Introduction

Several studies have reported a higher severity of asthma in women than in men, both in the use of health care and in admissions to hospital [1]. In a population-based study, women had a 70% higher risk than men of being admitted to hospital for asthma after controlling for asthma prevalence and smoking [2]. Gender differences in hospital admissions for asthma could relate to differences in the disease severity, perception and management. In a cross-sectional study from the European Network For Understanding Mechanisms Of Severe Asthma (ENFUMOSA), women were found to dominate the group of subjects with severe asthma as compared to the patients whose asthma was controlled by low doses of inhaled corticosteroids[3]. In a high-risk adult asthmatic cohort, two thirds of admissions were women, suggesting that women might suffer from a more severe form of asthma [4]. Women also report more dyspnoea [5].

In a population-based prospective cohort with a 25-year follow-up [6], women were more likely than men to have severe asthma (OR: 1.57[1.19–2.08])), especially if asthma had developed after the age of 2 years and was associated with reduced PEF.(Peak Expiratory Flow).

In a cross-sectional survey, asthma severity increased with BMI (Body Mass Index)only in women [7]. In a retrospective analysis, it has been suggested that late-onset asthma, which generally occurs during or after puberty, affects mainly women, and has a poor prognosis[8]. In an unselected birth cohort, female sex predicted persistence of asthma. In addition, lung function in males in whom asthma relapsed after remission closely resembled that in males with persistent asthma, whereas females with a relapse had worsened lung function only as adults[9]. To our knowledge, no longitudinal population-based study has investigated gender difference in asthma severity.

The purpose of this study was to examine whether the evolution of asthma severity was different in women and in men in a longitudinal population-based survey.

Methods

Results

All current asthmatics identified in ECRHS I and who participated in ECRHS II were eligible for this analysis. Of the 17579 participants examined at stage 2, 1485 currently had asthma in ECRHS-I. Of those, 1091 could be classified for asthma severity at Ec1 (missing data: 35 for FEV1, 46 had FEV1 value without ATS conformity, 181 for the number of asthma attacks, 178 for both admissions and asthma treatment) (figure 1).

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Figure 1. Study design.

https://doi.org/10.1371/journal.pone.0007146.g001

In men (n = 481):

• 183 were lost to follow-up at Ec2
• 150 were in remission at Ec2
• 148 were still asthmatic at Ec2

In women (n = 610):

• 194 were lost to follow-up at Ec2
• 215 were in remission at Ec2
• 201 were still asthmatic at Ec2

Comparison between participants and subjects lost to follow-up are shown in table 1. The mean follow-up was 8.65 yr (min 4.3-max 11.7). There were significantly more females and smokers in the second sample. Moreover, there was no significant difference according to FEV1%pred, atopy or severity of asthma. Stratification by gender in men and women demonstrated a high prevalence of smokers in the sample “lost to follow-up” (table 1).

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Table 1. Characteristics of subjects who provided respiratory data in the two assessments as compared with those not followed-up at the second survey by gender.

https://doi.org/10.1371/journal.pone.0007146.t001

According to the 1992 GINA classification, 40.7% of asthmatics at baseline were classified intermittent, 31.7% as mild persistent, 14% as moderate persistent, and 13.5% as severe persistent. The comparison of men and women in EC1 by GINA (p = 0.04) is weak (table 2).

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Table 2. Cross-sectional distribution of asthma severity in subjects with data available at both surveys.

https://doi.org/10.1371/journal.pone.0007146.t002

Using the Ronchetti score derived classification, the distribution of asthma severity was 58% mild, (intermittent and mild persistent), 25.8% moderate, and 15.4% severe.

Whatever the classification used, the distribution of asthma severity at baseline was not different in men and in women. At follow-up there was still no gender difference in the distribution of severity.

In subjects included in the second survey (n = 685, both followed and incident), the concordance of the two classifications was compared (GINA 1992 vs GINA 2004) at follow-up. The Kappa coefficient was 0.48 [0.20–0.58].

In contrast, gender differences were observed in the evolution of severity. Figure 2 shows the distribution of asthma severity between at follow-up, in incident asthmatics who had no asthma at the first survey, and in cases with asthma at baseline taking into account the severity of asthma at baseline.

