Filippo Gozzi

Background: The hemoglobin-to-red cell distribution width ratio (HRR) is a composite hematologic biomarker that integrates oxygen-carrying capacity and inflammation-related erythrocyte variability. Its prognostic value in idiopathic pulmonary fibrosis (IPF), and its relationship with right ventricular (RV) function, have not been established. Methods: We conducted a single-center retrospective study of 198 patients with IPF. A total of 165 patients with baseline hemoglobin, red cell distribution width (RDW) and date of diagnosis available constituted the analytical cohort. An HRR cutoff (≤0.86) was derived by time-dependent Receiver Operating Characteristic (ROC) curve analysis at 5 years. All-cause mortality from diagnosis was assessed by Kaplan–Meier and Cox regression, with bootstrap internal validation. Associations between hematologic markers and TAPSE (Tricuspid Annular Plane Systolic Excursion), PAPs (pulmonary arterial systolic pressure) and TAPSE/PASP were examined by linear and logistic regression, followed by joint stratification of HRR and RV–PA coupling. Results: Over a median follow-up of 70.3 months, 57 patients (34.5%) died. Low HRR was associated with higher mortality (72.7% vs. 15.5%; adjusted HR 3.07, 95% CI 1.68–5.63; optimism-corrected HR 2.37) and improved a clinical model beyond RDW (likelihood-ratio p = 0.012). HRR was not associated with TAPSE, PAPs, TAPSE/PASP or RV–PA uncoupling. In exploratory joint stratification, mortality rose from 11.7% with both markers preserved to 100% with both abnormal (age-adjusted HR 6.47, 95% CI 2.64–15.86). At 5 years, HRR and RDW showed similar discrimination (time-dependent AUC 0.70 and 0.71), higher than TAPSE/PASP (0.61). Conclusions: HRR is a simple, inexpensive and independent predictor of mortality in IPF that is unrelated to RV–PA coupling. The two markers provide complementary prognostic information, and their combination identifies a subgroup at very high risk. These findings require external validation.

Background: Generic formulations of pirfenidone are increasingly adopted in idiopathic pulmonary fibrosis (IPF), yet real-world evidence supporting their clinical equivalence to the originator remains limited. We aimed to evaluate whether switching from branded pirfenidone (Esbriet ^® ) to a generic formulation affects treatment efficacy or tolerability. Methods: We conducted a retrospective, within-patient observational study including consecutive patients with IPF treated with Esbriet ^® for ≥ 6 months before switching to generic pirfenidone. Pulmonary function was assessed at three time points: 6 months before the switch (T − 6), at switch (T0), and 6 months after (T + 6). The primary endpoint was the within-patient percentage change in FVC over two consecutive 6-month periods (T − 6 → T0 vs T0 → T + 6), analysed within a pre-specified equivalence framework (± 5 percentage points). Secondary endpoints included DLCO changes and treatment-related adverse events (AEs), analysed at the patient level using paired comparisons. Results: Sixty-five patients (median age 77.0 years [72.3–80.0] years, 78% male) had complete functional follow-up. The mean percentage decline in FVC was − 1.9% before the switch and − 1.7% after the switch. The estimated between-period difference in FVC change was 0.2 percentage points (95% CI − 1.1 to 1.5), fully contained within the pre-specified equivalence margins. Similar findings were observed for DLCO, with no significant difference between periods. Overall, 43% of patients experienced at least one AE during treatment. Gastrointestinal AEs were the most frequent, but paired analyses showed no significant difference in patient-level AE occurrence between branded and generic periods. No severe AEs or treatment discontinuations were observed. Conclusions: In this real-world cohort of patients with IPF, switching from branded to generic pirfenidone was not associated with clinically meaningful differences in lung function decline or treatment tolerability.

Background: idiopathic pulmonary fibrosis (IPF) causes progressive and irreversible changes in the lung parenchyma, leading to respiratory failure. Its pathogenesis involves several damage/repair mechanisms leading to fibrosis, whilst alterations of genes implicated in these processes contribute to the development of the disease. At present, next-generation sequencing (NGS) analyses investigate single-nucleotide or small indel variants, and no evaluation of genomic rearrangements has been so far reported. Methods: In order to identify predisposing variants, we analyzed—both by NGS and by comparative genomic hybridization/single-nucleotide polymorphism (CGH-SNP array) array—37 patients with a diagnosis of familial pulmonary fibrosis. Results: a total of 17 patients (46%) harbored copy number variations (CNVs), 10 (27%) did not harbor any CNVs, 5 (13.5%) showed a mosaic deletion of the Y chromosome, and 5 (13.5%) showed a run of homozygosity (ROH). NGS identified causative variants (including a novel one) in five patients (5/37, 13.5%) and confirmed the high prevalence of MUC5B promoter polymorphism rs35705950, including the detection of a previously unreported form in IPF SNP (indicated as “novel” in the main text), rs141420125 (23/37; 62%). Conclusions: CGH-SNP array identified CNVs containing genes involved in mechanisms (i.e., oxidative stress, mitophagy, NF-Kb pathway) that have been shown to play a role in the pathogenesis of IPF. Therefore, the application of CGH-SNP array or other quantitative tests should be considered in the diagnostic setup of these patients

