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Article: The Renin-Angiotensin System in COVID-19: Can Long COVID Be Predicted?

König, Simone / Vollenberg, Richard / Tepasse, Phil-Robin

2023 Volume 13, Issue 7

Abstract: 1) Background: Co-morbidities such as hypertension and cardiovascular disease are major risk factors for severe COVID-19. The renin-angiotensin system (RAS) is critically involved in their pathophysiology and is counter-balanced by both angiotensin- ... ...

Abstract	(1) Background: Co-morbidities such as hypertension and cardiovascular disease are major risk factors for severe COVID-19. The renin-angiotensin system (RAS) is critically involved in their pathophysiology and is counter-balanced by both angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV-2, and the kallikrein-kinin system (KKS). Considerable research interest with respect to COVID-19 treatment is currently being directed towards the components of these systems. In earlier studies, we noticed significantly reduced carboxypeptidase N (CPN, KKS member) activity and excessive angiotensin-converting enzyme (ACE, RAS member) activity in the sera of both hospitalized COVID-19 patients and a subgroup of convalescent patients. The data had been obtained using labeled bradykinin (BK) as a reporter peptide, which is a target of both CPN and ACE. The data were supplemented with mass-spectrometry-based serum proteomic analysis. Here, we hypothesize that the degree of BK serum degradation could be indicative of Long COVID. (2) Review and Discussion: The recent literature is briefly reviewed. The fact that the levels of the BK serum degradation products did not reach normal concentrations in almost half of the patients during convalescences could have been partially due to a dysregulated RAS. (3) Conclusions: Standard tests for routine patient care in Long COVID come often back normal. We suggest that the measurement of selected members of the RAS such as ACE and angiotensin II or the use of our BK degradation assay could identify Long COVID candidates. Clinical studies are required to test this hypothesis.
Language	English
Publishing date	2023-06-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life13071462
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Article ; Online: A comparative analysis of the doctoral regulations at the medical faculties in Germany.

Altenberger, Sarah / Leischik, Roman / Vollenberg, Richard / Ehlers, Jan Peter / Strauss, Markus

International journal of medical sciences

2024 Volume 21, Issue 4, Page(s) 732–741

Abstract: Objective: ...

Abstract	Objective:
MeSH term(s)	Humans ; Education, Medical ; Faculty, Medical ; Germany ; Curriculum ; Physicians
Language	English
Publishing date	2024-02-12
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2151424-0
ISSN	1449-1907 ; 1449-1907
ISSN (online)	1449-1907
ISSN	1449-1907
DOI	10.7150/ijms.92167
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Article: Vaccination against SARS-CoV-2 in Patients with Inflammatory Bowel Diseases: Where Do We Stand?

Tepasse, Phil-Robin / Vollenberg, Richard / Nowacki, Tobias Max

Life (Basel, Switzerland)

2021 Volume 11, Issue 11

Abstract: Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBDs). Immunosuppressive medication is the main therapeutic approach to reducing inflammation of the gastrointestinal tract. Immunocompromised patients are more vulnerable to ...

Abstract	Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBDs). Immunosuppressive medication is the main therapeutic approach to reducing inflammation of the gastrointestinal tract. Immunocompromised patients are more vulnerable to severe courses of illness after infection with common pathogens. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen of the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 leads to acute respiratory distress syndrome (ARDS) following severe pulmonal damage in a significant number of cases. The worldwide circulation of SARS-CoV-2 has led to major concerns about the management of IBD patients during the pandemic, as these patients are expected to be at greater risk of complications because of their underlying altered immunological condition and immunosuppressive therapies. Vaccination against SARS-CoV-2 is considered the main approach in containing the pandemic. Today, several vaccines have been shown to be highly effective in the prevention of SARS-CoV-2 infection and severe disease course in subjects without underlying conditions in respective registration studies. Patients with underlying conditions such as IBD and/or immunosuppressive therapies were not included in the registration studies, so little is known about effectiveness and safety of SARS-CoV-2 vaccination in immunocompromised IBD patients. This review provides an overview of the recent knowledge about vaccine response in IBD patients after vaccination against SARS-CoV-2.
Language	English
Publishing date	2021-11-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life11111220
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Article ; Online: The Dysregulation of the Renin-Angiotensin System in COVID-19 Studied by Serum Proteomics: Angiotensinogen Increases with Disease Severity.

