Alizadeh Aghdam, Mehran

Hack, C. Erik

Hofman, Zonne L.M.

Knulst, André C.

Lebens, Ans

Maas, Coen

Meertens, Michelle

Röckmann, Heike

Utrecht University Repository

    |  3673LETTERSDOI: 10.1111/all.15437  Recombinant human C1 esterase inhibitor as prophylactic treatment in idiopathic non- histaminergic angioedemaTo the Editor,Idiopathic angioedema is characterized by cutaneous and mucosal swellings in the absence of diagnostic laboratory parameters and family anamnesis.1 Patients who do not respond to prophylactic anti-histamine therapy are diagnosed as idiopathic non- histaminergic AE (InH- AAE) according to the definition of the Hereditary Angioedema International Working Group.2 Recombinant human C1 esterase in-hibitor ([rhC1- INH], Conestat alfa/Ruconest®) is an effective and safe treatment for acute attacks and prophylaxis of angioedema (AE) in hereditary angioedema (HAE) type 1 and 2.3 Given the unrespon-siveness to antihistamines in part of Inh- AAE patients, indicating possible involvement of the bradykinin route, we investigated the effectiveness and safety of rhC1- INH prophylaxis in InH- AAE.In this phase 2, explorative, prospective, single- centre, open- label study, six patients with InH- AAE were enrolled (Table 1)(eth-ics approval number 17– 139). A four- week observation period was followed by an eight- week treatment period with rhC1- INH (twice weekly 50 IU/kg; max 4200 IU), and another four- week observa-tion period (Figure 1; see also supplemental for detailed informa-tion about inclusion criteria, study design and funding source). In patient 1, attack frequency was reduced by 85% (6.7- fold) (3 versus 20 attacks, respectively; Figure 1). Angioedema activity scores over 28 days4 (AAS28) decreased 8- fold with an accumulated AAS score of 29 in the two treatment months versus 233 in the two observa-tional months. Of patients 2 to 6, none showed a clinical response to rhC1- INH. rhC1- INH treatment did not lead to adverse events, or thrombotic events. The percentage of cleaved high molecular weight kininogen (%cHK), C1- esterase inhibitor (C1- INH), high molecular weight kininogen (HK), plasma kallikrein (PK) and factor XII (FXII) (see Figures S1, S2 and supplemental for method) did not differ between treatment and observation period and were not indicative of treat-ment response. Mean D- dimer, C- reactive protein (CRP) and leuko-cyte counts in patients were within, or slightly above normal. None of the patients had an AE attack during blood sampling. Genetic analysis in patient 1 supported the diagnosis InH- AAE, since no known gene mutations associated with HAE were identified (Table S1).Post- trial, patient 1 restarted rhC1- INH treatment achieving again rapid and complete remission for 6 months, even being able to extend the treatment interval to 5 days. Due to health insurance limitations, treatment was switched to omalizumab 300 mg/4 weeks and tranexamic acid 1000 mg twice daily for 3 months, resulting in recurrence of frequent and severe attacks. Restarting treatment with 1000 IU plasma derived C1- INH (pdC1- INH) every 3– 4 days for 1 year led to immediate and complete symptom control. After 1 year, treatment was switched to 4200 IE rhC1- INH since herewith, remis-sion could be achieved with longer intervals of 5– 6 days. Similar response to pdC1- INH and rhC1- INH, but not to omalizumab, made a placebo response unlikely. Patients 2, 5 and 6 (rhC1- INH non- responders) also initiated omalizumab treatment, with good/near complete response in patients 2 and 6, respectively, and no effect in patient 5 (Table 1). Patient 5 also showed no response to icatibant attack treatment. This first prospective trial showed suc-cessful rhC1- INH treatment in one out of six patients with InH- AAE. Three previous case reports described effectiveness of plasma derived (p)dC1- INH prophylaxis in four patients with InH- AAE.5– 7 Our data show that only a proportion of patients may respond to C1- INH treatment. Failure of rhC1- INH in the other 5 InH- AAE pa-tients may suggest that bradykinin is not involved or a dose of 50 IU rhC1- INH per kg was too low. None of the measured biomarkers of the bradykinin route was indicative for the observed effect in the responding patient. However, recent studies showed that in InH- AAE the clinical picture might be caused by different and in part unknown genetic defects, leading to impairment of different fac-tors of the contact system and resulting in a reduced control of the kallikrein system and alteration of bradykinin as main mediator.8,9 Levels of bradykinin might provide a better biomarker for such acti-vation, however, obtaining reliable samples during an attack is com-plex. According to the current guidelines, omalizumab is the first choice of treatment for patients with idiopathic angioedema not responding to high dose antihistamins.10 Response to omalizumab may support mast cell driven disease mechanisms in patients 2 and 6. However, bradykinin cannot completely be ruled out as the main mediator of AE even in conditions commonly associated with mast cell activation, for example in anaphylaxis.11 This study was limited by its monocentric design and the small sample size. In conclusion, rhC1- INH treatment was effective in 1 of the 6 InH- AAE patients, and omalizumab in 2 out of 4 suggesting a heterogeneous pathogen-esis of AE and, consequently, the need for personalized treatment.