Summary
Background
Chronic rhinosinusitis with nasal polyps (CRSwNP), an inflammatory disease of the paranasal mucosa, is primarily characterized by type 2 inflammation. Three antibodies (dupilumab, omalizumab, and mepolizumab) are now approved for the treatment of severe CRSwNP. Documentation of disease severity during the course of treatment is essential.
Methods
A literature search of Medline, PubMed, and the national and international trial and guideline register, and the Cochrane Library was performed to analyze the immunology of CRSwNP and determine the evidence for the effect of dupilumab, omalizumab, and mepolizumab in this disease. This has resulted in 3 position papers prepared by our group of authors, which form the basis of this summarizing review.
Results
Based on the information from the international literature, recommendations for the use of dupilumab, omalizumab, and mepolizumab in CRSwNP in the German health care system are given by an expert panel.
Conclusion
Dupilumab, omalizumab, and mepolizumab are approved for patients 18 years of age and older with CRSwNP as add-on therapy to intranasal corticosteroids when, for dupilumab and mepolizumab, therapy with systemic corticosteroids and/or surgery does not achieve sufficient disease control. Therapy with omalizumab is indicated when therapy with intranasal corticosteroids does not result in sufficient disease control. Dedicated recommendations for the documentation of the use in the German health care system are given, which are based on the position papers of our author group already published on this topic.
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Introduction
Chronic rhinosinusitis (CRS) is an inflammatory disease of the mucous membranes of the nose and sinuses [1,2,3,4,5]. CRS affects approximately 5–12% of the general population worldwide, and the cost to health care systems and national economies is substantial [1,2,3,4, 6]. CRS is divided into a phenotype with (CRSwNP) and one without the development of nasal polyps (CRSsNP) [5,6,7,8]. CRSwNP is also called polyposis nasi et sinuum and is associated with endoscopic and/or radiological evidence of polypous-hyperplastic tissue in the nasal cavity and/or paranasal sinuses. CRSwNP is an immunologically triggered chronic inflammatory disease of mucosa and subepithelial tissue, for which specific endotype-oriented immunologic therapies have been developed only in the last decade [9,10,11,12], whereas immunotherapies [13,14,15,16,17] for exogenous-allergic nasal mucosal diseases have been therapeutic standard for a long time.
In various position papers, we have given general recommendations for the diagnosis and therapy of CRSwNP and formulated criteria according to which the currently approved biologics dupilumab, omalizumab, and mepolizumab should be used in the German health care system [11, 18, 19].
We summarize these results in the following publication and provide concrete and reliable recommendations on treatment documentation, adapted to the specific conditions in the German health care system.
Polyposis nasi as an immunological disease of the airway mucosa
Regarding the immunology of CRSwNP, we refer to several reviews [12, 20,21,22,23,24]. Cyto- and chemokines have specific functions in this regard. IL‑4 is a mediator and modulator of the immune and inflammatory response and is mainly produced by Th2 cells. In addition, IL‑4 is able to promote the differentiation of CD4+ T cells into Th2 cells and also to inhibit IFN‑γ production and Th1 response [25, 26]. In nasal polyps, upregulation of IL‑4 occurs, whereas no differences were found between nasal polyps and healthy nasal tissue for IFN‑γ [23, 27, 28]. IL‑5 is the major eosinophil-activating cytokine, promotes the survival of mature eosinophils in tissue [29, 30], and is upregulated in nasal polyps [31]. Eosinophil cationic protein (ECP) and eotaxin (CCL11) are also found to be elevated in polyp tissue and promote attraction and activation of eosinophils [22, 23, 32]. IL‑6, as a proinflammatory cytokine, inhibits neutrophil recruitment [33,34,35], while IL-25 and IL-33 maintain Th2-dominated inflammation [36,37,38].
IL-33 is a local endogenous danger signal for various immune cells and a chemoattractant for Th2 cells. It promotes the production of Th2 cytokines such as IL‑4, IL‑5, and IL-13 and is produced by epithelial cells, while its receptor is expressed by eosinophils and Th2 lymphocytes, among other cells [39,40,41]. IL-33 plays a significant role in the maintenance of Th2-mediated eosinophilic inflammation [42].
The cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) also have effects on type 2 innate lymphoid cells (ILC2) [43]. ILCs are lymphocyte-like cells that do not express antigen-specific T‑cell receptors. ILC2 cells are considered as non-antigen-specific Th2-like cells because both cell types produce Th2 cytokines such as IL‑4, IL‑5, and IL-13 [44]. ILC2s are abundant in nasal polyps and are associated with increased numbers of eosinophils in the blood and tissues of patients with CRSwNP and severe clinical symptoms [45, 46].
Comorbidities and therapies of CRSwNP
CRSwNP is often accompanied by comorbidities such as bronchial asthma, allergies, N‑ERD (NSAID-exacerbated respiratory disease), also known as Samter’s triad or Widal’s triad [7, 47,48,49]. Asthma affects 30–70% of CRSwNP patients at the same time [48, 50,51,52]. The severity of asthma disease is associated with the presence of CRSwNP [53, 54]. In mild asthma, only 10–30% have CRSwNP, whereas in severe asthma, 70–90% of patients have CRSwNP [53, 54]. Type 2 inflammation (T2 inflammation) is the most common immunological endotype for both diseases [52, 55,56,57]. This is characterized by eosinophilic inflammation associated with the detection of Th2-type cytokines such as IL‑4, IL‑5, and/or IL-13 and circulating and/or local IgE [52, 58, 59].
