Immediate-type hypersensitivity reaction to bulevirtide and successful desensitization in a patient with HBV/HDV-associated compensated cirrhosis
2022; Elsevier BV; Volume: 77; Issue: 1 Linguagem: Inglês
10.1016/j.jhep.2022.03.004
ISSN1600-0641
AutoresCaroline Schwarz, David Chromy, Christine Bangert, Michael Schwarz, Mathias Jachs, Thomas Reiberger, Michael Gschwantler,
Tópico(s)Drug-Induced Hepatotoxicity and Protection
ResumoIn July 2020, bulevirtide (BLV) – a new HDV hepatocyte entry-inhibitor – was licensed for the treatment of HBV/HDV coinfection in Europe.[1]EMA. Hepcludex product information [Internet]. Available from: https://www.ema.europa.eu/en/documents/product-information/hepcludex-epar-product-information_en.pdf.Google Scholar BLV showed excellent drug tolerability and safety in clinical trials and during the first months of clinical use.[2]Bogomolov P. Alexandrov A. Voronkova N. Macievich M. Kokina K. Petrachenkova M. et al.Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study.J Hepatol. 2016; 65: 490-498Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar,[3]Loglio A. Ferenci P. Uceda Renteria S.C. Tham C.Y.L. van Bömmel F. Borghi M. et al.Excellent safety and effectiveness of high-dose myrcludex-B monotherapy administered for 48 weeks in HDV-related compensated cirrhosis: a case report of 3 patients.J Hepatol. 2019 Oct; 71: 834-839Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Notably, no allergic reactions associated with BLV have been recorded so far. We report a case of immediate-type hypersensitivity reaction to BLV and present a clinical approach for desensitization.A 35-year-old female patient of Romanian descent with HBV/HDV-associated compensated cirrhosis (Child-Pugh A, liver stiffness of 17.5 kPa on transient elastography in October 2020) had been treated with tenofovir (TDF) and pegylated interferon alpha (PEG-IFN) since July 2018 and June 2019, respectively.[4]Wedemeyer H. Yurdaydin C. Hardtke S. Caruntu F.A. Curescu M.G. Yalcin K. et al.Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial.Lancet Infect Dis. 2019 Mar; 19: 275-286Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Due to progressive thrombocytopenia and anemia as well as persisting HDV-viremia (HDV-RNA 10.040 copies/ml) under TDF and PEG-IFN, PEG-IFN was discontinued in exchange for BLV in December 2020. After unremarkable subcutaneous application of the first dose of BLV 2 mg at our outpatient clinic, the patient continued self-administered daily treatment according to current recommendations.[1]EMA. Hepcludex product information [Internet]. Available from: https://www.ema.europa.eu/en/documents/product-information/hepcludex-epar-product-information_en.pdf.Google ScholarAfter the sixth dose of BLV, the patient reported progressive pruritus and swelling of the upper extremities, of the face and lips as well as dyspnea starting after the third injection of BLV, indicative of type-1 allergic reaction. BLV was stopped immediately and the patient recovered quickly without any further intervention, therefore no corticosteroids were administered. Concurrent medication at this time included TDF, vitamin D substitution, and on-demand treatment with metamizole for recurrent headaches.Although the relation between treatment initiation and onset of symptoms (and symptom resolution after treatment cessation) was suggestive of a type-I allergic reaction, potential differential diagnoses were considered: Normal tryptase serum levels after all symptoms had resolved ruled out systemic mastocytosis. No intercurrent infections were reported and symptoms did not persist longer than 6 weeks, thus acute and chronic spontaneous urticaria were ruled out. No atopic predisposition was assumed as both serum IgE and eosinophil counts were within the normal range, and the patient reported an unremarkable family history regarding allergies. Of note, the patient reported a previous anaphylactic reaction to clarithromycin.Further diagnostic steps were performed at Department of Dermatology at the Vienna General Hospital: (a) prick testing with BLV (1 mg/ml) and (b) intradermal/intracutaneous skin testing with BLV (1:100, 0.01 mg/ml) did not provoke any reaction, however, higher intradermal/intracutaneous BLV concentrations (1:10 0.1 mg/ml; undiluted 1 mg/ml) induced an immediate reaction.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google ScholarPositive intracutaneous skin testing is typically induced by IgE-mediated mast cell degranulation causing type-I hypersensitivity.