Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Mepolizumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem ­ Empfehlungen des Ärzteverbandes Deutscher Allergologen (AeDA) und der AGs Klinische Immunologie, Allergologie und Umweltmedizin und Rhinologie und Rhinochirurgie der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie (DGHNOKHC).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy is to be monitored, what follow-up documentation is necessary, and when it should be terminated if necessary. METHODS: A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered. RESULTS: Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals and possible therapy breaks, as well as termination of therapy when using mepolizumab for the indication CRSwNP in the German health care system are given on the basis of a documentation sheet. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention.

Persisting chemosensory dysfunction in COVID-19 - a cross-sectional population-based survey.

BACKGROUND: Chemosensory dysfunction (CD) has been reported as a common symptom of SARS-CoV-2 infection, but it is not well understood whether and for how long changes of smell, taste and chemesthesis persist in infected individuals. METHODOLOGY: Unselected adult residents of the German federal state of Schleswig-Holstein with Polymerase Chain Reaction (PCR)-test-confirmed SARS-CoV-2 infection were invited to participate in this large cross-sectional study. Data on the medical history and subjective chemosensory function of participants were obtained through questionnaires and visual analogue scales (VAS). Olfactory function (OF) was objectified with the Sniffin Sticks test (SST), including threshold (T), discrimination (D) and identification (I) test as well as summarized TDI score, and compared to that in healthy controls. Gustatory function (GF) was evaluated with the suprathreshold taste strips (TS) test, and trigeminal function was tested with an ampoule containing ammonia. RESULTS: Between November 2020 and June 2021, 667 infected individuals (mean age: 48.2 years) were examined 9.1 months, on average, after positive PCR testing. Of these, 45.6% had persisting subjective olfactory dysfunction (OD), 36.2% had subjective gustatory dysfunction (GD). Tested OD, tested GD and impaired trigeminal function were observed in 34.6%, 7.3% and 1.8% of participants, respectively. The mean TDI score of participants was significantly lower compared to healthy subjects. Significant associations were observed between subjective OD and GD, and between tested OD and GD. CONCLUSION: Nine months after SARS-CoV-2 infection, OD prevalence is significantly increased among infected members of the general population. Therefore, OD should be included in the list of symptoms collectively defining Long-COVID.

Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Dupilumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the nasal and paranasal mucosa. A Type-2 inflammation is described as the most common endotype. Since October 2019 the anti-IL-4/-IL-13 antibody dupilumab has been approved in Germany as an add-on therapy to intranasal corticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps, when systemic corticosteroids alone or surgery do not provide adequate disease control. While recommendations for the use of dupilumab in CRSwNP exist at both national and international levels, until now it has not been adequately established, how therapy should be monitored and when it should be discontinued in the German Health Care System. METHODS: A literature search was performed analyzing previous data on the treatment of CRSwNP with dupilumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to 05/2022 were included. RESULTS: Based on international literature and previous experience, recommendations are given by an expert panel for follow-up and possible therapy breaks, therapy intervals or termination of therapy when using dupilumab for the indication CRSwNP in the German health care system based on a documentation form. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens new non-surgical therapy approaches with biologics for patients with severe courses. The authors give recommendations for follow-up, possible therapy breaks, therapy intervals and a termination for dupilumab treatment as add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.

EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.

In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

[Orphan disease of the nose and paranasal sinuses]. / Ausgewählte seltene rhinologische Krankheitsbilder Pathogenese - Klinik - Therapie.

Rare rhinological diseases are a diagnostic challenge. From the primary manifestation until the final diagnosis it may take several months or even up to years in which the disease progress is uncontrolled and the disease insufficiently treated. This results in (irreversible) damage and possibly life-threatening situations. The unexpected course of a (misdiagnosed) disease should lead to further diagnostic considerations and steps to detect the orphan disease at a stage as early as possible. In the present work granulomatous diseases of the nose and sinuses caused by mycobacteria, treponemes, klebsiella, fungi and protozoa as well as vasculitis, sarcoidosis, rosacea, the cocaine-induced midline destruction, the nasal extranodal NK/T-cell lymphoma and cholesterol granuloma are discussed. Furthermore diseases with disorders of mucociliary clearance as the primary ciliary dyskinesia and cystic fibrosis are presented taking into account the current literature.

Molecular signatures of a disturbed nasal barrier function in the primary tissue of Wegener's granulomatosis.

Wegener's granulomatosis (WG) is a complex autoimmune disease of unknown etiology, frequently involving localized inflammation of the nasal mucosa as an early manifestation. The current hypothesis suggests that the disease is triggered by a disturbed interaction between genetic and environmental effects, such as an altered microflora at mucosal layers. In this study, a systematic assessment of 49 transcripts with potential pathophysiological relevance was performed using quantitative real-time PCR in nasal mucosa samples of more than 80 individuals, including normal control (NC) individuals and disease controls. In addition, colonization with Staphylococcus aureus was quantified in the same individuals to assess its impact on transcriptomic signatures. Transcription profiles show an increased heterogeneity in diseased individuals. In all, 10 transcripts were identified to be differentially expressed (P≤0.05, false discovery rate ≤0.05) between patients with WG and NC individuals. These transcripts include antimicrobial peptides (human ß-defensin (DEFB)1: fold-change WG vs. controls: +4.45, lysozyme: -3.4, DEFB4 and S100A7 (S100 calcium-binding protein A7): both "switched on" in WG), innate immune receptors (Toll-like receptor 4: -2.1, NOD-like receptor C3: -2.1, scavenger receptor CD36: +2.9), and cytokines (interferon-γ: -14, transforming growth factor-ß 1: -1.4, interleukin-17D: -2.7). These transcriptional profiles are independent of S. aureus colonization. This study for the first time describes that, on the basis of data obtained from the primary nasal tissue, WG exhibits molecular features that allow its differentiation from other inflammatory disorders with involvement of the nasal mucosa. Further studies based on these findings may enable the identification of subphenotypes, which are currently discussed as an important target for a personalized medicine approach, aiming to reduce side effects and the number of therapy non-responders.