The basis of treatment for both CRSwNP and asthma is anti-inflammatory therapy with local glucocorticosteroids (GCS) [6, 60, 61]. If this is not sufficient, short-term applications of oral/systemic GCS (usually for a maximum of 2–3 weeks) are the therapeutic standard for CRSwNP [62, 63]. Adaptive deactivation treatment with acetylsalicylic acid (aspirin) can also be given, but may be associated with side effects (e.g., gastrointestinal complaints) [62,63,64,65]. Surgical intervention of CRSwNP is considered the treatment of choice if standard therapy fails [66,67,68]. As of November 2019, three biologic therapies have been approved to date that can effectively target T2 inflammation and interfere with the inflammatory process at different sites. Dupilumab, which binds to the common alpha subunit of interleukin receptors 4 and 13, inhibiting IL-4/IL-13 signaling and thus TH‑2 inflammation [69, 70]. This was followed by omalizumab (inhibition of IgE-mediated immune responses) and mepolizumab (inhibition of interleukin [IL]-5 immune responses).
Therapeutic options for CRSwNP
Therapy with biologics in adults
For CRSwNP patients who continued to suffer from recurrent polyps under drug treatment and/or surgical intervention to date, not achieving sufficient symptom control, and thus suffered from refractory, uncontrolled CRSwNP, no therapeutic alternatives existed until the approval of biologics. Biologics are also recommended as standard therapy for another group of CRSwNP patients in whom an improvement in control of their CRSwNP can be achieved with long-term therapy with systemic GCS), but only with toleration of associated adverse effects [11].
In recent years, various immunomodulating antibodies have been introduced for therapy in indications such as bronchial asthma, urticaria, or atopic dermatitis. These interfere either with IgE-mediated immune responses (omalizumab), or with IL-5- (mepolizumab, benralizumab) or IL-4-/IL-13- (dupilumab) mediated immune responses [71,72,73]. Dupilumab, mepolizumab, and omalizumab are approved for the treatment of CRSwNP.
Cost-effectiveness requirement for biologics prescriptions in the German statutory health insurance (SHI) system: sufficient, appropriate, necessary
We had already pointed out the need for economic prescribing, taking into account the socioeconomic importance of the high direct, indirect, and intangible costs of CRSwNP in our position papers [11]. In this context, the cost-effectiveness of interventions is derived from the benefits of the measures in relation to the expenditures used for them, especially the costs. Essential topics of the cost–benefit assessment are the costs of disease as well as the cost-effectiveness of therapeutic measures and the existence of therapeutic alternatives.
Infobox The definition of the efficiency requirement in SGB V § 12 reads
“The performance must be sufficient, appropriate and economical; they must not exceed what is necessary. Performances that are not necessary cannot be provided by insured persons, cannot be provided by service providers, and cannot be granted by health insurance funds”.
Cost-effectiveness is assumed to be given if the contract physician (service provider) provides the (necessary, sufficient and expedient) services at the lowest possible cost (in the sense of expenditure by the health insurance funds). The terms “expedient”, “sufficient” and “necessary” are to be interpreted as follows (KBV Training No. 9):
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A medical measure is considered appropriate if it is objectively suitable for the intended purpose, i.e. successful treatment.
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Services are sufficient if they are adapted to the individual case, correspond to the generally recognized state of medical knowledge and take medical progress into account. The performance must be sufficient to achieve the desired healing effect. The service provider or service initiator is obliged to consider the quantity of his actions.
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Necessary is treatment that does not go beyond the scope of what is indispensable in the individual case to maintain or restore health. Necessary is everything that the physician cannot waive in treating a patient according to the state of medical knowledge, otherwise the treatment is insufficient.
If the criteria expedient and sufficient aim at ensuring that not less happens than has to happen to achieve the healing success, the criterion necessary aims at ensuring that not more happens than corresponds to this aim.
Transferred to the therapy of CRSwNP with biologics, this means that initially a standard therapy with INCS, among others, must always be applied in order to achieve a sufficient and appropriate healing success. If this cannot be achieved, an additional therapy with biologics may also be sufficient, appropriate and necessary and indispensable for the restoration of health.
Analogous to our preceding position papers [11, 18, 19], we provide the following practical recommendations for the use of biologics in CRSwNP based on scientific evidence and the current state of medical knowledge.
Practical recommendations for the use of dupilumab in CRSwNP (according to [74])
Dupilumab was the first biologic approved in Germany for the indication CRSwNP and is indicated on the label as add-on therapy with intranasal corticosteroids for the treatment of adults with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.
According to the expert information, treatment should be started by a physician experienced in the diagnosis and treatment of diseases for which dupilumab is used. Dupilumab is offered in a prefilled syringe or a prefilled pen for single use. Prefilled syringe and prefilled pen contain 300 mg dupilumab in 2 ml solution (150 mg/ml).
The recommended dosage for dupilumab for the treatment of CRSwNP in adult patients is 300 mg every 2 weeks.
