October 2015 Phoenix Pulmonary Journal Club: Lung Volume Reduction

The October 2015 pulmonary journal club focused on the review of older studies evaluating lung volume reduction surgery and how this has transitioned toward the development of non-surgical modes of lung volume reduction. The physiology behind dyspnea in chronic obstructive pulmonary disease (COPD) is a complex process. One of the proposed mechanisms has been hyperinflation associated with air trapping. In the mid 1990s studies by Cooper and Peterson (1) offered a promising approach in which lung volume reduction (LVR) could improve ventilatory mechanics and improve dyspnea. As the procedure gained more popularity, additional larger scale trials were performed to support its validity.

We reviewed 2 studies looking at lung volume reduction. The first was "The Effect of Lung Volume Reduction Surgery In Patients With Severe Emphysema” (2) . This was a smaller, randomized controlled trial (RCT) that looked at 2 groups of 24 patients. Once group received LVR while the other received medical therapy. The primary outcome was mortality at 6 months and change in FEV1. The study did not show any mortality benefit but showed there was an increase in FEV1 of 150 ml by 6 months in the surgical group whereas the medical group showed no improvement. We reviewed a larger subsequent study, “A Randomized Trial Comparing Lung Volume Reduction Surgery with Medical Therapy for Severe Emphysema”, a RCT that included 1218 patients divided into 2 groups of 608 pts (surgical) and 610 pts (medical) (3). The primary outcome was mortality at 2 years and exercise capacity. The results showed that there was no overall mortality benefit, but there was an overall increase in exercise capacity. A subgroup analysis showed that patients that had poor baseline exercise tolerance and upper lobe predominant emphysema did the best with lower mortality rate and increased exercise capacity. This study was useful in defining a subset of patients most likely to benefit from LVR surgery.

The cost, expertise and risk of complications associated with lung volume reduction surgery led to expanding the physiology of reducing lung volumes via nonsurgical approaches. The use of one way endobronchial valves in allowing air to leave bronchial segments to promote lung volume reduction via atelectasis has been explored for over a decade. Our group was involved in the earlier trials which evaluated efficacy and safety of endobronchial valves (4) . The results from our experience did not show that the endobronchial valves reduced lung volumes. 

A subsequent study, "A Randomized Study of Endobronchial Valves for Advanced Emphysema" was reviewed (5). This was a large RCT that divided a total of 321 pts in a 2:1 format to 2 groups of 220 patients that received endobronchial valves pts and 101 patients that received medical treatment. The primary outcome was change in FEV1 and distance in 6 minute walk test. The placement of endobronchial valves was via bronchoscopy was guided based on emphysema seen on CT of the chest. The large majority of valves were placed in either right upper lobe (52%) or left upper lobe (14%). The study did show a mild increase in FEV1 of 4.3% in the patients treated with endobronchial valves and also resulted in an increase in 6 min walk distance of 9.3 m. However, patients receiving the endobronchial valves also noted higher rates of hemoptysis and COPD exacerbations. The reason for less than optimal results has been explained by the persistence of hyperinflation through collateral ventilation.

The physiologic basis why lung volume reduction may work in COPD remains the same. The surgical resection of apical emphysematous regions may be of some benefit in patients with apical emphysema and decreased exercise tolerance. The role of volume reduction via use of endobronchial valves may become useful if subsequent studies show that collateral ventilation does not lead to persistent hyperinflation and the reduction n volumes shows a sustained increase in FEV1 and 6 min walk test.

Manoj Mathew, MD FCCP

References

1. Cooper JD, Patterson GA. Lung volume reduction surgery for severe emphysema. Semin Thorac Cardiovasc Surg. 1996;8(1):52-60. [PubMed]
2. Geddes D, Davies M, Koyama H, Hansell D, Pastorino U, Pepper J, Agent P, Cullinan P, MacNeill SJ, Goldstraw P. Effect of lung-volume-reduction surgery in patients with severe emphysema. N Engl J Med. 2000;343(4):239-45. [CrossRef] [PubMed]
3. Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood DE; National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348(21):2059-73. [CrossRef] [PubMed]
4. Shah PL, Slebos DJ, Cardoso PF, Cetti E, Voelker K, Levine B, Russell ME, Goldin J, Brown M, Cooper JD, Sybrecht GW; EASE trial study group. Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial. Lancet. 2011;378(9795):997-1005. [CrossRef] [PubMed]
5. Sciurba FC, Ernst A, Herth FJ, Strange C, Criner GJ, Marquette CH, Kovitz KL, Chiacchierini RP, Goldin J, McLennan G; VENT Study Research Group. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. 2010 Sep 23;363(13):1233-44. [CrossRef] [PubMed] 