[6]Vultaggio A. Matucci A. Nencini F. Bormioli S. Vivarelli E. Maggi E. Mechanisms of drug desensitization: not only mast cells.Front Pharmacol. 2020 Dec 23; 11: 590991Crossref PubMed Scopus (10) Google Scholar Desensitization can be considered for IgE-mediated hypersensitivity under certain preconditions.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar Due to the strong indication for HDV-active treatment and the previously insufficient response to PEG-IFN, BLV represented the only therapeutic option in this patient. Comedication with corticosteroids was not considered a rationale option due to the long-term treatment indication. Therefore, we decided to perform desensitization to BLV in an in-patient setting with emergency treatment being readily available. Since our patient demonstrated a strong skin reaction at 0.1 mg/ml (1:10 dilution) BLV, the starting dose was cautiously determined as 1/100 (0.03 mg) of the target dose (2 mg).[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar Over the course of 3 days, the patient received consecutive doses of BLV every 30 minutes. Doses were doubled each time until the per-day target dose was reached. Concomitantly, antihistaminergic treatment (levocetirizine 5 mg) was administered once daily (Table 1). Once regular dosing was established, the patient was discharged and self-administered subcutaneous treatment with BLV was continued at the recommended dosage of 2 mg once daily. Concomitant treatment with levocetirizine was discontinued 8 weeks after the re-initiation of BLV. No local or systemic adverse reactions were observed during re-exposure to BLV nor after withdrawal of the antihistaminergic comedication.Table 1Bulevirtide desensitization protocol used for our patient.Day 1 – 2 mg bulevirtide/2 ml aquaDay 2 – 2 mg bulevirtide/1 ml aquaDay 3 – 2 mg bulevirtide/1 ml aquaStart:0.03 ml (0.03 mg)0.50 ml (1 mg)1.0 ml (2 mg)30 min:0.05 ml (0.05 mg)0.50 ml (1 mg)60 min:0.15 ml (0.15 mg)90 min:0.30 ml (0.30 mg)120 min:0.50 ml (0.50 mg)150 min:0.97 ml (0.97 mg) Open table in a new tab Based on this case, the potentially life-threatening consequences of an immediate-type hypersensitivity reaction to BLV have to be considered in clinical application and in patients' counselling, especially since the distinction between common BLV-associated pruritus and incipient allergic reactions may be difficult.[1]EMA. Hepcludex product information [Internet]. Available from: https://www.ema.europa.eu/en/documents/product-information/hepcludex-epar-product-information_en.pdf.Google Scholar Importantly, HDV-related liver disease progression and complications will constitute the major prognostic factor in most HBV/HDV-coinfected individuals.7Kamal H. Westman G. Falconer K. Duberg A.-S. Weiland O. Haverinen S. et al.Long-term study of hepatitis delta virus infection at secondary care centers: the impact of viremia on liver-related outcomes.Hepatol Baltim Md. 2020 Oct; 72: 1177-1190Crossref PubMed Scopus (25) Google Scholar, 8Urban S. Neumann-Haefelin C. Lampertico P. Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease.Gut. 2021 Sep; 70: 1782-1794Crossref PubMed Scopus (47) Google Scholar, 9Jachs M. Binter T. Schmidbauer C. Hartl L. Strasser M. Laferl H. et al.Hepatitis D virus (HDV) prevalence in Austria is low but causes considerable morbidity due to fast progression to cirrhosis.United Eur Gastroenterol J. 2021 Dec; 9: 1119-1127Crossref PubMed Scopus (6) Google Scholar, 10Schmidbauer C. Chromy D. Schmidbauer V.U. Schwarz M. Jachs M. Bauer D.J.M. et al.Epidemiological trends of HBV and HDV coinfection among Viennese HIV+ patients.Liver Int Off J Int Assoc Study Liver. 2021 Nov; 41: 2622-2634PubMed Google ScholarBLV, which is marketed as a soluble powder, does not contain any other potential allergens aside from BLV itself.[1]EMA. Hepcludex product information [Internet]. Available from: https://www.ema.europa.eu/en/documents/product-information/hepcludex-epar-product-information_en.pdf.Google Scholar While several mechanisms have been proposed to cause immediate-type hypersensitivity reactions, IgE-mediated hypersensitivity remains the "typical" pathway for type-I reaction. Positive skin testing confirmatory for IgE-mediated hypersensitivity supported our clinical approach to initiate desensitization, which was originally designed for IgE-mediated reactions.