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Figure 2. Distribution of asthma severity at EC2 in subjects without current asthma at EC1 (ECI-0) and in subjects with asthma, according to asthma severity at EC-1.

https://doi.org/10.1371/journal.pone.0007146.g002

There was no gender difference for severity in incident asthmatics. Using the Ronchetti score, the proportion of incident cases classified as having “mild” asthma was 62% in men and 69% in women (p = 0.7). There was also no gender difference in the distribution of asthma severity according to GINA for patients with incident asthma.

Using the Ronchetti classification (Fig. 2A), around 80% of subjects with mild asthma at baseline still had mild asthma, or had no “current asthma” at follow-up. According to both classifications, men with moderate-to-severe asthma at EC-1 were more likely than women to have moderate-to-severe asthma at EC-2: using Ronchetti-score, 53.3% of men vs. 36.2% of women with moderate-to-severe asthma at EC-1 were still moderate-to-severe at EC-2, (p = 0.03).

Using the GINA classification (Fig. 2B), 69.2% of men vs. 53.1% of women, with moderate-to-severe asthma at EC-1 were still moderate-to-severe at EC-2, (p = 0.09).

In contrast, in asthmatics with intermittent asthma at EC-1, the likelihood to develop moderate-to-severe asthma at EC-2 was higher in women (16.3% using GINA) than in men (8.8%), although the difference was not significant (p = 0.15). Using Ronchetti score, the likelihood to develop moderate-to-severe asthma at EC-2 was higher in women (20%) than in men (14.5%) (NS).

As regards hospitalization, respectively, 18%, and 22% of subjects with moderate persistent asthma, and severe persistent asthma were hospitalized for asthma during the previous year, without any significant difference between men and women.

As regards symptoms and lung function of subjects with severe asthma, 19.3% of women reported >12 asthma attacks in the preceding year or had FEV1<60% (“poor asthma control”) versus 30.2% of men. Conversely, 52.7% of men versus 37.1% of women with severe asthma were receiving a treatment that was “lower” than the one recommended for their level of severity.

Finally, in order to identify the factors related to change in asthma severity, we analyzed the subsample of subjects with moderate-to-severe asthma in the first survey (n = 127) and separated them into two groups: those who still had moderate-to-severe asthma in the second survey and those whose severity improved whatever the classification used, forty-seven subjects had an unchanged severity while 19 subjects were changed.

In women with moderate-to-severe asthma at baseline, sensitization to cat was associated with a higher risk of having no improvement in asthma severity at the second follow-up (59.3% vs 33%; p = 0.04). In contrast, in men three main factors were associated with no change in asthma severity: age at the second survey (more than 45 years) (52.8% vs 26%; OR: 0.76[0.59–0.98] p = 0.04), smoking history (66.6% vs 30.4%, OR: 0.85 [0.68–0.90] p = 0.006), and sensitization to molds (41.6% vs 9%; OR: 0.6[0.55–0.85] p = 0.008).

Discussion

This investigation using two approaches is the first to study the evolution of asthma severity in a population-based longitudinal cohort of men and women. Whatever the classification, there was no difference in the overall distribution of asthma severity between men and women. However, investigating change in severity over time suggested that asthma severity might be more stable in men than in women. In particular, 69.2% of men with moderate-to-severe asthma at baseline still had moderate-to-severe asthma after a median follow-up of 8.7 years, whereas only 53.1% of women with moderate-to-severe asthma remained moderate-to-severe. In men with moderate-to severe asthma, factors significantly associated with the risk of remaining at the same level of severity were age, smoking status, and sensitization to mold. In women with moderate-to-severe asthma, only sensitization to cat was associated with no improvement in asthma severity at follow-up.

Various factors have been suggested to explain gender differences in asthma prevalence and incidence such as hormonal modulation[5], gender difference in hyper reactivity [18], [19], [20], preferential exposure of women to environmental triggers such as aeroallergens, and ventilatory response to PcO2[4].

However, it is unclear whether men or women generally suffer worse symptoms and greater deficits in lung function. Prevalence of asthma and allergies had been mapped by several international standardized studies[21], but little is known about the distribution of asthma severity in the general population from an epidemiologic point of view.

Assessment of severity is one of several keys to asthma management. Guidelines and consensus statements have been formulated by international panels of experts with regard to degree of severity and treatment[13], [15]. Asthma is characterized by various clinical symptoms such as episodic breathlessness, wheezing and chest tightness, with seasonal variability. According to the guidelines, severity may be judged by measurements of symptoms, lung function, and medication requirements. However, medication use might not be fully adequate for accurate severity classification, because it depends both on the practitioner and adherence to treatment by the patient, with the concomitant risk of under- or over-treatment. In addition, doses of inhaled corticosteroids may be subject to recall bias. Other factors, including comorbidity medical conditions that mimic asthma such as vocal cord dysfunction, may also lead to potential misclassification of patients with severe asthma [22].