Tepasse, Phil-Robin / Vollenberg, Richard / Steinebrey, Nico / König, Simone

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 8

Abstract: 1) Background: ACE and CPN serum activity correlated with disease severity in an earlier study of 45 hospitalized COVID-19 patients. The serum protein profile was investigated in the same cohort here to shed more light on the involvement of the renin- ... ...

Abstract	(1) Background: ACE and CPN serum activity correlated with disease severity in an earlier study of 45 hospitalized COVID-19 patients. The serum protein profile was investigated in the same cohort here to shed more light on the involvement of the renin-angiotensin system (RAS). (2) Methods: High-definition mass spectrometry-based protein expression analysis was performed, followed by multivariate statistical and network analyses. (3) Results: The protein profiles of hospitalized patients (HoP) differed significantly from those of convalescent and healthy probands. Surprisingly, HoP samples separated into six groups according to their protein profiles: group (G) 1 represented the youngest and the least afflicted patients, and G6 the oldest and critically ill patients. At least two major pathophysiological schemes were indicated based on differing involvement of the kallikrein-kinin system (KKS), the RAS and complement activation. The serum angiotensinogen concentration increased with disease severity. (4) Conclusions: The important role of the RAS in the response to COVID-19 infection was substantiated, but other pathways such as the KKS, plasminogen activation and complement activation influence the systemic response to the infection.
MeSH term(s)	Angiotensinogen/metabolism ; COVID-19/complications ; Humans ; Peptidyl-Dipeptidase A/metabolism ; Proteomics ; Renin-Angiotensin System/physiology ; Severity of Illness Index
Chemical Substances	Angiotensinogen (11002-13-4) ; Peptidyl-Dipeptidase A (EC 3.4.15.1)
Language	English
Publishing date	2022-04-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27082495
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Article ; Online: Significantly Reduced Retinol Binding Protein 4 (RBP4) Levels in Critically Ill COVID-19 Patients.

Vollenberg, Richard / Tepasse, Phil-Robin / Fobker, Manfred / Hüsing-Kabar, Anna

Nutrients

2022 Volume 14, Issue 10

Abstract: The SARS-CoV-2 virus is the causative agent of the COVID-19 pandemic. The disease causes respiratory failure in some individuals accompanied by marked hyperinflammation. Vitamin A (syn. retinol) can exist in the body in the storage form as retinyl ester, ...

Abstract	The SARS-CoV-2 virus is the causative agent of the COVID-19 pandemic. The disease causes respiratory failure in some individuals accompanied by marked hyperinflammation. Vitamin A (syn. retinol) can exist in the body in the storage form as retinyl ester, or in the transcriptionally active form as retinoic acid. The main function of retinol binding protein 4 (RBP4), synthesized in the liver, is to transport hydrophobic vitamin A to various tissues. Vitamin A has an important role in the innate and acquired immune system. In particular, it is involved in the repair of lung tissue after infections. In viral respiratory diseases such as influenza pneumonia, vitamin A supplementation has been shown to reduce mortality in animal models. In critically ill COVID-19 patients, a significant decrease in plasma vitamin A levels and an association with increased mortality have been observed. However, there is no evidence on RBP4 in relation to COVID-19. This prospective, multicenter, observational, cross-sectional study examined RBP4 (enzyme-linked immunosorbent assay) and vitamin A plasma levels (high-performance liquid chromatography) in COVID-19 patients, including 59 hospitalized patients. Of these, 19 developed critical illness (ARDS/ECMO), 20 developed severe illness (oxygenation disorder), and 20 developed moderate illness (no oxygenation disorder). Twenty age-matched convalescent patients following SARS-CoV-2 infection, were used as a control group. Reduced RBP4 plasma levels significantly correlated with impaired liver function and elevated inflammatory markers (CRP, lymphocytopenia). RBP4 levels were decreased in hospitalized patients with critical illness compared to nonpatients (p < 0.01). In comparison, significantly lower vitamin A levels were detected in hospitalized patients regardless of disease severity. Overall, we conclude that RBP4 plasma levels are significantly reduced in critically ill COVID-19 patients during acute inflammation, and vitamin A levels are significantly reduced in patients with moderate/severe/critical illness during the acute phase of illness.
MeSH term(s)	COVID-19/blood ; Critical Illness ; Cross-Sectional Studies ; Humans ; Prospective Studies ; Retinol-Binding Proteins, Plasma/analysis ; Vitamin A/blood
Chemical Substances	RBP4 protein, human ; Retinol-Binding Proteins, Plasma ; Vitamin A (11103-57-4)
Language	English
Publishing date	2022-05-10
Publishing country	Switzerland
Document type	Journal Article ; Multicenter Study ; Observational Study
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu14102007
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Article: Impaired Humoral Immunity with Concomitant Preserved T Cell Reactivity in IBD Patients on Treatment with Infliximab 6 Month after Vaccination with the SARS-CoV-2 mRNA Vaccine BNT162b2: A Pilot Study.

