Cytomegalovirus: an unrecognised potential contributor to cystic fibrosis disease progression?

Abstract

Cytomegalovirus (CMV) is a betaherpesvirus, the impacts of which are well known to clinicians providing post-transplant cystic fibrosis care. Lung transplant recipients have the highest risk of any solid-organ transplant for CMV reactivation and ganciclovir resistance [1, 2]. Furthermore, CMV reactivation increases the risk of chronic lung allograft dysfunction. However, even in general populations, CMV seropositivity is associated with adverse outcomes including cognitive impairment, frailty, heart disease and all-cause mortality [3-5]. How CMV may contribute to disease is not evident but many streams of evidence suggest CMV replication in inflamed sites contributes to exaggerated inflammation and tissue injury [6]. Individuals with cystic fibrosis experience chronic inflammation within the airways leading to remodelling and eventually respiratory failure. Indeed, inflammatory biomarkers in the sputum and serum of cystic fibrosis patients correlate with short-and long-term outcomes [7]. We hypothesised that CMV may represent an unrecognised contributor to cystic fibrosis lung disease. We performed a detailed chart review of all Calgary Adult Cystic Fibrosis Clinic patients who were referred for lung transplantation, where CMV IgG testing would be performed. CMV serostatus, demographics, infecting pathogens, markers of nutrition and lung function from last clinical encounter were recorded for those who were transplanted or succumbed to disease. Our primary outcome was a composite end-point of age at lung transplantation/death without transplant. We also analysed the outcomes of death and lung transplant separately by CMV serostatus, and conducted a stratified analysis per time period to account for improvements in care

High cytomegalovirus serology and subsequent COPD-related mortality: a longitudinal study

“…In this context, the association of CMV with COPD mortality may be the consequence of direct effects of the virus in the lung, a common site of viral reactivation [26]. This scenario would be consistent with recent observations that CMV may accelerate lung disease progression in cystic fibrosis [27]. Lung function deficits in COPD may also originate in response to interactions between the virus and environmental triggers of the diseasefirst and foremost, cigarette smokingalthough in our study, we did not observe an increased effect of CMV on COPD mortality among smokers.…”

Cytomegalovirus serology in young to mid‐adult life and decline of lung function

“…CMV serology results at enrollment were calculated as a ratio of the median fluorescence intensity (MFI) of CMV-antigencoupled microspheres and the MFI of negative control microspheres tested at the Myriad-RBM laboratory (Austin, TX, USA) using the Human MAP infectious panel. Although this infection panel included measurements of antibodies directed against other bacteria and viruses, a priori we included only CMV in this study because of the mounting evidence [1][2][3][4][5] in support of its involvement in obstructive lung diseases and because of the unique infectious cycle of this virus with periodic reactivations possibly leading to immunosuppressive and proinflammatory effects. CMV serology was validated with the Serion ELISA classic CMV IgG (QED Bioscience Inc., San Diego, CA, USA) on 64 randomly selected serum samples (ρ = 0.64, p < 0.0001).…”

“…CMV infection has been associated with immunosenescence and increased mortality risk in adults. Recently, several reports [1][2][3][4][5] have indicated a possible involvement of CMV in the inception and progression of obstructive lung diseases. In a lung virome study, detection of CMV in sputum samples was associated with asthma severity and lung function deficits.…”

“…In a lung virome study, detection of CMV in sputum samples was associated with asthma severity and lung function deficits 1 . Similarly, seropositivity for CMV was linked to immune and inflammatory responses among patients with chronic obstructive pulmonary disease (COPD), 2 disease progression in patients with cystic fibrosis, 3 and airflow limitation (the hallmark of COPD) 6 among US veterans 4 . In line with these observations, in a previous study, we found that CMV serology in younger adults (<55 years) predicted risk for COPD‐related mortality in the population‐based cohort of the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) 5 .…”