Assessment of asthma severity in cohort studies has been mainly based on respiratory function [9]. Several studies have attempted to define severity scores using different approaches in children[16] and in adults[14]. Liard et al. proposed a classification using GINA guidelines [14] in a population of asthmatics recruited by chest physicians. By contrast, other authors included emergency visits or hospitalizations in severity assessment [16], [17]. Emergency visits and hospitalizations are usually used to describe the impact of the disease, which is related to asthma morbidity. It has been shown that acute asthma exacerbation is often life-threatening in patients who attend accident and emergency departments because of inadequate treatment, mainly due to under use of corticosteroids and inappropriate admission rates according to exacerbation severity[23]. However, including hospitalizations in the assessment of asthma severity is still a subject of debate. Recently, in a selected population of patients with difficult-to-treat asthma (TENOR), Miller et al. compared asthma severity assessment according to three methodologies[24]. They showed that classification of asthma severity on the basis of current asthma symptoms and lung function may be useful but not completely reflective of a patient's true asthma condition. Clinical assessment of asthma severity should consider a patient's medication use and consumption of health care resources for asthma exacerbation. They suggested that many adults with a history of moderate-to-severe allergic asthma in childhood had irreversible lung function deficits[25]. In addition, urgent care visits for asthma per year is now included in the criteria for defining severe/refractory asthma (20).

In our study, we found no gender difference in the overall distribution of asthma severity in the cross-sectional analyses, whatever the classification used. “In many studies investigating severe asthma, women are found to dominate the severe asthma group, with 59% to 82%(*) of severe asthmatics being women[22]. However, women also generally dominate the non-severe asthma group, and there are reports from other population-based studies showing no difference in the overall distribution of asthma severity between asthmatic men and asthmatic women [7]. In the ENFUMOSA study, however, the male to female ratio was still higher in the severe asthma group than in the group of asthmatics whose asthma was controlled by low doses of inhaled corticosteroids (male to female ration: 4.4∶1 vs. 1.6∶1, respectively; p<0.001)[3].

Differences in the procedure to identify and select asthmatic cases, and differences in severity definitions may explain the differences observed. In a recent study published by the TENOR group, females reported significantly greater healthcare utilization than males, significantly more asthma control problems and lower asthma-related quality of life. Despite their overall worse health outcomes, female subjects demonstrated better lung function, had similar treatment patterns, and showed no differences in physician-assessed asthma severity when compared with males [26]. In our study, moderate-to-severe asthma was more particularly characterized by a decrease in FEV1 (<60%pred) in men whereas in women it was associated with more intensive treatment. There was no significant difference between men and women with regard to hospitalization increases with asthma severity at the two surveys. These two results suggest that a significant gender difference exists for severity of the disease and for management (i.e. treatment). In our subjects, prevalence of remission was 23%. Remission diminished whereas asthma severity increased both in men and women. In the study by Sears et al.[9], remission was defined as the absence of wheezing after wheezing had been reported at two or more successive prior assessments. As in our study, similar remission rates (around 15%) were observed in men and in women. To our knowledge, little is known about gender difference in remission according to level of asthma severity.

Although no gender differences were observed in the overall distribution of asthma severity, differences were observed in the evolution of severity between the two surveys. In a cross-sectional analysis of the subjects with asthma from the ECRHS dataset at baseline, Zureik et al. showed that asthma severity was associated with sensitization to airborne moulds[17]. An other cross-sectional analysis showed that subjects with severe asthma at follow-up had poorer FEV1% predicted at baseline, poorer symptom control, higher IgE levels, and higher prevalence of chronic cough/mucus hypersecretion than patients with intermittent asthma. This study is the first to report on gender differences in changes in asthma severity, taking into account severity at baseline. Women were not more exposed to risk factors of change than men, suggesting that hormonal factors could explain changes in asthma severity during adulthood. However, another explanation could be that subjects whose severity changed could have had poorly controlled asthma at the first survey. Evaluation of asthma control is still difficult in clinical practice and is difficult to evaluate in epidemiological studies. Asthma is a complex, chronic disease varying from minutes to years. Our findings suggest that evolution of asthma severity is different in men and in women, and this difference is to be taken into account when investigating the variability of asthma severity in epidemiological studies.