Cite as: Mathew M. October 2015 Phoenix pulmonary journal club: lung volume reduction. Southwest J Pulm Crit Care. 2015;11(5):215-6. doi: http://dx.doi.org/10.13175/swjpcc138-15 PDF

January 2015 Tucson Pulmonary Journal Club: Withdrawal of Inhaled Glucocorticoids in COPD

Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285-94. [CrossRef] [PubMed]

GOLD guidelines recommend various combinations of inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic agonists (LAMA) to treat patients with chronic obstructive pulmonary disease (COPD) who are at high risk of exacerbation.  A substantial portion of patients are ultimately prescribed triple-therapy at some point. The WISDOM trial examined the risk of exacerbation among patients taking triple therapy who were subsequently weaned from their ICS treatment.

The present WISDOM trial was a randomized, double-blind, non-inferiority trial sponsored by Boehringer Ingelheim Pharma. Over 4 years, approximately 2500 participants in 23 non-US countries with severe or very severe COPD were randomized. Participants were eligible if they were >40 years of age, were current or former smokers with ≥10 pack-year history, and had at least one exacerbation within the year prior to screening. Numerous exclusion criteria included significant comorbidity, prior lung resection, asthma or bronchiectasis, chronic oxygen use, oral steroid requirement, recent exacerbation, respiratory tract infection, or pulmonary rehabilitation. The study had 90% power to evaluate a pre-specified non-inferiority margin of 1.20 for the upper limit of the 95% confidence interval for the hazard ratio.

All participants received an initial 6 week treatment with fluticasone 500 mcg BID, salmeterol 50 mcg BID, and tiotropium 18 mcg daily. Based on random assignment, participants either continued triple therapy or had their fluticasone withdrawn in a step-wise fashion. The primary outcome was the time to first moderate or severe COPD exacerbation during the 52 week study period. Eighty-three percent of participants were men, the overall mean age was 64 years, and the mean FEV₁ was 0.93 liters (33% of predicted). Approximately 40% were receiving triple therapy prior to enrollment. Approximately 20% of participants did not complete the study.

The non-inferiority margin was confirmed with a hazard ratio of 1.06 (CI_95% 0.94 - 1.19). The mean reduction in FEV₁ for the ICS withdrawal group was 38 mL greater than the reduction for the control group at week 18, and this difference increased to 43 mL by the end of the study (p<0.001). The difference in the St. George’s Respiratory Questionnaire (SGRQ) score were statistically significant at week 52, an increase of 1.15 in the withdrawal group vs. decrease of 0.07 in the continuation group (p = 0.047). Adverse events did not differ among the two groups.

The results suggest that gradual withdrawal of ICS from a triple therapy regimen is not associated with a meaningfully increased risk of exacerbation among patients with moderate-to-severe COPD. However, there were statistically significant, but perhaps not clinically meaningful, deterioration in FEV₁ and SGRQ scores. Strengths of this study included a large participant population, a year-long follow-up, and use of clinically relevant and patient-centered outcomes. While the study was conducted in many countries, most participants were white and male. The homogeneity of this group makes it difficult to generalize to other patient groups. Patients who had no exacerbations in the prior year (arguably the group most appropriate to step-down therapy) were not included. It also does not provide information on the safety of abrupt withdrawal of ICS. The long-term consequences of the small reductions in FEV₁ and health status are uncertain. For patients intolerant to or reluctant to consider ICS treatment, dual LABA and LAMA treatment appears to yield clinically similar outcomes.

