IRD-ILD has increasingly become the focus of clinical and scientific considerations in recent years, also in the light of new available therapeutic options.
To the best of our knowledge, the present study is the first to evaluate HRCT and immunological BAL patterns in a population of newly diagnosed, immunosuppressive-naïve patients with IRD- ILD.
HRCT is currently the gold standard for the detection of IRD-ILD [4–6]. Typical HRCT patterns in IRD-ILD include GGO, NSIP, and UIP. In the literature, GGO has been described as being associated with alveolitis [11], whereas NSIP and UIP patterns are the main HRCT features in pulmonary fibrosis [12, 13].
In the first step of our investigation, the HRCT patterns were assigned to the different IRDs. The data showed that the HRCT patterns of GGO, NSIP, and UIP are not specific for a disease entity of IRD-ILD.
In a second step, we evaluated the IRD-ILD and HRCT patterns taking into account the results of the immunological BAL classified according to the ATS criteria. The lymphocytic cellular BAL pattern was most commonly associated with GGO, and the neutrophilic and lymphocytic cellular BAL findings with NSIP and UIP patterns, respectively.
For the total study cohort, the main HRCT patterns were NSIP (43.6%), GGO (34.5%), and UIP (16.4%), whereas no HRCT pattern was specific for any IRD subtype at the time of the diagnosis. Oliveira et al. reported 60% NSIP and 36% UIP as dominant HRCT pattern [14] with a mean duration of IRD of nine years [15]. In our study, only patients with the initial diagnosis of IRD were included, who were diagnosed with lung involvement by comprehensive screening according to the algorithm developed by Hoffmann et al. [2]. Therefore, at the time of the initial diagnosis of IRD with ILD, a different distribution of HRCT patterns with GGO predominating was found. This observation is supported by data from Shah et al., who also demonstrated GGO as the most common HRCT pattern (66%) at initial diagnosis of ILD in patients with SSc [16]. When HRCT is performed at a very early stage or at the initial diagnosis of IRD, GGO is the predominant primary HRCT pattern. As ILD progresses, fibrotic HRCT changes with the NSIP and UIP patterns come to the fore [17].
Given the described changes in HRCT patterns over time from GGO to fibrotic patterns such as NSIP and UIP, it is of great interest how the HRCT patterns can be classified in relation to immunological BAL. It is generally accepted, that this technique can be used for diagnosing lung diseases and various ILD such as sarcoidosis [5, 18–20]. Our study results demonstrated that this cannot be transferred to IRD, as no BAL pattern was specific for IRD. Therefore, the immunological BAL is not an appropriate technique for diagnosing IRD.
However, we revealed in our study in patients at the onset of IRD and signs of ILD other clinically relevant findings such as a predominantly inflammatory cellular pattern with increased lymphocytes and neutrophils in the BAL differential cell profile in patients with GGO on HRCT. Orlandi et al. described the association of a lymphocytic cellular pattern with inflammatory alveolitis [20]. It is possible that this disease represents the starting point of IRD-ILD which, if left untreated, progresses longitudinally to fibrosis [21] and can subsequently be classified as NSIP and UIP patterns on HRCT.
Furthermore, in the NSIP pattern, interstitial inflammation can be detected histologically in addition to fibrosis [15, 22]. This explains our finding of a combined neutrophilic and lymphocytic cellular pattern (both 34.3%) in the immunological BAL. This is corroborated by the data of an older study by Silver et al. in patients wit SSc showing that the presence of neutrophils was associated with more advanced radiographic features of interstitial fibrosis in patients with disease of more than one year's duration [21].
The results of our study have relevant therapeutic implications. In patients with initially diagnosed IRD and ILD, inflammatory changes in the lung dominate, represented by GGO on HRCT and the lymphocytic cellular pattern on immunological BAL. The treatment of choice should therefore be anti-inflammatory drugs, as ILD-patients with a BAL lymphocytosis showed a good response to anti-inflammatory treatment with glucocorticoids or in combination with immunosuppressive drugs (e.g., azathioprine, cyclosporine A, tacrolimus or cyclophosphamide) [23]. In the case of NSIP or UIP on HRCT, a lymphocytic and neutrophilic cell pattern can be detected in the immunological BAL. This suggests a fibrotic component in addition to the inflammation. As a result, a combined anti-inflammatory and anti-fibrotic therapy should be initiated in these patients [24–27].
A limitation of our investigation is the descriptive nature of the data. However, our study includes one of the largest cohorts of patients with ILD at the time of initial diagnosis of IRD who were not receiving immunosuppressive therapy. Therefore, our findings provide insights into the cellular immunological processes in IRD-ILD, which may have direct implications for the treatment of pulmonary involvement in patients with IRD.