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

August 2012 Pulmonary Journal Club

While Dr. Mathew was away, we reviewed 5 articles. Some of the fellows helped out and their names are at the end of the articles they reviewed.

Butler JP, Loring SH, Patz S, Tsuda A, Yablonskiy DA, Mentzer SJ. Evidence for adult lung growth in humans. N Engl J Med 2012;367:244-7. (Click here for abstract)

This is a case presentation of a 33 year old female, post pneumonectomy for treatment of right hilar adenocarcinoma, and the observation of what appears to be lung growth in the remaining left lung by means of CT and MRI imaging utilizing techniques to evaluate tissue density, alveolar microstructure (radial dimension of the acinar airways and alveolar depth), as well as utilizing spirometry.  This observation had not previously been described in adult humans, placing the idea that lung growth and regeneration only occurring perinataly and in early youth at question.  There have been several publications with observation of lung growth in other mammals which have been noted to occur over months to years (1).

This is a very interesting observation of lung growth post-pneumonectomy in a mid 30s female. The impact of this observation is that even after early youth, the capacity to grow lung tissue is still at hand; albeit slightly altered, as was described with the decreased alveolar depth and underlying heterogeneity. Nonetheless, if the understanding of the mechanisms by which this growth takes place, the ability to manipulate and expedite cellular function and regeneration can make a great impact on future practice and management of patients with functional lung tissue loss from any etiology.  This impact may be a valuable tool in, not only post-pneumonectomy patients with underlying malignancy, but also in lung volume reduction surgery for COPD, amongst other common causes of lung disease and alveolar destruction that have at least some viable lung tissue remaining. 

Joshua Jewell, MD

Navani N, Lawrence DR, Kolvekar S, et al. Endobronchial ultrasound-guided transbronchial needle aspiration prevents mediastinoscopies in the diagnosis of isolated mediastinal lymphadenopathy: a prospective trial. Am J Respir Crit Care Med 2012;186:255-260. (Click here for abstract)

Endobronchial ultrasound –guided transbronchial needle aspiration (EBUS-BRNA) is emerging as an alternate diagnostic test for the staging of the non-small cell lung cancer compared to mediastinoscopy (1). The authors tested EBUS-TBNA as a first diagnostic test instead of mediastinoscopy, the “Gold Standard” for patients who present with isolated mediastinal lymphadenopathy. A prospective, multicenter single arm study was undertaken in south east England with 77 patients with isolated mediastinal adenopathy. EBUS-TBNA  providing accurate diagnosis in 67 patients (87%). When economic analysis was done on the decision tree model, the cost for EBUS-TBNA strategy was $2998 and for mediastinoscopy alone was $5115. On statistical analysis EBUS-TBNA has a sensitivity of 92%, diagnostic accuracy of 92% but only a 40% negative predictive value. Based on the low negative predictive value, the authors recommended that patients who had negative EBUS-TBNA should undergo mediastinoscopy.

This study has some limitations requiring a tertiary center with expert pulmonologists and experienced pathologists able to obtain and interpret the EBUS-TBNA samples. It was done in an area where fungal diseases are not endemic perhaps limiting its application in the Southwest. It also excluded patients who had anterior mediastinal lymphadenopathy which can’t be approached by EBUS-TBNA.

The above study lends further support to the performance of EBUS-TBNA prior to mediastinoscopy in patients with isolated mediastinal lymphadenopathy.

Suresh Uppalapu, MD

Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-98. (Click here for full text of article)

The authors performed a randomized trial to determine whether azithromycin decreased the frequency of COPD exacerbations. A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. Azithromycin reduced the median time to the first exacerbation (P<0.001) and the frequency of exacerbations (P=0.01) compared to placebo. Hearing decrements were more common in the azithromycin group (25% vs. 20%, P=0.04) but there was no increase in death or cardiovascular deaths (see article below).

The reduction of COPD exacerbations is quite plausible since erythromycin, another macrolide, has been previously reported to reduce COPD exacerbations (3). Macrolides are known to have anti-inflammatory effects which may explain the reduction in COPD exacerbations. Other antibiotics such as the tetracyclines also have anti-inflammatory effects and could be an alternative if an antibiotic other than a macrolide is appropriate.

Richard A. Robbins, MD

Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881-90. (Click here for full text of article)

Macrolides are frequently used as therapy for acute infections and are increasingly being used as chronic therapy for chronic lung diseases such as cystic fibrosis, asthma or COPD (see article review above). However, several published reports have associated azithromycin with QT prolongation and resultant arrhythmias. The authors studied a Tennessee Medicaid cohort to detect an increased risk of death related to short-term cardiac effects of azithromycin, amoxicillin, or no antibiotics. During 5 days of therapy, patients taking azithromycin had an increased risk of both cardiovascular death and death from any cause compared to amoxicillin or no antibiotic. However, the incidence was low with an estimated 47 additional cardiovascular deaths per 1 million courses. For patients in the highest decile of cardiovascular risk scores, there were an estimated 245 additional cardiovascular deaths per 1 million 5-day courses of azithromycin therapy.