Dupilumab is intended for long-term treatment. In patients who do not respond to treatment of CRSwNP after 24 weeks, termination of treatment with dupilumab should be considered. If necessary, this may include a trial of therapy with another biologic. Some patients with an initial partial response may benefit from continued treatment beyond 24 weeks. If a dose is missed, it should be made up as soon as possible. Thereafter, dosing at the regular scheduled time should be resumed. No dose adjustment is recommended in elderly patients (≥ 65 years of age), nor in patients with mild or moderate renal impairment. Very limited data are available for patients with severe renal impairment and for patients with hepatic impairment.
No body weight-based dose adjustment is recommended for adults with CRSwNP. Safety and efficacy in children under 18 years of age with CRSwNP have not been established, as no data are available for this purpose.
Dupilumab should be injected subcutaneously into the upper arm or thigh or into the abdominal wall, except within 5 cm of the umbilicus.
It is recommended to choose a different injection site for each injection. Dupilumab must not be injected into sensitive, injured or scarred skin sites or into skin sites with hematomas.
If deemed appropriate by the treating physician, dupilumab may be injected by the patient or by a caregiver. In this case, patients and/or caregivers must be instructed on how to prepare and administer dupilumab prior to use in accordance with the instructions for use provided in the package insert. The manufacturing company provides appropriate training material.
Dupilumab should be stored in a refrigerator at 2–8 °C and should not be frozen. Both prefilled syringe and prefilled pen should be stored in the original packaging to protect the contents from light. If necessary, prefilled syringes or prefilled pens may be stored at room temperature up to 25 °C for a maximum of 14 days. Do not store above 25 °C.
Practical recommendations for the use of omalizumab in CRSwNP (according to [75])
Omalizumab is the second biologic approved in Germany for the indication CRSwNP and is indicated on the label as an add-on therapy to intranasal corticosteroids for the treatment of adults with severe CRSwNP in whom therapy with intranasal corticosteroids cannot achieve sufficient disease control. In contrast to the indication “allergic asthma”, no reference to IgE-mediated genesis of CRSwNP is listed as a prerequisite in the Summary of Product Characteristics (SmPC). However, the dosage of omalizumab is based on the baseline serum IgE level.
According to the SmPC, treatment should be initiated by a physician experienced in the diagnosis and treatment of CRSwNP. In the SmPC of omalizumab, the conversion of the dosage to the number of prefilled syringes, the number of injections and the total amount injected per administration as well as the dose determination are tabulated (Table 1).
The efficacy of ongoing therapy should be evaluated every 6–12 months based on the degree of symptom control. Dose setting after interruptions in treatment of less than one year should be based on serum IgE levels determined at the time of the initial dose setting, otherwise IgE levels will be erroneously measured. Total serum IgE levels should be redetermined for dose setting if treatment has been interrupted for one year or longer.
Under ongoing omalizumab therapy, if significant changes in body weight occur, the dose should be adjusted (Table 2) using the initially determined total IgE value. Limited data are available on the use of omalizumab in patients over 65 years of age; it is assumed that dose adjustment is not required.
Omalizumab must be stored in a refrigerator at 2–8 °C and should be administered subcutaneously. Doses greater than 150 mg should be divided between two or more injection sites. There is limited experience with self-administration of omalizumab. Initial administration by or under the supervision of a healthcare professional is recommended for the first 3 applications. Patients without a known history of anaphylaxis may self-administer omalizumab beginning with the fourth application or have a caregiver inject omalizumab (approved for self-injection since 2018) if deemed appropriate by the physician. The patient or caregiver should be trained in the administration and possible early signs of adverse reactions and allergic reactions. The manufacturing company will provide appropriate training materials. To improve the traceability of biological medicinal products, the name of the medicinal product and the batch number of omalizumab should be clearly documented according to the expert information and indicated in case of adverse reactions. Here, we recommend that the manufacturer provide ready-made labels with the batch numbers to simplify documentation.
Practical recommendations for the use of mepolizumab in CRSwNP (according to [76])
Mepolizumab, as the third biologic approved for CRSwNP, is indicated as add-on therapy with INCS for the treatment of adults with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention. The biologic is available as 100 mg solution for injection in a prefilled pen, 100 mg solution for injection in a prefilled syringe, or 100 mg powder for solution for injection. Prefilled syringe and prefilled pen for single use each contain 100 mg mepolizumab in 1 ml solution (100 mg/ml).
Mepolizumab should be stored in a refrigerator at 2–8 °C and should not be frozen. Both prefilled syringe and prefilled pen should be stored in the original packaging to protect the contents from light. If necessary, the prefilled pen and prefilled syringe may be removed from the refrigerator and stored in the original unopened package for up to 7 days at room temperature (up to 30 °C) away from light.
Mepolizumab should be prescribed by physicians experienced in the diagnosis and treatment of severe CRSwNP. The recommended dose of mepolizumab is 100 mg administered subcutaneously once every 4 weeks and is intended for long-term treatment. In patients who do not respond to treatment for CRSwNP after 24 weeks, alternative treatments may be considered. Some patients with an initial partial response may benefit from continued treatment beyond 24 weeks.
The dosage of mepolizumab is independent of weight or other factors. No dose adjustment is required in elderly patients and patients with renal or hepatic impairment.
