May 2013 Pulmonary Journal Club

Shah PL, Zoumot Z, Singh S, Bicknell SR, Ross ET, Quiring J, Hopkinson NS, Kemp SV for the RESET trial Study Group. endobronchial coils for the treatment of severe emphysema with hyperinflation (RESET): a randomised controlled trial. Lancet Respiratory Medicine. 2013;1(3):233-40. Abstract 

Despite advances in pharmacologic therapies, chronic obstructive pulmonary disease (COPD) remains a challenging respiratory disease. It is currently the third leading cause of death. Prior invasive treatment strategies such as endobronchial valves and surgical lung volume reduction have had limited success. Surgical lung volume reduction remains an option in patients with heterogeneous upper lobe predominant emphysema, poor exercise tolerance and FEV1 < 35% (1). The placement of endobronchial coils has been studied in smaller cohort studies and shown to reduce hyperinflation. This study is a larger randomized control trial looking at the efficacy and safety of endobronchial lung volume reduction coils (LRVC).

The study was performed between January 2010 and October 2011 among 3 centers in the United Kingdom. Inclusion criteria included patients with FEV1 < 45%. A total of 47 patients were included in the study. Twenty-four patients were randomized to receive standard medical therapy for COPD and 23 patients were randomized to LRVC. The characteristics of the patients were similar; however there were more men in the medical treatment arm, while the LRVC arm had patients with more severe baseline disease.

The procedure was not blinded. Patients undergoing LRVC received a total of 2 sessions 14 days apart. Procedures were done bronchoscopically under moderate conscious sedation or anesthesia. The procedure entailed deploying an endobronchial coil under fluoroscopic guidance 35mm away from pleural surface. Outcomes were measured at 90 days. The primary outcome was an improvement in quality of life as measured by The St. George’s Respiratory Questionnaire. Secondary outcomes looked at response of FEV1, residual volume and 6 minute walk test. 

In this study the results showed an improvement in quality of life, as well and an increase in 6 minute walk test by 51 meters within the LRVC group when compared to the medical therapy group. There were also improvements in FEV1 and a reduction in residual volume with in the LRVC arm. Side effects within the LRVC included 2 pneumothorax episodes but no fatalities.

Findings from this study look promising but there were several imitations. The study was funded by PneumRx which makes the coils being studied. The lack of blinding, no reported smoking status, and no standardized medications within the medical treatment arm further limit the study. Additional larger trials with long term follow up are needed to further validate this new treatment modality.

Manoj Mathew, MD FCCP MCC

Reference

1. Meyers BF, Patterson GA. Chronic obstructive pulmonary disease: bullectomy, lung volume reduction surgery, and transplantation for patients with chronic obstructive pulmonary disease. Thorax. 2003;58:634-8. doi:10.1136/thorax.58.7.634

Reference as: Mathew M. May 2013 pulmonary journal club. Southwest J Pulm Crit Care. 2013;6(5):243-4. PDF

January 2013 Pulmonary Journal Club

Kartalija M, Ovrutsky AR, Bryan CL, Pott GB, Fantuzzi G, Thomas J, Strand MJ, Bai X, Ramamoorthy P, Rothman MS, Nagabhushanam V, McDermott M, Levin AR, Frazer-Abel A, Giclas PC, Korner J, Iseman MD, Shapiro L, Chan ED. Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes. Am J Respir Crit Care Med. 2013;187(2):197-205. Abstract

Among patients with nontuberculous mycobacterial (NTM) lung disease is a subset of previously healthy women with a slender body morphotype, often with scoliosis and/or pectus excavatum. The authors enrolled 103 patients with NTM and 101 uninfected control subjects of similar demographics. Patients with

NTM had significantly lower body mass index and body fat and were significantly taller than control subjects. Scoliosis, pectus excavatum and gastroesophageal reflux were significantly more prevalent in patients with NTM. The normal relationships between the adipokines and body fat were lost and IFN-g and IL-10 levels were significantly suppressed in stimulated whole blood of patients with NTM.

The description in this article extends the description of the “Lady Windermere syndrome” first described in the early 1990’s by Reich and Johnson (1). They described 6 elderly women who were immunocompetent, had no significant smoking history or underlying pulmonary disease, and developed Mycobacterium avium complex (MAC). They hypothesized that these women could have had the habit of voluntary suppression of cough, responsible for the inability to clear secretions from the lung. However, it is now known that the adiopectins have immunomodulatory functions and the findings suggest that the underlying pathophysiology may be an immune deficit.

Søyseth V, Bhatnagar R, Holmedahl NH, Neukamm A, Høiseth AD, Hagve TA, Einvik G, Omland T. Acute exacerbation of COPD is associated with fourfold elevation of cardiac troponin T. Heart. 2013;99(2):122-6. Abstract

The authors investigated if acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with myocardial injury, expressed as elevated cardiac troponin T (Trop). In a cross-sectional study, Trops in patients hospitalized for AECOPD were compared with COPD patients in their stable state. Mean Trops were elevated in the AECOPD group (25.8 ng/l) compared to the reference group (4.55 ng/l).  Higher Trops were associated with the presence of pathological q-waves (p=0.012) and electrocardiographic left ventricular hypertrophy (p=0.039), long-term oxygen treatment (p=0.002) and decreasing forced expiratory volume in 1 s (p=0.014).

Slight elevations of Trops in patients admitted to the hospital are common, including AECOPD patients. This study suggests that elevated Trops do no necessarily indicate underlying cardiac disease and that cardiac consultation and/or workup is not necessarily indicated in every AECOPD patient with a slight elevation in Trops. Clinical judgment as to whether a cardiac condition coexists with the AECOPD must be used.

