Hypereosinophilia during dupilumab treatment in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: Increased blood eosinophil count (BEC) is common in patients under dupilumab treatment for chronic rhinosinusitis with nasal polyps (CRSwNP). This study investigated the prevalence and consequences of hypereosinophilia and to help define patients at risk. METHODS: Real-life, prospective observational cohort study of patients treated with dupilumab for severe CRSwNP. Eligible patients were adult and biological-naive (N=334). All BEC values at baseline and during treatment were reported. Patients with a follow-up of >= 1 year were included to define patients at risk for hypereosinophilia by comparing baseline BEC values (N=218). Furthermore, clinical characteristics and therapeutic consequences for patients with BEC >= 3.0 were noted. RESULTS: Hypereosinophilia developed in a minority of patients, with a peak at week 12 (16.2% with BEC >= 1.5, and 1.7% >= 3.0) in cross-sectional analysis. BEC >= 1.5 developed in 28.9% and BEC >=3.0 in 4.6% of cases with a minimal 1-year follow-up. Baseline BEC was significantly higher for patients developing BEC >= 1.5 and BEC >=3.0, with an optimal cut-off point of 0.96 to predict developing BEC >= 3.0. CONCLUSIONS: Blood eosinophil count (BEC) >= 1.5 is transient and usually abates with no therapeutic interventions and BEC >= 3.0 is rare. Hypereosinophilic syndrome did not occur and switching to a different biological was rarely employed. A baseline BEC of >=1.0 can be a reason for extra caution.

Eosinophils are the dominant type2 marker for the current indication of biological treatment in severe uncontrolled chronic rhinosinusitis with nasal polyps.

The latest European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) defines markers for type2 inflammation in the context of indicating biological therapy in severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) as either a total serum immunoglobulin E (total-IgE) <100 kU/L, a blood eosinophil count (BEC, expressed as -109 cells / L) >=0.25, or a tissue eosinophil count >=10 per high power field (HPF) (1). Recently, an EPOS/EUFOREA expert panel advised to lower the threshold for BEC from >=0.25 (EPOS2020) to >=0.15 (EUFOREA2023) to align with thresholds used for biological indication in asthma patients (2). As far as we know, there is no literature supporting the cut-off value for total-IgE.

Measuring control of disease in Chronic Rhinosinusitis; assessing the correlation between SinoNasal Outcome Test-22 and Visual Analogue Scale item scores.

BACKGROUND: In chronic rhinosinusitis (CRS), aim of treatment is control of disease. EPOS2020 suggests the use of visual analogue scale (VAS) measurements on several symptoms. We aim to determine if individual VAS items can be replaced by widely used SinoNasal Outcome Test-22 (SNOT-22) items when determining control of disease, to avoid using double measurements and to stimulate its use in clinical practice. METHODS: Analyses were made on correlations between individual SNOT-22 scores and symptom-specific questions from consecutive patients with CRS visiting our tertiary referral rhinologic clinic for the first time. RESULTS: 157 CRS patients were included. Correlations of individual items were strong (r greater than 0.8). Best parity in sensitivity, specificity, positive predicting value, negative predicting value, odds ratio and Receiver Operating Characteristic curves were found in individual item score of VAS greater than 5 and SNOT item-score. This cut off is valid for measuring control of disease, combining several nasal, facial pain and sleep symptoms (controlled, partially controlled and uncontrolled). CONCLUSION: There is strong correlation between individual items measured as SNOT or VAS. For the definition of CRS disease control, as proposed in EPOS2020, the use of symptoms specific SNOT 23 is predictive of VAS greater than 5.

