November 2012 Pulmonary Journal Club

Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA 2012;308:987-97. Full Text

No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. The authors compared adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms in 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy. There were no significant differences in time to treatment failure, the primary end point.

This study was designed to be a superiority study to show that one approach was superior to another. Although these 3 strategies did not demonstrate a difference, we cannot conclude noninferiority or equivalence. The absence of superiority is not the same as equivalence. There were few minority patients and about 17% of the patients dropped out of the study.

Based on this trial it seems unlikely that exhaled nitric oxide adds much to asthma management in patients with mild persistent asthma. It remains to be seen whether patients with moderate or severe asthma might benefit from a biomarker approach such as exhaled nitric oxide.

 Richard A. Robbins, MD

Reference as: Robbins RA. November 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;5: 268. PDF

October 2012 Pulmonary Journal Club

Lee GM, Kleinman K, Soumerai SB, Tse A, Cole D, Fridkin SK, Horan T, Platt R, Gay C, Kassler W, Goldmann DA, Jernigan J, Jha AK. Effect of nonpayment for preventable infections in U.S. hospitals. N Engl J Med 2012;367:1428-37. Full Text

This article looked at the results of a pay for performance program initiated in 2008 by Medicare and Medicaid. The program was designed to reduce the rates of catheter related blood stream infections (CRBSI) and catheter related urinary tract infections (CRUTI) by financial disincentives, meaning reducing payments for diagnosis codes indicating CRBSI and CRUTI. The study looked at the rates of CRBSI, CRUTI before 2008 and after 2008 when the program was initiated. A total of 398 hospitals were included and data from the periods of January 2006 and March 2011 were included.

The results of the study showed no difference in the incidence rates of CRBSI or CRUTI post policy implementation.  The authors concluded that the lack of response may be attributed to factors such as change in ICD codes, hospital based quality assurance programs that were initiated prior to financial disincentives, and the possibility that the financial penalties were not severe enough to change practice patterns.

Our discussion of this article confirmed several notions. First, our overall practice patterns have not changed, we still perform procedures when needed regardless of a pay for performance policy. Second, complications may be preventable but sometimes they are inevitable.  We must be cautious that in our attempt to be perfect that we do substitute what is most appropriate for patient care for what is more appropriate in coding and reimbursement. I will argue that real advancement and progress in patient care still comes through medical research, and with physicians at the bedside.  The more we lean on policy and guidelines to incentivize us the further we drift from the ‘ART’ of medicine.

Manoj Mathew, MD  MCCM FCCP

Reference as: Mathew M. October 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;5:230. PDF

September 2012 Pulmonary Journal Club

Dr. Mathew was away this month and we reviewed 4 articles.

Kelly HW, Sternberg AL, Lescher R, Fuhlbrigge AL, Williams P, Zeiger RS, Raissy HH, Van Natta ML, Tonascia J, Strunk RC; CAMP Research Group. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012;367:904-12.

The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children but it is unclear whether the child is permanently shortened or attains a normal adult height. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. The authors measured adult height in 943 of 1041 participants (90.6%). Mean adult height was 1.2 cm lower the budesonide group than in the placebo group (P = 0.001) A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height. This article is somewhat reassuring. Although there was a reduction in adult height, the decrease was minimal and not progressive or cumulative.

Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med 2012;367:913-21.

Exacerbations of chronic obstructive pulmonary disease (COPD) are major causes of morbidity and mortality in COPD. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations. The authors measured pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) using CT scanning. Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; P<0.001). This is useful information that is biologically logical. Although performing a CT scan solely to measure a PA:A ratio is unwarranted, detection of an increased ratio might prompt one to consider therapies that reduce exacerbations such as long-acting bronchodilators and/or chronic antibiotic therapy.

Peters-Golden M, Klinger JR, Carson SS; for the ATS Research Advocacy Committee. The case for increased funding for research in pulmonary and critical care. Am J Respir Crit Care Med. 2012;186:213-215.

With the possibility of sequestration looming and the current economic and political climate, the future funding of the National Institutes of Health (NIH) and other federal biomedical research programs are threatened. This editorial reviews NIH funding in general and allocations directed at respiratory-related research. The authors advocate that is an opportune time to expand investments in biomedical research and that doing so makes sense from the perspectives of improving health, curtailing health care expenditures, job creation and economic growth. They further argue that current levels of allocation toward respiratory research are incommensurate with the medical, economic, and societal burden of respiratory disease in the United States. The editorial is of course self-serving which is why the fellows were asked to review it. They found the article quite convincing and agreed with the authors that research funding for pulmonary, critical care and sleep needs to be increased.

