Symptoms Increase, Worsening Quality of Life

By Annette M. Boyle

Sanjay Sethi, MD

Sanjay Sethi, MD

BUFFALO, NY – Patients with chronic obstructive pulmonary disease (COPD) commonly have bacteria in their lungs. This has been considered inconsequential except during exacerbations, but now it seems that those bacteria are not as innocuous as thought and might trigger worsening of symptoms such as shortness of breath and coughing.

“COPD is very common in veterans, occurring about twice as often as in the general population,” said Sanjay Sethi, MD, division chief of pulmonary, critical care and sleep medicine, director of the COPD Study Clinic and staff physician at the VA Western New York Healthcare System in Buffalo, NY, and professor of medicine at the University of Buffalo.

Nearly one million veterans receive treatment for COPD through the VHA, at an annual cost of more than $5.5 billion. Exacerbations of the disease frequently send patients to the hospital; within the VA system, COPD ranks as the fourth most common diagnosis among hospitalized veterans ages 65-74. While symptoms can be managed, no treatments cure the disease or slow its progression.

Sethi and colleagues at the Buffalo VA and University of Buffalo conducted a longitudinal prospective observational study of 41 veterans with COPD from October 2005 to January 2009 and found that bacterial colonization in the lungs of COPD patients correlates with higher daily respiratory symptoms as a result of increased inflammatory response in the airway.1

“These increased symptoms and greater inflammation were not at the level where the patients would come into the office or go to the hospital. Several studies show that half to two-thirds of symptomatic worsenings or mild exacerbations go unreported,” Sethi told U.S. Medicine.

The increase in symptoms might be related to changes in the strain of colonizing bacteria or increased numbers of bacteria. “If the persistence of these bacteria contributes to increased symptoms and inflammation in the lungs in stable COPD, we should regard this as a chronic infection, not innocuous colonization,” according to Sethi.

Those unreported exacerbations might not lead to disease progression, but they do erode quality of life. “This is an extremely common and important problem; we need to treat veterans with COPD more effectively and help them feel better,” Sethi said.

Understanding more about unreported exacerbations might be key to improving care. “We need to ask about unreported exacerbations. Patients may have several bad days in a row and tough it out. They may say they’ve only had antibiotics once in a year, but they may have had these episodes every month,” he added.

New Treatments Needed

Standard treatments for COPD include mono- and combination therapy with long and short-acting bronchodilators and anti-inflammatory agents, typically inhaled corticosteroids. The long-acting antimuscarinic agent (LAMA) tiotropium frequently is used, particularly for patients who have respiratory problems and severe airflow obstruction or frequent exacerbations.

Macrolides have been shown to have some value in reducing chronic infection and exacerbations in COPD, but they are also associated with significant side effects, including increased bacterial resistance in the treated patient and surrounding community. 2

Schema depicting the proposed role of microbial organisms in propagating pathogenic mechanisms in COPD. Source: Gadgil A, Duncan SR - Int J Chron Obstruct Pulmon Dis (2008)

Schema depicting the proposed role of microbial organisms in propagating pathogenic mechanisms in COPD. Source: Gadgil A, Duncan SR – Int J Chron Obstruct Pulmon Dis (2008)

“I only use long-term antibiotics if all other treatments have failed,” said Sethi. “We need to develop non-antibiotic therapies that control the colonization directly. We also need better drugs to deal with mucus in COPD, because it acts as the nidus of infection in the lungs and we don’t have a good way to deal with that.”

COPD increases mucus production and retention in many patients as a result of inflamed airways and irritation.

The VA/DOD Guidelines for Management of Patients with COPD in the Outpatient Setting, released at the end of last year, notes that other medications may be used to treat symptoms of the disease but generally recommends that these drugs be used only in consultation with a pulmonologist. Certain phosphodiesterase inhibitors, such as roflumilast, are in this category, as are theophylline and macrolides.

The guidelines also note that the evidence for use of N-acetylcysteine preparations in patients with stable COPD who continue to have dyspnea and cough is not strong enough to recommend or advise against at this point.

A number of pharmaceutical companies are currently trying to develop more effective anti-inflammatories that could help COPD patients. Some agents that have gained Food and Drug Approval for other indications may reduce inflammation associated with COPD, including statins, the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, and various monoclonal antibodies. Other potential anti-inflammatory agents for COPD in development include chemokine receptor antagonists and a number of enzyme inhibitors. 3, 4

Many of these newer treatments augment the lungs’ inherent defense mechanisms, an approach urged by the Buffalo research team. These therapies make “the airway milieu less hospitable to bacterial colonization, [and] could have significant impact on the daily symptom burden and unreported exacerbations of COPD.

1 Desai H, Eschberger K, Wrona C, Grove L, Agrawal A, Grant B, Yin J, Parameswaran GI, Murphy T, Sethi S. Bacterial colonization increases daily symptoms in patients with chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014 Mar;11(3):303-9.

2 Serisier DJ. Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. Lancet Respir Med 2013;1:262-74.

3 Gross NJ. Novel antiinflammatory therapies for COPD. Chest. 2012 Nov;142(5):1300-7. doi: 10.1378/chest.11-2766.

4 Loukides S, Bartziokas K, Vestbo J, Singh D. Novel anti-inflammatory agents in COPD: targeting lung and systemic inflammation. Curr Drug Targets. 2013 Feb;14(2):235-45.