Publications by authors named "Theresa Hippchen"

13 Publications

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

PLoS One 2021 30;16(7):e0255513. Epub 2021 Jul 30.

Heidelberg Institute of Global Health, Heidelberg University Hospital, Heidelberg, Germany.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255513PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323911PMC
August 2021

Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study.

Clin Infect Dis 2021 Jul 5. Epub 2021 Jul 5.

Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.

Background: Long COVID is defined as the persistence of symptoms beyond 3 months after SARS-CoV-2 infection. To better understand the long-term course and etiology of symptoms we analyzed a cohort of COVID-19 patients prospectively.

Methods: Patients were included at 5 months after acute COVID-19 in this prospective, non-interventional follow-up study. Patients followed until 12 months after COVID-19 symptom onset (n=96, 32.3% hospitalised, 55.2% females) were included in this analysis of symptoms, quality of life (based on a SF-12 survey), laboratory parameters including antinuclear antibodies (ANA), 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%), dyspnoea (37.5%), concentration problems (39.6%), problems finding words (32.3%), and sleeping problems (26.0%). Females showed significantly more neurocognitive symptoms than males.ANA titres 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 titre ≥1:160 compared to <1:160. Compared to patients without symptoms, patients with at least one 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 to patients without symptoms.

Conclusions: Neurocognitive long COVID symptoms can persist at least for one year after COVID-19 symptom onset, and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titre elevations. This may indicate autoimmunity as cofactor in aetiology of long COVID.
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http://dx.doi.org/10.1093/cid/ciab611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394862PMC
July 2021

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

PLoS One 2021 1;16(7):e0254129. Epub 2021 Jul 1.

Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254129PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248692PMC
July 2021

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

Viruses 2021 04 24;13(5). Epub 2021 Apr 24.

Infections and Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), 69120 Heidelberg, Germany.

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 or HEK293 cells. Assay performance was assessed in a COVID-19 case cohort ( = 48 hospitalized patients from Heidelberg) as well as = 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.
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http://dx.doi.org/10.3390/v13050749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147094PMC
April 2021

Solid organ transplantation is not a risk factor for COVID-19 disease outcome.

Transpl Int 2021 02 10;34(2):378-381. Epub 2021 Jan 10.

Department of Internal Medicine I, Department of Gastroenterology, Hepatology, Nephrology, Infectiology, Endocrinology and Diabetology, University Hospital Bonn, Bonn, Germany.

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http://dx.doi.org/10.1111/tri.13795DOI Listing
February 2021

Coronataxi Brings Outpatient Care to COVID-19 Patients.

Ann Emerg Med 2020 12 5;76(6):811-812. Epub 2020 Jun 5.

Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1016/j.annemergmed.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274638PMC
December 2020

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

Hemasphere 2020 Dec 10;4(6):e492. Epub 2020 Nov 10.

Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1097/HS9.0000000000000492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665253PMC
December 2020

Vitamin D Deficiency and Outcome of COVID-19 Patients.

Nutrients 2020 Sep 10;12(9). Epub 2020 Sep 10.

Department of Internal Medicine IV, University of Heidelberg, 69121 Heidelberg, Germany.

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, < 0.001 and HR 14.73, 95% CI 4.16-52.19, < 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.
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http://dx.doi.org/10.3390/nu12092757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551780PMC
September 2020

Evaluation of two functional CD24 polymorphisms in primary sclerosing cholangitis.

Scand J Gastroenterol 2020 May 24;55(5):581-587. Epub 2020 Apr 24.

Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.

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). This retrospective study aimed to evaluate the impact of two functional CD24 SNPs on clinical features and disease progression in patients with PSC. 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. 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 ( = .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 ( = .01).There was no influence of both CD24 SNPs with clinical end points or transplantation-free survival in our PSC cohort. 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.
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http://dx.doi.org/10.1080/00365521.2020.1755357DOI Listing
May 2020

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

J Gastrointestin Liver Dis 2019 Sep 1;28(3):303-310. Epub 2019 Sep 1.

Department of General, Visceral and Tansplant Surgery, University Hospital of Heidelberg, Heidelberg, Germany.

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.
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http://dx.doi.org/10.15403/jgld-212DOI Listing
September 2019

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

BMC Gastroenterol 2019 Aug 27;19(1):153. Epub 2019 Aug 27.

Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1186/s12876-019-1075-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712727PMC
August 2019

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

Gut 2019 12 25;68(12):2170-2178. Epub 2019 Mar 25.

Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1136/gutjnl-2018-316801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872453PMC
December 2019

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

World J Gastroenterol 2018 Mar;24(12):1353-1360

Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg 69120, Germany.

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 ( = 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.
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http://dx.doi.org/10.3748/wjg.v24.i12.1353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871830PMC
March 2018
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