In the present study, the most common alterations in chest CT scan of GL-ILD patients (observed in more than 50% of cases) were bronchiectasis (commonly central and of low severity), small nodules (usually randomly distributed) (Fig. 2), consolidations (Fig. 3), GGO, parenchymal bands and enlarged mediastinal lymphnodes. At variance, previous works reported consolidations and GGO as less usual findings[13, 28]. In our opinion, this difference could be related to different phases of the disease and/or enrollment criteria for CT evaluation: in our study, the low frequency of fibrotic ILD (Fig. 4) compared to consolidation and GGO, suggests that these latter were usually sustained by early-inflammatory disease, while features of fibrotic ILD may be expression of an end-stage ILD. We also observed that reticulations and fibrotic ILD were associated with a reduction of FEV1%, FVC%, TLC% and DLCO% predicted, as observed in pulmonary fibrosis[29, 30]: the high proportion of patients with reticulation that had also features of fibrotic ILD could justify the results. Alternatively, reticulations might also be the expression of tiny fibrosis in absence of traction bronchiectasis and parenchymal distortions. Consolidations and GGO were commonly found as associated in our cohort, with no obvious signs of infections. Notably, presence of consolidations were the only almost significantly increased CT item reported in patients subsequently treated for GL-ILD.
GL-ILD was usually predominant at lower fields (Fig. 2), confirming that lung bases are the most involved parts, as firstly observed by Torigian et al.[21], in few patients, and confirmed by Pac et al.[20], in a small cohort of subjects with primary immunodeficiency, mostly CVID. Moreover, considering the chronic evolutions of ILDs, the observation that reticulations and fibrotic ILD were significantly more frequent in lower fields raises the hypothesis that lung bases are firstly involved in a temporal perspective, too.
Another interesting finding regards the distribution of nodules. Radiologically, nodules that are centered in the secondary lobule without contact with pleural, peri-bronchovascular surfaces or interlobular septa may be described as a centrilobular pattern, usually sustained by a bronchiolar spread of inflammation. Conversely, if nodules are predominantly located along pleural, septal or peri-bronchovascular surfaces, they are more likely peri-lymphatic. Lastly, if they are uniformly distributed without any predominance, a random pattern may be defined, usually considered a manifestation of hematogenous metastatic or infective spread[31]. In our study, nodules were usually non-perylymphatic. This result was partially unexpected, since a perilymphatic distribution is the hallmark of lung diseases involving the lymphatic structures and was also described in some small cohort of patients with CVID or primary antibody deficiencies[20, 21]. However, in our opinion, in CVID patients, small inhaled antigens could determine a peribronchiolar reaction with an increase in centrilobular nodules, justifying the CT appearance.
Therefore, a predominant lower field involvement and a predominant non-perylimphatic nodules distribution may be helpful in differential diagnosis, in particular with sarcoidosis, typically involving the middle-upper fields with perylimphatic nodules[5]. Moreover, in sarcoidosis, bronchiectasis are part of the fibrotic manifestation as traction bronchiectasis[18]. In our patients, fibrotic ILD was a way less common than bronchiectasis: this suggests that, in GL-ILD, bronchiectasis may be observed as a “pure” finding (Fig. 6) rather than secondary to fibrotic ILD. In line with this hypothesis, we did not find a relationship between bronchiectasis and DLCO reduction[30]; non-traction bronchiectasis may thus be not a specific feature of GL-ILD, but the result of chronic airways damage[1]. However, the possible coexistence of a non-traction bronchiectasis pattern with ILD might at least raise a suspicion of an underlying immunodeficiency, suggesting that characterization of both airways and parenchymal disease may be useful to identify GL-ILD. Lastly, although enlarged lymphnodes may be observed in both affections (Fig. 5), we found no mediastinal lymphnodes calcifications, a finding that might instead suggest sarcoidosis rather than GL-ILD[18]. Other potential concerns for differential diagnosis are represented by consolidations, tree in bud appearance, bronchial wall thickening and mucous plugs, all possible signs of infections but that may also be part of the GL-ILD picture. Similarly, we often observed a halo sign surrounding solid lung nodules, that may be a manifestation of both organizing pneumonia and some types of infections, i.e opportunistic infection as invasive aspergillosis[23]. However, we did not observe cavitation/necrosis, a CT finding that could instead support the hypothesis of a superimposed infective pneumonia[1, 19]. Another challenging differential diagnosis may be represented by lung lymphomas, in this at-risk population; unfortunately lymphomas have a polymorphic appearance[17] and we are not aware of any feature for a confident CT differential diagnosis.
