Identifying the Risk of Acute Exacerbation in Idiopathic Pulmonary Fibrosis: A Step Forward.

The clinical course of idiopathic pulmonary fibrosis (IPF) is unpredictable (1), characterized in a significant number of patients by episodes of acute deterioration that heavily affects the prognosis of the disease. These events, named “acute exacerbations” (AEs), remain idiopathic in some cases, whereas in others, known risk factors, such as lung surgery, chemotherapy, radiotherapy, or other conditions, including pulmonary embolism, heart failure, and infections, are recognized (2). Nevertheless, the pathogenic mechanisms of AE in IPF remain largely unclear, causing a substantial lack of effective therapeutic approaches. In this issue of the Journal, McElroy and colleagues (pp. 550–562) explore in detail the role of the response to bacterial and viral infections in AE in patients with IPF (3). The starting point of this interesting research is a previous study published by the same authors showing that an SNP of Toll-like receptor 3 (TLR3), Leu412Phe (TLR3 L412F), is associated with a worse prognosis in patients with IPF (4). In the present study, this observation has been extended to establish if the same SNP could affect the response to infections and if that is associated with AE-related death in IPF (AE-IPF). To accomplish this, the authors studied 228 patients with IPF, and 107 of them were either 412F heterozygous or 412F homozygous. Interestingly, they report a significant increase of AE-related deaths in patients with 412F-variant IPF compared with patients with wild-type L412 IPF. The authors hypothesize that the increased risk of AE-related death in patients with 412F-variant IPF was related to some degree of inability to respond to infections. Indeed, they demonstrate that primary human lung fibroblasts, expressing the polymorphism, and derived from patients with IPF, have a reduced host immune response to different TLR pathogen-associated molecular patterns as well as a diminished transcription of IFN-stimulated genes, thus suggesting an impaired response to both bacterial and viral infections. The relevance of this observation is confirmed by a “hierarchical heat map analysis” performed by the authors on nasopharyngeal lavage samples of patients with IPF during AEs. The results of this analysis showed the contemporary presence of viruses and bacteria and, even more interestingly, specific combinations of them, such as influenza virus and Staphylococcus aureus or rhinovirus, respiratory syncytial virus, and Streptococcus pneumoniae. This intriguing observation was also supported by the analysis of bacterial populations in BAL of patients with IPF that revealed a specific bacterial profile, mainly composed of Streptococcus and Staphylococcus spp. in 412F-heterozygous patients as compared with L412 wild-type patients, where the level of Prevotella spp. was instead significantly higher. These data fully support the fascinating hypothesis that the TLR3 L412F polymorphism may alter the regulation of the lung microbiome, facilitating the occurrence of AE in patients with IPF.

On the basis of these results, McElroy and colleagues conclude that the TLR3 L412F polymorphism “is significantly associated with an enhanced risk of death by AE in IPF,” stating that the main reason for this predisposition is related to a weaker antiinfective response due to the modified gene–environment interaction that characterizes patients with 412F IPF (3). The study can be considered a significant step forward in the understanding of some of those pathogenic mechanisms that contribute to explaining the occurrence of AEs in patients with IPF. The general topic of this article is within a very important area of investigation because the identification of the mechanisms behind AEs may help to improve the current therapeutic strategies. Some limitations of the study are also worthy of mention. Even if the total number of patients with IPF was high (n = 228), the number of AEs observed and studied was relatively low (n = 8). Moreover, although not considered as AE-related deaths, a total of 28 patients in the Edinburgh cohort died of pneumonia, and it should be underlined that in the case of pneumonia infections, the presence or not of the polymorphism and its supposed “predisposition” to infection was irrelevant. In the L412 wild-type group, 16 patients died of pneumonia, whereas 11 patients died of the same cause in the group of patients with 412F IPF. In addition, because of the lack of high-quality evidence, AE-IPF treatment can be very heterogeneous, potentially affecting both survival and microbiome balance. Because the use of antibiotics and/or steroids could have affected the microbiological results of the study, it would be important to have more information about the medical treatment of patients with IPF across the different cohorts of patients and, more specifically, if medical treatment was homogeneous in the K.U.M.S. cohort of patients with AE-IPF who had nasopharyngeal lavage samples, in the Brompton cohort of patients who had BAL samples, and obviously among the eight patients who died of AEs in the Edinburgh cohort. Furthermore, upper airway sampling, which according to the literature provides an imperfect but reliable representation of the BAL microbiota (5), was performed during the course of an AE-IPF. In contrast, in BAL, microbiological differences, both in bacterial burden and in bacterial populations, were detected in patients during a stable state. Indeed, it has previously been shown that in AE-IPF, the microbiome is substantially different, with an increased BAL bacterial burden and a shift in the composition of the respiratory microbiota compared with stable disease (6). There is another issue, already raised by the authors, that is worth further discussion. The authors investigated the role of the polymorphism exclusively on primary lung fibroblasts even if the in vivo pathogenic scenario could be much more complex. It is true, as underlined by authors, that fibroblasts are not merely bystander cells, but it is even more evident that airway epithelial cells and alveolar macrophages represent the very first line of defense against infections (7, 8). Both cells recognize and interact with pathogen-associated molecular patterns via a series of receptors, including TLR3, and thus actively participate in the inflammatory response to TLR agonists (9). In perspective, the role of their antiinfective activity should be investigated, possibly looking at the gene–environment interactions suggested in this study.

In conclusion, the results of this study are relevant because they identified for the first time an SNP of TLR3 that could represent a significant risk factor for mortality secondary to AEs in patients with IPF. However, these results need to be validated in larger studies, ideally using a prospective and multicenter design, with the aim to confirm the crucial role of this specific polymorphism in this deadly condition.