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Original Investigations

Are Transbronchial Cryobiopsies Ready for Prime Time?

A Systematic Review and Meta-Analysis

Sethi, Jaskaran MSc, MD*; Ali, Muhammad S. MSc, MD; Mohananey, Divyanshu MSc, MD; Nanchal, Rahul MSc, MD; Maldonado, Fabien MD§; Musani, Ali MD

Author Information
Journal of Bronchology & Interventional Pulmonology: January 2019 - Volume 26 - Issue 1 - p 22-32
doi: 10.1097/LBR.0000000000000519


Lung biopsies are often required for diagnosing pulmonary diseases. These can be obtained either surgically or bronchoscopically. Currently, transbronchial forceps biopsies (TBFB) are the most common bronchoscopic modality for obtaining tissue specimens in diffuse parenchymal lung diseases (DPLD). However, TBFB are often limited by their small sample size and crush artifacts1 which adversely impact the diagnostic yield. The diagnostic yield for TBFB in DPLD has been reported to be 20% to 30%.2,3 Even though TBFB are relatively safe, due to their low diagnostic yield many patients end up requiring surgical lung biopsies (SLB) to obtain adequate tissue samples.

It is well-known that larger biopsy specimens increase the diagnostic yield.4 SLB allows for the retrieval of significantly larger samples with fewer artifacts and is considered the standard of reference. However, they carry a significant risk of morbidity and mortality. The in-hospital mortality with SLB is around 2%. However, it can be as high as 16% in certain patient populations.5 Therefore, there has been a growing need for novel techniques to improve diagnostic yield with an acceptable safety profile. In the past jumbo forceps were studied, they retrieved larger specimens with fewer crush artifacts but were limited by the need for deep sedation and rigid bronchoscopy.6

Recently, transbronchial cryobiopsies (TBCB) have been used to increase the yield of bronchoscopy for the diagnosis of DPLD. Cryotechnology has been utilized for both therapeutic and diagnostic purposes since the 1970s.7 Cryoprobes utilize the Joules Thomson effect.8 They work by applying cooling agents (eg, carbon dioxide or nitric oxide) under high pressure. As these gases expand due to sudden release to atmospheric pressure, there is a rapid drop in temperature (−80 to −90°C) at the probe tip. Pulmonary tissue firmly adheres to the cold probe tip and is easily extracted when the cryoprobe is withdrawn from the lung.

A number of meta-analyses have previously evaluated the performance of TBCB for diagnosing DPLD.9–14 Unfortunately, these analyses have been limited by the small number of studies included. Moreover, most of these analyses only included published studies and excluded conference abstracts, while failing to report any formal assessment for publication bias. It is a well-established fact that published studies tend to show a greater treatment impact as compared with unpublished studies.15,16 This is probably because authors and reviewers are less likely to publish studies with less significant or negative results.17 Moreover, studies from larger academic centers with greater expertise and more favorable outcomes are more likely to be published. Therefore, only including published studies in a meta-analysis will induce publication bias and potentially lead to an exaggerated assessment of the treatment impact. Many experts have previously warned against this practice.18,19

We have therefore, performed a comprehensive meta-analysis of both published and unpublished studies assessing the performance of TBCB. Our goal is to minimize the risk of publication bias and ensure that the results are generalizable across a large spectrum of clinical settings.


Search Strategy

A comprehensive and systematic search of MEDLINE (PubMed and OVID), EMBASE (Scopus), and Google Scholar was done in August 2017. We used “cryobiopsy” OR “cryoprobe” OR “cryotechnology” AND “diffuse parenchymal lung disease” OR “interstitial lung disease” as search terms to identify relevant studies. Additional studies were identified by reviewing reference lists of the considered articles. Conference abstract books were searched for additional studies that had been presented but not published as manuscripts.

Study Selection

Study selection was independently performed by 2 authors (J.S. and M.S.A.). Studies were initially screened by titles and abstracts. Where possible, full-text review was done for the screened studies to identify studies meeting the following selection criteria: (a) study employed TBCB in patients with DPLD; (b) diagnosis was confirmed either based on characteristic histopathologic findings or after a multidisciplinary team discussion; (c) study described the procedure-related complications or provided adequate data for the calculation of the diagnostic yield. Our exclusion criteria were: (a) case reports or series with <10 patients; (b) studies where TBCB was performed for pulmonary nodules or posttransplant surveillance bronchoscopies; (c) review papers. Non-English studies were also considered if they met the inclusion criteria.