The prefilled pen or prefilled syringe may only be injected subcutaneously. Administration may be performed by the patient or by a person caring for the patient if the healthcare professional has decided that this is appropriate and the patient or the person caring for the patient has been trained in injection techniques (see information in the SmPC). If self-administered by the patient, the recommended injection sites are the abdominal wall or thigh. A person caring for the patient may also inject mepolizumab into the upper arm. Detailed instructions for subcutaneous administration of mepolizumab in a prefilled pen or syringe are provided in the instructions for use in the package insert.
The powder must be reconstituted before use and should be used immediately. The reconstituted solution containing mepolizumab 100 mg/ml is intended for subcutaneous injection only and should be administered only by healthcare professionals. It may be injected into the upper arm, thigh, or abdominal wall. For doses requiring more than one injection, it is recommended that each injection be administered at least 5 cm apart. Each vial of mepolizumab should be used for a single patient and any remainder in the vial should be discarded.
There is limited experience (less than 300 pregnancy outcomes) with the use of mepolizumab in pregnant women. There are no data on whether mepolizumab passes into breast milk in humans or whether it has an effect on fertility in humans.
Documentation forms for indication and therapy control
In order to facilitate indication, documentation forms have been developed for all three biologics approved to date, which can serve as a basis for documentation. (Figs. 1, 2 and 3).
Discussion
Currently, there are three approved monoclonal antibodies in Germany and Europe for the treatment of CRSwNP with dupilumab, mepolizumab, and omalizumab [11, 18, 19].
The aim of this publication is to summarize the current recommendations for the indication and documentation of therapy with biologics in CRSwNP in the German health care system.
CRSwNP is a chronic inflammatory disease of the mucous membranes of the nose and paranasal sinuses based on different immune processes, which has been phenotypically classified so far. Depending on the nature of the underlying immunology, different endotypes are characterized, exhibiting differential signaling pathways from the process of inflammation initiation, maintenance and chronification to tissue destruction [12, 21]. Accordingly, biologics are endotype-based treatment approaches, as they intervene in the pathological immune processes in a regulatory manner. So far, in CRSwNP, they target T2-based, IgE- and/or eosinophil-dominated inflammation [55]. These include dupilumab (anti-IL-4/13), mepolizumab (anti-IL-5), benralizumab (anti-IL-5Rα), and omalizumab (anti-IgE) [12, 21, 77, 78].
Biologics are cost-intensive drugs, which is why compliance with the economic efficiency requirement in SGB V § 12 is of particular importance for their use in the German statutory health insurance (SHI) system. SHI-accredited physicians must provide the necessary, sufficient, and appropriate performance at the lowest possible cost to the health insurance funds. This will always be the case if therapeutic alternatives have already been used unsuccessfully or are not applicable due to unacceptable side effects. In the case of surgery, a high surgical risk or lack of anesthetic capability can also be a reason, as well as the rejection of surgery by the patient. The German Patients’ Rights Act (Gesetz zur Verbesserung der Rechte von Patientinnen und Patienten), which came into force in February 2013, is particularly significant here. It establishes regulations for the standardization of the treatment contract and the associated obligations of those providing treatment, such as in particular the concrete formulation of the obligations to provide information and clarification, regulations on the documentation of treatment and the patient’s right to inspect medical records, as well as the introduction of rules on the burden of proof. According to Section 630e “Obligations to inform”, the following applies: (1) The healthcare provider is obligated to inform the patient about all circumstances that are essential for consent. This includes, in particular, the type, scope, implementation, expected consequences and risks of the measure, as well as its necessity, urgency, suitability and prospects of success with regard to the diagnosis or therapy. The information must also refer to alternatives to the measure if several methods that are medically equally indicated and customary can lead to significantly different burdens, risks or chances of recovery.
This is likely to be clearly fulfilled in the weighing of the therapy alternatives “surgery” or “biologics administration”, which is why we recommend referring to biologics in the patient information prior to surgical interventions in CRSwNP.
The selection of the appropriate biologic among the currently approved dupilumab, omalizumab, and mepolizumab for CRSwNP is based on the freedom of therapy of the treating physician. Here, criteria such as the pathophysiological mechanisms involved, practical aspects (dosage, dosing interval, etc.), concomitant diseases (approval for severe asthma and atopic eczema for dupilumab, for severe allergic [IgE-mediated] asthma and chronic spontaneous urticaria for omalizumab, for severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis [EGPA] and hypereosinophilic syndrome [HES] for mepolizumab), but also different side effect profiles should be considered.
In Germany, only INCS with the active ingredients budesonide and mometasone furoate are approved for the treatment of CRSwNP [79, 80]. The recommended initial dose for mometasone furoate is 1 × 2 sprays of 50 µg per side of the nose (i.e., 100 µg per side of the nose once daily). After 5–6 weeks without symptom improvement, the dose may be increased to 2 × 2 sprays per nostril (i.e., 100 µg per side of the nose twice daily). The permanent dosage for mometasone furoate should be adjusted to the lowest amount at which good symptom control can be achieved. For budesonide, an initial dose of 2 × 2 spray bursts of 50 µg per side of the nose is recommended (i.e., 100 µg per side of the nose twice daily). Once good symptom control has been achieved, the dosage can be reduced on a trial basis to 2 × 1 sprays per side of the nose (i.e., 50 µg per side of the nose twice daily) [79, 80]. We consider a consistent uninterrupted use of at least 3 months necessary to assess whether an additive therapy with a biologic is necessary under this standard therapy.