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. 13989995, 2022, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.15437 by Utrecht University Library, Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License3674  |    LETTERSTABLE 1 Demographic and clinical characteristics of included patientsWeight (kg)Disease duration (months)aAttack interventionaAttack frequency/monthaBaseline C1- INH functionBaseline C4 levelBaseline total IgEDose of rhC1INHPost- trial prophylactic treatment during follow- upEffectiveIneffectivePatient 131 y/oFemale10047ER visit 1×Adrenalin i.m. 0.3 mg 4×b Prednisone 0.5 mg/kg 3×AH 1dd 1- 2×2.81.250.302754200 UrhC1- INH(1000 IE 2/w)pdC1- INH(4200 IE 2/w)PrednisoloneOmalizumab (300 mg/4 w)TA (1000 mg 3 d)Patient 237 y/oFemale726ER visit 1×Adrenalin 1×b Prednisone 0.5 mg/kg 6×AH 1- 2dd 8×3.70.950.151633615 UOmalizumab (600 mg/3 w)Patient 356 y/oMale85103Prednisone 60 mg 1×2.61.190.272544200 UPatient 433 y/oMale748Prednisone 30 mg 8×15.81.540.52983715 UTA (500 mg 3 d)AH(5 mg 1 d)Patient 525 y/oFemale8584– 2.81.700.34874200 UOmalizumab (300 mg/4 w)Icatibant (attack treatment)Patient 660 y/oFemale11621AH 1dd 2×4.21.210.23954200 UOmalizumab(300 mg/4 w)Note: Reference values for C1- INH function: 0.63– 1.82 U/mL. C4 level: 0.1– 0.47 g/L. IgE level: 0– 100 kU/L. All patients used four times the standard daily dose antihistamines during follow- up.Abbreviations: TA, tranexamic acid; AH, antihistamine; ER, emergency room; w, weekly; d, daily; i.m., intramusculair; i.v., intravenous; p.o., Per os (orally).a Number of attack interventions during 6 months before study.b Equivalent dose of other glucocorticosteroid. 13989995, 2022, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.15437 by Utrecht University Library, Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License    |  3675LETTERSFUNDING INFORMATIONThis study is financed in part by Pharming Group N.V.ACKNOWLEDG MENTSWe would like to thank the patients, and Dutch AE patient organiza-tion for their participation in support of this study. We thank Simone Smits, Stans den Hartog Jager, Henny Otten, Mignon van den Elzen and Paco Welsing for their contributions and thoughts regarding the laboratory analysis and methodology setup. We thank Luca Bellizzi, Tobias Suiter, Elly Sakiman and Pharming Technologies for their sup-port and insight.CONFLIC T OF INTERE S TMehran Alizadeh Aghdam received speakers fee from Novartis to in-stitution. Zonne Hofman received contribution to publication cost the-sis from Pharming Technologies. André Knulst is a member of advisory board, Novartis. Health care innovation grant from Novartis to institu-tion. Coen Maas has been advisor to Shire/Takeda and Biomarin. Heike Röckmann is a member of national advisory board Novartis, Sanofi. Michelle Meertens: None. Erik Hack: None. Ans Lebens: None.Mehran Alizadeh Aghdam1,2Zonne L. M. Hofman2,3Michelle Meertens1,2Ans Lebens1C. Erik Hack2André C. Knulst1,2Coen Maas3Heike Röckmann1,21Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands2Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands3CDL Research, University Medical Center Utrecht, Utrecht University, Utrecht, The NetherlandsCorrespondenceMehran Alizadeh Aghdam, Department of Dermatology, University Medical Centre Utrecht, Heidelberglaan 100, PO box 85500, 3584 CX Utrecht, The Netherlands.Email: m.alizadehaghdam@umcutrecht.nlORCIDMehran Alizadeh Aghdam  https://orcid.org/0000-0003-3584-9250 R E FE R E N C E S 1. Temino VM, Peebles RS Jr. The spectrum and treatment of an-gioedema. Am J Med. 2008;121(4):282- 286. 2. Cicardi M, Aberer W, Banerji A, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the hereditary angioedema international working group. Allergy. 2014;69(5):602- 616. 3. Riedl MA, Grivcheva- Panovska V, Moldovan D, et al. Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio- oedema: a phase 2, multicentre, randomised, double- blind, placebo- controlled crossover trial. Lancet. 2017;390(10102):1595- 1602. 4. Weller K, Groffik A, Magerl M, et al. Development, validation, and initial results of the angioedema activity score. Allergy. 2013;68(9): 1185- 1192.F I G U R E  1  Four- month study sequence and attack episodes per month. Trial visits at which blood is drawn (V2, V4, V9, V17, V18) are indicated with an arrow. Treatment visits occur twice a week during the treatment months in which rhC1- INH is administered. Visit 18 marks the end of the trial, no pdC1- INH was administered during this visit. One attack episode is indicated with a vertical line and could last for multiple days. Cumulative angioedema (AE) attacks in the observation months (O) versus the treatment months (T) is presented. *AE attack occurred 7 days after last rhC1- INH administration due to a missed treatment visit 13989995, 2022, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.15437 by Utrecht University Library, Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License3676  |    LETTERS 5. Gravante C, Carucci L, Bova M, Petraroli A, Genovese A, Marone G. Prophylactic treatment with plasma- derived C1 inhibitor in id-iopathic non- histaminergic angioedema. Pediatr Allergy Immunol. 