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar,[6]Vultaggio A. Matucci A. Nencini F. Bormioli S. Vivarelli E. Maggi E. Mechanisms of drug desensitization: not only mast cells.Front Pharmacol. 2020 Dec 23; 11: 590991Crossref PubMed Scopus (10) Google Scholar Notably, the underlying mechanism of desensitization is currently not fully understood.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar,[6]Vultaggio A. Matucci A. Nencini F. Bormioli S. Vivarelli E. Maggi E. Mechanisms of drug desensitization: not only mast cells.Front Pharmacol. 2020 Dec 23; 11: 590991Crossref PubMed Scopus (10) Google Scholar While patients have to be informed about the risk of a recurrent hypersensitivity reaction during re-exposure and its general experimental approach, successful desensitization may enable HDV-active antiviral therapy with BLV in patients with confirmed previous hypersensitivity reactions to BLV.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar Importantly, adequate safety precautions have to be taken during re-exposure and uninterrupted treatment with BLV must be ensured after successful desensitization to avoid recurrent hypersensitivity reactions.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google ScholarFinancial supportThe authors received no financial support to produce this manuscript. In July 2020, bulevirtide (BLV) – a new HDV hepatocyte entry-inhibitor – was licensed for the treatment of HBV/HDV coinfection in Europe.[1]EMA. Hepcludex product information [Internet]. Available from: https://www.ema.europa.eu/en/documents/product-information/hepcludex-epar-product-information_en.pdf.Google Scholar BLV showed excellent drug tolerability and safety in clinical trials and during the first months of clinical use.[2]Bogomolov P. Alexandrov A. Voronkova N. Macievich M. Kokina K. Petrachenkova M. et al.Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study.J Hepatol. 2016; 65: 490-498Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar,[3]Loglio A. Ferenci P. Uceda Renteria S.C. Tham C.Y.L. van Bömmel F. Borghi M. et al.Excellent safety and effectiveness of high-dose myrcludex-B monotherapy administered for 48 weeks in HDV-related compensated cirrhosis: a case report of 3 patients.J Hepatol. 2019 Oct; 71: 834-839Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Notably, no allergic reactions associated with BLV have been recorded so far. We report a case of immediate-type hypersensitivity reaction to BLV and present a clinical approach for desensitization. A 35-year-old female patient of Romanian descent with HBV/HDV-associated compensated cirrhosis (Child-Pugh A, liver stiffness of 17.5 kPa on transient elastography in October 2020) had been treated with tenofovir (TDF) and pegylated interferon alpha (PEG-IFN) since July 2018 and June 2019, respectively.[4]Wedemeyer H. Yurdaydin C. Hardtke S. Caruntu F.A. Curescu M.G. Yalcin K. et al.Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial.Lancet Infect Dis. 2019 Mar; 19: 275-286Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Due to progressive thrombocytopenia and anemia as well as persisting HDV-viremia (HDV-RNA 10.040 copies/ml) under TDF and PEG-IFN, PEG-IFN was discontinued in exchange for BLV in December 2020. After unremarkable subcutaneous application of the first dose of BLV 2 mg at our outpatient clinic, the patient continued self-administered daily treatment according to current recommendations.[1]EMA. Hepcludex product information [Internet]. Available from: https://www.ema.europa.eu/en/documents/product-information/hepcludex-epar-product-information_en.pdf.Google Scholar After the sixth dose of BLV, the patient reported progressive pruritus and swelling of the upper extremities, of the face and lips as well as dyspnea starting after the third injection of BLV, indicative of type-1 allergic reaction. BLV was stopped immediately and the patient recovered quickly without any further intervention, therefore no corticosteroids were administered. Concurrent medication at this time included TDF, vitamin D substitution, and on-demand treatment with metamizole for recurrent headaches. Although the relation between treatment initiation and onset of symptoms (and symptom resolution after treatment cessation) was suggestive of a type-I allergic reaction, potential differential diagnoses were considered: Normal tryptase serum levels after all symptoms had resolved ruled out systemic mastocytosis. No intercurrent infections were reported and symptoms did not persist longer than 6 weeks, thus acute and chronic spontaneous urticaria were ruled out. No atopic predisposition was assumed as both serum IgE and eosinophil counts were within the normal range, and the patient reported an unremarkable family history regarding allergies. Of note, the patient reported a previous anaphylactic reaction to clarithromycin. Further diagnostic steps were performed at Department of Dermatology at the Vienna General Hospital: (a) prick testing with BLV (1 mg/ml) and (b) intradermal/intracutaneous skin testing with BLV (1:100, 0.01 mg/ml) did not provoke any reaction, however, higher intradermal/intracutaneous BLV concentrations (1:10 0.1 mg/ml; undiluted 1 mg/ml) induced an immediate reaction.