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.

Positionspapier: Empfehlungen zur Anwendung von Mepolizumab bei chronischer Rhinosinusitis mit Polyposis nasi (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 Hals-Chirurgie (DGHNO-KHC).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the paranasal sinus mucosa with eosinophilic inflammation as the most common endotype. The anti-IL5 antibody mepolizumab was approved for the treatment of severe CRSwNP in the EU in November 2021. METHODS: A literature search was performed to analyze the immunology of CRSwNP and determine the available evidence by searching Medline, Pubmed, and the German national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 12/2021 that investigated the effect of mepolizumab in CRSwNP were considered. RESULTS: Based on the international literature and previous experience, recommendations for the use of mepolizumab in CRSwNP in the German health care system are given by an expert panel on the basis of a documentation form. CONCLUSIONS: Understanding about the immunological basis of CRSwNP opens new non-surgical therapeutic approaches with biologics for patients with severe courses. Mepolizumab is approved since November 2021 for add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP who cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.

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.

Treatment of hypertrophic palatine tonsils using bipolar radiofrequency-induced thermotherapy (RFITT.).

CONCLUSION: Radiofrequency volume reduction of palatine tonsils is a gentle and safe treatment method in selected patients, which should carefully be considered as an alternative to tonsillectomy or tonsillotomy. OBJECTIVES: The aim of this study was the evaluation of bipolar radiofrequency-induced thermotherapy (RFITT) compared to standard blunt dissection tonsillectomy (TE) for the volume reduction of palatine tonsils in chronic tonsillar hypertrophy. PATIENTS AND METHODS: A total of 137 patients (98 children) were treated in two groups in a prospective controlled, randomized clinical trial. The TE group underwent standard tonsillectomy using blunt dissection. The RFITT group underwent interstitial RF ablation. Perioperative blood loss and duration of surgery were monitored. Tonsil volume reduction in the RFITT group was measured by sonography. Postoperative pain, as well as difficulty in swallowing and speaking, were evaluated using visual analog scales. RESULTS: In the RFITT group, we found an average tonsil volume reduction of 40%, at about 3 weeks after treatment. Postoperative pain, swallowing and speaking difficulties, and perioperative blood loss were significantly lower, and the duration of surgery was significantly shorter (all p<0.05) in the RFITT group. Preservation of the treatment results was monitored until 6 months after treatment, with no after effects during this time period.

Characterization of a hexokinase encoding cDNA of the parasitic nematode Hhaemonchus contortus.

The nematode Haemonchus contortus is an important parasite of cattle and sheep. We describe here the cloning of a cDNA encoding a 53 kDa hexokinase (EC 2.7.1.1). The deduced protein shows 73% identity to a 50 kDa hexokinase deduced from a Caenorhabditis elegans cosmid. Alignment with mammalian hexokinases reveals two short amino acid insertions in the H. contortus hexokinase. Software tools for structural protein analysis (ExPASy server, Geneva) localize these insertions on the surface of the molecule, suggesting these surface changes as potential target sites for chemotherapeutic drugs.

Testosterone-induced diminution of two peptides in spleen cells from testosterone-immunosuppressed B10 mice.

High-performance liquid chromatography (HPLC) is used to detect testosterone (T)-sensitive peptides in spleen cells isolated from female C57BL/10 mice immunosuppressed against Plasmodium chabaudi malaria by T treatment. Two peaks with retention times of about 25 min and 34 min, respectively, were identified to be diminished by about 52% and 47%, respectively, in spleen cells from T-treated mice compared to those from untreated mice. Amino acid sequencing revealed that the 24 min peak consisted of the dipeptide Met-Phe and the 34 min peak contained a degradative fragment of the alpha-chain of hemoglobin. Our data suggest that the immunosuppressive T treatment of B10 mice induces a perturbation of erythrophagocytosis in spleens.

Testosterone-induced susceptibility to Plasmodium chabaudi malaria: variant protein expression in functionally changed splenic non-T cells.