2016;27(6):658- 659. 6. Shroba J, Hanson J, Portnoy J. Current treatment options for id-iopathic angioedema. Ann Allergy Asthma Immunol. 2015;115(5): 429- 433. 7. Stahl MC, Harris CK, Matto S, Bernstein JA. Idiopathic nonhistami-nergic angioedema successfully treated with ecallantide, icatibant, and C1 esterase inhibitor replacement. J Allergy Clin Immunol Pract. 2014;2(6):818- 819. 8. Bork K, Wulff K, Rossmann H, et al. Hereditary angioedema coseg-regating with a novel kininogen 1 gene mutation changing the N- terminal cleavage site of bradykinin. Allergy. 2019;74(12):2479- 2481. 9. Bova M, Suffritti C, Bafunno V, et al. Impaired control of the con-tact system in hereditary angioedema with normal C1- inhibitor. Allergy. 2020;75(6):1394- 1403. 10. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema- the 2021 revision and update. Allergy. 2022;77:1961- 1990. 11. Sala- Cunill A, Bjorkqvist J, Senter R, et al. Plasma contact system activation drives anaphylaxis in severe mast cell- mediated allergic reactions. J Allergy Clin Immunol. 2015;135(4):1031- 43 e6.SUPPORTING INFORMATIONAdditional supporting information can be found online in the Supporting Information section at the end of this article.DOI: 10.1111/all.15438  The nasopharyngeal and salivary microbiomes in COVID- 19 patients with and without asthmaTo the Editor,So far, our understanding of the associations between respiratory infections and severe acute respiratory syndrome coronavirus 2 (SARS- CoV- 2) in the context of asthma is limited. Although our previous study and others did not find a correlation between pre-existing asthma and increased risks of severe coronavirus disease 2019 (COVID- 19) outcomes,1– 3 people with asthma usually have an increased vulnerability to conventional respiratory viral infections. Thus, continuous investigation on SARS- CoV- 2 infection in people with asthma is important.People with asthma harbor altered airway microbiota, which has been suggested to mediate an increased susceptibility to severe ill-nesses upon viral respiratory infections.4 However, the microbiomes of patients with asthma during SARS- CoV- 2 infection have not yet been characterized. To this end, we performed a microbiome study using nasopharyngeal samples and saliva samples from COVID- 19 patients with and without preexisting asthma.This study was approved by the Institutional Review Board of Washington University in St. Louis (IRB number 202003085), and all patients who were enrolled in the study provided informed consent. A total of 105 samples were collected from patients with COVID- 19 within 14 days from the onset of any relevant symptoms between March and September of 2020. For the nasopharyngeal samples, seven were from patients with asthma and 41 were from patients with no asthma diagnosis. For the salivary samples, 16 were from patients with asthma and 41 were from patients with no asthma di-agnosis. Demographics and clinical characteristics of the COVID- 19 patients are shown in Table S1. Study participants were enrolled in both outpatient and inpatient settings. Nine patients (n = 3 asthma, and n = 6 non- asthma) provided both saliva and nasopharyngeal samples. The detailed methods and sequencing analysis procedures are presented in the Appendix S1. The read number of each sample and rarefaction curves are plotted in Figure S1A, B. The microbial communities of the nasopharyngeal and saliva samples were sig-nificantly different in alpha diversity represented by the Shannon Index (p- value <0.001, Figure 1A) and beta diversity based on weighted UniFrac distances (p- value = 0.001, Figure 1B). For the 48 nasopharyngeal samples, seven were from COVID- 19 patients with asthma and 41 were from those who did not have an asthma diagnosis. There were no marked differences in relative abundance for any of the top five abundant phyla in nasopharyngeal samples between the asthma and non- asthma groups (Figure 1C). For the 57 saliva samples, the relative abundance of phylum Actinobacteria was significantly decreased in COVID- 19 patients with asthma compared with those without preexisting asthma (adjusted p- value = 0.02, Figure 1D). The top ten abundant genera in the naso-pharyngeal samples and saliva samples are displayed in Figure 1E, F, respectively.Differences at the genus- level, but not at the community level (Figure S2), were observed in the nasopharyngeal and salivary mi-crobiomes between patients with and without preexisting asthma. In differential abundance tests using DESeq2 for nasal samples, seven genera were significantly different between the two groups, with all being less abundant (including Porphyromonas, Haemophilus, © 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. 13989995, 2022, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.15437 by Utrecht University Library, Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Recombinant human C1 esterase inhibitor as prophylactic treatment in idiopathic non-histaminergic angioedema

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Recombinant human C1 esterase inhibitor as prophylactic treatment in idiopathic non-histaminergic angioedema

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