Candy Wong MD, Cristine Berry MD and Joe Gerald PhD

University of Arizona

Tucson, AZ

Reference as: Wong C, Berry C, Gerald J. January 2015 Tucson pulmonary journal club: withdrawal of inhaled glucocorticoids in COPD. Southwest J Pulm Crit Care. 2015;10(2):79-80. doi: http://dx.doi.org/10.13175/swjpcc019-15 PDF

September 2014 Tucson Pulmonary Journal Club: PANTHEON Study

Zheng JP, Wen FQ, Bai CX, Wan HY, Kang J, Chen P et al. for the PANTHEON study group. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomized, double-blind placebo-controlled trial. Lancet Respir Med. 2014; 2(3):187-94. [CrossRef] [PubMed]

Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity, mortality, and healthcare utilization. Oxidative stress is thought to be important in COPD pathogenesis, and thus antioxidant therapy has been of great interest, including N-Acetylcysteine (NAC). However, prior studies of NAC in COPD patients have shown varied results. The PANTHEON study was designed to examine the effects of NAC on exacerbation rate in Chinese patients with COPD using a daily dose that is twice as high as that previously studied.

PANTHEON was a randomized double-blinded placebo-controlled trial that enrolled patients aged 40-80 years with GOLD class II, III and IV COPD from 34 academic pulmonary clinics in China. Patients with asthma, oxygen dependence, or poor compliance were excluded. The primary outcome was the COPD exacerbation rate following one year of observation. Exacerbations were defined using the Anthonisen instrument which relies on daily diary reporting. Important secondary outcomes included time to first exacerbation, time to subsequent exacerbations, number of patients requiring antibiotics or steroids, and number of patients requiring hospitalization. The enrollment goal was 1250 patients which would have provided have 95% power to detect a 20% reduction in the exacerbation; however, only 1006 patients were actually randomized. Nevertheless, the study was adequately powered for the primary outcome.

More than 80% of the patients were males; 46% had GOLD II severity, 53% had GOLD III severity, and 1% had GOLD IV severity. Mean FEV1 was 1.2 L. Twenty-five percent were non-smokers; 48% were using both ICS and a long-acting bronchodilator at enrollment; and 27% were taking theophylline.

As compared to placebo, twice daily treatment with 600mg of NAC led to a significant reduction in the annual COPD exacerbation rate (RR 0.78, 95% CI 0.67–0.90; p=0.001) and the rate of steroid or antibiotic-requiring exacerbations (RR 0.83 95% CI 0.69-0.99; p=0.04) but not the annual rate of hospitalizations. Interestingly, the time to first exacerbation did not differ between the groups but the time to second and third exacerbations was longer in the NAC group.

This study suggests that NAC, a relatively inexpensive compound that is available over-the-counter, may reduce exacerbation risk among patients with COPD. Given that NAC is safe and the costs would be borne entirely by the patient, it is reasonable to advise patients of this potential treatment option. Patients should be cautioned that the data supporting the benefits of NAC are not conclusive and the magnitude of benefit is likely to be modest. The major limitation includes reliance on a Chinese population of COPD patients in whom the benefits may not be generalizable to US patients. Of unknown importance is the fact that treatment benefits were limited to self-reported outcomes rather than objective observation of hospitalizations. To the extent that the self-reported data is free of bias, the failure to detect differences in hospitalizations may not matter to patients.

Bhupinder Natt MD¹, Christine Berry MD¹, Joe K. Gerald MD, PhD²

¹Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Arizona Medical Center; Tucson, AZ

²College of Public Health, University of Arizona Medical Center; Tucson, AZ

Reference as: Natt B, Berry C, Gerald JK. September 2014 Tucson pulmonary journal club: PANTHEON study. Southwest J Pulm Crit Care. 2014;9(4):249-50. doi: http://dx.doi.org/10.13175/swjpcc144-14 PDF

August 2014 Phoenix Pulmonary Journal Club: The Use of Macrolide Antibiotics in Chronic Respiratory Disease

This month's journal club reviewed  the role of macrolide antibiotics in chronic respiratory disease. Macrolide usage was suggested from observational studies in Japan in diffuse panbroncholitis, a disorder associated with chronic respiratory infection, usually Pseudomonas aeruginosa (1). Clinical improvement was noted despite doses of antibiotics well below the minimal inhibitory concentration (MIC) of the antibiotic. This  suggested the antibiotic was likely working by an anti-inflammatory effect. These observations were extended to cystic fibrosis (CF) where prophylactic macrolide therapy in CF patients infected with Pseudomonas has become standard therapy (2). More recently, low dose macrolide therapy has been applied to non-CF lung diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis and asthma.