This study investigates the effects of the male sex hormone, testosterone (Te), on self-healing of Plasmodium chabaudi malaria as well as on protein expression and functional properties of total spleen cells and splenic T cells in females of the mouse strain C57BL/10. About 90% of the B10 females survive a challenge with 10(6) P. chabaudi-infected erythrocytes. The percentage of self-healers, however, is reduced to about 60%, 40%, and 0% after pretreatment with Te for 1, 2, and 3 weeks, respectively. The progressive loss of the capability of self-healing is correlated with an increasing expression of five proteins in splenic non-T cells as revealed by two-dimensional fluorography after metabolic labelling of total spleen cells and T cells with [35S]methionine. These have molecular masses (isoelectric points) of about 10 kDa (pI 5.7), 14 kDa (pI 6.3), 14 kDa (pI 6.4), 38 kDa (pI 6.5), and 46 kDa (pI 5.5), respectively. Splenic non-T cells from mice treated with Te for 3 weeks have gained an increased capability to stimulate the concanavalin A-induced proliferative response of T cells. Te induces the changes in functional properties and protein expression of splenic non-T cells only in vivo and not in vitro. This suggests that the changes in splenic non-T cells as well as the prevention of self-healing P. chabaudi malaria are not directly induced by Te but rather indirectly, i.e. by a Te metabolite and/or Te-induced factor(s).

Enhanced expression in spleen macrophages of the mouse homolog to the human putative tumor suppressor gene ZFM1.

We have characterized the cDNA of MZFM, the mouse homolog to the novel human putative tumor suppressor gene ZFM1. The total length of the cDNA is 2,637 nucleotides with an open reading frame for a protein of 548 amino acids containing 4.7% methionine and 17.2% proline. The predicted molecular mass of 59 kD fits the 62-kD band experimentally determined by NaDodSO4-PAGE from in vitro translation products of in vitro-transcribed MZFM cDNA. The MZFM cDNA best matches to that ZFM1-isoform without the so-called 0.25-kb E-domain and to the L49345 cDNA recently identified in a human leukemia cell line. Northern analysis reveals expression of MZFM only in spleen macrophages. Reverse transcription polymerase chain reaction (RT-PCR) in combination with Southern analysis also detects a low basal expression in splenic T cells and B cells, as well as in other tissues such as heart, kidney, brain, liver, testis, bone marrow, adrenal gland, lymph nodes, pancreas, and thymus. In splenic macrophages, MZFM mRNA is alternatively spliced yielding a 3.6-kb transcript with E-domain, a 3.0-kb transcript without E-domain, and a 2.7-kb transcript with E-domain. The predicted MZFM protein contains diverse functional domains, i.e., a nuclear localization signal, a metal binding motif, a glutamine/proline stretch, proline-clusters, a CGA-motif, and a QUA1-KH-QUA2 region, thus indicating multiple functions of MZFM. Presumably, MZFM is a new member of those proteins combining features of signal transduction and RNA activation (STAR-proteins). The different MZFM-isoforms may be part of a macrophage-inherent program of transduction of environmental signals into different activational states of macrophages.

Genomic organization of mouse gene zfp162.

We report the cloning and characterization of the alternatively spliced mouse gene zfp162, formerly termed mzfm, the homolog of the human ZFM1 gene encoding the splicing factor SF1 and a putative signal transduction and activation of RNA (STAR) protein. The zfp162 gene is about 14 kb long and consists of 14 exons and 13 introns. Comparison of zfp162 with the genomic sequences of ZFM1/SF1 revealed that the exon-intron structure and exon sequences are well conserved between the genes, whereas the introns differ in length and sequence composition. Using fluorescent in situ hybridization, the zfp162 gene was assigned to chromosome 19, region B. Screening of a genomic library integrated in lambda DASH II resulted in the identification of the 5'-flanking region of zfp162. Sequence analysis of this region showed that zfp162 is a TATA-less gene containing an initiator control element and two CCAAT boxes. The promoter exhibits the following motifs: AP-2, CRE, Ets, GRE, HNF5, MRE, SP-1, TRE, TCF1, and PU.1. The core promoter, from position -331 to -157, contains the motifs CRE, SP-1, MRE, and AP-2, as determined in transfected CHO-K1 cells and IC-21 cells by reporter gene assay using a secreted form of human placental alkaline phosphatase. The occurrence of PU.1/GRE supports the view that the zfp162 gene encodes a protein involved not only in nuclear RNA metabolism, as the human ZFM1/SF1, but also in as yet unknown macrophage-inherent functions.