Quality Assessment and Risk of Bias

Quality Assessment, Data Abstraction and Synthesis-2 (QUADAS-2) tool was used to assess the quality of eligible studies for risk of bias and applicability.20 It comprises of 4 main components: patient selection, index test, reference standard and, flow and timing. Signaling questions are used to assess each of these components for risk of bias as low, high or uncertain. Similarly, the first 3 domains are also assessed for concerns about lack of applicability. Two authors (M.A. and D.M.) separately assessed the quality of included studies. Inter-rater agreement between the 2 authors was assessed using the Kappa statistic.

Data Synthesis

Two authors (M.S.A. and J.S.) independently reviewed titles and identified studies from the previously identified sources. They independently reviewed abstracts and manuscripts (for published studies) to select studies meeting the inclusion criteria. Disagreements were settled by consensus, after having a third author weigh in. Following data was collected: study design, type of publication, mean/median age of participants, procedural protocols, final diagnoses, frequency of crush artifacts, mean size of biopsied specimens, type and frequency of complications and mortality data. The primary outcome was the diagnostic yield, which was calculated by dividing the number of successfully diagnosed cases (either based on characteristic histopathologic findings or multidisciplinary team discussion) by the total number of cases. Bleeding severity was classified as mild (resolved with simple suctioning), moderate (required wedging the bronchoscope into the effected segment to create a tamponade), and severe (required additional interventions such as bronchial blockers, topical fibrin sealant, blood transfusions or ICU admission).21 Moderate and severe bleeding episodes were considered significant. Any pneumothorax seen on the postprocedure x-ray was considered significant, whether or not it needed chest tube drainage.

Data Analysis

MedCalc (version 17.2) was used to conduct the meta-analysis. A P-value of <0.05 was considered statistically significant. Inverse variance weighting was used to aggregate diagnostic yield proportions across studies. I2 index was used to assess study heterogeneity and I2 index of >40% was considered to be indicative of significant heterogeneity. If significant heterogeneity was identified, random effects model was utilized for data analysis. Publication bias was assessed using a funnel plot. Begg and Mazumdar, Duval and Tweedie’s trim and fill, and Egger tests were also performed for further assessment of publication bias. These additional tests for publication bias were performed using Comprehensive Meta-analysis software (version 3).


Search and Study Selection

Our search returned 457 titles on initial search across MEDLINE, EMBASE, and other sources. After removing duplicates total 252 titles and abstracts were screened. After initial screening 44 studies (28 published studies, 16 abstracts) were considered for inclusion and full-text review (where applicable). Amongst these 13 studies (10 published studies, 3 abstracts) were excluded. Four studies had overlapping study populations and were excluded to prevent duplication of patients.22–25 Three studies were excluded since they were not deemed to have enough diagnostic or safety data.26–28 Three studies were excluded because they evaluated cryobiopsies for endobronchial lesions, 2 were excluded because they used TBCB for posttransplant surveillance and 1 study was excluded because it used TBCB for diagnosing suspected lung cancer.29–34 A total of 31 studies (18 published, 13 abstracts) were included in the analysis.13,35–64 Included studies were published between February 2009 and August 2017. Four of these studies only provided safety-related data, therefore they were only used while analyzing safety profile.36,51,53,54 Only 1 non-English study was included. It was published by Fournier and colleagues in French. Figure 1 shows the Prisma flow diagram for the meta-analysis. Basic characteristics of the included studies are outlined in Table 1.

PRISMA flow diagram showing summary of literature search and study selection.
Summary of the Basic Study Characteristics

Study Assessment

Application of QUADAS-2 tool showed low risks of bias and lack of applicability in the patient selection and index test domains. Most of the studies did not refer the patients for SLB, therefore these studies had undetermined risks of bias and lack of applicability in the reference standard domain. Details of application of QUADAS-2 tool are summarized in Table 2. Inter-rater agreement between the authors was good, with a Kappa statistic of 0.9 [95% confidence interval (CI), 0.7-1.0]. The funnel plot (Supplementary Fig. 1, Supplemental Digital Content 1, was not asymmetric which reflected the absence of publication bias. Similarly, Begg and Mazumdar, Duval and Tweedie’s trim and fill, and Egger tests also did not suggest publication bias.

Study Quality Assessment by Quality Assessment, Data Abstraction and Synthesis-2 Tool

Diagnostic Yield

Data were pooled from 27 studies, with 1443 patients with DPLD, for the calculation of the diagnostic yield. Between studies the diagnostic yield ranged from 40% to 95.1%. The inverse variance–weighted diagnostic yield for TBCB for the diagnosis of DPLD was 72.9% (95% CI, 67.9%-77.7%). I2 index of 75.4% (95% CI, 64.3-83.0) indicated significant heterogeneity. Figure 2 shows the forest plot for the meta-analysis.

Forest plot: diagnostic yield for transbronchial cryobiopsies.

