Researchers have backed use of transbronchial cryobiopsy as a first step to confirming ILD in patients requiring lung tissue assessment, on results of the first randomised controlled trial to compare two diagnostic strategies head to head.

The multi-centre COLD study compared a step-up strategy – in which patients first underwent cryobiopsy and, if inconclusive, a subsequent surgical lung biopsy (SLB) – to immediate SLB.

In the trial, published in The Lancet Respiratory Medicine (link here), patients were randomised to 1:1 to either diagnostic strategy, and followed up 12 weeks after the initial procedure.

According to the authors, the findings favoured the step-up method as this resulted in a significantly reduced burden on patients and hospital stay while achieving a similar diagnostic yield than a first SLB.

Unexpected chest tube drainage, the primary endpoint, occurred in 11% (of 28) patients in the step-up group, while in the SLB group the chest tube could not be removed within 24 hours in 46%.

“The difference in primary outcome was 35% (11–56%) in favour of the step-up approach (p=0.0058), with a corresponding OR for unexpected chest tube drainage of 0.14 (CI 0·03-0·60),” the authors noted.

Chest tube was not needed in 86% of patients who started with cryobiopsy, and when it was necessary the duration of the procedure was longer in the SLB group, at a median of 30 hours versus 25 hours for the step-up strategy.

“Adjusted for baseline forced vital capacity and the Hb-corrected diffusion capacity of the lungs for carbon monoxide values, the OR of 0.18 (0.04–0.87) was in favour of the step-up approach (p=0.033), according to the paper.

Importantly, the step-up strategy produced a similar diagnostic yield (82% after cryobiopsy and 89% after subsequent SLB) versus SLB alone (88%), but had the advantage that four of five SLBs could be avoided.

Also of note, total in-hospital stay was substantially reduced in the step-up strategy at 1 day versus 5 days for the SLB group, while a significant reduction in serious adverse events was also observed (4% versus 50%, respectively).

“In patients with an undiagnosed ILD in whom the multidisciplinary team advised a lung biopsy for an accurate diagnosis, this study shows that starting with a transbronchial cryobiopsy, followed by an SLB only if the transbronchial cryobiopsy is inconclusive, appears to result in a significant reduction in patient burden,” the authors said.

“Although maintaining a similar high diagnostic yield, patients in the step-up strategy had reduced chest tube drainage, a shorter in-hospital stay, less pain, and fewer serious adverse events compared with immediate SLB.”

However, the authors also noted that while the diagnostic yield of both strategies was similar, it was not possible to establish whether they were “equally close to the true diagnosis”.

“More long-term data including large prospective cohorts are needed, using the final multidisciplinary team diagnosis as the diagnostic endpoint because of the uncertainty of a histopathological diagnosis alone,” they stressed.

Several limitations of the study were also highlighted, including its small sample size of 52 (although it was sufficiently powered for the primary endpoint), and its non-masked nature thus increasing vulnerability to bias.

Also, less than 10% of the final diagnoses were IPF with most determined to be chronic hypersensitivity pneumonitis.

However, results of the COLD study “justify starting with transbronchial cryobiopsy and pursuing additional surgical tissue sampling in the case that transbronchial cryobiopsy is inconclusive for classifying ILD diagnosis”, the authors concluded.