Occupational exposure influences control of disease in patients with chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a frequent condition that is treated by endoscopic sinus surgery (ESS) when medical treatment fails. Irritating or sensitizing airborne agents can contribute to uncontrolled CRS. A prior study showed a linear correlation between occupational exposure and the number of ESS. METHODS: In this cross-sectional study we tested the hypothesis that occupational exposure is a risk for undergoing ESS. We sent questionnaires enquiring occupational exposure in patients with CRS with nasal polyps (CRSwNP) or CRS without nasal polyps (CRSsNP). An expert assessed blindly the reported work exposures to inhaled agents. The relationship between occupational exposure on undergoing ESS was analysed. RESULTS: Among all patients who underwent ESS (n=343), 30% reported a relevant occupational exposure, which is significantly higher than the 4.8% found among CRS patients that underwent no prior sinus surgery (n=21). Besides occupational exposure, self-reported doctor-diagnosed asthma were independent variables contributing to the chance of undergoing ESS. CONCLUSION: In our study we confirm occupational exposure as a risk factor for uncontrolled CRS, if defined by undergoing ESS. In CRS patients with uncontrolled symptoms, despite maximal conservative therapy, the clinician should explore the possible contribution of occupational exposure.

The Amsterdam Classification of Completeness of Endoscopic Sinus Surgery (ACCESS): a new CT-based scoring system grading the extent of surgery.

BACKGROUND: A debate is ongoing on the role of the extent of sinus surgery in disease control in chronic rhinosinusitis (CRS). The newly developed Amsterdam Classification on Completeness of Endoscopic Sinus Surgery (ACCESS) score provides a way to quantify extent of surgery. This study aimed to validate the ACCESS scoring system and to report its interrater agreement compa- red to the widely used Lund-Mackay (LM) scoring system. METHODOLOGY: Forty hand-picked anonymized computed tomography scans of sinuses of patients with varying pathology and degree of previous sinus surgery were independently scored by six rhinologists. Interrater agreement was determined by the intraclass correlation (ICC) statistic. RESULTS: The interrater agreement of the ACCESS score was excellent, comparable to the LM score. The ACCESS interrater agree- ment was not influenced by degree of opacification or diagnosis. The ACCESS score reliably measured predicted differences induced by sinus surgery. CONCLUSIONS: the ACCESS score is an easy-to-use valid tool to assess extent of sinus surgery with an excellent interrater agree- ment. Further validation in a random group of CRS cases is required.

EUFOREA Rhinology Research Forum 2016: report of the brainstorming sessions on needs and priorities in rhinitis and rhinosinusitis.

The first European Rhinology Research Forum organized by the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) was held in the Royal Academy of Medicine in Brussels on 17th and 18th November 2016, in collaboration with the European Rhinologic Society (ERS) and the Global Allergy and Asthma European Network (GA2LEN). One hundred and thirty participants (medical doctors from different specialties, researchers, as well as patients and industry representatives) from 27 countries took part in the multiple perspective discussions including brainstorming sessions on care pathways and research needs in rhinitis and rhinosinusitis. The debates started with an overview of the current state of the art, including weaknesses and strengths of the current practices, followed by the identification of essential research needs, thoroughly integrated in the context of Precision Medicine (PM), with personalized care, prediction of success of treatment, participation of the patient and prevention of disease as key principles for improving current clinical practices. This report provides a concise summary of the outcomes of the brainstorming sessions of the European Rhinology Research Forum 2016.

Long-term results of functional endoscopic sinus surgery in children with chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is rare in children and has a major impact on Quality of Life (QoL). Functional endoscopic sinus surgery (FESS) has proven to be an effective treatment, but it is still unclear what long-term outcomes are in children with CRSwNP. The objective of this study was to assess long-term results of FESS in children with CRSwNP. METHODOLOGY: We performed a combined prospective and retrospective study. A QoL questionnaire was send to all children with CRSwNP who received FESS between the year 2000-2010. Almost half of these children also filled in this questionnaire preoperatively. RESULTS: Forty-four Children underwent FESS. From 18 patients, we also prospectively collected preoperative QoL questionnaires. The mean follow-up period was 4.0 years (+- 2.9). The mean age at surgery was 13 years (+-2.9). Of these children, 9 had CF and 10 children asthma. R-SOM scores showed a significant improvement both in general symptoms as well as several different domains when comparing pre- and postoperative questionnaires. Only 5 of 44 patients needed a subsequent intervention. In children with CF this was 3 of 9. CONCLUSION: This study demonstrates that long-term results of FESS in children with CRSwNP are good. QoL has improved significantly, especially in nasal symptoms, showing that FESS is a good treatment in children with CRSwNP. Furthermore, even children with CF show good results.