In order to explore the causes of heterogeneity we performed subgroup analyses. Analyses were separately performed for retrospective and prospective studies, abstracts and full manuscripts. We also analyzed subgroups of prospective studies published as full manuscripts, studies which used only 1.9 mm probes and high-quality studies. High-quality studies were defined as the studies which had a low risk of bias in all 4 domains, that is patient selection, index test, reference standard, and flow and timing. All of these subgroups continued to have high heterogeneity, reflecting that the high over all heterogeneity was unlikely to be related to the differences in study design (retrospective vs. prospective), type of publication (abstract vs. manuscript), the differences in the cryoprobe sizes and the disparity in the study quality as assessed by QUADAS-2 tool. The results of our subgroup analyses are summarized in Table 3.

Results of Subgroup Analyses to Explore the Causes of Heterogeneity

Specimen Area

Specimen area was reported by 9 studies. Two of these studies had previously been excluded to prevent duplication of cases.23,24 Pooled mean specimen size of TBCB specimens was 23.4 mm2 (95% CI, 9.6-37.3 mm2). Significant heterogeneity was observed with I2 index was 87.61%. Forest plot for this meta-analysis is shown in Supplementary Figure 2 (Supplemental Digital Content 2,

Crush Artifacts

Five studies commented on the crush artifacts. Kronborg-White et al44 reported crush artifact in just one sample. Pajares and colleagues reported crush artifacts as the proportion of samples with >75% artifact-free area. In all, 66.6% of the TBCB specimens had a >75% artifact-free area as compared with 31.6% of TBFB specimens (P=0.012).59 Jabbardarjani et al61 reported that the proportion of TBCB specimens with crush artifacts was significantly lower than TBFB specimens; however, it was not mentioned as to how the crush artifacts were quantified. Hernández-González et al55 and Babiak et al64 reported that they did not observe crush artifacts on any of the cryobiopsy specimens.

Complication Rates

The overall complication rate was 23.1%. Most commonly reported complications were bleeding and pneumothoraces. A total of 30 studies reported data regarding the incidence of pneumothorax. The pooled incidence of pneumothoraces was 9.4% (95% CI, 6.7%-12.5%). Supplementary Figure 3 (Supplemental Digital Content 3,, shows the forest plot for this analysis. In contrast, the pooled incidence of significant (moderate and severe) bleeding was 14.2% (95% CI, 7.9%-21.9%). This analysis was based on 27 studies and Supplementary Figure 4 (Supplemental Digital Content 4,, shows the forest plot. A total of 33 studies reported mortality. There was a total of 6 deaths within 30 days of the procedure. Procedural mortality was 0.3%. The details of complications for each of the study are presented in supplementary Table 1 (Supplemental Digital Content 5,

Final Diagnoses

Supplementary Table 2 (Supplemental Digital Content 5,, summarizes the final diagnoses in different studies. There were marked differences in the prevalence of different DPLDs in different studies. This may have contributed to the high overall heterogeneity.


To our knowledge, this is the largest meta-analysis evaluating diagnostic performance and safety of TBCB for the diagnosis of DPLD. The overall, inverse variance–weighted diagnostic yield of 72.9% is higher than TBFB’s previously reported diagnostic yield.2,3 TBFB are often limited by small specimen size and crush artifacts. In our analysis TBCB yielded larger sample sizes [mean area 23.4 mm2 (95% CI, 9.6-37.3 mm2)] when compared with previous reports for TBFB. In addition, less crush artifact and more alveolar tissue was reported with TBCB specimens.

The 72.9% diagnostic yield in our meta-analysis appears to be in line with the diagnostic yields previously reported in other TBCB meta-analyses. Table 4 lists the pooled diagnostic yields from recent TBCB meta-analyses. The pooled complication rates in our meta-analyses are also similar to those reported previously. Table 5 lists the rates of significant bleeding and pneumothoraces from recent meta-analyses. According to American Thoracic Society(ATS)/European Respiratory Society (ERS) guidelines, SLB remains the reference standard.65 However, they are not without risks and are often associated with significant morbidity and mortality. Most recent studies show a 30-day mortality of between 3% and 10.6%, with a greater risk in patients undergoing open lung biopsy.66–68 Because of these risks pursuing bronchoscopic biopsies which are much safer, before SLB is a lucrative option. TBFB are limited in terms of their diagnostic yield (20% to 30%) but have a low rate of complications. The rate of pneumothorax is 0.7% to 2%, while the rate of significant bleeding is 1% to 4%.12,69

Diagnostic Yields From Recent Transbronchial Cryobiopsies Meta-Analyses
Complication Rates From Recent Cryobiopsy Meta-Analyses

On the basis of the results of our meta-analysis TBCB when compared with TBFB, increased the diagnostic yield from 20%-30% to 74.6%. However, there is a significant concomitant increase in the risks of pneumothorax (from 0.7%-2% to 9.4%) and significant bleeding (1-4% to 14.2%). Some of the benefit in terms of the improved diagnostic yield appears to be off set by the marked increase in the risk of complications. Also, there is a concern about the reporting of mortality data. Most of the studies only reported those 30-day deaths which the authors deemed to be related to TBCB. Therefore, the true 30-day postprocedure mortality is likely higher than 0.3% reported in our meta-analysis.