Time did not permit a review of all studies so a representative sample was discussed. In patients with COPD, the four randomized, placebo-controlled trials reviewed all suggested that chronic therapy with macrolide antibiotics reduced COPD exacerbations (3-5). This beneficial effect was confirmed by 2 recent meta-analysis (6,7). Similarly,  three recent randomized trials in bronchiectasis demonstrated a reduction in exacerbations (8-10). In asthma the data is not as clear. A recent trial did not demonstrate an overall reduction in asthma exacerbations or lower respiratory tract infections (11). However, in the patients with non-eosinophilic, predominantly neutrophilic, asthma there was a reduction.  An excellent review of the use of macrolides in acute and chronic asthma was recently published. (12). The article includes a review of the anti-inflammatory and immunomodulatory properties of the macrolides.

The respiratory disorders where macrolides have been shown to have clinic benefit such as diffuse panbroncholitis, cystic fibrosis, COPD, bronchiectasis and non-eosinophilic asthma are all diseases associated an influx of neutrophils into the airways. The beneficial clinic effects of macrolides are consistent with their effect in reducing neutrophil chemotactic factors such as interleukin (IL)-8 (13). However, macrolides have also been reported to have adverse clinical effects such as QT prolongation in patients with heart disease, impaired hearing and development of bacterial resistance (4,6,14). Whether all COPD patients should be treated with macrolides is controversial but most in the audience used these in patients with frequent exacerbations. It was also pointed out that other antibiotics such as the tetracyclines also have anti-inflammatory effects and have been shown to be efficacious in some respiratory diseases (15). Whether the tetracyclines are equally or more effective than the macrolides with fewer serious side effects is unknown.

Richard A. Robbins, MD¹

Allen R. Thomas, MD²

Manoj Mathew, MD³

¹Phoenix Pulmonary and Critical Care Research Foundation, ²Phoenix VA Medical Center, ³Banner Good Samaritan Medical Center.

References

1. Nagai H, Shishido H, Yoneda R, Yamaguchi E, Tamura A, Kurashima A. Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration. 1991;58(3-4):145-9. [CrossRef] [PubMed] 
2. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW 3rd; Macrolide Study Group. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290(13):1749-56. [CrossRef] [PubMed]
3. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178(11):1139-47. [CrossRef] [PubMed]
4. 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(8):689-98. [CrossRef] [PubMed]
5. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van't Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2(5):361-8. [CrossRef] [PubMed]
6. Li H, Liu DH, Chen LL, Zhao Q, Yu YZ, Ding JJ, Miao LY, Xiao YL, Cai HR, Zhang DP, Guo YB, Xie CM. Meta-analysis of the adverse effects of long-term azithromycin use in patients with chronic lung diseases. Antimicrob Agents Chemother. 2014;58(1):511-7. [CrossRef] [PubMed]
7. Herath SC, Poole P. Prophylactic antibiotic therapy in chronic obstructive pulmonary disease. JAMA. 2014;311(21):2225-6. [CrossRef] [PubMed]
8. Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, Milne D, Fergusson W, Tuffery C, Sexton P, Storey L, Ashton T. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):660-7. [CrossRef]  [PubMed]
9. Altenburg J, de Graaff CS, Stienstra Y, Sloos JH, van Haren EH, Koppers RJ, van der Werf TS, Boersma WG. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013;309(12):1251-9. [CrossRef] [PubMed] 
10. Serisier DJ, Martin ML, McGuckin MA, Lourie R, Chen AC, Brain B, Biga S, Schlebusch S, Dash P, Bowler SD. Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA. 2013;309(12):1260-7. [CrossRef] [PubMed]
11. Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, Verleden G, Demedts IK, Verhamme K, Delporte A, Demeyere B, Claeys G, Boelens J, Padalko E, Verschakelen J, Van Maele G, Deschepper E, Joos GF. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013 Apr;68(4):322-9. [CrossRef] [PubMed] 
12. Wong EH, Porter JD, Edwards MR, Johnston SL. The role of macrolides in asthma: current evidence and future directions.  Lancet Respir Med. 2014 2:657-70. [CrossRef] [PubMed]
13. Abe S, Nakamura H, Inoue S, Takeda H, Saito H, Kato S, Mukaida N, Matsushima K, Tomoike H. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2000;22(1):51-60. [CrossRef] [PubMed] 
14. Albert RK, Schuller JL; COPD Clinical Research Network. Macrolide antibiotics and the risk of cardiac arrhythmias. Am J Respir Crit Care Med. 2014;189(10):1173-80. [CrossRef] [PubMed] 
15. Rempe S, Hayden JM, Robbins RA, Hoyt JC. Tetracyclines and pulmonary inflammation. Endocr Metab Immune Disord Drug Targets. 2007;7(4):232-6. [CrossRef] [PubMed] 