In addition to current therapeutic options, biologics may help to realize the principle of “personalized medicine” also for polyposis nasi in the future.
Abbreviations
- CRS:
-
Chronic rhinosinusitis
- CRSsNP:
-
Chronic rhinosinusitis sine nasal polyps
- CRSwNP:
-
Chronic rhinosinusitis with nasal polyps
- GCS:
-
Glucocorticosteroids
- INCS:
-
Intranasal corticosteroids
- NCS:
-
Nasal Congestion Score
- NPS:
-
Nasal Polyp Score
- SHI:
-
Statutory health insurance
- SmPC:
-
Summary of Product Characteristics
- SNOT-22:
-
Sino-nasal outcome test 22
- TNSS:
-
Total nasal symptom score
- UPSIT:
-
University of Pennsylvania Smell Identification Test
References
Hastan D, Fokkens WJ, Bachert C, Newson RB, Bislimovska J, Bockelbrink A, et al. Chronic rhinosinusitis in Europe—an underestimated disease. A GA²LEN study. Allergy. 2011;66:1216–23.
Hirsch AG, Stewart WF, Sundaresan AS, Young AJ, Kennedy TL, Greene SJ, et al. Nasal and sinus symptoms and chronic rhinosinusitis in a population-based sample. Allergy. 2017;72:274–81.
Ostovar A, Fokkens WJ, Vahdat K, Raeisi A, Mallahzadeh A, Farrokhi S. Epidemiology of chronic rhinosinusitis in Bushehr, southwestern region of Iran: a GA2LEN study. Rhinology. 2019;57:43–8.
Shi JB, Fu QL, Zhang H, Cheng L, Wang YJ, Zhu DD, et al. Epidemiology of chronic rhinosinusitis: results from a cross-sectional survey in seven Chinese cities. Allergy. 2015;70:533–9.
Stuck BA, Beule A, Jobst D, Klimek L, Laudien M, Lell M, et al. Guideline for “rhinosinusitis”-long version : S2k guideline of the German College of General Practitioners and Family Physicians and the German Society for Oto-Rhino-Laryngology, Head and Neck Surgery. HNO. 2018;66:38–74.
Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl. 2012;23:3. preceding table of contents, 1–298.
Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology. 2012;50:1–12.
Rosenfeld RM. Clinical practice guideline on adult sinusitis. Otolaryngol Neck Surg. 2007;137:365–77.
Agarwal A, Spath D, Sherris DA, Kita H, Ponikau JU. Therapeutic antibodies for nasal polyposis treatment: where are we headed? Clinic Rev Allerg Immunol. 2019;59:141–9.
Franzese CB. The role of biologics in the treatment of nasal polyps. Immunol Allergy Clin North Am. 2020;40:295–302.
Klimek L, Förster-Ruhrmann U, Becker S, Chaker A, Strieth S, Hoffmann TK et al. Position paper: use of biologics in chronic rhinosinusitis with polyposis nasi (CRSwNP) in the German health care system-recommendations of the Association of German Allergists (AeDA) and the WGs Clinical Immunology, Allergology and Environmental Medicine and Rhinology and Rhinosurgery of the German Society of Otolaryngology, Head and Neck Surgery (DGHNOKHC) Laryngorhinootology 2020; 99(8):511–27.
Koennecke M, Klimek L, Mullol J, Gevaert P, Wollenberg B. Subtyping of polyposis nasi: phenotypes, endotypes and comorbidities. Allergo J Int. 2018;27:56–65.
Jutel M, Van de Veen W, Agache I, Azkur KA, Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy and novel ways for vaccine development. Allergol Int. 2013;62:425–33.
Klimek L, Bachert C, Pfaar O, Becker S, Bieber T, Brehler R, et al. ARIA guideline 2019: treatment of allergic rhinitis in the German health system. Allergol Select. 2019;3:22–50.
Klimek L, Brehler R, Hamelmann E, Kopp M, Ring J, Treudler R, et al. Development of subcutaneous allergen immunotherapy (part 2): preventive aspects of SCIT and innovations. Allergo J Int. 2019;28:107–19. CME Certified Continuing Education.
Klimek L, Brehler R, Hamelmann E, Kopp M, Ring J, Treudler R, et al. Evolution of subcutaneous allergen immunotherapy (part 1): from the beginnings to immunologically oriented therapy concepts. Allergo J Int. 2019;28:78–95. CME continuing education.
Klimek L, Casper I, Bergmann KC. Therapy of allergic rhinitis in routine care: evidence-based benefit assessment of combined use of various active ingredients. Therapy of allergic rhinitis in routine care: evidence-based benefit assessment of freely combined use of various active ingredients. Allergology. 2020;43:476. Position paper.
Klimek L, Förster-Ruhrmann U, Beule AG, Chaker AM, Hagemann J, Huppertz T, et al. Position paper: recommendations for the use of omalizumab in chronic rhinosinusitis with polyposis nasi (CRSwNP) in the German health care system—recommendations of the Ärzteverband Deutscher Allergologen (AeDA) and the WGs Klinische Immunologie, Allergologie und Umweltmedizin and Rhinologie und Rhinochirurgie of the Deutsche Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie (DGHNOKHC). Laryngo-Rhino-Otology. 2021;100:952–63.