The microdebrider, a step forward or an expensive gadget?

BACKGROUND: Although the use of the microdebrider (shaver) is well known in endoscopic sinus surgery (FESS), there is lack of evidence from comparative studies focussing on the difference in operating time, intra-operative blood loss and user-friendliness between the microdebrider and traditional operating techniques. In this study we compared the use of the microdebrider to conventional instruments in FESS in these areas. METHODS: A prospective randomised double blind controlled trial in 60 patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) undergoing bilateral FESS. Each subject received FESS using only traditional instruments (Blakseley forceps) on one side and the other side with the additional use of the microdebrider, this way serving as their own control. The primary outcome was operation time, intra-operative blood loss and user friendliness and secondly safety and postoperative healing with a follow-up period at different time points up to three months postoperative. RESULTS: We found a 37% longer operating time when operating without a microdebrider. This difference was highly significant. The microdebrider scored significantly higher on every different parameter of user friendliness, except on the preparation of the instrument needed before surgery. For estimated blood loss during surgery we found no differences. Also there was no significant difference in postoperative healing at any point of time. CONCLUSIONS: This study demonstrates that operating patient with CRSwNP with the microdebrider is efficient and that the microdebrider at the same time is safe and easy to use.

Evidence for a role of protein kinase C zeta subspecies in maturation of Xenopus laevis oocytes.

A number of studies have demonstrated the activation of phospholipase C-mediated hydrolysis of phosphatidylcholine (PC-PLC) both by growth factors and by the product of the ras oncogene, p21ras. Evidence has been presented indicating that the stimulation of this phospholipid degradative pathway is sufficient to activate mitogenesis in fibroblasts as well as that it is sufficient and necessary for induction of maturation in Xenopus laevis oocytes. However, the mechanism whereby PC-PLC transduces mitogenic signals triggered by growth factors or oncogenes remains to be elucidated. In this study, data are presented that show the involvement of protein kinase C zeta subspecies in the channelling of the mitogenic signal activated by insulin-p21ras-PC-PLC in Xenopus oocytes as well as the lack of a critical role of protein kinase C isotypes alpha, beta, gamma, delta, and epsilon in these pathways.

Phospholipase C-mediated hydrolysis of phosphatidylcholine is a target of transforming growth factor beta 1 inhibitory signals.

Cell growth and tumor transformation can be restrained in certain cell systems by the action of transforming growth factor beta (TGF-beta). It has been established that the mechanism whereby TGF-beta 1 inhibits cell growth does not interfere with the triggering of early mitogenic signal transduction mechanisms. Phospholipase C-catalyzed hydrolysis of phosphatidylcholine (PC) is a relatively late step in the cascade activated by growth factors. Therefore, conceivably activation of phospholipase C-catalyzed hydrolysis of PC could be the target of TGF-beta 1 action. In the study reported here, we demonstrate that TGF-beta 1 inhibits the coupling of ras p21 to the activation of PC hydrolysis, which appears to be critical for the antiproliferative effects of TGF-beta 1.

Phospholipase C-mediated hydrolysis of phosphatidylcholine is activated by muscarinic agonists.

The phospholipase C-catalysed breakdown of inositol-containing phospholipids is an important source of diacylglycerol in cells stimulated by several agonists. However, recent experimental evidence suggests that major phospholipids such as phosphatidylcholine may also be substrates of the phosphodiesteratic hydrolysis activated by hormones, growth factors and oncogene products. We show here that stimulation of muscarinic agonists activates the release of phosphocholine, which, along with diacylglycerol, is a metabolic product of phospholipase C-mediated hydrolysis of phosphatidylcholine. Fluoroaluminates mimic this muscarinic effect, strongly suggesting that carbachol-activated release of phosphocholine may be mediated by a guanine-nucleotide-binding protein. Evidence for this was obtained from experiments using permeabilized cells in which non-hydrolysable analogues of GTP activated phosphocholine release synergistically with carbachol.

