Lucero Castellanos

Long-Term Outcomes of Acute Irritant-induced Asthma

RATIONALE The long-term outcomes of acute irritant-induced asthma (IIA) are mostly unknown. OBJECTIVES To study the long-term outcomes of IIA. METHODS We reassessed 35 subjects who experienced IIA at a mean interval of 13.6 +/- 5.2 years. MEASUREMENTS AND MAIN RESULTS The causal agent was chlorine in 20 cases (57%). At diagnosis, the mean +/- SD FEV(1) was 74.5 +/- 19.5% predicted, and all subjects showed bronchial hyperresponsiveness. At reassessment, all subjects reported respiratory symptoms, and 24 (68%) were on inhaled steroids. There were no significant improvements in FEV(1) and FEV(1)/FVC values. Twenty-three subjects had a methacholine test, and only six subjects had normal levels of responsiveness. Of the remaining 12 subjects, six had improvement in FEV(1) after bronchodilator >or=10%. In samples of induced sputum obtained from 27 subjects, six had eosinophils >or=2%. Levels of inflammatory and remodeling mediators were higher than in control subjects but were no different from subjects with occupational asthma due to sensitization. Quality of life score was 4.4 +/- 1.5 on a 0 (worst) to 7 (best) scale. Twelve subjects had an abnormal depression score. CONCLUSIONS This study provides the first evidence of significant long-term impact of acute IIA on various outcomes.

Long-term pathologic consequences of acute irritant- induced asthma

BACKGROUND Acute irritant-induced asthma (IrIa) or reactive airways dysfunction syndrome is caused by exposure to a high concentration of an agent. The long-term pathologic consequences of IrIa remain thus far unknown. OBJECTIVE The aim of our study was to investigate the chronic airway inflammation and remodeling that occur in association with IrIa. METHODS Ten subjects with a history of IrIa (mean interval of 10.9 years, minimum of 4 years, since the inhalational accident) underwent bronchoscopy followed by bronchoalveolar lavage and bronchial biopsies. Immunologic and morphologic data from patients with IrIa were compared with those of patients with mild to moderate asthma as well as healthy controls. RESULTS Bronchoalveolar lavage fluid analysis showed increased eosinophil and neutrophil counts in 30% and 60% of subjects with IrIa, respectively. In the supernatant of bronchoalveolar lavage, we found a significant increase in the majority of mediators compared with healthy subjects and a significant increase in eosinophilic cationic protein, IL-8, basic fibroblast growth factor, and matrix metalloproteinase 1 compared with control patients with asthma. Evaluation of basement membrane thickness (subepithelial fibrosis) demonstrated a significant increase in patients with IrIa compared with healthy subjects and subjects with asthma. Basement membrane thickness also significantly correlated with the PC(20) value. The epithelial cell detachment showed an elevated although not significant trend compared with subjects with asthma and control subjects. Immunocytochemical analysis demonstrated increases in the number of eosinophil cationic protein and TGF-beta1-positive cells compared with healthy controls. CONCLUSION This study provides evidence of a significant eosinophilic and neutrophilic inflammation as well as remodeling in IrIa many years after an inhalational accident.

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.

Matrix Metalloproteinase-9 Increases in the Sputum from Allergic Occupational Asthma Patients after Specific Inhalation Challenge.

Background: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a role in the pathogenesis of asthma. MMP-9 increases in the sputum of asthmatic patients after bronchial challenge with common allergens. We sought to assess whether a high-molecular-weight occupational allergen was able to induce changes in MMP-9 as well as in other MMPs and TIMPs in subjects with occupational asthma. Methods: Ten patients underwent specific inhalation challenge (SIC) on 2 consecutive days. We monitored changes in lung function by measuring FEV1 for 7 h. Induced sputum test was performed at 6 h after sham and flour challenge. The total and differential cell counts were analyzed. Levels of MMPs (specifically MMP-2, MMP-7, MMP-9 and MMP-13) were measured using Fluorokine® MultiAnalyte Profiling kits and a Luminex® Bioanalyzer, while levels of TIMP-1 and TIMP-2 were measured by ELISA. Results: Flour challenge increased the percentage of eosinophils in sputum samples. Asthmatic reactions induced by flour were associated with a significant increase in the sputum level of MMP-9 (p = 0.05), but not in the levels of MMP-2, MMP-7, MMP-13, TIMP-1 and TIMP-2. Sputum levels of MMP-9 measured after flour challenge were nearly significantly correlated (r = 0.67; p = 0.06) with the maximal fall in FEV1 observed during the asthmatic reaction, but they did not correlate with the number of neutrophils (r = 0.18; p = 0.7) and eosinophils (r = 0.55; p = 0.2). Conclusions: This study showed that MMP-9 increases in sputum samples from sensitized occupational asthma patients after SIC with flour.

