This study has demonstrated that hexagonal pattern can be a useful finding for differentiating fibrotic HP from IPF.
HP is a diffuse interstitial pneumonia caused by immune response to inhaled antigen. Inhaled substances are usually most likely deposited at the level of the respiratory bronchioles, and small particles of 2.5 µm or less reach the alveolar region via diffusion, are phagocytosed by alveolar macrophages, and then enter the lymphatics. The distribution of lymphatic vessels in the lungs is largely divided into two routes. One lymphatic flow follows the bronchovascular bundles to the hilum in the inner layers. The other route starts at the perivenular area in the secondary lobule, runs through the interlobular septa or subpleural lymphatic vessels, and ends at the hilum [15]. In experiments using inhaled antigens, the most frequent site of granuloma formation in response to antigens is from the respiratory bronchioles to the alveolar dusts, as has been reported [16]. The deposition of inhaled substances into the respiratory bronchial habit is thought to be involved in the formation of lobular central lesions, whereas deposition by lymphatic flow is thought to be involved in the fibrosis of the lobular margins, i.e., subpleural and interlobular septal predominance.
Centrilobular nodules, extensive GGO, mosaic attenuation, air trapping, diffuse axial distribution, and upper or mid-lung predominance have been reported as useful HRCT findings for fibrotic HP diagnosis in previous reports [4, 6, 8, 17]. However, these studies differed in patient backgrounds or diagnostic methods, including with or without lung biopsy: some studies included nonfibrotic HP and fibrotic HP and other studies included other ILDs and IPF as control diseases.
The study comparing IPF with bird-related chronic HP that had histological UIP pattern reported that upper or mid-lung predominance and profuse micronodules were reported as key findings in chronic HP diagnosis [8]. The usefulness of the three-density pattern for differentiating fibrotic HP from IPF was reported, but in this study, not all patients underwent SLB [7]. The present study did not include cases with three-density pattern, and no significant difference in the presence of mosaic attenuation was observed between the two groups. This may be because this study included only those cases that required SLB as clinical information and radiological findings did not lead to the diagnosis. This suggests that the hexagonal pattern may be useful for differentiating fibrotic HP from IPF, even without a three-density pattern.
Fibrosis of HP manifesting as irregular reticulation is often visible on HRCT, which appears as thickened interlobular septa [1, 18, 19]. This finding usually correlates with the presence of fibrosis predominantly affecting the periphery of acini and the secondary lobule rather than the septa themselves. The study about HP in North India has reported that septal thickening was observed in nearly 30% of patients [20]. However, patients with IPF or other ILD with UIP pattern also often have irregular interlobular septal thickening [18].
This study proposed that not only the presence of interlobular septal thickening just below the pleura but also the extension of interlobular septal thickening to the inner layers, exhibiting a tortoiseshell-like pattern (hexagonal pattern), may be more characteristics of fibrotic HP than IPF.
In the case presented in Figure 2, the area showing a hexagonal pattern was biopsied, and the hexagonal pattern in the HRCT was thought to correspond to perilobular fibrosis. However, in this study, SLB was not performed at selected sites with hexagonal pattern; thus, the HRCT findings and pathology in all patients enrolled have not been compared in this study. Since hexagonal pattern is a shadow that extends to the inner layers, in some cases, the shadow is found in the inner layers beyond the area that can be sampled by SLB.
Recently, the utility of TBLC has been reported in the diagnosis of diffuse lung disease [21–24]. Cryoprobe-retrieved specimens are larger than those of transbronchial forceps biopsies and less crush. TBLC tends to sample more proximal portion of the lung apart from the pleura compared with SLB. In the future, TBLC and SLB may be useful for comparing the imaging and pathology of the cases with hexagonal pattern in HRCT.
This study has several limitations. First, this was a single-center retrospective study, which may be subjected to various biases. External validation studies are warranted in the future. Second, this study included only patients who underwent SLB. Fibrotic HP and IPF, which can be diagnosed by clinical information, HRCT findings, and histological findings by transbronchial forceps biopsies or TBLC, were not included. However, the problem in clinical practice is the differentiation between IPF and fibrotic HP, which requires SLB. It is noteworthy that in this study, the hexagonal pattern was useful for differentiating between the two diseases, even in cases that the diagnosis could not be made based on clinical and imaging findings. Future studies including a cohort comprising of patients with fibrotic HP diagnosed without SLB should be conducted. Finally, we did not examine whether the hexagonal pattern is useful in differentiating fibrotic HP from diffuse lung diseases other than IPF. In the future, we are planning to compare the HRCT findings of fibrotic HP with other diffuse lung diseases.