Hunt LM, Kreiner M, Brody H. The changing face of chronic illness management in primary care: a qualitative study of underlying influences and unintended outcomes. Ann Fam Med 2012;10:452-60.

Recently, there has been dramatic increase in the diagnosis and pharmaceutical management of common chronic illnesses. Using qualitative data collected in primary care clinics, the authors assessed how these trends play out in clinical care focusing on management of type 2 diabetes and hypertension. Based on interviews with 58 clinicians and 70 of their patients, and observations of 107 clinical consultations, clinicians focused on helping patients achieve test results recommended by national guidelines, and most reported combining 2 or more medications per condition to reach targets. Medication selection and management was the central focus of the consultations observed. Polypharmacy was common among patients, with more than one-half of the patients taking 5 or more medications. The authors discuss the influence of the pharmaceutical industry on guidelines and pay for performance and conclude that this results in polypharmacy, sometimes at the expense of patient well-being. Although the manuscript deals with primary care, the principles probably apply to the specialties of medicine and give a disturbing insight into the factors that influence medical decisions.

Richard A. Robbins, MD

Reference as: Robbins RA. September 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;5:150-1. (click here for a PDF version of the journal club)

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)

July 2012 Pulmonary Journal Club

Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, Fiss E, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010;181:116-24. (Click here for full text version of the reviewed manuscript)

Bronchial Thermoplasty is a procedure that inserts a radiofrequency catheter to deliver thermal energy to the bronchial smooth muscle. The procedure is done via bronchoscopy. The application of thermal energy reduces smooth muscle mass and contraction, thereby reducing bronchoconstriction and airflow obstruction. Preliminary investigations were performed in 2004 with larger nonrandomized trials to follow in 2006. This study was the first large randomized, double-blinded, sham-controlled trial looking at the effects of bronchial thermoplasty on asthma related quality of life.

This study was performed in 30 centers over 6 countries. The primary endpoint was the effect of this procedure on asthma quality of life questionnaire (AQLQ). Secondary endpoints looked at symptom free days, morning peak expiratory flow values, FEV1, asthma exacerbations, emergency room visits and doctor visits and missed day from work. Inclusion criteria were age 18-65, asthma diagnoses with need for inhaled corticosteroid and long acting beta agonist, nonsmoker x 1 year, FEV1 > 60%, and an AQLQ of < 6.25. All patients were followed up to 1 year at intervals of 3, 6, 9, and 12 months. A total of 297 patients were included in the study with 198 pts in the treatment arm and 101 patients in the sham group. The treatment group received application of bronchial thermoplasty at intervals of 0, 3, and 6 weeks. The bronchoscopist was unblinded to the treatment arm but patients as well as all follow up personnel remained blinded throughout the study.

The results of the study showed that patients receiving bronchial thermoplasty did improve their AQLQ score by 1.35 vs. 1.16 in the SHAM group. A value of > 1.0 in the AQLQ is considered to me a moderate improvement. Secondary outcomes showed a 32% reduction in severe asthma exacerbations within the treatment arm when compared to SHAM. In addition there was also a decrease in days lost from work/school in the treatment arm. Interestingly enough the treatment arm did not show an improvement in FEV1 when compared to SHAM. Main side effects were post procedure bronchoconstriction and asthma exacerbations with a higher rate of side effects in the treatment group.

With our current institution now offering this procedure we find ourselves asking “who is now the ideal candidate for bronchial thermoplasty?” Phenotypes in asthma vary greatly and I believe we need to identify the correct phenotype before this procedure gains mass appeal and acceptance. Given the post procedure rates of acute exacerbations and need for hospital admissions, the procedure needs to be used with caution. The long term data and safety profile look promising, however we still need more information on the histologic response to bronchial thermoplasty. For now this new technology remains exciting but further longitudinal studies are needed to identify efficacy, safety and phenotype selection.

Manoj Mathew, MD

Associate Editor, Pulmonary Journal Club

Reference as: Mathew M. July 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;5:52-3. (Click here for a PDF version of the journal club)