Azithromycin has been the best studied of the macrolides. In addition to its antimicrobial effects, macrolides also have anti-inflammatory effects which may explain its efficacy, at least in part, in some chronic disorders. Other antibiotics such as the tetracyclines also have anti-inflammatory effects but have not been studied nearly as extensively as the macrolides.

How one should use this data is unclear. Pulmonologists often treat elderly, sick patients with macrolides for acute disorders such as an exacerbation of COPD. These patients are at an increased risk for death not only because of their underlying lung disorder but also because of age and associated diseases, including cardiovascular disease. If a patient with an exacerbation of COPD was given azithromycin and died, a not infrequent occurrence, it seems unlikely that azithromycin contributed to the patient’s death. It is more likely, but still rare, if the patient has known cardiovascular disease. On the other hand, discretion might suggest it may be medically/legally advisable to use another antibiotic. This is especially true in those with known cardiovascular disease or those receiving another drug known to cause QT prolongation such as amiodarone.

Richard A. Robbins, MD

Tyrrell GJ, Lovgren M, Ibrahim Q, et al. Epidemic of invasive pneumococcal disease, western Canada, 2005-2009. Emerg Infect Dis 2012;18:733-40. (Click her for full text of article)

In western Canada an epidemic of serotype 5 invasive pneumococcal disease was reported: 52 cases during 2005, 393 during 2006, 457 during 2007, 104 during 2008, and 42 during in 2009. These patients were more likely to be younger, male, First Nations heritage or homeless. Restriction fragment-length polymorphism typing indicated that the epidemic was caused by a single clone, which multilocus sequence typing identified as sequence type 289.

At first read, this appears to be a catastrophe with large number of patients dying from an epidemic of an aggressive pneumococcus. Note the title where invasive and epidemic are used, but the title is misleading. Invasive pneumococcal disease is defined as isolation of S. pneumoniae from a normally sterile site. For the large majority of cases this means blood with 95% of the isolates coming from blood in this series. However, large observational studies have not demonstrated an increased mortality or complications in patients with a positive blood culture compared to those whose blood is sterile (4). In this article, identification of type 5 invasive pneumococcal disease was actually associated with a decreased mortality compared to other invasive pneumococcal serotypes (3.2% vs. 14.1%). Furthermore, although the cases of serotype type 5 increased, it is unclear if there was an increase in pneumococcal disease. The incidence of pneumococcal pneumonia, the most common clinical manifestation of S. pneumonia, is known to vary from year. Figure 2 of the manuscript suggests that if there was an increase in isolation of invasive pneumococcal serotypes this was accompanied by an increase in both serotype 5 as well as other serotypes.

This is an interesting epidemiologic study but the use of words such as epidemic and invasive, although technically correct, are misleading. Clinicians need to be aware of the definitions of these terms in order to prevent overreaction to reports such as this one.

Richard A. Robbins, MD

References

1. Yilmaz C, Ravikumar P, Merill Dane D,  Bellotto D, Johnson Jr R. Noninvasive quantification of heterogeneous lung growth following extensive lung resection by high-resolution computed tomography. J Appl Physiol 2009;107:1569-78.
2. Vincent, El-Bayoumi E, Hoffman B, Doelken P, DeRosimo J, Reed C, Silvestre GA. Real-time endobronchial ultrasound-guided transbronchial lymph node aspiration. Ann Thoracic Surgery 2008; 85:224-30.
3. Seemungal TAR, Wilkinson TMA, 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;178:1139-47.
4. Jackson LA, Neuzil KM, Yu O, et al. Effectiveness of pneumococcal polysaccharide vaccine in older adults. N Engl J Med 2003;348:1747-55.

Reference as: Jewell J, Uppalapu S, Robbins RA. August 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;5:100-3. (Click for a PDF version of the journal club)

March 2012 Pulmonary Journal Club

Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-98. (Click here for full text of article)

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and the major cost of COPD care. Chronic use of macrolide antibiotics have been shown to benefit patients with cystic fibrosis, bronchiectasis and COPD by preventing exacerbations presumably by their anti-inflammatory rather than their antibiotic effects. Albert et al. performed a randomized, placebo-controlled, double-blinded trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD. A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. Azithromycin improved the median time to the first exacerbation (266 days vs.174 days, p<0.001); the frequency of exacerbations was (1.48 vs. 1.83 per patient-year, p= 0.01); scores on the St. George’s Respiratory Questionnaire (2.8±12.8 vs.0.6±11.4, p = 0.004); and the percentage of participants with more than the minimal clinically important difference of −4 units (43% vs. 36% p= 0.03). Hearing decrements were slightly more common in the azithromycin group than in the placebo group (25% vs. 20%, p = 0.04). Colonization with respiratory pathogens was lower in the azithromycin group (12 vs. 31%, p<0.001) although when present colonization with macrolide resistant organisms was more frequent (81 vs. 41%, p<0.001). Mortality was low and did not differ between the groups.