Together with the above mentioned altered lung function parameters, we also identified some peculiar immunological features related to the CT abnormalities. As already reported, low IgA and IgG are associated with GL-ILD diagnosis[9], and low IgA are described also in CVID patients with bronchiectasis[3, 32]. Thus, it was not surprising to find a correlation between some radiological items (namely fibrosis, GGO and bronchiectasis) and low immunoglobulin levels in our cohort. On the contrary, the association of low white blood cells count and higher CD4 + T cells in peripheral blood with GGO, may reflect a GL-ILD-related perturbation in leukocytes trafficking, with preferential accumulation of CD4 + T cells in the lungs airways[33] and parenchima[34], and possible expansion of memory CD4 + T cells differentiated towards a CXCR3 + CCR6- Th1 phenotype[35].
We then focused on identifying the relevant factors, available at the time of the first GL-ILD radiological suspicion, possibly related with the likelihood of subsequent GL-ILD specific treatment. In literature, we found no similar approaches regarding this specific topic, as the available studies focus mainly on longitudinal evaluation of pulmonary function tests prior to GL-ILD treatment, in order to define progressive. A recent study[9] also reported the performance of a CT scoring system in predicting progressive vs stable disease, which is, in our knowledge, the only attempt made to identify radiological elements related to GL-ILD worsening. At present, even though no guidelines exist providing specific indication for the initiation of immunosuppressive treatment in GL-ILD, it is accepted that immunosuppression is required in patients with deteriorating pulmonary function, and/or with relevant symptoms and/or with worsening radiological abnormalities36. We thus considered our CT findings, clinical and immunological parameters, finally identifying a small number of immunological and radiological variables functional to obtain a better model performance to possibly foresee the need for a specific GL-ILD therapy even without evidence of radiological progression or decline of lung function parameters. As radiological parameters, we selected the presence of parenchymal consolidations, that was superior to any basal lung function parameter in increasing the model performance for GL-ILD treatment prediction, and mediastinal lymphnodes enlargement, which may provide not only evidence of active GL-ILD, but are also useful and easy-to-detect elements for evaluating treatment response[36]. In terms of immunological variables, we included in our model serum IgA levels at CVID diagnosis and circulating MZ B cells at the time of the CT scan. MZ B cells are functionally considered both a first line defense, especially against encapsulated bacteria, and a housekeeping B cellular subset, because of self-antigen and foreing-antigen clearance activity (through their poly-reactive B cell receptors) and secretion of natural IgM antibodies. Given the intrinsic auto reactivity and high sensitivity to stimulation through Toll-like receptors, MZ B cells compartment is tightly regulated, and currently available evidence suggests it may be implicated in human autoimmunity[37]. Furthermore, extra splenic MZ B cells can localize in tertiary lymphoid structures, including ectopic germinal centers, that are often formed in target tissues of autoimmune processes38 and, interestingly, have also been described in GL-ILD[34]. In this environment, MZ B cells can favor antigen delivery to ectopic germinal centers[39] and/or directly present antigens to T cells[40]. Such peculiar migration may explain our finding of reduced circulating MZ B cells in patients with active GL-ILD. On the contrary, CD21low B cells have been found to be expanded in CVID patients with immune dysregulation (and to correlate with GL-ILD diagnosis), probably because of the strong T cell-derived IFN-gamma environment in blood and secondary lymphoid organs[35]. Accordingly, in our study, radiological signs of active lung inflammation (like GGO) and GL-ILD treatment itself correlated with increased CD4 + T cells percentage and CD21 low B cells expansion, respectively. However, we decided not to include CD21low expansion in the multivariate model for predicting the treatment of GL-ILD in order to minimize the number of variables entered and because its elimination resulted in a minimal loss of the explained variance. These results need further confirmation; however, in addition to the already known relevance of CD21low, MZ B cells could in the future gain importance if studied ad hoc to verify their prognostic impact on the need for treatment.
Lung function parameters were not found helpful in improving the model performance; this is possibly due to the single measurement at the time of CT scan, with no possibility to evaluate decline, and/or to the potentially earlier evaluation compared to other studies.
Our study presents some limitations. Firstly, being this a retrospective study, all the laboratory and pulmonary function tests, as well as CT parameters, were performed in different centers without a previous definition of shared protocols/settings. Then, most of the CT alterations were not assessed with a quantitative or semiquantitative score, that may be useful to better define, for instance, the prevalence of alterations between upper and lower fields. Moreover, to confirm the usefulness of the provided elements for a differential diagnosis, a comparison with patients with the other aforementioned diseases is needed. Finally, because the present study was not designed to specifically investigate the impact of the different B cell subpopulations on the physiopathology of GL-ILD, further studies are needed to specifically address these findings.