Klimek L, Förster-Ruhrmann U, Beule AG, Chaker AM, Hagemann J, Huppertz T, et al. Position paper: recommendations for the use of mepolizumab in chronic rhinosinusitis with polyposis nasi (CRSwNP) in the German health care system-recommendations of the Ärzteverband Deutscher Allergologen (AeDA) and the AG’s Klinische Immunologie, Allergologie und Umweltmedizin and Rhinologie und Rhinochirurgie of the Deutsche Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie (DGHNOKHC). Laryngorhinootology. 2022;101:284–94.
Annunziato F, Romagnani S. Heterogeneity of human effector CD4+ T cells. Arthritis Res Ther. 2009;11:257.
Klimek L, Koennecke M, Hagemann J, Wollenberg B, Becker S. Immunology of chronic rhinosinusitis with nasal polyps as a basis for treatment with biologicals. HNO. 2019;67:15–26.
Plager DA, Kahl JC, Asmann YW, Nilson AE, Pallanch JF, Friedman O, et al. Gene transcription changes in asthmatic chronic rhinosinusitis with nasal polyps and comparison to those in atopic dermatitis. Plos One. 2010;5:e11450.
Van Zele T, Claeys S, Gevaert P, Van Maele G, Holtappels G, Van Cauwenberge P, et al. Differentiation of chronic sinus diseases by measurement of inflammatory mediators. Allergy. 2006;61:1280–9.
Zygmunt B, Veldhoen M. T helper cell differentiation more than just cytokines. Adv Immunol. 2011;109:159–96.
Kopf M, Le Gros G, Bachmann M, Lamers MC, Bluethmann H, Köhler G. Disruption of the murine IL‑4 gene blocks Th2 cytokine responses. Nature. 1993;362:245–8.
Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, et al. Inhibition of Th1 development mediated by GATA‑3 through an IL-4-dependent mechanism. Immunity. 1998;9:745–55.
Danielsen A, Tynning T, Brokstad KA, Olofsson J, Davidsson A. Interleukin 5, IL6, IL12, IFN-gamma, RANTES and Fractalkine in human nasal polyps, turbinate mucosa and serum. Eur Arch Otorhinolaryngol. 2006;263:282–9.
Derycke L, Eyerich S, Van Crombruggen K, Pérez-Novo C, Holtappels G, Deruyck N, et al. Mixed T helper cell signatures in chronic rhinosinusitis with and without polyps. Plos One. 2014;9:e97581.
Li Z, Zhang Y, Sun B. Current understanding of Th2 cell differentiation and function. Protein Cell. 2011;2:604–11.
Prussin C, Yin Y, Upadhyaya B. T(H)2 heterogeneity: Does function follow form? J Allergy Clin Immunol. 2010;126:1094–8.
Bachert C, Wagenmann M, Hauser U, Rudack C. IL‑5 synthesis is upregulated in human nasal polyp tissue. J Allergy Clin Immunol. 1997;99:837–42.
Bachert C, Gevaert P, Holtappels G, Cuvelier C, van Cauwenberge P. Nasal polyposis: from cytokines to growth. Am J Rhinol. 2000;14:279–90.
Hurst SM, Wilkinson TS, McLoughlin RM, Jones S, Horiuchi S, Yamamoto N, et al. Il‑6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity. 2001;14:705–14.
Jones SA. Directing transition from innate to acquired immunity: defining a role for IL‑6. J Immunol. 2005;175:3463–8.
Kaplanski G, Marin V, Montero-Julian F, Mantovani A, Farnarier C. IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol. 2003;24:25–9.
Chin D, Harvey RJ. Nasal polyposis: an inflammatory condition requiring effective anti-inflammatory treatment. Curr Opin Otolaryngol Head Neck Surg. 2013;21:23–30.
Kato A. Immunopathology of chronic rhinosinusitis. Allergol Int. 2015;64:121–30.
Lam EPS, Kariyawasam HH, Rana BMJ, Durham SR, McKenzie ANJ, Powell N, et al. IL-25/IL-33-responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa. J Allergy Clin Immunol. 2016;137:1514–24.
Arend WP, Palmer G, Gabay C. IL‑1, IL-18, and IL-33 families of cytokines. Immunol Rev. 2008;223:20–38.
Kim D‑K, Jin HR, Eun KM, Mo J‑H, Cho SH, Oh S, et al. The role of interleukin-33 in chronic rhinosinusitis. Thorax. 2017;72:635–45.
Reh DD, Wang Y, Ramanathan M, Lane AP. Treatment-recalcitrant chronic rhinosinusitis with polyps is associated with altered epithelial cell expression of interleukin-33. Am J Rhinol Allergy. 2010;24:105–9.
Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H. A novel IL‑1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol. 2008;121:1484–90.
Mjösberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, Piet B, et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol. 2011;12:1055–62.
Robinette ML, Colonna M. Immune modules shared by innate lymphoid cells and T cells. J Allergy Clin Immunol. 2016;138:1243–51.
Ho J, Bailey M, Zaunders J, Mrad N, Sacks R, Sewell W, et al. Cellular comparison of sinus mucosa vs polyp tissue from a single sinus cavity in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2015;5:14–27.
Ho J, Bailey M, Zaunders J, Mrad N, Sacks R, Sewell W, et al. Group 2 innate lymphoid cells (ILC2s) are increased in chronic rhinosinusitis with nasal polyps or eosinophilia. Clin Exp Allergy. 2015;45:394–403.