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar Positive intracutaneous skin testing is typically induced by IgE-mediated mast cell degranulation causing type-I hypersensitivity.[6]Vultaggio A. Matucci A. Nencini F. Bormioli S. Vivarelli E. Maggi E. Mechanisms of drug desensitization: not only mast cells.Front Pharmacol. 2020 Dec 23; 11: 590991Crossref PubMed Scopus (10) Google Scholar Desensitization can be considered for IgE-mediated hypersensitivity under certain preconditions.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar Due to the strong indication for HDV-active treatment and the previously insufficient response to PEG-IFN, BLV represented the only therapeutic option in this patient. Comedication with corticosteroids was not considered a rationale option due to the long-term treatment indication. Therefore, we decided to perform desensitization to BLV in an in-patient setting with emergency treatment being readily available. Since our patient demonstrated a strong skin reaction at 0.1 mg/ml (1:10 dilution) BLV, the starting dose was cautiously determined as 1/100 (0.03 mg) of the target dose (2 mg).[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar Over the course of 3 days, the patient received consecutive doses of BLV every 30 minutes. Doses were doubled each time until the per-day target dose was reached. Concomitantly, antihistaminergic treatment (levocetirizine 5 mg) was administered once daily (Table 1). Once regular dosing was established, the patient was discharged and self-administered subcutaneous treatment with BLV was continued at the recommended dosage of 2 mg once daily. Concomitant treatment with levocetirizine was discontinued 8 weeks after the re-initiation of BLV. No local or systemic adverse reactions were observed during re-exposure to BLV nor after withdrawal of the antihistaminergic comedication. Based on this case, the potentially life-threatening consequences of an immediate-type hypersensitivity reaction to BLV have to be considered in clinical application and in patients' counselling, especially since the distinction between common BLV-associated pruritus and incipient allergic reactions may be difficult.[1]EMA. Hepcludex product information [Internet]. Available from: https://www.ema.europa.eu/en/documents/product-information/hepcludex-epar-product-information_en.pdf.Google Scholar Importantly, HDV-related liver disease progression and complications will constitute the major prognostic factor in most HBV/HDV-coinfected individuals.7Kamal H. Westman G. Falconer K. Duberg A.-S. Weiland O. Haverinen S. et al.Long-term study of hepatitis delta virus infection at secondary care centers: the impact of viremia on liver-related outcomes.Hepatol Baltim Md. 2020 Oct; 72: 1177-1190Crossref PubMed Scopus (25) Google Scholar, 8Urban S. Neumann-Haefelin C. Lampertico P. Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease.Gut. 2021 Sep; 70: 1782-1794Crossref PubMed Scopus (47) Google Scholar, 9Jachs M. Binter T. Schmidbauer C. Hartl L. Strasser M. Laferl H. et al.Hepatitis D virus (HDV) prevalence in Austria is low but causes considerable morbidity due to fast progression to cirrhosis.United Eur Gastroenterol J. 2021 Dec; 9: 1119-1127Crossref PubMed Scopus (6) Google Scholar, 10Schmidbauer C. Chromy D. Schmidbauer V.U. Schwarz M. Jachs M. Bauer D.J.M. et al.Epidemiological trends of HBV and HDV coinfection among Viennese HIV+ patients.Liver Int Off J Int Assoc Study Liver. 2021 Nov; 41: 2622-2634PubMed Google Scholar BLV, which is marketed as a soluble powder, does not contain any other potential allergens aside from BLV itself.