Roberto Castano

EAACI position paper on occupational rhinitis

The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item.

Systemic inflammatory markers as independent prognosticators of head and neck squamous cell carcinoma.

The purpose of this study was to investigate the prognostic value of the pretreatment inflammatory markers platelet‐to‐lymphocyte ratio (PLR) and the neutrophil‐to‐lymphocyte ratio (NLR) in patients with head and neck squamous cell carcinoma (HNSCC).

Occupational rhinitis in workers investigated for occupational asthma

Background: The links between asthma and rhinitis are now referred to as united airways disease (UAD). Current evidence shows that the UAD model seems to be applicable to occupational rhinitis (OR) and occupational asthma (OA). A study was undertaken to objectively assess, in the context of specific inhalation challenge (SIC) testing, the concomitance of bronchial and nasal reaction in the investigation of OR and OA. Methods: 43 subjects with a history of work-related asthma symptoms underwent SIC for confirmation of OA and investigation of OR. Changes in bronchial calibre were measured by spirometry and nasal patency and airway inflammation were assessed by acoustic rhinometry and nasal lavage. Results: A positive nasal challenge was observed in 25 SIC tests and a positive bronchial challenge was observed in 17 SIC tests. A concomitant positive nasal and bronchial challenge was observed in 13 instances. This association was significant (risk ratio = 1.7; 95% CI 1.0 to 2.4; p = 0.04) and more frequent in subjects challenged with high molecular weight agents (n = 11/22) than with low molecular weight agents (n = 2/21). In subjects with a positive nasal challenge, nasal lavage showed a significant increase in eosinophils 30 min after exposure which correlated with changes in nasal patency. Conclusion: The results of this study provide objective evidence to support the concept of UAD using OR and OA as a model to demonstrate a significant concomitant physiological reaction of the nose and lungs after challenge. This study shows that OR can be assessed by objective means; it often coexists with OA but can be present without OA.

Evidence of Association of Interleukin-1 Receptor-Like 1 Gene Polymorphisms with Chronic Rhinosinusitis:

Background Chronic rhinosinusitis (CRS) is a common complex respiratory disease, with a potential genetic component to its development. The protein encoded by the Interleukin-1 receptor-like 1 (IL1RL1) gene is an important effector molecule of T-helper type 2 responses and may potentially be involved in the persistent inflammatory process observed in CRS. We investigated whether certain polymorphisms in the IL1RL1 gene are differentially present in patients with surgery-unresponsive CRS and in control subjects. Methods DNA extracted from an existing population of 206 adult patients with surgery-unresponsive CRS and 196 postal-code-matched controls was used. A set of 15 tagging single nucleotide polymorphisms (SNPs) was selected from the HapMap data set and genotyped. DNA sequencing was performed in a subgroup of 15 CRS patients. Results Statistically significant allelic associations with CRS were noted for 5 SNPs (rs10204137, p = 0.04; rs10208293, p = 0.03; rs13431828, p = 0.008; rs2160203, p = 0.03, and rs4988957, p = 0.03). The analysis showed a consistent significant protective effect against CRS for all the SNPs, yielding an odds ratio (OR) ranging from 0.56 to 0.72. The loci rs13431828 showed the highest association with CRS (p = 0.008; OR = 0.56; 95% CI, 0.36–0.86). A subanalysis revealed that the observed associations were stronger among patients with more severe disease. Sequencing identified five additional known nonsynonymous coding SNPs in linkage disequilibrium with genotyped SNPs. Conclusion Pending replication of these results, this study suggests that polymorphisms within the IL1RL1 gene may be associated with CRS, conferring a protective effect, particularly among those with severe disease.

Polymorphisms in the nitric oxide synthase 1 gene are associated with severe chronic rhinosinusitis.

Background Nitric oxide (NO), is a biological messenger molecule and a component of innate immunity, with important roles in the regulation of inflammation and in defense against bacterial biofilms. Polymorphisms in genes regulating NO production have the potential for a role in the development of chronic rhinosinusitis (CRS). The purpose of this study was to determine whether polymorphisms in genes regulating NO synthesis are associated with CRS. Methods An established population of 206 individuals with severe CRS and 196 postal code–matched controls was previously screened using a pooling genome-wide associations study to estimate allelic frequency. Genes regulating NO synthesis with a maximal probability of association were identified. High-probability single nucleotide polymorphisms SNPs from the NO synthase (NOS1) and its ligand NOS1 adaptor protein (NOS1AP) genes were retained for individual genotyping. PLINK software was used to determine association. Results Sixteen SNPs were genotyped successfully with a genotype distribution in agreement with Hardy-Weinberg equilibrium. Two SNPs for NOS1 (rs1483757 and rs9658281) were significantly associated with CRS, with a protective effect. The severe subphenotype showed stronger associations. Subgroup analysis for the presence of nasal polyps, origin, and gender did not influence strength of associations. Conclusion These data suggest that polymorphisms in the NOS1 gene may play a role in the susceptibility to develop CRS. Study findings apply to patients with severe CRS, unresponsive to surgery.

Occupational rhinitis and asthma: where do we stand, where do we go?

This review provides an overview of current and emerging issues regarding occupational rhinitis (OR) and occupational asthma (OA), focusing on studies discussing concepts and results that are relevant to both diseases. OA and OR are conditions that affect the upper and lower airways, are characterized by reduced airway caliber and hyperresponsiveness and by inflammation, and are caused by agents present in the workplace. To explain disease expression, research is moving from the T-helper type 1/type 2 cells paradigm to consider the contribution of diverse alternative pathways such as neural inflammation, a dysfunctional epithelial barrier, and autoimmune mechanisms, among others. Objective assessment of OR and OA has been improved and tested for research and, currently, clinical application. Further developments in the field of OR are expected to lead to more generalized clinical applications, following the example of what has been achieved for OA.