Ca2+-induced changes in the secondary structure of a 60 kDa phosphoinositide-specific phospholipase C from bovine brain cytosol.

The purification to homogeneity of a 60 kDa phosphoinositide-specific phospholipase C from bovine brain cytosol is reported here. This enzyme exhibits the same properties, in terms of response to Ca2+, as does the cytosolic activity in a variety of cell types. We show here that Ca2+ does not appear to modulate the binding of the enzyme to the substrate, but induces dramatic changes in its secondary structure. Therefore we suggest that a decrease in the alpha-helix content of this enzyme correlates with its ability to be activated by Ca2+.

Kinetic evidence of a rapid activation of phosphatidylcholine hydrolysis by Ki-ras oncogene. Possible involvement in late steps of the mitogenic cascade.

A novel phospholipase C specific for phosphatidylcholine has been shown to be activated by several agonists. Also, recent evidence suggests that transformation mediated by the ras oncogene possibly involves the activation of this novel phospholipid degradative pathway which would account for the increased diacylglycerol levels associated with transformation. Here we use a mutant of Ki-ras which is temperature-sensitive for transformation to investigate the kinetics of activation of the phosphodiesterase-mediated turnover of phosphatidylcholine. Upon shift to the permissive temperature, products of the activated phosphatidylcholine-specific phospholipase C were detected by 30 min and reached maximal levels by 1-2 h. These results suggest that the product of the ras oncogene rapidly activates the phosphodiesteratic hydrolysis of phosphatidylcholine. Furthermore, the fact that at least 4 h are required for serum to activate this phospholipase C strongly suggests that the ras oncogene product might be involved in late steps of the mitogenic signaling cascade.

Evidence for a role of phosphatidylcholine-hydrolysing phospholipase C in the regulation of protein kinase C by ras and src oncogenes.

The products of ras and src oncogenes are thought to be important components in pathways regulating cell proliferation and differentiation. In fibroblasts transformed by these oncogenes, increased diacylglycerol levels have been found which most probably arise from activation of the turnover of phosphatidylcholine. Diacylglycerol is a key activator of protein kinase C whose role in cell growth and transformation has been proposed. We demonstrate here by using immunochemical techniques that transformation by ras or src oncogenes is associated with permanent translocation of protein kinase C to the cytoplasmic membrane. However, no down-regulation of the enzyme is observed despite its permanent activation in these transformants. Importantly, the lack of down-regulation observed in ras and src transformed cell lines is mimicked by chronic treatment of NIH 3T3 fibroblasts with exogenous Bacillus cereus phosphatidylcholine-hydrolysing phospholipase C, but not with phorbol myristate acetate or exogenous Bacillus thuringiensis phosphatidylinositol-hydrolysing phospholipase C. These results strongly suggest that diacylglycerol derived from phosphatidylcholine but not from phosphoinositide turnover is responsible for the atypical regulation of protein kinase C in cell lines transformed by ras and src oncogenes.

Phospholipase C-mediated hydrolysis of phosphatidylcholine is an important step in PDGF-stimulated DNA synthesis.

Recent evidence suggests the involvement of phosphatidylcholine (PC) hydrolysis both in the control of normal cell growth and in transformation. We show here that the simple exogenous addition of Bacillus cereus PC-hydrolyzing phospholipase C (PC-PLC) is sufficient to elicit a potent mitogenic response in Swiss 3T3 fibroblasts by a mechanism that is independent of protein kinase C. Our results on the additivity and synergism between B. cereus PC-PLC, PDGF, and insulin in the mitogenic response indicate that this novel phospholipid degradative pathway may be important in the mitogenic signaling cascade activated by PDGF.

