Asthma: from airway inflammation to phenotypes

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Over 300 million people are affected worldwide and in Belgium 5-10%of adults and 15% of children has asthma. The disease can be triggered by manyfactors: allergy, infection, exercise, etc. Patients with asthma experiencedifficulties during expiration because of narrowed airways or excessive mucusproduction. An airway inflammatory reaction is responsible for thesecomplaints. Therefore, patients with asthma are treated with two types ofdrugs, one type that causes dilatation of the airways and another type thatlowers the airway inflammation. However, a small group of asthmatics (10-15%)still has complaints despite currently available treatment.<p class="MsoNormal" style="margin-top:6.0pt;margin-right:0in;margin-bottom:6.0pt;margin-left:0in;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-ascii-font-family:Cambria;mso-hansi-font-family:Cambria;mso-ansi-language:EN-GB" lang="EN-GB"><span style="mso-ascii-font-family:Cambria;mso-hansi-font-family:Cambria;mso-ansi-language:EN-GB" lang="EN-GB">Asthma is one of the most common chronicdiseases. Over 300 million people are affected worldwide and in Belgium 5-10%of adults and 15% of children has asthma. The disease can be triggered by manyfactors: allergy, infection, exercise, etc. Patients with asthma experiencedifficulties during expiration because of narrowed airways or excessive mucusproduction. An airway inflammatory reaction is responsible for thesecomplaints. Therefore, patients with asthma are treated with two types ofdrugs, one type that causes dilatation of the airways and another type thatlowers the airway inflammation. However, a small group of asthmatics (10-15%)still has complaints despite currently available treatment.<p class="MsoNormal" style="margin-top:6.0pt;margin-right:0in;margin-bottom:6.0pt;margin-left:0in;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-ascii-font-family:Cambria;mso-hansi-font-family:Cambria;mso-ansi-language:EN-GB" lang="EN-GB"><span style="mso-ascii-font-family:Cambria;mso-hansi-font-family:Cambria;mso-ansi-language:EN-GB" lang="EN-GB">Scientific research during the past 10 yearshas shown that the airway inflammatory response in asthma can be heterogeneous.Therefore, new therapies that block specific components of the airwayinflammation are under development. In the current research project, weevaluated cytokines in the airways to study the heterogeneous inflammatoryresponse. Currently, several studies are ongoing that block one ore more ofthese cytokines in patients with asthma. Our study showed marked differences ofthe cytokine profile in the airways of asthmatics. This explains why blockingone single cytokine can never be beneficial in all patients and it can lead toincreased efficacy of targeted therapies in patients with an increase of thatparticular cytokine. Similarly, patients with cancer are nowadays treated withvery specific drugs. Before these therapies can be used to treat patients or todetermine their prognosis, the presence of the mutated gen must first beidentified.<p class="MsoNormal" style="margin-top:6.0pt;margin-right:0in;margin-bottom:6.0pt;margin-left:0in;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-ascii-font-family:Cambria;mso-hansi-font-family:Cambria;mso-ansi-language:EN-GB" lang="EN-GB">In the first study we evaluated airway cytokinepatterns, more specifically the simultaneous elevation of cytokines in theairways of a limited number (66) of asthma patients. Normal levels of thesecytokines were determined based on the expression in individuals without asthmaor other respiratory disease. In contrast to other studies, we used anon-invasive technique (sputum induction) to obtain cells from the lowerairways. During sputum induction, a hypertonic salt solution is nebulized for 3times 7 minutes and the patient inhales the vapour via the mouth. Thereby,sputum is more easily expectorated. In a second phase, a larger cohort (299) ofasthma patients was recruited to identify separate clusters of asthma patientsvia a computer-based model. Twelve cytokines were evaluated in sputum and eightof these cytokines were required to determine 7 separate groups of asthmapatients. Six of these groups have an elevation of one or more cytokines andone group is characterized by a low expression of all cytokines. <p class="MsoNormal" style="margin-top:6.0pt;margin-right:0in;margin-bottom:6.0pt;margin-left:0in;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-ascii-font-family:Cambria;mso-hansi-font-family:Cambria;mso-ansi-language:EN-GB" lang="EN-GB">In two other studies we evaluated theinfluence of certain environmental factors on the airway inflammatory response.First, we studied the influence of exercise in combination to cold air inpatients with asthma. Secondly, we studied the influence of intensive exercisein swimmers, basketball players, volleyball players and control individualperforming sports at a recreational level.