April 2015 Phoenix Pulmonary Journal Club: Endo-Bronchial Ultrasound in Diagnosing Tuberculosis

Lin SM, Chung FT, Huang CD, Liu WT, Kuo CH, Wang CH, Lee KY, Liu CY, Lin HC, Kuo HP. Diagnostic value of endobronchial ultrasonography for pulmonary tuberculosis. J Thorac Cardiovasc Surg. 2009;138(1):179-84. [CrossRef] [PubMed]

The diagnosis of tuberculosis in patients with inability to produce sputum or in patients that remain acid-fast bacilli (AFB) smear negative with high index of clinical suspicion remains a challenge and often results in treatment delay. This study examined the role in using endobronchial ultrasound (EBUS) to locate parenchymal infiltrates to allow for more accurate sampling of bronchial lavage fluid and transbronchial biopsies. The study examined 121 patients divided into 2 groups, 73 patients received EBUS guided bronchoscopy and 48 pts received conventional bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. It should be noted that patients undergoing transbronchial biopsies in the non-EBUS group appeared to have biopsies done without the use of fluoroscopy. The results showed that when EBUS was used to locate the parenchymal infiltrate the BAL smear was positive 31% vs 12% in non-EBUS patients and the transbronchial biopsies were positive in 24% vs 4.2% in non-EBUS. The study had several limitations as it did not utilize fluoroscopic guided biopsies or fluid sampling which would of likely increased the diagnostic yield in the non EBUS group. The study however does point out a seldom used approach to transbronchial biopsy by using EBUS to look for air bronchograms and tissue echogenicity. Perhaps utilizing EBUS in more centrally located infiltrates or nodules may offer a benefit over performing blind biopsies or biopsies in which fluoroscopy may be of limited view.

Geake J, Hammerschlag G, Nguyen P, Wallbridge P, Jenkin GA, Korman TM, Jennings B, Johnson DF, Irving LB, Farmer M, Daniel P. Steinfort DP. Utility of EBUS-TBNA for diagnosis of mediastinal tuberculous lymphadenitis: a multicentre Australian experience. J Thorac Dis 2015;7 (3):439-48. [CrossRef]

This was a retrospective study that evaluated the utility of EBUS guided mediastinal lymph node biopsy and culture in patients with suspected mediastinal tuberculosis. Mediastinal tuberculosis was based on clinical suspicion with no lung parenchymal lesions seen on CT scan. 159 patients received EBUS guided biopsy and culture. A total of 39 patients were diagnosed with mediastinal tuberculosis either based on culture (23 patients) or pathology showing granulomatous inflammation with negative cultures and response to tuberculosis treatment. 120 patients were negative for tuberculosis but did receive an alternative diagnosis. Alternative diagnosis of sarcoidosis (78 patients) and reactive lymphoid tissue (20 patients) were the most common alternative diagnosis. Although no mediastinoscopy was performed to confirm truly negative specimens, the presence of alternative diagnosis is reassuring that the combination of negative culture and pathology could results in the reported 98% negative predictive value. The study was limited by its design and smaller sample size, however using EBUS as a first line diagnostic modality makes sense as it may yield either the suspected or an alternative diagnosis in a large proportion of the cases.

Manoj Mathew MD, FCCP, MCCM

Banner University Good Samaritan Medical Center

Phoenix, AZ

Reference as: Mathew M. April 2015 Phoenix pulmonary journal club: endo-bronchial ultrasound in diagnosing tuberculosis. Southwest J Pulm Crit Care. 2015;10(4):197-8. doi: http://dx.doi.org/10.13175/swjpcc061-15 PDF

June 2014 Phoenix Pulmonary Journal Club: New Therapies for IPF and EBUS in Sarcoidosis

Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-82. [CrossRef] [PubMed]

Nintedanib is a tyrosine kinase inhibitor that has been shown to decrease the decline of FVC in phase 2 trials of idiopathic pulmonary fibrosis (IPF). This study was a phase 3 trial in which 2 replicate trials comparing nintedanib 150 mg twice daily to placebo. The trials were randomized double blind placebo controlled performed over 205 sites in 24 countries. Inclusion criteria were an age > 40, FVC > 50% and DLCO 30-79%. Patients were excluded if on prednisone > 15 mg/day or any other treatment for IPF. Patients were followed for 52 weeks and underwent spirometry at weeks 2, 4, 6, 12, 36 and 52. The primary endpoint was decline in FVC and the secondary endpoint was exacerbations of IPF. The results of the 2 trials showed the treatment groups had a 1 year decline in FVC of 114.7 and 113.6 verses 239ml and 207ml in the placebo groups. There was a decrease in acute exacerbations in the Inpulsis 2 group while there was an increase in the time to 1^st exacerbation in the Inpulsis 1 group. The most common side effect was diarrhea, which resulted in treatment cessation in 25 patients. The trial was well done and hit its primary endpoint. A near 50% preservation of FVC at 1 year is impressive and additional longitudinal studies are needed to see if the effects are sustained. A dose adjustment may be needed to help correct the effect of diarrhea and further studies looking at the effect of dose on FVC decline will also be needed.