Vollenberg, Richard / Tepasse, Phil-Robin / Lorentzen, Eva / Nowacki, Tobias Max

Journal of personalized medicine

2022 Volume 12, Issue 5

Abstract: Introduction: The Coronavirus Disease 2019 (COVID-19) pandemic has been caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The most important approach to prevent severe disease progression and to contain the pandemic is the use ... ...

Abstract	Introduction: The Coronavirus Disease 2019 (COVID-19) pandemic has been caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The most important approach to prevent severe disease progression and to contain the pandemic is the use of COVID-19 vaccines. The aim of this study was to investigate the humoral and cellular response in immunosuppressed patients with inflammatory bowel disease (IBD) on treatment with anti-TNF (infliximab, adalimumab) and anti-α4ß7-Integrin (vedolizumab) 6 months after mRNA vaccination against SARS-CoV-2 compared to healthy subjects. Methods: In this prospective study, 20 IBD patients and 9 healthy controls were included 6 months after the second BNT162b2 vaccination. In addition to quantitative determination of IgG antibody levels against the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein subunit S1, a SARS-CoV-2 surrogate neutralization test (sVNT) was used to assess potential neutralization capacity. SARS-CoV-2-specific T-cell responses were measured using an interferon-γ (IFN-γ) release assay (IGRA; Euroimmun Medical Laboratory Diagnostics, Lübeck, Germany). Results: S-IgG could still be detected in the majority of IBD patients 6 months after second vaccination. Compared to healthy controls, IBD patients treated with anti-TNF agents showed both lower neutralizing activity in sVNT (percent inhibition of ACE2 receptor binding by RBD protein) and lower IgG-S (AU/mL) antibody levels (AB) (sVNT: 79% vs. 2%, p < 0. 001; AB: 1018 AU/mL vs. 141 AU/mL, p = 0.025). In contrast, patients on therapy with vedolizumab showed no impairment in humoral immune response (sVNT, S-IgG) compared with healthy controls. Specific T-cellular reactivity was detected in 73% of IBD patients and in 67% of healthy controls independent of immunosuppressive therapy (anti-TNF., vedolizumab) (p = 0.189). Conclusion: Six months after BNT162b2 vaccination, this study found significantly decreased antibody levels in patients under anti-TNF therapy. IBD patients under anti-TNF and vedolizumab therapy had no impairment of T-cellular reactivity compared to healthy controls at this time point. Further studies with larger collectives for confirmation should follow.
Language	English
Publishing date	2022-04-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662248-8
ISSN	2075-4426
ISSN	2075-4426
DOI	10.3390/jpm12050694
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Article: High Angiotensin-Converting Enzyme and Low Carboxypeptidase N Serum Activity Correlate with Disease Severity in COVID-19 Patients.

Tepasse, Phil-Robin / Vollenberg, Richard / Steinebrey, Nico / König, Simone

Journal of personalized medicine

2022 Volume 12, Issue 3

Abstract: 1) Background: Angiotensin-converting enzyme 2 (ACE2) is a functional receptor of SARS-CoV-2 and counter-balances ACE in the renin-angiotensin system (RAS). An imbalance of the RAS could be associated with severe COVID-19 progression. (2) Methods: ... ...

Abstract	(1) Background: Angiotensin-converting enzyme 2 (ACE2) is a functional receptor of SARS-CoV-2 and counter-balances ACE in the renin-angiotensin system (RAS). An imbalance of the RAS could be associated with severe COVID-19 progression. (2) Methods: Activities of serum proteases angiotensin-converting enzyme (ACE) and carboxypeptidase N (CPN) for 45 hospitalized and 26 convalescent COVID-19 patients were investigated vs. healthy controls using labeled bradykinin (DBK) degradation with and without inhibition by captopril as a read-out. Data were correlated to clinical parameters. (3) Results: DBK degradation and CPN activity were significantly reduced gender-independently in COVID-19 and returned to normal during convalescence. ACE activity was over-active in severe disease progression; product DBK1-5 was significantly increased in critically ill patients and strongly correlated with clinical heart and liver parameters. ACE inhibitors seemed to be protective, as DBK1-5 levels were normal in moderately ill patients in contrast to critically ill patients. (4) Conclusions: CPN and ACE serum activity correlated with disease severity. The RAS is affected in COVID-19, and ACE could be a therapeutic target. Further proof from dedicated studies is needed.
Language	English
Publishing date	2022-03-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662248-8
ISSN	2075-4426
ISSN	2075-4426
DOI	10.3390/jpm12030406
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Article ; Online: Familial Mediterranean fever and COVID-19. An ancient disease in a pandemic of the new millennium: is it an epiphenomenon of infection?