This study confirms a previous study by Seemungal et al. (1) who also performed a randomized, double-blind, placebo-controlled study of another macrolide, erythromycin, administered at 250 mg twice daily to 109 patients with COPD over 12 months. Exacerbations for the erythromycin-treated patients were reduced compared with placebo-treated patients (p<0.003). These two well done, randomized studies lend strong support to chronic use of macrolide antibiotics in COPD. In both studies complications were low and antibiotic resistance remained mostly a laboratory observation rather than a clinical problem. Details such as the optimal doses and frequency of antibiotic administration will need further investigation. Other antibiotics such as the tetracyclines also have anti-inflammatory effects and may be alternatives to macrolides (2). It now seems that the concept of chronic use of some antibiotics as anti-inflammatories is well established in respiratory disease and I would urge consideration of their usage in patients who have had or are likely to have a COPD exacerbation.

Richard A. Robbins, M.D.

Editor, Southwest Journal of Pulmonary and Critical Care

 References

1. 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;178:1139-47.
2. Rempe S, Hayden JM, Robbins RA Hoyt JC. Tetracyclines and pulmonary Inflammation. Endocrine, Metabolic & Immune Disorders - Drug Targets 2007;4:232-6.

Reference as: Robbins RA. March 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;4:78-9. (Click here for a PDF version of the journal club)

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

July 2011 Pulmonary Journal Club

Reference as: Mathew MJ. July, 2011 pulmonary journal club. Southwest J Pulm Crit Care 2011;3:25-6. (Click here for PDF version)

Donohue JF, Fogarty C, Lötvall J, Mahler DA, Worth H, Yorgancioglu A, Iqbal A, Swales J, Owen R, Higgins M, Kramer B; INHANCE Study Investigators. Once-Daily Bronchodilators for Chronic Obstructive Pulmonary Disease: Indacaterol Versus Tiotropium. Am J Resp Crit Care 2010;182:155-162. (Click here for full manuscript)

The once-daily, long-acting, beta-2 agonist, indacaterol was initially released in Europe in 2009. On July 1st 2011 it was approved by the FDA for the United States under the trade name Arcapta Neoinhaler. There have been studies demonstrating Indacaterol as an efficacious alternative to twice daily bronchodilators such as formoterol (1). We reviewed the study published by Donahue et al. and examined how Indacaterol compared to the only other once daily long acting bronchodilator tiotropium.

This was a large, two stage, randomized, controlled study performed between April, 2007 – August, 2008. The inclusion criteria were an age > 40, smoking history of > 20 pack/yrs and GOLD criteria COPD of moderate – severe COPD. The study was performed in 2 stages. A total of 2059 patients were included in the 1st stage which was performed to test dose efficacy. In this stage patients were randomized to receive either once daily indacaterol at doses of 75 ug, 150 ug, 300 ug or 600 ug, formoterol, tiotropium or placebo. At the end of this stage, two doses of indacaterol were selected for the second stage based on efficacy and safety. In the second stage, 1683 patients were randomized to once daily indacaterol 150 ug, 300 ug, tiotropium or placebo.

Primary endpoints were FEV1 response against placebo at 24 hours, and again at 12 weeks. The secondary endpoint was to compare FEV1 at 12 weeks against

tiotropium. A total of 1291 patients completed the study. The results showed there was a statistically significant increase in FEV1 at 24hrs and 12 weeks when compared to placebo. The study also demonstrated non-inferiority to tiotropium at 12 weeks with regards to improvement in FEV1 (see table below).

The study was not designed to measure clinical outcomes but noted were a decrease in the use of daily albuterol, a decrease in daytime symptoms and nocturnal awakenings in the indacaterol arm vs. placebo. The medication was well tolerated with main side effects being reported as cough, tachycardia and dry mouth.

The study was well done and it accomplished its primary endpoint. The main limitations were the lack of blinding in the tiotropium arm and the relative short study period of 26 weeks. It would have also been useful to extend the study period to 1 year to obtain clinical outcome data.

The availability of a once-daily, long-acting beta-2 agonist is now a promising alternative in the treatment of COPD. Although more studies are needed to demonstrate an improvement in clinical outcomes (such as a reduction in COPD

exacerbations) the once a day dosing offers at the very least, a compliance advantage. The cost of the medication (which is currently unknown) and formulary restrictions will limit initial availability.

Manoj Mathew, MD MCCM, FCCP

References

1. Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax 2010;65:473–9.