What doesn’t kill you makes you weaker

Chronic obstructive pulmonary disease (COPD) is a leading cause of disease and death around the world. COPD is a collective term that represents a variety of chronic lung disorders characterized by progressive and irreversible loss of lung function. Persistent airflow limitation in COPD is associated with progressive loss of function, increasing symptoms, and greater vulnerability to lung infections. Infections in COPD patients result in “acute exacerbation” defined as a sudden worsening of symptoms that can persist for several days. Exacerbations in COPD dramatically worsen the rate of lung function decline and often require hospitalization further increasing healthcare cost. Since exacerbations are the key difference between a relatively stable or a rapidly progressing disease, it is important to improve our understanding of pathogenic mechanisms that predispose COPD patients to infections (7, 10).

Various viral pathogens have been detected in COPD lungs after the onset of exacerbations. Often, following full recovery from viral exacerbation patients undergo secondary bacterial colonization that further precipitates in more exacerbations (5). There are several hypotheses for the increased susceptibility of COPD patients to viral infections such as decreased antiviral immunity, diminished protective tissue barriers and mucociliary clearance defense, and greater use of immunomodulatory corticosteroids and antibiotics (2). In addition, viruses are also detected in stable COPD and are known to contribute to the maintenance of chronic airway inflammation (9). Presence of a large number of inflammatory cells such as neutrophils, macrophages, and cytotoxic T cells in COPD lungs might suggest ideal preparation to defend against microbial pathogens. However, as shown by Mallia et al. (6), increased inflammatory cells correlate with a greater number of viruses in COPD lungs.

Several groups have explored the nuances of impaired antiviral defense in preclinical models and COPD patients. For example, airway epithelial cells and immune cells from smokers and COPD patients were shown to be deficient in type I interferon (IFN) responses to viral challenge or double-stranded RNA (dsRNA) from respiratory viruses that is recognized by host pathogen recognition receptors (2). Similarly, rhinovirus challenge in stable COPD patients exhibited deficient IFN release despite apparent exacerbation-like symptoms and increased inflammation (6). However, the concept of impaired antiviral response has been challenged by contradictory increases in antiviral responses observed in some studies suggesting defective immunity might not be uniformly prevalent across all COPD patients and is likely to be a factor of disease severity (1). These topical concerns regarding the prevalence and contribution of antiviral immunity to COPD exacerbations is the focus of an exciting new study from Singanayagam and colleagues (8) published in this issue of American Journal of Physiology-Lung Cellular and Molecular Physiology. This study investigated if COPD patients prone to frequent exacerbations may have a greater reduction in antiviral immunity as compared with infrequent exacerbators. Based on total exacerbations in the preceding year, COPD patients (n = 40) were grouped as infrequent exacerbators (0–1 exacerbations) or frequent exacerbators (>2 exacerbations). The cohort consisted of 17 frequent and 23 infrequent exacerbators. Lung samples were collected at baseline and during any exacerbation events in the follow-up period that extended to 6 months or more. In frequent exacerbators, gene expression of type I and type III IFNs, IFNβ, and IFNλ2/3 was decreased at stable state, and IFNβ, IFNλ1 and IFNλ2/3 and interferon-stimulated genes (ISGs) 2′–5′OAS and CXCL10/IP-10 were low during exacerbations. Finally, rhinovirus-induced mRNA expression of IFNλ1, 2′–5′OAS, and viperin was reduced in primary bronchial epithelial cells isolated from frequent exacerbators, mirroring previous work that showed inefficient interferon release in COPD is likely associated with decreased expression of viral pattern recognition receptors RIG-I and MDA-5 (3).

In contrast to a previous study that observed a higher number of exacerbations in COPD patients classified as frequent exacerbators at baseline (4), 17 frequent exacerbators experienced 11 exacerbation events (viral, bacterial, or unknown pathogen) whereas 16 events were noted in 23 infrequent exacerbators (64.7% vs. 69.6%). Of these exacerbations, 7 out of 11 of exacerbations among frequent exacerbators were of viral origin while 11 out of 16 exacerbations in infrequent exacerbators were related to viruses (63.6% vs. 68.7%). Thus, compared with infrequent exacerbators there were no significantly greater number of exacerbations in frequent exacerbators. This is likely due to differences in the duration of patient follow-up (>1,000 days vs. a min of 180 days). Thus, a longer prospective study will be needed to clarify if the reduced antiviral response can predict the frequency of future exacerbations. Such an extended perspective study may also permit capturing the influence of seasonal variations in viral infections that likely were not apparent in the short follow-up period used in this study.

Infectious exacerbations are known to occur at all stages of COPD. Considering that a greater number of exacerbations occur in severe COPD, it is not surprising that 8 out of 23 infrequent exacerbators were GOLD-0, while none in frequent exacerbator group met GOLD-0 classification. While this might appear as a possible confounder, this is reflective of recently adopted disease classification guidelines in COPD (Groups A, B, C, and D) that not only focus on the degree of airflow obstruction but also adequately consider symptoms and exacerbations as important variables. Moreover, frequent exacerbators reported higher usage of inhaled corticosteroids that likely impacted immune responses against viruses. Since differences in antiviral responses were also evident in in vitro experiments with isolated airway epithelial cells from frequent exacerbators, it is possible that the effect of corticosteroids was long term and potentially irreversible.

Two weeks after the onset of viral exacerbation, COPD lungs exhibited secondary bacterial colonization suggesting implications for compromised antiviral immunity in bacterial exacerbations. Interestingly, secondary bacterial colonization did not associate with changes in antibacterial peptide [secretory leukocyte protease inhibitor (SLPI), elafin, lactoferrin, and surfactant protein D] release implying alternative mechanisms for increased bacterial burden. Essentially, the study by Singanayagam and colleagues concludes that pronounced deficiency in their antiviral innate immunity may underlie frequent exacerbations in subgroups of COPD patients. These data support evaluation of emerging therapeutics that can augment antiviral immunity such as interferon replacement therapy to prevent/treat viral exacerbations. If successful, antiviral interventions may also reduce secondary bacterial infections and improve overall COPD outcomes.

GRANTS

This work has been supported in part by National Heart, Lung, and Blood Institute Grants R35HL135816, National Institute on Alcohol Abuse and Alcoholism Grant 1R01AA027528, National Institute of Diabetes and Digestive and Kidney Diseases Grant P30DK072482, National Institute of Allergy and Infectious Diseases Grant 1R21AI133445, and Flight Attendants Medical Research Association Grant YFA130008.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

S.V.R. drafted manuscript; edited and revised manuscript; approved final version of manuscript.