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Transbronchial Cryobiopsy for Interstitial Lung Disease

Is it too Late to Put the Toothpaste Back in the Tube?

Culver, Daniel A. DO*; Grutters, Jan C. MD, PhD†,‡

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Journal of Bronchology & Interventional Pulmonology: April 2018 - Volume 25 - Issue 2 - p 85-87
doi: 10.1097/LBR.0000000000000487
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Diffuse parenchymal lung diseases (DPLD) are always among the most popular sessions at any large society meeting, for good reason: proper diagnosis and management of DPLD can be extremely challenging, even for seasoned clinicians. In this context, a procedure that would offer useful histopathologic information at a low risk would be welcomed with open arms. The rise of transbronchial cryobiopsy (TBC) has occurred simply because of a perceived need for an efficient, less-invasive means to obtain diagnostic tissue. With the supposition that TBC is broadly safer than conventional thoracoscopic surgical lung biopsy (SLB), all that remains is to demonstrate its diagnostic noninferiority compared with SLB. In this regard, within the past 5 years, a large number of reports have described the safety and diagnostic benefits of TBC.1–6 Patients now routinely seek out centers that perform TBC.

In this issue, Lentz et al7 describe the TBC experience in a US tertiary academic center. A key strength of the current report is the high proportion of patients (86 of 104, 83%) with a high-resolution computed tomography pattern inconsistent with usual interstitial pneumonia (UIP), exactly the patients who most often challenge clinicians’ diagnostic skills. UIP representing idiopathic pulmonary fibrosis (IPF) was ultimately diagnosed in only 22 of 104 (21%) patients, with a total of 19 different final diagnoses reached. As such, this study spans a wide range of the patients encountered in any interstitial lung disease (ILD) clinic. The authors used a careful and systematic TBC procedure, which may in part account for the extremely low rate of complications in this series. The technique itself was meticulously documented, and accords with a recent expert statement.8

In the United States, there are currently more than 250 board-certified interventional pulmonologists, and several-fold that number performing advanced diagnostic bronchoscopy. It is likely that the number of institutions with routine full-fledged, expert-level, multidisciplinary discussions (MDD) is far fewer. However, the current and previous data both underscore that the benefit of TBC relies largely on the availability of the MDD. In fact, in most tertiary academic centers, alternate diagnoses are commonly given after MDD for patients who had first been evaluated in smaller centers, even after SLB. This fact may relate to greater clinician experience with uncommon diseases and to the use of a systematic multidisciplinary evaluation of complex patients. However, many of the cases evaluated even in the most renowned institutions pose significant diagnostic challenges. With TBC, for the rarer or more diagnostically challenging interstitial diseases, the margin for error will narrow even further as the (histopathologic) field of view shrinks. Coupled with the technical challenges of TBC, we urge circumspection regarding the arms race mentality that is driving its widespread adoption. At the least, individual practitioners should be extremely cautious to assume that the usefulness of TBC will be reproducible in his or her own institution.

Similar to other reports of TBC, in the current study, a large proportion of the patients were diagnosed by attaining an (arbitrary) degree of diagnostic confidence after MDD. Is this an adequate standard on which to base clinical decision-making for individual patients, for use in clinical trials, or for promulgation as standard of care? It is not difficult to argue that diagnostic confidence is an illusory standard: the concept itself is tautological. Any marginal aliquot of further information, especially for those who have preconceived belief in the usefulness of the additional quantum of data, will necessarily improve confidence. It would be interesting to know whether confidence would be increased similarly after a transbronchial forceps biopsy, especially for those diagnoses that rested very often on the clinicoradiologic impression (eg, hypersensitivity pneumonitis (HP) and chronic aspiration). The additional diagnostic certainty obtained by TBC is not ascertainable in the current report. Although it has been observed that diagnostic confidence increased similarly after TBC and SLB,9 the level of confidence is again subject to an identical preconceived observer bias about the utility of the samples. Finally, the fact that the TBC led to a difference in management in the current report is likewise unsurprising, given that it is routine to wait for all the data before deciding on a therapeutic approach.