Olfactory dysfunction in Wegener's granulomatosis.

Necrotizing granulomatous inflammation of the upper respiratory tract is one of the hallmarks of Wegener's granulomatosis (WG), which may explain the reason for olfactory dysfunction in WG. However, a systematic analysis using modem olfactory testing tools has not been performed and potential causes of dysfunction at different levels of olfactory information processing remain obscure so far. In this study a group of 76 WG-patients was examined with sniffin'sticks screening 12, odour threshold (T)/discrimination (D)/identification (I) TDI-score, active anterior rhinomanometry and a standardized questionnaire for olfactory function. WG-patients were aware of their olfactory dysfunction, as proven by psychophysiological test results. An altered olfactory function was significantly correlated to local administration of mupirocin and to the time interval between first diagnosis and study entry. None of the other variables had a statistical significant effect on the olfactory dysfunction.

Severe impaired respiratory ciliary function in Wegener granulomatosis.

OBJECTIVE: The pathogenesis of granulomatous inflammation in the respiratory tract and autoimmunity in Wegener granulomatosis (WG) are poorly understood. Since mucociliar clearance represents the first major line of defence in the respiratory tract and its breakdown facilitates chronic inflammation, we investigated ciliary beat frequency (CBF) in WG. METHODS: Nasal epithelial cells were obtained from 30 patients with WG with involvement of the upper respiratory tract, 12 patients with other inflammatory rheumatic disease and 10 healthy controls. CBF was measured at 5 and 24 h after collection. RESULTS: were correlated with clinical data. Results: CBF was significantly reduced in WG compared to disease and healthy controls after 5 and 24 h. In WG, CBF almost stagnated after 24 h. Reduction of CBF correlated with the cumulative number of immunosuppressive agents in WG, but not in disease controls. No correlation was found between CBF impairment and cyclophosphamide levels, disease extent, disease activity, disease duration, serological and microbiological findings, or inflammation markers. CONCLUSION: CBF is severely impaired in WG, potentially influenced by immunosuppressive treatment. To what extent CBF impairment and subsequent barrier dysfunction are caused by other factors still has to be elucidated. Supportive measures to improve mucociliary clearance should be discussed in patients with WG.

[Diagnosis, therapy and current research aspects of selected chronic inflammatory diseases with head and neck involvement]. / Diagnostik, Therapie und aktuelle Forschungsaspekte ausgewählter chronisch-entzündlicher Erkrankungen mit Beteiligung im Kopf-Hals-Bereich.

Wegener's granulomatosis, Churg-Strauss syndrome and analgesics intolerance syndrome with polyps demonstrate non-specific manifestations in the head and neck region. These symptoms can often lead to early diagnosis and initiation of the correct therapy. However, symptoms are often ambiguous and many rare differential diagnoses must be borne in mind. This clinical picture presents a challenge for the otorhinolaryngologist, who is commonly the first contacted physician. Diagnostics and therapy have to be carried out in an interdisciplinary approach between rheumatologist, pulmonologist, pathologist, radiologist, ophthalmologist, infection specialist and nephrologist. Despite significant scientific and therapeutic advances, these diseases remain incurable. In recent decades they have lost their life-threatening character (Wegener's granulomatosis) and are now chronically relapsing diseases. Their aetiology, however, is still unclear and treatment leads to a wide spectrum of undesirable effects. Research work is needed to advance diagnostics and therapy in this field. Recent research aspects are presented in this article.

Head and neck manifestations of Wegener's granulomatosis.

Wegener's Granulomatosis (WG) is a necrotizing granulomatous angiitis that presents the classic ELK triad of ear, nose, throat (E), lung (L), and kidney (K) involvement. Its potential rapid and fatal outcome makes the early recognition--before irreversible organ involvement occurs--mandatory. The aetiology is still unknown. Today, immunosuppressive therapy makes WG a treatable disease with a chronically relapsing course. The otorhinolaryngologist plays an important role in early diagnosis of WG, because in up to 95% of the patients initial WG symptoms are observed in the head and neck region. The majority of these patients show nasal or sinunasal involvement. Common manifestations are sinusitis, crusting of the nose, and development of saddle nose deformity. Other head and neck problems are middle and inner ear symptoms and subglottic stenosis. Follow up and activity assessment of the disease are also important roles to play for the otorhinolarygologist.

Sentinel lymph-node biopsy in head and neck cancer.

The aim of the study was to assess the diagnostic value of the sentinel node method in patients suffering from squamous cell carcinoma of the upper aerodigestive tract. In 50 patients with oral, pharyngeal or laryngeal carcinomas staged N0 up to 50 MBq technetium-99m colloid were injected peritumorally. Sentinel nodes were localised using a gamma-probe in the setting of an elective neck dissection. Pathological findings of sentinel nodes and corresponding neck specimens were compared. In 46 patients sentinel nodes were detected. Of these 34 patients were free of metastatic disease in the sentinel nodes and in the neck specimens. In 12 patients clinically occult metastases were found in the sentinel nodes. Three metastases were detected only after additional sectioning of the sentinel nodes. In four patients, a sentinel lymph node could not be localised. Our results support the sentinel node concept in head and neck cancer and a definition of the sentinel nodes as the three nodes with the highest activity. Careful clinical staging of the neck and thorough pathological evaluation of the sentinel nodes are necessary to avoid false-negative results.