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The Cold Truth About Cryobiopsy Readiness

Akulian, Jason A., MD, MPH*; Yarmus, Lonny, DO, MBA, FCCP, ATSF

Journal of Bronchology & Interventional Pulmonology: January 2019 - Volume 26 - Issue 1 - p 4–5
doi: 10.1097/LBR.0000000000000560

*Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC

Department of Medicine, Division of Pulmonary and Critical Care, Johns Hopkins Hospital, Baltimore, MD

L.Y. has received educational grants from ERBE.

Disclosure: L.Y. holds a patent on a cryobiopsy device but has granted any potential earning to the Johns Hopkins University School of Medicine. J.A.A. has no conflict of interest or other disclosures.

Reprints: Jason A. Akulian, MD, MPH, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, 8007 Burnett Womack Bldg., CB 7219, Chapel Hill, NC 27599 (e-mail:

Historical diagnosis and management of diffuse parenchymal lung disease (DPLD) involved patient historical, radiographic, and surgical specimen histopathologic evaluation to achieve a unifying diagnosis. Surgical lung biopsy (SLB) has long been viewed as the gold standard in the histopathologic diagnosis of DPLD; however, this diagnostic modality has carried with it a significant risk of morbidity and mortality.1 These risks led to the adoption of transbronchial forceps biopsy (TBFB) as a “minimally invasive” method utilized in an attempt to achieve a histopathologic diagnosis of DPLD. Subsequent research has repeatedly reported poor diagnostic yield when using TBFB in the diagnosis of DPLD, which has led to both a specific lack of comment or an outright recommendation against their use, depending on the clinical scenario in the current ILD guidelines.2,3 Introduced as a tool for the diagnosis and treatment of large airway disease, the need for larger tissue samples and intact parenchymal architecture as well as the factors that have made SLB and TBFB unattractive has led to the evaluation of the cryoprobe as a method of transbronchial lung biopsy.

Since its introduction as a novel technique for transbronchial lung biopsy in 2009,4 transbronchial cryoprobe biopsy (TBCB) has been reported as a technique for peripheral lung biopsy in a myriad of pathologies.5–7 This wide range of applications and a reported increase in biopsy tissue size, parenchymal architectural preservation, and improved diagnostic yield have driven excitement toward TBCB adoption by the pulmonary community. Despite this, some cold water has been and needs to continue to be poured on this heated enthusiasm. In the systematic review and meta-analysis by Sethi and colleagues, the authors present the largest meta-analysis to date evaluating the use of TBCB in DPLD. Their pooled analysis included 31 studies, 4 of which only included procedural safety data. When evaluating the diagnostic yield of TCBC [72.9%; 95% confidence interval (CI), 67.9-77.7], the degree of heterogeneity noted even after study subgroup stratification suggested that the wide range of yields reported were not driven by study type, design, quality, or cryoprobe size. Furthermore, the pooled complication rates were significantly higher when compared with TBFB. The pooled rates of pneumothorax and significant bleeding were 9.4% (95% CI, 6.7%-12.5%) and 14.2% (95% CI, 7.9%-21.9%), respectively. These complication rates, particularly significant bleeding, were higher than in 3 of 5 previously published meta-analyses. The authors also noted a wide variation in procedural protocols, notably probe freeze times (2 to 8 s), number of samples taken,1–8 type of airway used, number of bronchoscopes used, and anesthesia type.8 These findings should leave one frozen with concern when considering the usage of TBCB due to a clear lack of insight and standardization of this procedure.

Although the Sethi analysis takes an updated look at TBCB, the procedure was first introduced in a publication almost 10 years ago, and it does not stand alone in painting a picture of a procedure that remains incomplete and unready for the mainstream. The first published recognition of the lack of standardization of TBCB occurred in 2015 when Poletti and Hetzel published a manuscript comparing the practice of TBCB in 15 studies performed between 2009 and 2015. In the manuscript, they illustrate an astounding degree of practice variability when evaluating types of airway and anesthesia used, use of bronchial blockers, cryoprobe size, and freeze times when performing TBCBs.9 Comparing and contrasting this manuscript with the meta-analysis by Sethi and colleagues 3 years later, you see an additional 16 studies evaluated, yet the same degree of procedural variability remains, and complication rates appear unchanged. Clearly, we have not learned our lessons. Further evaluation of the literature surrounding TBCB use in DPLD illustrates a lack of controlled prospective single arm (n=5) or randomized comparative (n=1) studies.

After painting such an icy and dark landscape of TBCB, one might ask, “Where do we go from here?” Should we abandon all hope, as suggested in the literary masterpiece by Dante Alighieri? Or should we soldier on blindly freezing and ripping pieces of lung parenchyma from trusting patients? Perhaps we take the middle ground and reset our approach to TBCB. Recent work appears to show that this reset may already be in progress with the formation of an international conference on TBCB in DPLD. Now in its fourth year, this group has recently published an expert statement developed during its third annual meeting held in 2016. In this document, they proposed paradigms for patient selection, pathologic consideration, contraindications, safety considerations, procedural protocols, and level of expertise needed to perform the TBCB.10 Further work is currently underway with the recent formation of an American College of Chest Physician Guideline Development Committee to review and recommend evidence-based approaches to TBCB for DPLD. Although both of these endeavors will certainly help to guide the field forward by suggesting minimal safety standards and practice protocols, a review of the literature will leave these expert statements lacking with regard to supportive evidence. Without properly designed prospective trials, we will continue to lack evidence to support the routine use of TBCB in the non–research-based clinical setting.

The need for alternatives to SLB and TBFB in diagnosing DPLD has led to the promisingly muddled yet concerning introduction of TBCB. With almost 10 years of research into the use of TBCB, we have been tantalized by the possibility of the technology but should now be warned of its potential risk. Sethi and colleagues have provided us with clarity with regard to both the possibility and risk associated with the adoption of this technology. The next phase of TBCB adoption should involve rigorous prospective evaluation of safety and procedural protocols followed by pathology-specific yield and comparative data. A wise person once said that with great power comes great responsibility, and, before we see a thaw in the use of cryobiopsy to diagnose DPLD, we need to take our responsibility to our patients seriously, and ensure we understand the benefits and limitations of this technology.

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