<p class="MsoNormal" style="margin-top:6.0pt;margin-right:0in;margin-bottom:6.0pt;margin-left:0in;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-ascii-font-family:Cambria;mso-hansi-font-family:Cambria;mso-ansi-language:EN-GB" lang="EN-GB">A small group (18) of asthmatics were studiedduring the preparation phase and an expedition to the Aconcagua mountain (6962m)to evaluate the influence of exercise and cold air on the airway inflammation.Two simulation experiments were performed to study the effect of exercise, highaltitude and cold air separately. An airtight room filled with 11% of oxygen(compared to at sea level: 21%) comparable to an altitude of 5500m was usedduring the first experiment. After 30 minutes rest, a maximal exercise protocolwas performed on a treadmill. We showed a minimal reduction of the lungfunction and a slight increase of airway inflammation after this exerciseprotocol. Furthermore, patients who desaturated (decrease of oxygenconcentration in blood) >60% after the exercise protocol had a higher chanceto develop acute mountain sickness during an expedition to high altitude.During a second simulation experiment the same group of patients resided for 24hours at an indoor ski centre (-5°C). We demonstrated a marked increase of thenumber of neutrophils (an inflammatory cell) in the airways together with adecrease of the lung function. We also evaluated these patients duringexpedition and immediately after the expedition. We concluded that airwayneutrophils are increased after expedition despite optimal asthma control atthe start of the expedition.<p class="MsoNormal" style="margin-top:6.0pt;margin-right:0in;margin-bottom:6.0pt;margin-left:0in;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-ascii-font-family:Cambria;mso-hansi-font-family:Cambria;mso-ansi-language:EN-GB" lang="EN-GB">In the last study the prevalence ofexercise-induced asthma, allergy and airway inflammation were studied in eliteathletes (38 swimmers, 13 basketball players or volleyball players (indoorathletes)) and control individuals (13) that perform sports at a recreationallevel. Swimmers are exposed to sustained intense exercise in combination toby-products of chlorination in the swimming pool. We showed thatexercise-induced asthma was more prevalent among swimmers then indoor athletesand controls. We demonstrated higher baseline eosinophils and neutrophils (twotypes of inflammatory cells) in the airways of swimmers and indoor athletescompared to controls. Furthermore, we found airway damage and epithelial cell(contact with the outer environment) activation in swimmers. Uric acid in theairways was higher in swimmers compared to controls. Moreover, an increase ofuric acid was found after swimming in swimmers but not in controls (afterswimming) or indoor athletes (after basket ball or volley ball). Uric acid maytherefore be used as an early marker of airway inflammation or asthma. On theother hand, we showed an increased Clara Cell protein-16 (CC-16, a marker ofepithelial or airway damage) in blood of swimmers and indoor athletes comparedto controls.<p class="MsoNormal" style="margin-top:6.0pt;margin-right:0in;margin-bottom:6.0pt;margin-left:0in;text-align:justify;text-justify:inter-ideograph;line-height:150%"><span style="mso-ascii-font-family:Cambria;mso-hansi-font-family:Cambria;mso-ansi-language:EN-GB" lang="EN-GB">Some social relevant research domains werestudied in this translational research project. In the first study weidentified several groups of patients with asthma that may benefit fromtargeted therapies. On the other hand we studied the effect of high altitude,exercise, cold air and swimming on the airway inflammatory response. Recently, increasedtrichloramine levels (responsible for the chlorine odeur in swimming pools),caused by a defect at the water filters, were detected in a Flemish swimmingpool. This resulted in a higher degree of respiratory complaints and airwayhyperreactivity in swimmers. Until now, no clear regulation is available forFlemish swimming pools. Our study and others suggest a modification of theVLAREM regulations (impose criteria for the air quality in indoor swimmingpools). No causal relationship could be identified between the high prevalenceof airway hyperreactivity, airway damage and high levels of trichloramine inthis study. However, it is reasonable that in elite swimmers, who inhale highamounts of air during intense exercise, develop airway damage that evolves inasthma at the long-term.status: publishe