a median observation period of 66 days (range 2-92), 23 patients required IMV. A total of 28 patients had IMV/D, including 16 deaths. Ninety-three (50%) patients required hospitalization (inpatient subgroup). A total of 41 (22%) patients were VitD deficient. When adjusted for age, gender, and comorbidities, VitD deficiency was associated with higher risk of IMV/D and death (HR 6.12, 95% CI 2.79-13.42, p < 0.001 and HR 14.73, 95% CI 4.16-52.19, p < 0.001, respectively). Similar correlations were observed in the inpatient subgroup. Our study demonstrates an association between VitD deficiency and severity/mortality of COVID-19, highlighting the need for interventional studies on VitD supplementation in SARS-CoV-2 infected individuals.

Multidrug-Resistant Bacteria and Disease Progression in Patients with End-Stage Liver Disease and after Liver Transplantation.

BACKGROUND: Multidrug-resistant (MDR) pathogens represent an emerging challenge in end-stage liver disease and in liver transplant recipients. METHODS: We evaluated the impact of MDR bacteria upon clinical outcomes in patients with end-stage liver disease (n = 777) at the time of enrollment on the liver transplant (LTx) waiting list, after first LTx (n = 645), and after second LTx (n = 128). RESULTS: Colonization/infection with MDR bacteria was present in 72/777 patients on the waiting list, in 98/645 patients at first LTx, and in 46/128 patients at second LTx. While on the LTx waiting list, the time until first hydropic decompensation (p = 0.021), hepatic encephalopathy (p < 0.001) and hepatorenal syndrome (p < 0.001) was reduced in the presence of MDR bacteria, which remained an independent risk factor of poor survival in multivariate analysis (p < 0.001). Following first and second liver transplant, MDR bacteria were associated with an increased risk of infection-related deaths (first LTx: p < 0.001; second LTx: p = 0.037) and reduced actuarial survival (first LTx: p < 0.001; second LTx: p = 0.046). CONCLUSIONS: We showed that MDR pathogens are associated with poor outcomes before, after first and after recurrent LTx.

Successful combination of direct antiviral agents in liver-transplanted patients with recurrent hepatitis C virus.

AIM: To analyze the safety and efficiency of direct-acting antiviral (DAA) regimens in liver-transplanted patients with hepatitis C virus (HCV) reinfection. METHODS: Between January 2014 and December 2016, 39 patients with HCV reinfection after liver transplantation were treated at our tertiary referral center with sofosbuvir (SOF)-based regimens, including various combinations with interferon (IFN), daclatasvir (DAC), simeprivir (SIM) and/or ledipasvir (LDV). Thirteen patients were treated with SOF + IFN ± RBV. Ten patients were treated with SOF + DAC ± RBV. Fiveteen patients were treated with fixed-dose combination of SOF + LDV ± RBV. One patient was treated with SOF + SIM + RBV. Three patients with relapse were retreated with SOF + LDV + RBV. The treatment duration was 12-24 wk in all cases. The decision about the HCV treatment was made by specialists at our transplant center, according to current available or recommended medications. RESULTS: The majority of patients were IFN-experienced (29/39, 74.4%) and had a history of hepatocellular carcinoma (26/39, 66.7%) before liver transplantation. Sustained virological response at 12 wk (SVR12) was achieved in 10/13 (76.9%) of patients treated with SOF + IFN ± RBV. All patients with relapse were treated with fixed-dose combination of SOF + LDV + RBV. Patients treated with SOF + DAC + RBV or SOF + LDV + RBV achieved 100% SVR12. SVR rates after combination treatment with inhibitors of the HCV nonstructural protein (NS)5A and NS5B for 24 wk were significantly higher, as compared to all other therapy regimens (P = 0.007). Liver function was stable or even improved in the majority of patients during treatment. All antiviral therapies were safe and well-tolerated, without need of discontinuation of treatment or dose adjustment of immunosuppression. No serious adverse events or any harm to the liver graft became overt. No patient experienced acute cellular rejection during the study period. CONCLUSION: Our cohort of liver-transplanted patients achieved high rates of SVR12 after a 24-wk course of treatment, especially with combination of NS5A and NS5B inhibitors.