Reference as: Robbins RA, Thomas AR, Mathew M. August 2014 Phoenix pulmonary journal club: the use of macrolide antibiotics in chronic respiratory disease. Southwest J Pulm Crit Care. 2014;9(2):130-2. doi: http://dx.doi.org/10.13175/swjpcc109-14 PDF

March 2014 Phoenix Pulmonary Journal Club: Palliative Care

Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010 Aug 19;363(8):733-42. [CrossRef] [PubMed]

The March journal club focused on the role of palliative care in respiratory diseases such as chronic obstructive lung disease (COPD) and lung cancer. Palliative care is specialized care that focuses on life threatening disease and the relief of pain and stress. Although often initiated near the end of life, palliative care should not be  considered as end of life care. This study reviewed the impact of introducing palliative care in conjunction with oncologic care in the treatment of metastatic non-small cell lung cancer versus oncologic care alone. This was a nonblinded, randomized control trial of 151 patients done at the Massachusetts General Hospital.  Seventy-seven patients were randomly assigned to early palliative care + oncologic care (P + O) and 74 patients were assigned to oncologic care only (O). P + O patients were seen by palliative care services within 3 weeks of enrollment and met with services monthly until their death. Primary outcome was quality of life at baseline and at 12 weeks. The results showed that P + O patients had less depressive symptoms (16% P + O vs. 38% O), received less aggressive end of life care (33% P + O vs. 54% O) , and lived 2.7 months longer (11.6 m P + O vs. 8.9 m O). Although this was a small, nonblinded study it showed that palliative care does not need to be exclusive of ongoing oncologic care and that early referral and involvement can help foster goals of therapy and better symptom control.

Carlucci A, Guerrieri A, Nava S. Palliative care in COPD patients: is it only an end-of-life issue? Eur Respir Rev. 2012 Dec 1;21(126):347-54.  [CrossRef] [PubMed]

The role of palliative care in COPD is underutilized and rarely initiated until the end stages of disease. This review on the role of palliative care in COPD emphasizes that COPD is often a more debilitating disease than lung cancer with even higher rates of anxiety and depression. Palliative care should not be considered as transitional or end of life care, but integrated early to improve symptom control and quality of life. The timing as to when to get palliative care services involved in the outpatient COPD population is debatable, as the resources are limited. This paper suggests that looking at parameters that delineate a decreased 5 year survival in COPD, such as THE BODE INDEX, may be useful.  Patients that have a BODE index score of 7 or more would certainly be good candidates and perhaps starting with a score of 5 or more may even be more appropriate. Palliative care should be considered an integrated and complimentary tool in the management of advanced COPD.

Manoj Mathew, MD FCCP MCCM

Reference as: Mathew M. March 2014 Phoenix pulmonary journal club: palliative care. Southwest J Pulm Crit Care. 2014;8(3):194. doi: http://dx.doi.org/10.13175/swjpcc034-14 PDF