Not just the common cold: Rhinovirus infection in lung allograft recipients

Abstract

Rhinoviruses (RV) are single-stranded RNA viruses of the picornavirus family that cause a mild self-limiting upper respiratory tract illness in individuals without co-morbid medical conditions. In patients with relative immune deficiency, such as those with chronic lung diseases, this otherwise relatively innocuous virus can infect the lower airways propagating severe and more prolonged illness through the induction of augmented airway inflammation, exacerbation of lower respiratory tract symptoms and increased likelihood of secondary bacterial infection. Evidence suggests that inflammatory airways diseases such as asthma and chronic obstructive pulmonary disease (COPD) may be associated with impaired antiviral immunity, and it is therefore logical that broad iatrogenic suppression of the immune system required for lung transplantation might similarly predispose individuals to increased disease severity from RV infection. In keeping with this hypothesis, RV has been shown to persist for up to 12 months in lung allograft recipients and may be associated with bacterial co-infection. There is some speculation that viral infection might be causally linked to acute rejection and the development of bronchiolitis obliterans syndrome(BOS) in lung transplant recipients, although evidence for this association remains limited, and a pooled analysis of 34 studies showed no link between respiratory viruses and acute lung rejection, with the recommendation that better designed prospective studies are needed. Azithromycin is a macrolide antibiotic that is prescribed for acute respiratory tract infections and also has protective effects against infection when used prophylactically in patients with chronic lung disease. In addition to antibacterial effects, there is increasing evidence from in vitro studies to indicate that macrolides can augment antiviral immunity and thus may confer protection against RV infections. Azithromycin is also commonly used in the context of lung transplant recipients who develop BOS, an intervention that is supported by data from a clinical trial showing that azithromycin prophylaxis can improve forced expiratory volume in 1 s (FEV1) following the establishment of BOS. Whether the beneficial effect observed is related to immunomodulatory effects of azithromycin impacting the well-recognized small airway inflammatory process observed in BOS or to anti-viral effects preventing virus-driven chronic rejection is unclear. In the study by Ling et al. in the current edition of Respirology, primary airway epithelial cells (AEC) sampled from large and small airways of lung transplant recipients were infected ex vivo with the minor group RV (RVA-1). RV infection induced cytotoxic effects and apoptosis in both large and small airway AEC, with greater cytotoxicity seen with higher virus titres and a negative correlation observed between the degree of apoptosis (a host cell protective response that limits viral replication) and cell viability. Whether the magnitude of these responses in lung allograft cells differs from those in cells from healthy subjects was not evaluated due to the lack of a control group, and therefore, it is difficult to infer from these data that virus-induced cytotoxic responses are important in driving chronic rejection. The authors also evaluated the effects of pretreatment with azithromycin and found no effect on apoptosis but significant attenuation of both viral replication and virus-induced pro-inflammatory cytokine/chemokine responses. These findings confirm, in cells from lung transplant recipients, those previously reported in AEC from healthy subjects and patients with chronic airway disease and likely relate to an augmentation of antiviral immunity by azithromycin rather than direct effects related to the amelioration of virus-induced cytotoxicity. Antiviral responses such as induction of type I and III interferons were not measured in the study by Ling et al., and this represents an area of future interest. What are the implications of these observations to the clinical management of lung transplant recipients? The findings of the current study further highlight that RV can infect the lower airway epithelium when encountered in the context of immunosuppression. The study also expands the growing body of evidence to suggest that macrolide antibiotics may have beneficial antiviral and anti-inflammatory effects in addition to the well-recognized antibacterial properties of these commonly used drugs. However, these findings should be interpreted with caution as the current study used solely in vitro methods, and the direct relevance to the complex immune system of a transplant recipient cannot be assumed, particularly given recent findings highlighting the complexities of cross talk between the microbiota and host responses, which may affect long-term outcomes following lung transplantation. Ultimately, more detailed in vitro studies and in vivo studies using immune phenotyping in virus-infected lung transplant recipients will be required to confirm that effects observed in the current study are indeed relevant to clinical disease. Our understanding of the more severe implications of RV beyond causation of the common cold in people with lung disorders continues to grow, and thus, the development of novel antiviral approaches to treat