Radial Endobronchial Ultrasonography with a Guide Sheath for the Diagnosis of Diffuse Parenchymal Lung Diseases


 Background
Radial-endobronchial ultrasonography (R-EBUS) is a useful bronchoscopic tool for the diagnosis of solitary pulmonary peripheral lesions. However, the utility of R-EBUS for the diagnosis of diffuse parenchymal lung disease (DPLD) remains unclear. This study aimed to examine the characteristics of R-EBUS patterns in association with computed tomography (CT) findings in diagnosing DPLD.

Methods
Transbronchial lung biopsy (TBLB) was performed using R-EBUS and a guide sheath (GS) in consecutive 35 patients with suspected DPLD on chest CT between March–November 2017. Consolidation, ground glass opacity (GGO), reticular, and nodular patterns were diagnosed, and the mean CT Hounsfield units in the sampled area were measured in patients with consolidation. R-EBUS characteristics and their association with CT findings and pathological diagnostic yield were evaluated.

Results
R-EBUS showed a dense pattern only in patients with consolidation, and a blizzard pattern in patients with consolidation, GGO, reticular, and nodular patterns on CT. The biopsied area’s mean CT value was significantly higher in patients with dense than with blizzard patterns (p < 0.0001), and pathological findings were also dense in patients with R-EBUS dense pattern. The pathological diagnostic yield was significantly higher in patients with overt R-EBUS patterns than in patients without R-EBUS patterns by obtaining better lung tissue samples with the GS (p < 0.0001).

Conclusions
Dense and blizzard R-EBUS patterns were novel findings in diagnosing DPLD, and TBLB with R-EBUS-GS may be a valuable tool in diagnosing DPLD

nodules [4] . In contrast to the blizzard and mixed blizzard patterns, in the present study, a dense pattern was defined as a darker and more homogeneous signal with irregularly-distributed mottling and linear hyperechoic areas, reflecting dense lung tissue and cellularity. R-EBUS characteristics in association with CT findings and pathological diagnostic yield were evaluated.

Statistical analysis
Descriptive statistics are presented as frequency, percentage, and median (range). Differences between groups were compared using Student's t-tests and Fisher's exact tests (for categorical variables). Data were analyzed using JMP 9 version 9.0.3 (SAS Institute Inc., Cary, NC, USA).
Differences were considered statistically significant at p < 0.05.

Baseline characteristics
The patient characteristics are shown in Table 1. The cases comprised 35 patients (10 female and 25 male) with a median age of 67 years. Chest CT of the biopsied area showed a reticular pattern in 6, consolidation pattern in 15, GGO pattern in 9, nodular pattern in 2, and no obvious findings in 3 of the 35 patients. Before obtaining lung tissue by bronchoscopy, all patients had suspected DPLD, specifically, IPF, idiopathic nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), unclassified interstitial pneumonia (UCIP) based on the 2013 idiopathic interstitial pneumonias classification [2] , collagen vascular disease associated with interstitial pneumonia, sarcoidosis, hypersensitivity pneumonitis (HP), drug-induced lung disease (DILD), acute eosinophilic pneumonia (AEP), allergic bronchopulmonary aspergillosis (ABPA), or HTLV-1 associated bronchioloalveolar disorder (HABA). Various types of CT findings were observed, and the clinico-radiological diagnosis was heterogeneous in these patients.
[Place Table 1 around here] 3.2 Correlation between chest CT findings and R-EBUS patterns Table 2 shows the correlation between the chest CT findings and R-EBUS patterns. CT findings where R-EBUS and TBLB were performed were evaluated in association with the R-EBUS patterns. All 6 patients with a reticular pattern, 9 with a GGO pattern, and 2 with a nodular pattern in the area of the biopsied lesion on chest CT showed a R-EBUS blizzard pattern. A blizzard pattern was found in 4 patients and a dense pattern in 11 patients with a consolidation pattern. A mixed blizzard pattern was not found in any case. Representative reticular, GGO, consolidation, and nodular patterns on chest CT and blizzard and dense patterns on R-EBUS are shown in Figures 1 and 2, respectively. The dense pattern was a novel R-EBUS pattern in patients with suspected DPLD and it was only observed in patients with a consolidation pattern. Conversely, the blizzard pattern was observed in patients with all types of CT findings.
[Place Table 2 around here]

Correlation between R-EBUS patterns and CT values in patients with consolidation patterns
In patients whose chest CT showed consolidation patterns on CT images, two R-EBUS patterns were found; blizzard and dense patterns. The mean CT value of the biopsied area was evaluated ( Figure 3); it was significantly higher in patients with a dense pattern than in patients with a blizzard pattern (p < 0.0001; Table 3). There was no significant difference in the evaluation area between the 2 groups (p = 0.5780). In the COP patient with consolidation on CT with a dense pattern on R-EBUS, there was organization in the alveoli and lymphocyte infiltration in the alveoli and alveolar wall and the histopathological density was high ( Figure 4). The COP patient with consolidation on CT with a blizzard pattern on R-EBUS had a greater amount of air space in the lung sample in addition to organization and lymphocyte infiltration than had the patient with consolidation and a dense pattern ( Figure 5).
The difference between dense and blizzard patterns depended on the difference in the radiological and pathological density.
[Place Table 3 around here] 3.4 R-EBUS pattern and its diagnostic value 3.4.1 Pathological diagnostic yield EBUS patterns. Therefore, R-EBUS patterns cannot provide specific clinical DPLD diagnosis and prediction of the effect of treatment.
Grade 3 pneumothorax was observed in only 1 case and it resolved with thoracic drainage without surgery. There was no severe hemorrhage and pneumothorax, suggesting that GS had a hemostatic effect via the bronchial wedge and that confirmation of the precise position by R-EBUS reduced the incidence of pneumothorax.
The study has some limitations; it was a retrospective analysis, performed in a single institute. The dense pattern was observed in only patients with consolidation and in most of OP patients; therefore, the usefulness of the dense pattern is unknown in patients other than those with OP with consolidation. Comparisons of pathological density between dense and blizzard R-EBUS patterns using a numerical score could not be performed because there were various types of infiltrated cells and organizations, and there were some crush artifacts in the lung tissues. Furthermore, the sample size in this study was small, and the pathological findings were highly heterogeneous. Lack of surgical lung biopsy limited our ability to evaluate the quality and quantity of the TBLB samples obtained using R-EBUS-GS. Prospective trials assessing the utility of R-EBUS for DPLD management are recommended.
There has been growing interest in transbronchial cryobiopsy, an innovative method of obtaining samples from DPLD patients. R-EBUS could be useful for cryobiopsy similar to TBLB, and thus a multicenter, prospective, clinical trial assessing the safety and utility of cryobiopsy with R-EBUS is currently underway in our hospital in collaboration with other institutions.

Conclusions
In conclusion, this was the first report showing the usefulness of the dense and blizzard patterns of R-EBUS in diagnosing DPLD. The positive R-EBUS patterns when also using a GS with TBLB may enable more precise lung-tissue sample acquisition. Therefore, R-EBUS-GS may be a valuable tool to combine with TBLB in diagnosing DPLD. Data are presented as the number of positive or negative lesions/total lesions (%). R-EBUS: Radialendobronchial ultrasonography  (2) slight inflammation of the alveolar wall and intraalveolar organization