Reproducibility of nasal lavage in the context of the inhalation challenge investigation of occupational rhinitis.

Background The nasal lavage (NAL) method is increasingly used to assess changes in upper airways inflammation in the investigation of occupational rhinitis (OR). A good reproducibility of the method is fundamental to accurately assess changes in markers of inflammation in nasal secretions before and after inhalation challenges. The main objective of this study was to assess the short-term reproducibility of cells and cellular markers of inflammation in NAL in the setting of specific inhalation challenge (SIC) investigating OR. An ancillary objective was to assess the reproducibility of NAL in the context of two different SIC methodologies. Methods Twenty-five subjects attended the laboratory for 2 separate days of NAL performed within the same week. On the first visit subjects underwent NAL before a SIC sham session and on the second visit before a SIC with the active agent. These prechallenge NAL measurements obtained on both days were used to analyze the reproducibility of the NAL method. Results The reproducibility for cell differential counts was satisfactory for neutrophils (intraclass correlation coefficient [ICC] = 0.68), for eosinophils (ICC = 0.95), for macrophages (ICC = 0.77), and for epithelial cells (ICC = 0.73). The reproducibility of total cell counting was poor (ICC = 0.12). The reproducibility of ECP concentrations was satisfactory (ICC = 0.67). Eosinophil counts were reproducible in the context of two different challenge methodologies. Conclusion The NAL method was shown to be sufficiently reproducible to be considered useful for the monitoring of upper airways inflammation during the investigation of OR by SIC.

Proinflammatory mediators in nasal lavage of subjects with occupational rhinitis

We sought to investigate the type and kinetics of late-phase nasal inflammatory response after nasal challenge with occupational allergens. Participants were 10 subjects experiencing work-related rhinitis symptoms who underwent specific inhalation challenge and tested positive for occupational rhinitis. During challenge, we monitored changes in inflammatory cells, eosinophil cationic protein, myeloperoxidase, and interleukin-8 in nasal lavage samples. The challenge with the active agent induced a significant increase in the percentage of eosinophils at 30 minutes as compared with prechallenge values (P = 0.04). A significant increase in eosinophil cationic protein levels after challenge with the control (P = 0.01) and active agent (P = 0.02) was observed in the late phase after challenge. No significant changes in nasal levels of neutrophils, myeloperoxidase, and interleukin-8 were observed on both control and active challenge days. Our results suggest a predominant nasal eosinophilic inflammatory response after occupational allergen challenge.

c-MET pathway involvement in chronic rhinosinusitis: A genetic association analysis

Objective: The c-MET receptor and its ligand hepatocyte growth factor (HGF) has been shown to be overexpressed in tissue from chronic rhinosinusitis (CRS) patients with nasal polyps compared with that from controls. We assessed the genetic association of polymorphisms in the met proto-oncogene (MET) gene with CRS. Study Design: Case-control genetic association study. Setting: Tertiary-care university hospital. Subjects and Methods: A total of 206 unrelated Canadian patients with CRS and 196 control subjects were enrolled. Subjects were genotyped for 33 polymorphisms in the MET gene. Results: The allelic association analysis showed eight single nucleotide polymorphisms in the MET gene (rs38850, rs38855, rs38857, rs2237717, rs2402118, rs193688, rs1621, rs42336) with a statistically significant association with CRS. The rs38850 T allele showed the strongest association and the highest risk for CRS (P = 0.004; odds ratio 1.65, 95% confidence interval 1.18-2.32); the association did not reach statistical significance after adjustment for genomic control (P = 0.06). The haplotype TGG constructed of markers rs38850, rs38855, and rs38857 represented a risk haplotype, resulting in a P value of 0.003 that remained significant after correction for multiple testing (P = 0.018). Conclusion: These data suggest that polymorphisms in the MET gene may play a role in the susceptibility to develop CRS. Study findings apply to patients with severe CRS unresponsive to surgery.

Reproducibility of acoustic rhinometry in the investigation of occupational rhinitis.

Background To diagnose occupational rhinitis, it is mandatory to conduct an objective assessment of changes in nasal patency during specific inhalation challenge (SIC). The reproducibility of acoustic rhinometry measurements in the setting of occupational challenges has never been examined. This study assessed the reproducibility of acoustic rhinometry during SIC investigation of occupational rhinitis. Methods Twenty-four subjects underwent acoustic rhinometry measurements during SIC investigation of occupational rhinitis. Subjects attended 3–6 days of SIC within a week by means of a realistic or closed-circuit apparatus methodology Results All of the within-day intraclass correlation coefficients (ICCs) for nasal volume (2–5 cm) and minimum cross-sectional area (MCA) based on a different number of measurements (2–7) were above 0.85; all of the coefficients of variation (CVs) for the same parameters were low (below 10%). The between-day CVs based on different numbers of SIC sessions ranged from 8.0 to 8.8% and from 6.8 to 8.8% for nasal volume and MCA, respectively. The between-day ICCs ranged from 0.80 to 0.88 and from 0.83 to 0.94 for nasal volume and MCA, respectively. Conclusion Acoustic rhinometry showed good within- and between-day reproducibility and can be recommended for the objective monitoring of nasal patency during SIC investigating occupational rhinitis.