Liao B, Liu JX, Li ZY, Zhen Z, Cao PP, Yao Y, et al. Multidimensional endotypes of chronic rhinosinusitis and their association with treatment outcomes. Allergy. 2018;73:1459–69.
Philpott CM, Erskine S, Hopkins C, Kumar N, Anari S, Kara N, et al. Prevalence of asthma, aspirin sensitivity and allergy in chronic rhinosinusitis: data from the UK National Chronic Rhinosinusitis Epidemiology Study. Respir Res. 2018;19:129.
Wu D, Bleier BS, Li L, Zhan X, Zhang L, Lv Q, et al. Clinical phenotypes of nasal polyps and comorbid asthma based on cluster analysis of disease history. J Allergy Clin Immunol Pract. 2018;6:1297–1305e1.
Khan A, Vandeplas G, Huynh TMT, Joish VN, Mannent L, Tomassen P, et al. The Global Allergy and Asthma European Network (GALEN rhinosinusitis cohort: a large European cross-sectional study of chronic rhinosinusitis patients with and without nasal polyps). Rhinology. 2018;57:32–42.
Langdon C, Mullol J. Nasal polyps in patients with asthma: prevalence, impact, and management challenges. J Asthma Allergy. 2016;9:45–53.
Tomassen P, Vandeplas G, Van Zele T, Cardell L‑O, Arebro J, Olze H, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol. 2016;137:1449–1456.e4.
Lin DC, Chandra RK, Tan BK, Zirkle W, Conley DB, Grammer LC, et al. Association between severity of asthma and degree of chronic rhinosinusitis. Am J Rhinol Allergy. 2011;25:205–8.
Shaw DE, Sousa AR, Fowler SJ, Fleming LJ, Roberts G, Corfield J, et al. Clinical and inflammatory characteristics of the European U‑BIOPRED adult severe asthma cohort. Eur Respir J. 2015;46:1308–21.
De Greve G, Hellings PW, Fokkens WJ, Pugin B, Steelant B, Seys SF. Endotype-driven treatment in chronic upper airway diseases. Clin Transl Allergy. 2017;7:22.
Seys SF, Scheers H, Van den Brande P, Marijsse G, Dilissen E, Van Den Bergh A, et al. Cluster analysis of sputum cytokine-high profiles reveals diversity in T(h)2-high asthma patients. Respir Res. 2017;18:39.
Zhang Y, Derycke L, Holtappels G, Wang XD, Zhang L, Bachert C, et al. Th2 cytokines orchestrate the secretion of MUC5AC and MUC5B in IL-5-positive chronic rhinosinusitis with nasal polyps. Allergy. 2018;74:131–40.
Bidder T, Sahota J, Rennie C, Lund VJ, Robinson DS, Kariyawasam HH. Omalizumab treats chronic rhinosinusitis with nasal polyps and asthma together—a real life study. Rhinology. 2018;56:42–5.
Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax. 2002;57:875–9.
GINA. Global Strategy for Asthma Management and Prevention (2019 update). 2019. https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf
Orlandi RR, Kingdom TT, Hwang PH, Smith TL, Alt JA, Baroody FM, et al. International consensus statement on allergy and rhinology: rhinosinusitis. International Forum of Allergy and Rhinology. 2016;6(Suppl 1):S22–S209.
Pundir V, Pundir J, Lancaster G, Baer S, Kirkland P, Cornet M, et al. Role of corticosteroids in functional endoscopic sinus surgery—a systematic review and meta-analysis. Rhinology. 2016;54:3–19.
Voorham J, Xu X, Price DB, Golam S, Davis J, Ling ZJJ, et al. Healthcare resource utilization and costs associated with incremental systemic corticosteroid exposure in asthma. Allergy. 2018;74:273–83.
Kirsche H, Klimek L. ASA intolerance syndrome and persistent rhinosinusitis : differential diagnosis and therapy. HNO. 2015;63:357–63.
Klimek L, Pfaar O. Aspirin intolerance: does desensitization alter the course of the disease? Immunol Allergy Clin North Am. 2009;29:669–75.
Hopkins C, Surda P, Bast F, Hettige R, Walker A, Hellings PW. Prevention of chronic rhinosinusitis. Rhinology. 2018;56:307–15.
Kilty SJ, Lasso A, Mfuna-Endam L, Desrosiers MY. Case-control study of endoscopic polypectomy in clinic (EPIC) versus endoscopic sinus surgery for chronic rhinosinusitis with polyps. Rhinology. 2018;56:155–7.
Rudmik L, Soler ZM, Hopkins C, Schlosser RJ, Peters A, White AA, et al. Defining appropriateness criteria for endoscopic sinus surgery during management of uncomplicated adult chronic rhinosinusitis: a RAND/UCLA appropriateness study. Rhinology. 2016;54:117–28.
Gandhi NA, Pirozzi G, Graham NMH. Commonality of the IL-4/IL-13 pathway in atopic diseases. Expert Rev Clin Immunol. 2017;13:425–37.
Sanofi-Aventis_Germany_GmbH. Dupixent® 300 mg solution for injection in a prefilled syringe, R.L.S. GmbH—Expert information. Rote Liste Service GmbH Frankfurt 2020:p. 21.
