Abstract
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Gender differences have been described in CF-associated disease: Females have poorer survival, worse lung function, and microbiologic variation, such as earlier colonization and mucoid conversion of Pseudomonas aeruginosa. 3 –5 Because of the absence of clear mechanistic explanation in the past, some have disputed the existence of such observations and instead suggested that such findings may be accounted for by therapeutic advances coupled with gender-based treatment and compliance differences. Recent evidence, however, reaffirms the “true” existence of the CF gender gap despite significant improvements in both CF care and median survival. 6 –8
Critically, gender differences in the acquisition and conversion of the major adult pathogen and colonizer P. aeruginosa have been described. Females with CF acquire P. aeruginosa before males do and convert to the more persistent and aggressive mucoid phenotype in advance, conferring worse clinical outcomes. 9,10
In this issue of the Journal of Women's Health, Harness-Brumley et al. utilized the US Cystic Fibrosis Foundation patient registry (CFFPR) to address two issues. 11 First, a reassessment of gender-based survival differences was performed; second, a determination for the presence of gender-based variation in common CF microorganisms other than P. aeruginosa was made. Using a retrospective cohort analysis of n=32,766 CF patients recorded on the registry over a 13-year period, the researchers demonstrated that females had a decreased life expectancy of 2.7 years when compared to males. Female gender represented a significant risk factor for death despite correcting for multiple variables agreeing with prior published work. 6,7,12,13 Time-dependent variables accounted for included height, body mass index (BMI), pulmonary function, and exacerbation rate; time-independent inclusions were race, CF genotype, age, cause of death, sweat chloride concentration, and pancreatic and diabetic status. Importantly, the “two-lag method” was employed to account for time-related progression of illness severity and the use of greater treatment burden in later CF life. The major novel finding, however, from this work stems from the identification that women with CF become colonized significantly earlier with several other CF-related microorganisms in addition to P. aeruginosa when compared to males, which in turn is linked to worse clinical outcome. This for the first time suggests that in addition to the CF gender-based survival difference that exists, a microbiologic one occurs in parallel—coined the “microbiologic gap.” Although P. aeruginosa is the founding member of this “gap,” organisms identified from this work include Burkholderia, nontuberculous mycobacteria (NTM), Staphylococcus aureus (both methicillin-sensitive Staphylococcus Aureus [MSSA] and methicillin-resistant Staphylococcus Aureus [MRSA]), Haemophilus influenzae, Achromobacter xylosidans, and Aspergillus species (spp). 11
Such findings are both important and timely in light of significant advances made to our understanding of the CF microbiome and the availability of molecular-based detection techniques that allow identification of organisms previously undetectable through culture alone. 14,15 Interestingly, the authors detected the largest gender differences in NTM, whereas MRSA conferred similar risks of death to that of P. aeruginosa, indicating that gender-driven mechanisms may not be unique to Pseudomonas spp. Importantly, some of the organisms were acquired by CF females preceding puberty, suggestive of mechanisms other than those driven solely by sex hormones. 16 –20
Although this work is the first publication to illustrate gender-based differences in CF microbiology beyond that of P. aeruginosa, it must be considered that data collection within the CFFPR did change over the study period, conferring inherent weaknesses to the conclusions drawn. 11 The reporting nature of the microbiologic data is one such key example wherein data collection improved from annually to quarterly within the CFFPR over the study period. To overcome this, the authors considered annual recordings for their analysis, which, although providing standardization, may potentially overlook shorter-term microbiologic variation in hormonally responsive microbial populations, as previously demonstrated elsewhere for P. aeruginosa. 17 The retrospective nature of their analysis is an unavoidable weakness counteracted by the strength of the large data set over a prolonged time period. The recent emergence of novel approaches to CF therapeutics is likely to alter the future microbiologic landscape in CF disease. Considering this, an important limitation of this current work is the absence of accounting for medication use and socioeconomic and environmental differences, all of which have an impact on assessment of gender-related outcomes.
This current publication, combined with past gender observations in CF, does illustrate that gender and now microbiologic differences are an important consideration in CF care; however, they crucially do not explain why they exist. This elucidation of basic mechanism is essential if in the future we are to offer therapeutic intervention directed toward narrowing the gender and now described “microbiologic gap.” Our group has previously demonstrated that high circulating estrogen states in CF females confers a blunted innate immune response, promotes mucoid conversion of P. aeruginos, and is related to infective exacerbations in CF females. 16 –18 When combined with a compromised airway surface liquid (ASL) and impact upon ciliary beat frequency known to occur in high circulating E2 states, this possibly creates an environment during a particular fortnight each month for CF females during which they will be more susceptible to both acquire infection and subsequently be less able to respond appropriately. 19,20
Such hormonal and gender-driven immune, inflammatory, and infectious consequences are likely not restricted to CF or P. aeruginosa in isolation. Other respiratory diseases with potential gender and hormonal influences include lymphangioleiomyomatosis (LAM), pulmonary hypertension, non-CF bronchiectasis, interstitial lung disease, and such malignancies as adenocarcinoma and mesothelioma. Emerging fields of “microbial endocrinology” and the “airway microbiome” are likely to influence future work in all these pathologies, and the evidence provided by Harness-Brumley et al. is an important first step in supporting prospective study and future investment to further define specific mechanisms of interaction between hormones, infection, and the immune response that may be amenable to therapeutic intervention. 11