Role of GTPase activating protein in mitogenic signalling through phosphatidylcholine-hydrolysing phospholipase C.

Recent evidence has accumulated showing that activation of PLC-catalysed hydrolysis of phosphatidylcholine (PC-PLC) is a critical step in mitogenic signal transduction both in fibroblasts and in oocytes from Xenopus laevis. The products of ras genes activate PC-PLC, bind guanine nucleotides, have intrinsic GTPase activity, and are regulated by a GTPase-activating protein (GAP). It has been suggested that, in addition to its regulatory properties, GAP may also be necessary for ras function as a downstream effector molecule. In this study, evidence is presented that strongly suggests that the functional interaction between ras p21 and GAP is sufficient and necessary for activation of maturation promoting factor (MPF) H1-kinase activity in oocytes, and that PC hydrolysis is critically involved in this mechanism. Therefore, we identify GAP as a further step required for signalling through PC-PLC, and necessary for the control of oocyte maturation in response to ras p21/insulin but not to progesterone.

Mechanism of inhibition of adenylate cyclase by phospholipase C-catalyzed hydrolysis of phosphatidylcholine. Involvement of a pertussis toxin-sensitive G protein and protein kinase C.

The phospholipase C-mediated hydrolysis of phosphatidylcholine has been shown recently to be activated by a number of agonists. Muscarinic receptors, which trigger various signal transduction mechanisms including inhibition of adenylate cyclase through Gi, have been shown to be potent stimulants of this novel phospholipid degradative pathway. We demonstrate here, by exogenous addition of Bacillus cereus phosphatidylcholine-hydrolyzing phospholipase C, that phosphatidylcholine breakdown mimics the ability of carbachol to inhibit adenylate cyclase. This effect is sensitive to pertussis toxin and is entirely dependent on the presence of protein kinase C. This kinase is also required for the inhibition by carbachol of adenylate cyclase. These results suggest that the activation of phosphatidylcholine breakdown by phospholipase C may play an important role linking or favoring the coupling muscarinic receptors to Gi. Results presented here also show that phospholipase C-mediated hydrolysis of phosphoinositides by exogenous addition of Bacillus thuringiensis phosphoinositide-hydrolyzing phospholipase C does not affect adenylate cyclase, despite the fact that protein kinase C is translocated to an extent similar to that produced by the hydrolysis of phosphatidylcholine. According to the results shown here, both phospholipases also differ in their ability to down-regulate protein kinase C as well as to phosphorylate p80 and to transmodulate the binding of epidermal growth factor, two well established effects of protein kinase C in Swiss 3T3 fibroblasts. This emphasizes the complexity, from a functional point of view, of protein kinase C activation "in vivo."

Efficacy and safety of metamizol vs. acetylsalicylic acid in patients with moderate episodic tension-type headache: a randomized, double-blind, placebo- and active-controlled, multicentre study.

We assessed the efficacy and safety of oral single doses of 0.5 and 1 g metamizol vs. 1 g acetylsalicylic acid (ASA) in 417 patients with moderate episodic tension-type headache included in a randomized, double-blind, placebo- and active-controlled, parallel, multicentre trial. Eligibility criteria included 18-65 years of age, history of at least two episodes of tension-type headache per month in the 3 months prior to enrollment, and successful previous pain relief with a non-opioid analgesic. Treatment arms were metamizol 0.5 g (n = 102), metamizol 1 g (n = 108), ASA 1 g (n = 102) and placebo (n = 105). The analgesic efficacy of 0.5 and 1 g metamizol vs. placebo was highly statistically significant (alpha: 0.025; one-sided) for sum of pain intensity differences, maximum pain intensity difference, number of patients with at least 50% pain reduction, time to 50% pain reduction, maximum pain relief and total pain relief. A trend towards an earlier onset of a more profound pain relief of 0.5 and 1 g metamizol over 1 g ASA was noticed. All medications including placebo were almost equally safe and well tolerated.