Gender-specific differences in COPD and alpha-1 antitrypsin deficiency

Dr. Julia Carmen Schäfer and PD Dr. Franziska Trudzinski, Alpha1 Deutschland eV, as published in Alpha1 Journal 2/2022.

The course of the disease, the severity of symptoms, and the associated comorbidities (co-occurring diseases) are known to vary considerably between the sexes in almost all internal medicine diseases; this also applies to chronic obstructive pulmonary disease (COPD).1

 

Different risk factors

This may be partly due to different risk factors or intrinsic physiological differences. Historically, men had higher prevalence rates of COPD than women, as cigarette smoking, the main risk factor, was historically more prevalent in men. However, several studies conducted over time, with an increasing proportion of female smokers, have shown that they tend to have a higher probability of developing COPD from cigarette smoking than men. After adjusting for the intensity of nicotine use, women also exhibit a faster and more pronounced decline in certain lung function parameters due to smoking.²

One reason for this could be anatomical, as women have smaller lung volumes and airway diameters than men. Another possibility is the effect of sex hormones on airway hyperreactivity. This, in turn, is reflected in a higher proportion of concomitant asthma among female COPD patients. ³

 

Different comorbidities

In general, COPD is associated with a number of comorbidities; in particular, due to the similar risk profile, with cardiovascular comorbidities. These contribute significantly to mortality in COPD and substantially influence the symptoms and course of the disease.1 Therefore, early detection and appropriate treatment play a crucial role.

Here, too, a difference between the sexes is evident. As suspected, men more frequently exhibit cardiovascular comorbidities such as coronary artery disease, peripheral arterial disease (PAD), or arterial hypertension. In contrast, women are more likely to be diagnosed with mental disorders or osteoporosis. ³

Cardiac diseases, in particular, often limit patients' prognosis. However, these are frequently underdiagnosed in COPD patients, resulting in treatment that does not adhere to guidelines. One reason for this is the often overlapping or inconsistent symptoms, such as shortness of breath, which are not clearly attributable to a single disease.⁴ Furthermore, there are no clear, universally applicable recommendations for screening for specific comorbidities. Since women are known to often present with atypical symptoms, especially in cardiac diseases, this presents a further obstacle to identifying comorbidities and initiating appropriate treatment.

 

Different symptoms and manifestations

Men and women also exhibit different symptom presentations of the disease. The COPD Assessment Test (CAT) is a universally accepted and widely used tool for assessing symptom severity and classifying patients into the various GOLD AD groups.

Although the overall CAT score does not differ significantly between the sexes, the individual items, especially 1 (cough), 2 (mucus), 5 (activity) and 8 (energy), show significant differences.

Furthermore, the individual questions in the CAT correlate differently with possible comorbidities in both sexes. For example, CAT item 8 (energy) should be an indicator of cardiac comorbidity in men, while in women this seems to be more closely associated with item 5 (activities).¹

The manifestation or phenotype of COPD also differs between the sexes. While women are more likely to develop a bronchitis-like phenotype, the emphysema-like phenotype is more common in men.⁵ Due to the different symptoms and often atypical presentation, there is sometimes a significant delay in diagnosis, particularly in female patients.⁵

This illustrates that different clinical findings have different diagnostic relevance between the sexes and can provide different indications of comorbidities.

 

Alpha-1 antitrypsin deficiency

In general, the time until diagnosis is often far too long, especially in the case of rare diseases, which also applies to alpha-1 antitrypsin deficiency and the associated lung disease.

Alpha-1 antitrypsin deficiency (AATD) is caused by a mutation in the SERPINA1 gene. The most common mutations, occurring in 95% of cases, are Z and S mutations. In practice, the disease typically manifests in the lungs and liver. In the lungs, it leads to a specific form of COPD, while in the liver, it can cause cirrhosis, among other things. With a prevalence of 1:5,000–1:15,000, AATD is among the more common rare genetic disorders.⁵ As with non-AATD COPD, cigarette smoking is the main risk factor for developing lung disease in AATD.

Currently, there is limited data on the influence of sex on the course, clinical presentation, and survival of AATD. However, since sex influences a number of factors in smoking-related COPD, it is reasonable to assume that this could also be the case for AATD.

In the German registry, the time to diagnosis is approximately 12.5 years for men, but 2 years longer for women, at 14.5 years.⁵

The development of COPD in AATD is generally highly variable. Patient clusters with different phenotypes (bronchitis, emphysema, and asthma overlap) have already been identified in registries.⁶ These do not appear to occur with different frequencies in women and men, unlike smoking-related COPD.⁵

While women with non-AAT-COPD tend to report a lower quality of life, the German AAT-COPD registry shows no difference in quality of life compared to male patients. However, as with non-AAT-COPD, women appear to develop the disease with lower tobacco exposure than men.⁵

In contrast, another study by DeMeo et al. showed that men (both smokers and non-smokers) generally have a higher risk of developing lung disease in AATM than women, and that they have lower spirometry values (FEV1).⁷

Furthermore, as mentioned above, the data on the influence of biological sex on the severity and course of AATD is very limited. While there are some indications of sex's relevance, further studies will be needed in the future for deeper insights.

Dr. Julia Carmen Schäfer and PD Dr. Franziska Trudzinski

 

Sources

1. Trudzinski, FC, et al., Gender-specific differences in COPD symptoms and their influence for the diagnosis of cardiac comorbidities. Clin Res Cardiol, 2021.
2. Silverman, EK, et al., Gender-related differences in severe, early-onset chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2000.162(6): p. 2152-8.
3. Trudzinski, FC, et al., Sex-specific associations of comorbidoma and pulmorbidoma with mortality in chronic obstructive pulmonary disease: results from COSYCONET. Sci Rep, 2022. 12(1): p. 8790.
4. Alter, P., et al., Prevalence of cardiac comorbidities, and their underdetection and contribution to exertional symptoms in COPD: results from the COSYCONET cohort. Int J Chron Obstruct Pulmon Dis, 2019. 14: p. 2163-2172.
5. Fähndrich, S., et al., Sex differences in alpha-1-antitrypsin deficiency lung disease-analysis from the German registry. Copd, 2015. 12 Suppl 1: p. 58-62.
6. Piras, B., et al., Clinical phenotypes of Italian and Spanish patients with α1-antitrypsin deficiency. Eur Respir J, 2013. 42(1): p. 54-64.
7. Demeo, DL, et al., Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency. Thorax, 2007. 62(9): p. 806-13.