Background: Sarcoidosis is a multisystem inflammatory disease characterized by the immune-mediated formation of non-necrotizing epithelioid granulomas. Several commonly used medications can induce similar granulomatous reactions, known as drug-induced sarcoid-like reactions (DISRs), which closely mimic sarcoidosis. Despite their specificity in targeting molecular pathways, certain therapies—particularly targeted treatments—have increasingly been linked to DISRs. Methods: This narrative review was based on a PubMed search using the terms “SARCOID LIKE REACTION” and “DRUG”. A cross-check was performed with “SARCOID” combined with each identified drug to identify misclassified cases. Drugs with limited evidence or weak pathogenetic plausibility were excluded, leaving only molecularly targeted therapies for consideration. Sources included case reports, case series, and reviews selected based on their clinical and scientific relevance, without any restrictions on time or language. Results: In light of the available data, five main pharmacological groups were found to be associated to DISR: immune checkpoint inhibitors, TNF-α antagonists, BRAF inhibitors, monoclonal antibodies, and miscellaneous agents. Each group has distinct mechanisms of action and clinical indications, which likely affect the frequency, presentation, and timing of DISRs. Conclusions: Diagnosing DISRs is challenging, and a structured approach is crucial for differentiating them from other conditions. To support clinicians, we propose a diagnostic algorithm to guide decision-making in suspected cases. Management should be individualized, as most DISRs either resolve spontaneously or improve after the discontinuation of the causative drug. Important factors influencing therapeutic decisions include the severity of the underlying disease, the availability of alternative treatments, and the extent of DISR manifestations.

In recent years, several studies have examined the impact of sleep-disordered breathing (SBD) on the quality of life and prognosis of patients with idiopathic pulmonary fibrosis (IPF). Among these disorders, obstructive sleep apnea (OSA) and nocturnal hypoxemia (NH) are the most prevalent and extensively studied, whereas central sleep apnea (CSA) has only been documented in recent research. The mechanisms underlying the relationship between IPF and SBDs are complex and remain an area of active investigation. Despite growing recognition of SBDs in IPF, no standardized guidelines exist for their management and treatment, particularly in a population characterized by distinct structural pulmonary abnormalities. This review outlines the pathophysiological connections between sleep-breathing disorders (SBDs) and idiopathic pulmonary fibrosis (IPF), as well as current therapeutic options. A comprehensive literature search using PubMed identified relevant studies, confirming the efficacy of CPAP in treating severe OSA and CSA. While high-flow oxygen therapy has not been validated in this patient cohort, it may offer a potential solution for select patients, particularly the elderly and those with low compliance. Conventional oxygen therapy, however, is limited to cases of isolated nocturnal hypoxemia or mild central sleep apnea.

Recent advances in genetics and epigenetics have provided critical insights into the pathogenesis of both idiopathic and non-idiopathic interstitial lung diseases (ILDs). Mutations in telomere-related genes and surfactant proteins have been linked to familial pulmonary fibrosis, while variants in MUC5B and TOLLIP increase the risk of ILD, including idiopathic pulmonary fibrosis and rheumatoid arthritis-associated ILD. Epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs such as miR-21 and miR-29, regulate fibrotic pathways, influencing disease onset and progression. Although no standardized genetic panel for ILD exists, understanding the interplay of genetic mutations and epigenetic alterations could aid in the development of personalized therapeutic approaches. This review highlights the genetic and epigenetic factors driving ILD, emphasizing their potential for refining diagnosis and treatment.

Background: Chronic Eosinophilic pneumonia (CEP) is an idiopathic condition characterized by an abnormal accumulation of eosinophils in the lungs. The diagnosis is based on clinical, radiological findings and the presence of elevated eosinophils in BAL and in peripheral blood. Most patients are middle aged, approximatly 60% have asthma and respond rapidly to high corticosteroids doses. The disease tends to recur frequently after discontinuation of steroid treatment (75%), thus requiring chronic corticosteroid therapy or immunosuppresants. Objective: To administer Benralizumab, a monoclonal antibody against IL5-receptor, who determines a significant depleting in eosinophils as efficacy therapy in CEP. Methods: We enrolled 8 patients with CEP referring to the Rare Lung Disease Unit of Modena. At the discontinuation of corticosteroid therapy and worsening of respiratory symptoms we diagnosed asthma with bronchial reversibility on pulmonary function tests, therefore, considering an increasing level of blood eosinophils we could administer Benralizumab. We collected data about radiology, symptoms and blood tests. Results: After the administration of Benralizumab the patients showed a clinical and radiological improvement and normalization of blood tests (eosinophils, PCR), that allowed the discontinuation of corticosteroids with no side effects. Conclusions: In these cases of CEP, we tried to establish a diagnosis of severe asthma in order to permit the administration of eosinophil-depleting therapy. Considering the frequent relapses of CEP, the important side effects of corticosteroid and immunosuppressive long term therapy, Benralizumab could be a valid alternative therapy in CEP patients.