Forster-Ruhrmann U, Stergioudi D, Pierchalla G, Fluhr JW, Bergmann KC, Olze H. Omalizumab in patients with NSAIDs-exacerbated respiratory disease. Rhinology. 2020;58:226–32.
Ren L, Zhang N, Zhang L, Bachert C. Biologics for the treatment of chronic rhinosinusitis with nasal polyps—state of the art. World Allergy Organ J. 2019;12:100050.
Tsetsos N, Goudakos JK, Daskalakis D, Konstantinidis I, Markou K. Monoclonal antibodies for the treatment of chronic rhinosinusitis with nasal polyposis: a systematic review. Rhinology. 2018;56:11–21.
EMA. Dupixent: European medicines agency. 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/dupixent. Accessed 18 Nov 2021.
EMA. Xolair European medicines agency. 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/xolair. Accessed 18 Nov 2021.
EMA. Nucala: European medicines agency. 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/nucala. Accessed 18 Nov 2021.
Bachert C, Gevaert P, Hellings P. Biotherapeutics in chronic rhinosinusitis with and without nasal polyps. J Allergy Clin Immunol Pract. 2017;5:1512–6.
Kim DW, Cho SH. Emerging endotypes of chronic rhinosinusitis and its application to precision medicine. Allergy Asthma Immunol Res. 2017;9:299–306.
HEXAL. Expert information—Budes® Nasal Spray 50 microgram/spray puff nasal spray, suspension: Hexal AG. 2017. https://s3.eu-central-1.amazonaws.com/prod-cerebro-ifap/media_all/80132.pdf. Accessed 6 Jan 2017.
PHARMA A. SmPC—Mometasone furoate AL 50 micrograms/spray puff nasal spray: ALIUD PHARMA. 2018. http://fachinformation.srz.de/pdf/aliudpharma/mometasonfuroatal50mikrogrammspr%C3%BChsto%C3%9F.pdf. Accessed 6 Jan 2022.
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B. Wollenberg has received honoraria and/or research grants from MSD, Sanofi, Astra Zeneca, Novartis, and BMS Adboard outside of this work. J. Hagemann has received grants from Novartis Pharma GmbH for lectures. A. Chaker conducts consulting services (e.g. Advisory Boards, DSMBs), lectures or other activities for Allergopharma, ALK-Abello, Astra Zeneca, GSK, HAL Allergy, Mundipharma, Nexter, Immunotek, Lofarma, SanofiGenzyme and Regeneron through; has received clinical trials fees or research funding through the Technical University of Munich from ALK, Allergopharma, Astra Zeneca, Bencard/Allergen Therapeutics, ASIT Biotech, GSK, Novartis, Roche, and Zeller AG, as well as research funding from the Federal Environment Agency of the Federal Republic of Germany, EIT Health, and DZL (BMBF). AMC has also received honoraria and reimbursement of travel expenses from Bayerisches Ärzteblatt, the German Society for Allergology and Clinical Immunology (DGAKI) and the European Academy of Allergy and Clinical Immunology. H. Olze has received honoraria and/or research grants from F. Hoffmann-La Roche Ltd, Sanofi-Aventis Deutschland GmbH, AstraZeneca GmbH, and GlaxoSmithKline GmbH & Co. KG. L. Klimek reports grants and/or honoraria from Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT Biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, and Inmunotk, outside of those submitted Work; and membership in the following organizations: AeDA, DGHNO, German Academy for Allergology and Clinical Immunology, ENT-BV GPA, and EAACI. U. Förster-Ruhrmann has received lecture fees from Novartis, AstraZeneca, Sanofi, and GSK outside of the present work. S. Strieth reports grants from the German Research Foundation (DFG), Bonn, the Head and Neck Cancer Research Foundation, Wiesbaden, and Fresenius Kabi, Bad Hersfeld; grants and non-financial funding from MED-EL AG, Innsbruck; staff fees from Auris Medical, Basel, Merck Serono, Darmstadt, Otonomy, Inc., San Diego (USA), Sanofi Genzyme, Berlin, ALK-Abelló Arzneimittel, Hamburg, and Nordmark Arzneimittel, Uetersen; subsidy from Andreas Fahl Medizintechnik-Vertrieb, Cologne, Atos Medical, Troisdorf, and Tracoe Medical, Nieder-Olm; scholarships from Heimomed Heinze, Kerpen, and Bromepithetik, Heidelberg, outside of the submitted work. M. Cuevas has received honoraria from AstraZeneca, GSK, Sanofi and Novartis outside of this work. W. Schlenter, S. Becker, A.G. Beule, T. Deitmer, H.J. Welkoborsky, S. Dazert, T. Huppertz, T.K. Hoffmann, H. Wrede, C. Bergmann, F. Klimek and I. Casper have no conflicts of interest related to the present work.
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Recommendations of the German Society for Allergology (AeDA) and the German Society for Otorhinolaryngology, Head, and Neck Surgery (DGHNOKHC)
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Klimek, L., Förster-Ruhrmann, U., Beule, A.G. et al. Indicating biologics for chronic rhinosinusitis with nasal polyps (CRSwNP). Allergo J Int 31, 149–160 (2022). https://doi.org/10.1007/s40629-022-00220-x
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DOI: https://doi.org/10.1007/s40629-022-00220-x