Matrix metalloproteinases, IL‐8 and glutathione in the prognosis of workers exposed to chlorine

To cite this article: Maghni K, Malo J‐L, L’Archevêque J, Castellanos L, Gautrin D. Matrix metalloproteinases, IL‐8 and glutathione in the prognosis of workers exposed to chlorine. Allergy 2010; 65: 722–730.

Prospective outcome assessment of occupational rhinitis after removal from exposure.

Objective: To conduct a prospective evaluation of clinical and quality of life (QOL) outcomes of occupational rhinitis (OR) after cessation of exposure. Methods: We assessed changes in nasal symptoms, disease-specific QOL, nasal patency, and nasal inflammation in 20 subjects with confirmed OR. Olfactory function was assessed cross-sectionally at follow-up. Results: At follow-up, a significant decrease in the number of nasal symptoms and a significant improvement in QOL were observed. There were no significant differences in nasal patency outcomes. A not significant decrease in neutrophils number in nasal fluid and a significant decrease in macrophages were observed. As a group, study subjects showed a mild olfactory dysfunction at follow-up. Conclusions: We showed that cessation of exposure to causal agent improved QOL in patients with OR, leading to relief of rhinitis-associated symptoms and improvement in well-being.

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in nasal lavage after an inhalation challenge with flour.

The existence of nasal mucosa remodeling in allergic rhinitis is controversial. Few data are available on the dynamics of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in nasal fluid after an allergen challenge. We examined whether an immediate allergic reaction that induces nasal congestion and inflammation is able to also induce changes in remodeling parameters in nasal fluid.

Specific inhalation challenge with flour induced release of brain-derived neurotrophic factor in nasal fluid.

Neurotrophins may play a role in the pathophysiology of allergic occupational rhinitis (OR). We sought to investigate whether an immediate allergic reaction that induces nasal inflammation is also able to induce changes in levels of brain‐derived neurotrophic factor (BDNF) in nasal lavage (NAL) fluid from patients with allergic OR.

Inflammatory proteins in nasal lavage of workers exposed to occupational agents

Low‐molecular‐weight (LMW) and high‐molecular‐weight (HMW) agents have been recognized as causes of occupational rhinitis (OR). Immunological mechanisms underlying OR differ according to the type of exposure. While HMW agents act mainly through IgE‐mediated mechanisms, LMW agents appear to act through both immunological and non‐immunological mechanisms.

Effect of inhalation exposure to wheat flour on sputum levels of brain-derived neurotrophic factor.

These results reflect the characterization of pediatric tree sensitization, the most prevalent pediatric outdoor allergy, in a large cohort of children. Although these results reflect characteristics of our patients and may not be applicable to other patients in other regions, these results nonetheless illustrate several considerations in the approach to pediatric aeroallergen sensitization. In addition, because tree pollen season may be even longer for patients in other areas of the country compared with our cohort in the Northeast, it is likely that the significance of tree sensitization in children demonstrated here is generalizable to other areas of the country. Our results indicate that although outdoor sensitization is traditionally not expected or sought in younger children, tree sensitization may be present in a clinically significant fraction of children of all ages. With a notable prevalence (13.0%) in children younger than 4 years, the prevalence of tree pollen sensitivity approaches that of the most common indoor aeroallergen sensitivity by the age of 4 years.8 In our cohort, the tree allergen sensitization profile of children younger than 4 years (in whom maple tree sensitivity was most prevalent) was significantly different than children 4 years and older (in whom birch tree sensitivity was most prevalent). Moreover, the clinical relevance of these tree sensitivities in these children younger than 4 years was confirmed by reports of seasonal outdoor exacerbations of rhinitis or asthma symptoms in a large fraction of the children. In light of the important role for aeroallergen sensitivity in the pathogenesis of pediatric rhinitis and asthma,2,7 our results support consideration of performing SPTs to trees in children, including those younger than 4 years.9 Particular consideration for tree SPTs should be given to those children younger than 4 years who have a diagnosis of asthma, recurrent wheezing, or suspicious symptoms outdoors during tree pollen season.10 Ahmad R. Sedaghat, MD, PhD*,y,z William J. Sheehan, MDx Apinya Bharmanee, MDx Kendra Harrisx Wanda Phipatanakul, MD, MSx