Background: The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer development. HOXB7, a member of the homeobox (Hox) gene family, has been found involved in various cancers. Methods: Immunohistochemical (IHC) analysis was run on lung tissue samples from surgical lung biopsy (SLB) of 19 patients with IPF, retrospectively selected from the IPF database of the University Hospital of Modena. HOXB7 expression was analyzed and compared with that of five patients with no evidence of pulmonary fibrosis as controls. Results: The semi-quantitative analysis of IHC showed that HOXB7 protein expression was higher in IPF patients compared to controls (difference between means = 6.2 ± 2.37, p = 0.0157). Further, HOXB7 expression was higher in IPF patients with a higher extent of fibrosis (50–75%)—measured with high-resolution computer tomography—compared to those with a lower extent (0–25%) (difference between means = 25.74 ± 6.72, p = 0.004). Conclusions: The expression of HOXB7 is higher in the lung of IPF patients compared to controls, and was represented in different cellular compartments within the lung niche. Further investigations are needed to clarify its role in the pathogenesis and progression of IPF.

Background: Although patients with interstitial pneumonia pattern (ILD-UIP) and acute exacerbation (AE) leading to severe acute respiratory failure may require invasive mechanical ventilation (MV), physiological data on lung mechanics during MV are lacking. We aimed at describing the physiological effect of lung-protective ventilation in patients with AE-ILD-UIP compared with primary ARDS. Methods: Partitioned lung and chest wall mechanics were assessed in a series of AE-ILD-UIP patients matched 1:1 with primary ARDS as controls (based on BMI and PaO₂/FiO₂ ratio). Three PEEP levels (zero = ZEEP, 4–8 cmH₂O = PEEP_LOW, and titrated to achieve positive end-expiratory transpulmonary pressure P_L,EE = PEEP_TITRATED) were used for measurements. Results: Ten AE-ILD-UIP patients and 10 matched ARDS were included. In AE-ILD-UIP median P_L,EE at ZEEP was − 4.3 [− 7.6– − 2.3] cmH₂O and lung elastance (E_L) 44 [40–51] cmH₂O/L. At PEEP_LOW, P_L,EE remained negative and E_L did not change (p = 0.995) versus ZEEP. At PEEP_TITRATED, P_L,EE increased to 0.8 [0.3–1.5] cmH₂O and E_L to 49 [43–59] (p = 0.004 and p < 0.001 compared to ZEEP and PEEP_LOW, respectively). ΔP_L decreased at PEEP_LOW (p = 0.018) and increased at PEEP_TITRATED (p = 0.003). In matched ARDS control PEEP titration to obtain a positive P_L,EE did not result in significant changes in E_L and ΔP_L. Conclusions: In mechanically ventilated AE-ILD-UIP patients, differently than in patients with primary ARDS, PEEP titrated to obtain a positive P_L,EE significantly worsened lung mechanics.

Background: Excessive inspiratory effort could translate into self-inflicted lung injury, thus worsening clinical outcomes of spontaneously breathing patients with acute respiratory failure (ARF). Although esophageal manometry is a reliable method to estimate the magnitude of inspiratory effort, procedural issues significantly limit its use in daily clinical practice. The aim of this study is to describe the correlation between esophageal pressure swings (ΔP_es) and nasal (ΔP_nos) as a potential measure of inspiratory effort in spontaneously breathing patients with de novo ARF. Methods: From January 1, 2021, to September 1, 2021, 61 consecutive patients with ARF (83.6% related to COVID-19) admitted to the Respiratory Intensive Care Unit (RICU) of the University Hospital of Modena (Italy) and candidate to escalation of non-invasive respiratory support (NRS) were enrolled. Clinical features and tidal changes in esophageal and nasal pressure were recorded on admission and 24 h after starting NRS. Correlation between ΔP_es and ΔP_nos served as primary outcome. The effect of ΔP_nos measurements on respiratory rate and ΔP_es was also assessed. Results: ΔP_es and ΔP_nos were strongly correlated at admission (R² = 0.88, p < 0.001) and 24 h apart (R² = 0.94, p < 0.001). The nasal plug insertion and the mouth closure required for ΔP_nos measurement did not result in significant change of respiratory rate and ΔP_es. The correlation between measures at 24 h remained significant even after splitting the study population according to the type of NRS (high-flow nasal cannulas [R² = 0.79, p < 0.001] or non-invasive ventilation [R² = 0.95, p < 0.001]). Conclusions: In a cohort of patients with ARF, nasal pressure swings did not alter respiratory mechanics in the short term and were highly correlated with esophageal pressure swings during spontaneous tidal breathing. ΔP_nos might warrant further investigation as a measure of inspiratory effort in patients with ARF. Trial registration: NCT03826797. Registered October 2016.