Our study shows that male gender, overweight/obesity and lower age are independently associated with the presence of atopy in COPD. Moreover, atopic patients showed a higher prevalence of respiratory symptoms than non-atopics. Interestingly, atopic patients without ICS treatment more frequently developed respiratory symptoms than non-atopics, while atopic patients on treatment with ICS showed increased remission of respiratory symptoms compared to non-atopic patients.
We found that the prevalence of atopy is two times higher in males than females both in univariate and multivariate analyses. This confirms previous findings in the literature. Sears et al. found that boys (age of 13 years) had a higher prevalence of positive skin tests and a higher response to house dust mite and cat than girls with the same age
. With increasing age, a significant decrease in male/female ratio of sensitization was described after the age of 8 years although a male predominance persists
 also in older men
[19, 20]. This can be explained by a population study in adults which showed that atopy significantly decreased after menopause in both asthmatic and non asthmatic women, suggesting that the pathophysiology of atopy changes over the lifespan depends on the hormonal pattern
. We corroborate these findings by showing a male preponderance of atopy in COPD.
Younger age was also associated with the presence of atopy in our COPD patients. This finding is in line with results from studies in the general population showing that allergen sensitivity and the incidence of atopic disorders decreases with age
Another interesting finding in our study was that overweight/obesity was associated with the presence of atopy in COPD patients. The previous studies in the general population also showed a significant association between overweight/obesity and atopy in adolescents
 and in adults
. In asthma, it has been suggested that the systemic inflammatory effects of obesity itself may enhance eosinophilic airway inflammation
. We do not know whether this is also true for COPD and the atopy-overweight/obesity relationship in COPD has to be further explored.
With respect to respiratory symptoms, our study revealed a higher prevalence of cough and phlegm in atopic COPD patients compared to non-atopic COPD patients indicating that atopy (i.e. positive phadiatop) contributes importantly to symptoms in COPD. The association between atopy and a higher prevalence of respiratory symptoms was also found in the general population, as various respiratory symptoms have been associated with positive skin test reactivity
[10, 28] and eosinophilia
[28, 29]. But in COPD, according to our knowledge, there is no published paper showing an association between atopy and respiratory outcomes. One recent ATS abstract
 is in line with our findings, investigating 1424 COPD patients from “The National Health and Nutrition Examination Survey (NHANES)” III (1988–1994). The investigators defined allergic/atopic COPD subjects (n = 346) as the presence of any one of the following criteria: at least one positive skin prick test, self-reported doctor diagnosed hay fever, or symptoms induced by house dust, animals or pollen. They found that individuals with indications of allergic disease more likely reported having episodes of sinusitis, and an additional trend towards more frequent reporting of cough and wheeze
 compared to non-allergic individuals. Our study defined atopy objectively by specific IgE positivity and excluded subjects with a history of asthma, allergic rhinitis, or allergic eczema. As we excluded subjects with allergic diseases, we believe our data more closely reflects the effect of atopy on COPD-related cough. Regarding the importance of cough and phlegm, it should be noted that these symptoms are highly prevalent in COPD patients and have been reported to predict disease progression, exacerbations and hospitalizations
. It has been argued that these symptoms can constitute a sign of inflammation and may identify patients at higher risk of clinical worsening
. Thus, our finding that atopy associates with this clinical phenotype may have important consequences for future studies on intervention in this phenotype with an important clinical impact on COPD, as shown in our study.
Our study did not show a significant difference in lung function parameters between atopic and non-atopic patients, with the exception of FEV1 decline. Of interest, atopic female COPD patients not using ICS treatment demonstrated a slower decline in lung function than non-atopic females. Additionally, if atopic females used ICS this protective effect of atopy was no longer present. In established COPD, to our knowledge, such an effect of atopy has never been investigated. We do not have a clear explanation for the latter finding, but as this observation is not present in male subjects, we speculate that hormonal-related effects on the immune system play a role. However, the number of atopic females in our study was low (n = 32); so firm conclusions cannot be drawn.
It has been shown that atopy is associated with a lower level of lung function
[32, 33] and FEV1 decline
 in the general population and also FEV1 decline in healthy former and current smokers
. We conclude that, unlike in healthy subjects, atopy is not associated with accelerated decline in lung function in established COPD. It may well be that the effects of atopy are overshadowed by the effects of smoking in our COPD population.
Our study showed that in atopic COPD patients the use of budesonide is associated with higher remission rates of cough and phlegm, whereas placebo is associated with higher incidence rates. This is an important finding as cough and phlegm predict disease progression, exacerbations and hospitalizations
. Although this beneficial effect of budesonide may not be specific for atopic COPD and may be present in every atopic subject, the question rises whether we should treat all atopic COPD patients with an ICS (as EUROSCOP included only steroid-naïve patients). Indeed, already in 1978, Sahn suggested that atopic COPD patients are the ones who benefit most from corticosteroid treatment
. If we accept that atopic COPD patients from now on should be treated with ICS, this would widen the present indications for ICS as defined by GOLD (Global Initiative for Chronic Obstructive Lung Disease)
. At this moment GOLD recommends ICS use for symptomatic patients with an FEV1 < 50% predicted (stage III, severe COPD, and stage IV, very severe COPD) and repeated exacerbations
[37, 38]. However, before considering to add atopic status as a guideline for ICS treatment in COPD, more studies are needed confirming that atopy is a risk factor for worse COPD outcome.