In this retrospective analysis of 249 patients with an immune alveolitis profile on BAL, the main five ILD’s etiologies were Pneumocystis pneumonia (24%), followed by DILD (20%), viral pneumonia (14%), HP (10%) and granulomatosis (10%). Immunocompromised patients represented 65% of the overall population. In this subgroup, the most frequent diagnosis was by far PCP and HP diagnosis was retained in only two cases.
To the best of our knowledge, the diagnostic contribution of the immune alveolitis morphological profile has not been previously described in patients with PCP. However, lymphocytic alveolitis is commonly reported in PCP and prognosis relating to BAL cellular analysis has been evaluated (17). Lymphocytosis was found with an average rate of 31% in 166 non-HIV infected patients with PCP (18), which is consistent with our results. In addition, BAL cell type profile seems to have a prognostic value. In non-HIV infected patients, Lee et al. evaluated the prognosis impact of BAL cell profile in PCP. Alveolar lymphocytes appeared to be lower in patients with severe PCP compared to those with mild and moderate disease (18). Recently, Gaborit et al. analyzed prognostic factors in immunocompromised patients with Pneumocystis pneumonia (19). The presence of an immune alveolitis profile on BAL was an independent protective factor for mortality at 90 days. Based on these observations, additional investigations to evaluate the prognostic contribution of this profile in other ILDs are warranted.
Immune alveolitis profile on BAL has been yet poorly explored. It is usually considered as an immuno-allergic profile, which refers to the pathophysiology that was mainly described in HP during the 90’s (14–16). Recent ATS/ERS guidelines focus on lymphocyte counts and recommend to obtain BAL fluid in cases with suggestive diagnosis of non-fibrotic HP (20). Even though a 40% lymphocyte threshold has been identified as an important item for the diagnosis of HP (21), ATS/ERS guidelines do not set a lymphocyte threshold. Furthermore, immune alveolitis profile has not been detailed but could provide an additional value in distinguishing HP from others ILD related entities.
Many heterogeneous BAL cytological features can be associated with pulmonary drug toxicity and hamper BAL contribution in the diagnostic approach of DILD (22), Morphological description of BAL cells had focused on intra alveolar foamy macrophages in amiodarone pneumonitis (23). Apart from amiodarone (implicated in only 6% of DILD in our series), drugs that were the most frequently involved in our study were everolimus, followed by nivolumab and methotrexate.
The cytological profile of BAL has been well described in sarcoidosis and is characterized by a rather moderate lymphocytic alveolitis (about 30%) that may reach higher levels (50%) when the disease is active (24). The significant proportion of granulomatosis associated with an immune alveolitis profile, and especially sarcoidosis, is an unexpected result of our study. In some patients with a past history of sarcoidosis, immune alveolitis was found in a context of disease recurrence, leading to a resumption of immunosuppressive therapies. In view of these findings, immune alveolitis would be more likely present in the early and active phases of the disease.
Ten percent of the population did not have a definite etiological diagnosis at the end of data collection, which highlights the difficulty associated to the ILD diagnostic work-up. BAL is a recognized diagnostic tool to investigate ILD (9). When BAL is interpreted in combination with clinical data and HRCT findings, it holds a great potential in establishing ILD’s etiology. Validation of a new BAL morphological pattern will hopefully aim to reduce ILD differential diagnoses and limit the need for surgical lung biopsy. Indeed, the 5 most common diagnoses accounted for nearly 80% of the final etiologies in our study. In addition, when the immunocompromised status was considered, the main final etiologies were reduced to three: PCP, DILD and viral pneumonia.
Results from univariate analysis highlight clinical, radiological or biological factors that can help in the diagnostic process and consequently that need to be sought. For example, fever or the absence of extra thoracic signs seem indicative factors to reduce ILD etiologies, while corticosteroids use appears to be negatively associated with HP.
Our study had some limitations. Its retrospective design led to missing data, especially regarding the search for different antibodies (e.g., anti-nuclear, or serum precipitins). Another study limitation was a potential selection bias related to its monocentricity. Indeed, our tertiary hospital is a reference center for kidney, heart, lung and bone marrow transplants. As a consequence, 65% of our population was immunocompromised. This parameter had obviously an impact on the frequency of final etiologies, especially for PCP.