[1]EMA. Hepcludex product information [Internet]. Available from: https://www.ema.europa.eu/en/documents/product-information/hepcludex-epar-product-information_en.pdf.Google Scholar While several mechanisms have been proposed to cause immediate-type hypersensitivity reactions, IgE-mediated hypersensitivity remains the "typical" pathway for type-I reaction. Positive skin testing confirmatory for IgE-mediated hypersensitivity supported our clinical approach to initiate desensitization, which was originally designed for IgE-mediated reactions.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar,[6]Vultaggio A. Matucci A. Nencini F. Bormioli S. Vivarelli E. Maggi E. Mechanisms of drug desensitization: not only mast cells.Front Pharmacol. 2020 Dec 23; 11: 590991Crossref PubMed Scopus (10) Google Scholar Notably, the underlying mechanism of desensitization is currently not fully understood.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar,[6]Vultaggio A. Matucci A. Nencini F. Bormioli S. Vivarelli E. Maggi E. Mechanisms of drug desensitization: not only mast cells.Front Pharmacol. 2020 Dec 23; 11: 590991Crossref PubMed Scopus (10) Google Scholar While patients have to be informed about the risk of a recurrent hypersensitivity reaction during re-exposure and its general experimental approach, successful desensitization may enable HDV-active antiviral therapy with BLV in patients with confirmed previous hypersensitivity reactions to BLV.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar Importantly, adequate safety precautions have to be taken during re-exposure and uninterrupted treatment with BLV must be ensured after successful desensitization to avoid recurrent hypersensitivity reactions.[5]Cernadas J.R. Brockow K. Romano A. Aberer W. Torres M.J. Bircher A. et al.General considerations on rapid desensitization for drug hypersensitivity - a consensus statement.Allergy. 2010 Nov; 65: 1357-1366Crossref PubMed Scopus (257) Google Scholar Financial supportThe authors received no financial support to produce this manuscript. The authors received no financial support to produce this manuscript. Caroline Schwarz: received travel support from Gilead, Abbvie, and Gebro; speaking honoraria from Abbvie and Gilead; and payments for consulting from Gilead. David Chromy: received speaking honoraria and/or consultancy fees from MSD, Abbvie, and Gilead; and travel support from Abbvie and Gilead. Christine Bangert: received speaking honoraria and/or consultancy fees from Bayer, Mylan, LEO Pharma, Pfizer, Sanofi Genzyme, Eli Lilly, Novartis, Celgene, and AbbVie. Michael Schwarz: received travel support from MSD, Sandoz, BMS, Abbvie and Gilead; and speaking honoraria from BMS. Mathias Jachs: received speaking honoraria from Gilead. Thomas Reiberger: received grant support from Abbvie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche. Michael Gschwantler: received grant support from Abbvie, Gilead and MSD; speaking honoraria from Abbvie, Gilead, Janssen, Roche, Intercept, and MSD; consulting/advisory board fees from Abbvie, Gilead, Janssen, Roche, Intercept, Norgine, AstraZeneca, Falk, Shionogi and MSD; and travel support from Abbvie and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details. Supplementary dataThe following are the supplementary data to this article: Download .pdf (.37 MB) Help with pdf files Multimedia component 1 The following are the supplementary data to this article: Download .pdf (.37 MB) Help with pdf files Multimedia component 1 Authors' contributionsCaroline Schwarz: Conceptualization, methodology, investigation, data curation, writing - original draft. David Chromy: Conceptualization, methodology, investigation, data curation, writing - review & editing. Christine Bangert: Conceptualization, methodology, investigation, data curation, writing - review & editing. Michael Schwarz: Conceptualization, methodology, investigation, data curation, writing - review & editing. Mathias Jachs: Writing - review & editing. Thomas Reiberger: Supervision, writing - review & editing. Michael Gschwantler: Validation, writing - review & editing. Caroline Schwarz: Conceptualization, methodology, investigation, data curation, writing - original draft. David Chromy: Conceptualization, methodology, investigation, data curation, writing - review & editing. Christine Bangert: Conceptualization, methodology, investigation, data curation, writing - review & editing. Michael Schwarz: Conceptualization, methodology, investigation, data curation, writing - review & editing. Mathias Jachs: Writing - review & editing. Thomas Reiberger: Supervision, writing - review & editing. Michael Gschwantler: Validation, writing - review & editing.
Referência(s)