For the above reasons, it is apparent that more research is needed before the TBCB can be more widely adopted in a broad range of clinical settings. We found marked variations in the procedural protocols between studies. Flexible versus rigid bronchoscopy, laryngeal mask airway versus endotracheal tube, use of prophylactic bronchial blockers, the size of the cryoprobes, number of samples taken, contact time of cryoprobe, use of fluoroscopy, etc., are some of the areas where there was significant variation between the studies. Supplementary Table 3 (Supplemental Digital Content 5,, highlights the different procedure protocols followed by different investigators. Perhaps standardizing the procedure will help further increase the diagnostic yield and reduce the complication rates for TBCB. For example, Ravaglia and colleagues prophylactically used Fogarty balloons after each TBCB and no significant bleeding episodes were seen in their study. In contrast, most of the other investigators did not use prophylactic bronchial blockers, which may have led to higher bleeding rates. Other experts have also called on the community of interventional pulmonologists and interstitial lung disease experts, to shoulder the responsibility of formulating a consensus statement, guiding the implementation of TBCB.70

Future Directions

Randomized controlled trials can allow for head to head comparison between SLB, TBFB, and TBCB. Such trials will allow for standardization of the procedure and will also allow to better study the factors that might be associated with higher complications rates. An understanding of these factors can lead to a more informed patient selection which in turn will improve TBCB’s safety profile. Experts have also called for mandatory procedure-specific training for interventional pulmonologists before implementation of TBCB programs and creation of an international registry.70


There are several limitations of our meta-analysis. Firstly, several studies utilized a retrospective study design, which has an inherent potential for bias. Secondly, there was marked heterogeneity amongst the studies. We were unable to definitively find the reasons behind this heterogeneity; however, it may be related to the differences in the procedure protocols, disparities in the expertise of operators and the differences in the prevalence of various DPLDs in different studies. Thirdly, most of the patients who were diagnosed with TBCB did not undergo SLB, which is currently the standard of reference. It is therefore hard to assess if TBCB led to misclassification of some of the DPLD cases. Fourthly, studies did not report the TBCB diagnostic yield for specific DPLDs. It was not possible to assess if TBCB might have a higher yield for certain DPLDs as compared with others. Fifthly, in some circumstances the complication rates reported in our study might be higher than what is considered clinically significant. For example, an episode of bleeding that was controlled by wedging the bronchoscope is considered moderate (and hence significant) in our analysis; however, for some clinicians it may not be of much clinical consequence. Similarly, pneumothoraces which did not require chest tube insertion are considered significant in the current analysis however others may debate their clinical significance. Unfortunately, some studies just reported the significant bleeds without specifying the precise number of moderate and severe bleeds, therefore it is hard to calculate the true incidence of only severe bleeds. Never the less our definition of significant complications which includes both moderate and severe bleeds, and all pneumothoraces regardless of chest tube insertion and duration of air-leak, is in line with most of the available TBCB literature including prior meta-analyses. Sixthly, there is a difference in the definition of significant complications between the bronchoscopy and surgical literature. Therefore, it is hard to directly compare the complication rates of TBCB with SLB. As a result, we have relied on the mortality outcomes to compare the two. Lastly, 13 studies in our meta-analysis were conference abstracts. For some these studies assessing the study quality was hard, based on the limited information available in the published abstract.


Our meta-analysis shows that TBCB has a good diagnostic yield but at the cost of a significant risk of complications. These results are in line with the prior meta-analyses on this topic even though we included a higher number of studies. Our meta-analysis yet again highlights the marked heterogeneity in the procedural techniques at different centers. Randomized controlled trials comparing SLB, TBFB and TBCB are needed before more definitive recommendations can be made regarding TBCB’s place in DPLD’s diagnostic algorithm. Convening experts, offering procedure-specific training and forming an international registry are some of the other ways to standardize the procedure and improve its safety profile. Until then it is important that patients are carefully selected and the procedure is performed at centers with considerable experience.


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cryobiopsy; diffuse parenchymal lung diseases; bronchoscopy; transbronchial cryobiopsy; meta-analysis

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