King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-92. [CrossRef] [PubMed]

Pirfenidone has been a promising agent in the fight against IPF. Prior studies showed conflicting results on the medications efficacy in preserving lung function, specifically forced vital capacity (FVC). This phase 3 clinical trial was performed over 127 sites within 9 countries. 555 patients with either biopsy proven or radiographically proven IPF were randomized to receive placebo (277 pts) or 2403 mg of pirfenidone (278 pts) daily for 52 weeks. Inclusion criteria were a diagnosis of IPF, FVC > 50%, DLCO > 30%, FEV1 > 80% and a 6 minute walk > 150 meters. The primary outcome was the change in FVC at week 52. Secondary outcomes were 6 minute walk distance, dyspnea, progression free survival and death. The results showed that patients taking pirfenidone had 50% less decline in an FVC of > 10% and > 50% of patients had no loss of lung function. The pirfenidone group also had fewer patients with a loss of 50m or more in their 6 minute walk test. The medication was well tolerated with the main side effects being cough, nausea, headache and diarrhea.

It appears that pirfenidone will be the first drug approved specifically for the treatment of IPF. It has already been approved in Europe and it remains to be seen if the results seen in this trial are sustainable in more long term studies.

von Bartheld MB, Dekkers OM, Szlubowski A, Eberhardt R, Herth FJ, in 't Veen JC, de Jong YP, van der Heijden EH, Tournoy KG, Claussen M, van den Blink B, Shah PL, Zoumot Z, Clementsen P, Porsbjerg C, Mauad T, Bernardi FD, van Zwet EW, Rabe KF, Annema JT. Endosonography vs conventional bronchoscopy for the diagnosis of sarcoidosis: the GRANULOMA randomized clinical trial. JAMA. 2013;309(23):2457-64. [CrossRef] [PubMed]

Sarcoidosis is a granulomatous inflammatory condition with multisystem involvement. In 90% of cases the disease involves the lungs, mediastinal and hilar lymph nodes. Definitive diagnosis is obtained by histology obtained through either transbronchial needle aspiration of hilar or mediastinal lymph nodes, transbronchial parenchymal lung biopsy or cervical mediastinoscopy. Transbronchial lung biopsies have shown a sensitivity of 60% with risk of hemorrhage and pneumothorax in up to 6%. Endobronchial (EBUS) or endoscopic esophageal ultrasound (EUS) guided lymph node biopsy have been shown to increase sensitivity to 80% with less than a 1% risk of pneumothorax and hemorrhage. This study compared transbronchial lung biopsy and EUS/BUS in diagnosing sarcoidosis. The study was a randomized control trial done in 14 centers within 6 countries and included 304 patients. 149 patients underwent conventional bronchoscopic evaluation while 155 patients underwent EBUS/EUS evaluation. Bronchoscopic evaluation included bronchoalveolar lavage (BAL) CD4/CD8 ratios, at least 4 transbronchial lung biopsies and 4 endobronchial mucosal biopsy samples. Of note, fluoroscopy was only used in 39% of cases. In the endosonography group, EUS or EBUS was performed . The decision to perform an esophageal or endobronchial procedure was left to investigator. The results showed that EUS or EBUS identified granulomas in 74% of patients compared to 48% in the transbronchial group. It must be pointed out that the greatest yield was seen in with esophageal aspiration of subcarinal lymph nodes and that blind transbronchial needle aspiration of lymph nodes were not performed in the bronchoscopic group. The study had several limitations that deviates from standard practices. In our institution it is rare that a blind transbronchial needle biopsy of an accessible subcarinal node is not performed, in addition, fluoroscopy is routinely used in all parenchymal lung biopsies. Although the study did show that EBUS/EUS is superior to transbronchial lung biopsies and BAL, a study looking at blind transbronchial lymph node biopsies versus EBUS/EUS would have been more valid. However after performing EBUS it will be hard to dispute that direct real time lymph node visualization in conjunction with on-site cytology is now the standard of care in the diagnosis of Sarcoid with lymph node involvement.

Manoj Mathew, MD FCCP MCCM

Reference as: Mathew M. June 2014 Phoenix pulmonary journal club: new therapies for IPF and EBUS for sardoidosis. Southwest J Pulm Crit Care. 2014;8(6):340-2. doi: http://dx.doi.org/10.13175/swjpcc078-14 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)