Richard A. Robbins, MD

References

1. Reich JM, Johnson RE. Mycobacterium avium complex pulmonary infection presenting as isolated lingular or middle lobe pattern: the lady Windermere Syndrome. Chest 1992;101:1605-9.

Referece as: Robbins RA. January 2013 pulmonary journal club. Southwest J Pulm Crit Care 2013:6(1):41-42. PDF

October, 2011 Pulmonary Journal Club

Reference as: Zaner R, Mathew M. October, 2011 pulmonary journal club. Southwest J Pulm Crit Care 2011;3:87-89. (Click here for a PDF version)

Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689-98. (Click here for abstract)

Chronic obstructive pulmonary disorder, COPD, has a prevalence of approximately 10% in people over the age of 40 and an estimated 24 million adults in the United States suffer from symptoms of COPD. Acute exacerbations of chronic obstructive pulmonary disease result in an increased risk of death, decreased quality of life, and a more rapid decline in lung function than those patients with COPD who do not suffer from exacerbations.

This study was a randomized trial that recruited patients from 17 different sites to determine whether daily azithromycin decreased the frequency of acute exacerbations in patients with COPD. The study was a prospective, parallel-group, placebo-controlled trial that took place from March 2006 through June 2010. There were 1142 participants, 570 in the azithromycin group and 572 in the placebo group. Participants in the azithromycin group were to take 250mg by mouth daily for one year; participants in the placebo group also took a similar appearing tablet for one year.

Participants in both groups were at least 40 years of age, had a clinical diagnosis of COPD confirmed by pulmonary function testing, had received systemic glucocorticoids within the previous year, or used continuous supplemental oxygen, or had gone to the emergency department or been admitted to the hospital for an acute COPD exacerbation. The participants were not included in the study if they had an acute exacerbation within four weeks prior to joining the study. Participants were excluded from the study if they had asthma, a resting heart rate greater than 100 beats per minute, a prolonged QT interval (>450msec), hearing impairment confirmed by audiometric testing, or were also using drugs that could prolong the QT interval or were associated with torsades, with the exception of amiodarone. The breakdown of participants had approximately 26% at GOLD stage II, 40% GOLD stage III, and 34% GOLD stage IV at the time of the study in both the placebo and azithromycin groups.

Primary outcome of the study was the time to the first acute COPD exacerbation, which was defined as: increased or new onset of either cough, sputum, wheezing, chest tightness or dyspnea of at least three days requiring antibiotics or systemic steroids. The date of the exacerbation was documented via clinic visit or telephone contact and was recorded as the date treatment was prescribed.

Secondary outcomes of the study were quality of life determined by two different questionnaires, nasopharyngeal colonization of Staphylococcus aureus, Streptococcus pneumonia, Haemophilus influenza or Moraxella, and adherence to the drug regimen. Nasal swabs were done at enrollment and every three months during the study looking for colonization and macrolide resistant bacteria.

Results of the study showed 1641 acute COPD exacerbations, 741 in the azithromycin group and 900 in the placebo group. There was a significant difference in the time to first exacerbation between the two groups with a median time to the first exacerbation of 266 days in the azithromycin group and 174 days in the placebo group. Frequency of exacerbations was found to be significantly lower in the azithromycin group and the number needed to treat to prevent one exacerbation would be approximately three patients.

Secondary outcomes, however, had less significance. Although statistically significant improved quality of life per questionnaire the group did not meet the minimum goal they had set prior to the start of the study to establish improved quality of life. There proved to be no significant difference in the rate of adherence to azithromycin compared to placebo. There was an increase in hearing deficits in the azithromycin group by 5% when compared with placebo. Unfortunately all patients who suffered a hearing deficit were to be taken off azithromycin immediately, which did not occur in all patients due to a protocol error. There was also no significant difference seen in the rate of death between the two groups, which demonstrated three percent in the azithromycin group and four percent in the placebo group.

Regarding colonization of organisms in the nasopharynx, those patients not colonized at the beginning of the study who were placed on azithromycin had a decreased incidence of new colonization compared to those on placebo, and this was found to be significant with a P <0.001. However, in those people without colonization prior to the study who then became colonized during the study there was an increase in resistance to macrolides versus the placebo group, (81 percent vs. 41 percent) and this was also significant. However, there was no evidence showing that the exacerbations occurring in the azithromycin group were due to the new macrolide resistant bacteria. Those people already colonized prior to the study had no significant difference in the prevalence of resistance to macrolides, but this finding was not statistically significant.

The data from this study looks promising. We know that macrolides have immune modulatory and anti-inflammatory effects in addition to antibacterial effects, the former of which are likely offering much of the benefit observed in this study. However, it is still too soon to say that this should become the next step in preventing COPD exacerbations. Azithromycin is used in cystic fibrosis patients with bronchiectasis 500 mg by mouth three times a week to help prevent exacerbations, but we also see an increase in multidrug resistant bacteria in that population. This study does not follow patients long enough out to see if a similar result will occur with COPD. A larger study with longer follow up targeting GOLD stage III and IV participants already on appropriate medical management may be of benefit. In this study it was difficult to tell if those participants involved were already on appropriate medical management and receiving standard of care and if not would there have been similar results from implementing that without the risk of worsening macrolide resistance. That being said, for my own patient population, I would consider using azithromycin for COPD exacerbation prophylaxis in the patient that is suffering from severe disability from repeat COPD exacerbations, is already on optimal medical management and even on optimal management is still requiring frequent hospitalizations for acute exacerbations of COPD.

Rebecca Zaner, D.O.

Manoj Mathew MD, FCCP, MCCM

Associate Editor, Pulmonary Journal Club