Jul 102013

EUS with EBUS Superior at Diagnosing Sarcoidosis

Sarcoidosis affects tens of thousands of people in the U.S., but making the diagnosis can be tricky. A biopsy is almost always required, and since >90% of patients have involvement of the lungs and/or lymph nodes in the chest, bronchoscopy has been the standard procedure for obtaining tissue. If tissue biopsy reveals noncaseating granulomas, and other similarly-presenting diseases (tuberculosis, fungal disease, lymphoma, lung cancer) can be ruled out, sarcoidosis is the likely diagnosis.

Bronchoscopic biopsies have been traditionally done using miniature forceps on the end of a wire advanced to the lung periphery -- so-called transbronchial lung biopsies. However, this approach only has an estimated 60% sensitivity for finding noncaseating granulomas in people with proven sarcoidosis. Transbronchial lung biopsies also carry a 2-6% risk for significant hemorrhage and pneumothorax.

Endoscopic ultrasound (EUS or endobronchial ultrasound / EBUS) has a reported higher sensitivity of 80% for obtaining noncaseating granulomas from enlarged lymph nodes. In addition, EBUS is safer than transbronchial lung biopsy, with only about a 1% risk for significant bleeding, pneumothorax, or other complications.

However, EUS/EBUS and transbronchial lung biopsy have never been compared head-to-head in a randomized trial for the diagnosis of sarcoidosis. Until now, with the publication of the GRANULOMA trial in the June 2013 JAMA.

What They Did

Martin B. von Bartheld et al randomized 304 patients at 14 centers in 6 countries (in Europe & the UK) with suspected pulmonary sarcoidosis (mediastinal lymphadenopathy, with or without pulmonary infiltrates) to undergo either ultrasound-guided transbronchial needle aspiration of enlarged mediastinal lymph nodes, or traditional transbronchial forceps biopsies.

Ultrasound was done either via the esophagus or endobronchially -- outside the U.S., pulmonologists are usually trained to do both (here, GI and pulmonary maintain their divided organ system turfs, and EUS and EBUS are rarely done together). Bronchoalveolar lavage was also performed on all patients. Fluoroscopy (realtime X-ray vision) was only used on 39% of the patients undergoing transbronchial lung biopsy. Cultures, PCR and stains for mycobacteria and fungi were done on tissue and BAL samples.

What They Found

Two-thirds of those randomized to an ultrasound approach got EUS and about one-third were done with EBUS. The approach was determined by the preference of the operator, who was trained in both EUS and EBUS.

Endobronchial / esophageal ultrasound identified granulomas in 74% of patients -- far superior to transbronchial biopsy's 48% sensitivity for detecting granulomas in this trial. A few of these patients were later ruled to have not sarcoidosis, but another granulomatous disease. After excluding them, the "diagnostic yield" of EUS/EBUS (i.e., its sensitivity for diagnosing true-positive sarcoidosis) was 80%, while transbronchial biopsy's yield/sensitivity was only 54%.

From a practical perspective, 75 patients undergoing transbronchial biopsy had no diagnosis after the initial bronchoscopy, and 64 underwent repeat endoscopy procedures (securing a diagnosis in 64 or 85%). Among the EUS/EBUS-scoped patients, only 36 had no diagnosis after their procedure and 25 underwent more testing (finding granulomas in another 16).

The final diagnosis was sarcoidosis in 278 of the 303 patients, based on tissue biopsies with granulomas in 250 (83%) and clinical / radiographic follow-up in the rest. There were deemed to be no false positive sarcoidosis diagnoses.

Patients with sarcoidosis often have a high ratio of CD4/CD8 cells in bronchoalveolar lavage fluid. In this study, using a cut-off ratio of 3.5 CD4-to-CD8 cells on flow cytometry yielded a 54% sensitivity at diagnosing sarcoidosis, but an 89% specificity.  Cytospin analysis had similar specificity but only 23% sensitivity.

Adverse events occurred in 3 patients. In the transbronchial lung biopsy group, only one had a pneumothorax requiring chest tube placement -- a 0.6% risk for the group (in whom fluoroscopy was used only 39% of the time) -- and another needed noninvasive ventilation briefly after general anesthesia. After EUS fine needle aspiration through the esophagus, one patient acquired a mediastinal abscess and needed thoracotomy followed by long-course antibiotics.

What It Means

As it's tested more at experienced centers, endoscopic ultrasound (EUS/EBUS) is developing an impressive track record for diagnostic accuracy and safety. In ideal conditions, EBUS can spare patients mediastinoscopies and thoracotomies for suspected lung cancer, with potentially greater diagnostic accuracy. EBUS is safer than transbronchial biopsy, and this trial suggests that for those trained in both EUS and EBUS, an operator-dependent ultrasound-guided needle biopsy with either EUS or EBUS could be more sensitive at identifying granulomas to make the diagnosis of sarcoidosis or another disease.

EUS/EBUS together are not generally available in the U.S.; even EBUS alone is not widely available. In addition to the extra training required, the machines cost tens of thousands of dollars, a hard-to-recoup investment since insurance companies and Medicare have not paid doctors more to do bronchoscopies with EBUS-guided biopsies than in the traditional way. Some have argued that each EBUS may ultimately result in an additional $25,000 in revenue for the institution as a whole.

But where EUS & EBUS are available (i.e., in Europe), the real question raised by the GRANULOMA trial is, are transbronchial biopsies becoming obsolete for the diagnosis of sarcoidosis? We now know there is a higher risk of pneumothorax and bleeding with traditional transbronchial lung biopsy (although that wasn't seen here), and that EUS / EBUS could be more accurate, reducing the number of invasive procedures needed to make a diagnosis. Is transbronchial biopsy still appropriate to perform on patients with suspected sarcoidosis, in settings where EUS and EBUS are available in the same procedure?

Remember that this trial did not test EBUS alone against traditional transbronchial biopsy, and when you look at the subgroups' findings, EBUS (as opposed to EUS) did not outperform transbronchial biopsy. Hat tip and thanks to Dr Allan Walkey for pointing this out in the comments, which I've excerpted here:

That the majority of ultrasound-guided biopsies were done with EUS rather than EBUS implies that subcarinal lymph nodes were commonly the site of ultrasonographic-guided biopsy. Subcarinal lymph nodes are well-targeted with blind transbronchial needle biopsy, but were not sampled at all in the ‘traditional’ bronchoscopy group. The prevention of blind transbronchial needle lymph node sampling in the control group likely led to a lower yield than what would be achieved with combining blind transbronchial lung AND needle lymph node biopsies in the ‘traditional’ control group. As evidence, Pauli et al. (CHEST 1984;85(4):482-484.) showed 77% yield for sarcoidosis with combined transbronchial needle and endobronchial Bx, and Morales et al. (Chest. 1994;106(3):709-711.) showed a combined yield of 83-86%. Thus, as in all trials, the control group is all important.

For the pulmonologists out there: EBUS (yield 66%) was NOT as good as EUS (yield 88%). Thus, EBUS did not (p=.11) beat transbronchial biopsy, but EUS did (with caveats above).

EBUS also did not supplant transbronchial biopsy for diagnosis of sarcoidosis in this 2014 study of 130 patients in Chest.

Martin B. von Bartheld et al. Endosonography vs Conventional Bronchoscopy for the Diagnosis of Sarcoidosis: The GRANULOMA Randomized Clinical Trial. JAMA. 2013;309(23):2457-2464.

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EUS with EBUS beat transbronchial biopsies for diagnosis of sarcoidosis in RCT