Sensoy, Timur S / Vollenberg, Richard / Meier, Jörn A / Tepasse, Phil-Robin

Rheumatology advances in practice

2021 Volume 5, Issue 3, Page(s) rkab097

Language	English
Publishing date	2021-12-08
Publishing country	England
Document type	Journal Article
ISSN	2514-1775
ISSN (online)	2514-1775
DOI	10.1093/rap/rkab097
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Article: Tularemia Presenting Solely with Cervical Lymphadenopathy and Fever.

Boeckel, Göran Ramin / Adiprasito, Jan Basri / Froböse, Neele Judith / Schaumburg, Frieder / Vollenberg, Richard / Tepasse, Phil-Robin

Diagnostics (Basel, Switzerland)

2022 Volume 12, Issue 8

Abstract: A 52-year-old German female presented with cervical lymphadenopathy and fever. Despite the initial symptom-presentation leading to the consideration of sarcoidosis, lymphoma, tuberculosis, and toxoplasmosis, an extensive serologic and histo- and ... ...

Abstract	A 52-year-old German female presented with cervical lymphadenopathy and fever. Despite the initial symptom-presentation leading to the consideration of sarcoidosis, lymphoma, tuberculosis, and toxoplasmosis, an extensive serologic and histo- and molecular pathologic workup eventually indicated a likely diagnosis of tularemia. This case brings to light that tularemia is a diagnostic challenge and requires high reliance on the epidemiological context thorough patient history, and an extensive interdisciplinary diagnostic workup.
Language	English
Publishing date	2022-08-18
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics12082000
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Article: Humoral Immunity in Immunosuppressed IBD Patients after the Third SARS-CoV-2 Vaccination: A Comparison with Healthy Control Subjects.

Vollenberg, Richard / Lorentzen, Eva Ulla / Kühn, Joachim / Nowacki, Tobias Max / Meier, Jörn Arne / Trebicka, Jonel / Tepasse, Phil-Robin

Vaccines

2023 Volume 11, Issue 9

Abstract: Introduction: The COVID-19 pandemic is a result of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccination against COVID-19 is crucial for preventing severe illness and controlling the pandemic. This study aimed to examine how ... ...

Abstract	Introduction: The COVID-19 pandemic is a result of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccination against COVID-19 is crucial for preventing severe illness and controlling the pandemic. This study aimed to examine how immunosuppressed patients with inflammatory bowel disease (IBD) responded to the third mRNA vaccination against SARS-CoV-2. The patients were undergoing treatments such as anti-TNF (infliximab, adalimumab), anti-α4ß7 integrin (vedolizumab), anti-IL12/23 (ustekinumab) and azathioprine (purine analog). Their responses were compared to those of healthy individuals. Methods: In this prospective study, 81 IBD patients and 15 healthy controls were enrolled 2-4 months after receiving the third mRNA vaccination. This study measured IgG antibody levels against the SARS-CoV-2 spike protein's receptor binding domain (RBD) and assessed potential neutralization capacity using a surrogate virus neutralization test (sVNT). Results: Overall, immunosuppressed IBD patients (without SARS-CoV-2 infection) exhibited significantly lower levels of anti-S-IgG (anti-RBD-IgG) and binding inhibition in the sVNT after the third vaccination compared to healthy controls. Patients under anti-TNF therapy showed notably reduced anti-S-IgG levels after the booster vaccination, in contrast to those receiving ustekinumab and azathioprine ( Conclusion: Even after the third vaccination, immunosuppressed IBD patients exhibited diminished humoral immunity compared to healthy controls, especially those on anti-TNF therapy. Cases of penetrating infections led to considerably higher antibody levels in IBD patients under anti-TNF therapy compared to uninfected patients. Further investigation through prospective studies in immunosuppressed IBD patients is needed to determine whether this effectively safeguards against future infections or severe disease.
Language	English
Publishing date	2023-08-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines11091411
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