Having as much information as possible is probably most crucial for non-IPF lung disease. Comparing 7 expert ILD centers, interinstitutional agreement between MDDs was only fair for some of the most common alternative diagnoses, with weighted κ scores of 0.29 and 0.42 for chronic HP and non-specific interstitial pneumonia, respectively.10 Although it can be argued that lack of agreement reflects the absence of a universal gold standard set of diagnostic criteria, these data also underscore the extreme difficulty clinicians often face with non-IPF diagnoses. These other DPLD are increasingly relevant. For example, in India, chronic HP (47%) and connective tissue disease-ILD (14%) were the most common causes of new-onset ILD.11 Unclassifiable ILD, even after a biopsy, constitutes ∼10% to 25% of cases at expert ILD centers, and would never be confidently confirmed by TBC alone.12–15

For most patients with IPF, on the other hand, it seems that historical features, careful assessment for underlying connective tissue disease, and having a possible or definite UIP pattern on high resolution computed tomography are adequate to accurately confer a solid diagnosis. This approach has been validated16 and should substantially alter the population for which any biopsy of DPLD is entertained in future years. It is noteworthy that many of the reported experiences with conventional SLB, the basis for the widely held impression of high complication rates, were mainly driven by nonelective procedures, rapidly progressing ILD, and patients with IPF.17 Compared with other DPLD, IPF patients tend to be older, frailer, and more likely to experience acute exacerbation of ILD. Thus, as the current authors point out, comparing complication rates of TBC with historical series of SLB is fraught with risk of mis-estimation.

Another real possibility arising from the widespread adoption of TBC is the overuse of un-necessary invasive procedures for diagnosis. The experience and range of specialists available in larger interstitial disease centers is difficult to replicate broadly, yet it seems to be important for both the diagnostic process and the outcome.18,19 One key function of expert centers is to avoid testing when inappropriate, including TBC. We suggest that TBC only be entertained after a dedicated MDD suggests it as the best option, on a case-by-case basis.

How do we move forward now? Several pathways seem feasible. An obvious approach is to perform TBC and conventional SLB in the same patients, evaluating pathologic concordance of TBC versus the current gold standard. One claim will be that such an endeavor is unethical, on the grounds that TBC is securely established, warranting its use as a putatively less-risky procedure. In that case, certitude may be in the eye of the beholder. Recalling the rapid adoption of other eminently reasonable strategies such as routine pulmonary artery catheterization in the critically ill and anti-inflammatory treatment of IPF, and also the difficulty in eradicating such practices once established, it is our opinion that a trial of TBC directly compared with SLB is not unwarranted. Lower hanging fruit may perhaps be had by utilizing the MDD. For example, evaluating the durability of diagnoses based on TBC during follow-up, the rate of agreement between various MDD groups for cases utilizing TBC, or the prognostic accuracy of MDD-TBC diagnoses may provide avenues for better confirming the usefulness of TBC.10 Suggestions for a comprehensive registry of TBC cases should be heeded,8 but we recommend it also include baseline and follow-up assessment of the diagnoses reached, not only technical outcomes of the procedure.

Lentz et al7 successfully demonstrate the feasibility of adopting TBC as a reasonably safe outpatient procedure in experienced hands. A careful, systematic protocol and expert operators were probably key aspects of their outcomes. However, it remains unclear whether the current impression of TBC has set up SLB as a type of straw man, easily disparaged. The confluence of expertise in interventional bronchoscopy and in ILD is not routinely portable to most institutions. Moreover, the use of MDD confidence as an acceptable standard for changing patient care seems somewhat tenuous. We advocate further and more rigorous evaluation of TBC before its widespread acceptance as standard of care. In the “me too” stampede to adopt a promising technology, we wonder: is it too late to put the toothpaste back in the tube?


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