Sarcopenia in idiopathic pulmonary fibrosis: a prospective study exploring prevalence, associated factors and diagnostic approach.

BACKGROUND: Sarcopenia gained importance in the evaluation of patients with chronic respiratory diseases, including idiopathic pulmonary fibrosis (IPF), since it may impact negatively on clinical outcomes. AIM: Aim of this study is to evaluate the prevalence and factors associated with sarcopenia, defined according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) 2019 definition, and to evaluate the prevalence of the single criteria that define the EWGSOP2 definition (muscle strength, muscle quantity and physical performance), in a cohort of consecutive patients with IPF prospectively followed up in 9 hospitals in Northern Italy between December 2018 and May 2021. METHODS: Enrolled patients underwent an extensive pulmonary and nutritional assessment, including bioelectrical impedance analysis, dynamometry and 4-m gait speed test, both at IPF diagnosis and at 6-month follow-up. RESULTS: Out of the 83 patients (81% males, mean age 72.5 years) with IPF at disease diagnosis enrolled in the study, 19 (22.9%) showed sarcopenia, including 2 (2.4%) with severe sarcopenia, 5 (6.0%) with confirmed sarcopenia and 12 (14.5%) with probable sarcopenia. Sarcopenia was associated with a significantly higher severity of the disease and sedentary lifestyle, while no differences were observed in regards to body mass index, history of weight loss and comorbidities between patients with and without sarcopenia. Out of the 64 patients without sarcopenia at baseline, 16 cases showed alteration of muscle quantity and/or physical performance. In the 51 patients with complete data at 6-month follow-up, there were no cases of severe sarcopenia, 1 case (2.0%) showed confirmed sarcopenia, while the prevalence of probable sarcopenia was 19.6% (10 cases). No differences in regards to antifibrotic treatment received and onset of gastrointestinal side effects were observed between patients with and without sarcopenia at follow-up. CONCLUSIONS: The prevalence of sarcopenia in patients with IPF both at diagnosis and at 6-month follow-up was low but not negligible and was associated with higher severity of the disease and sedentary lifestyle. In IPF patients, a comprehensive diagnostic work-up including all the criteria defining the EWGSOP2 definition might be more useful than a series testing for prompt recognition of nutritional and physical performance abnormalities.

Immune Stroma in Lung Cancer and Idiopathic Pulmonary Fibrosis: A Common Biologic Landscape?

Idiopathic pulmonary fibrosis (IPF) identifies a specific entity characterized by chronic, progressive fibrosing interstitial pneumonia of unknown cause, still lacking effective therapies. Growing evidence suggests that the biologic processes occurring in IPF recall those which orchestrate cancer onset and progression and these findings have already been exploited for therapeutic purposes. Notably, the incidence of lung cancer in patients already affected by IPF is significantly higher than expected. Recent advances in the knowledge of the cancer immune microenvironment have allowed a paradigm shift in cancer therapy. From this perspective, recent experimental reports suggest a rationale for immune checkpoint inhibition in IPF. Here, we recapitulate the most recent knowledge on lung cancer immune stroma and how it can be translated into the IPF context, with both diagnostic and therapeutic implications.

CT-guided biopsy in the differential diagnosis of Sjogren syndrome associated cystic lung disease: A case of lung nodular AL-k amyloidosis.

Pulmonary involvement in Sjogren syndrome (SS) could manifest as cystic lung disease (CLD). CLD in SS includes lymphocytic interstitial pneumonia (LIP) and pulmonary amyloidosis. Differential diagnosis usually requires surgical lung biopsy, whereas CT-guided percutaneous fine needle aspiration biopsy (CT-FNAB) has not yet explored. We describe the case of a 63-year-old never smoker Caucasian female with a SS diagnosis who displayed a newly detected diffuse CLD at high-resolution computed tomography, though totally asymptomatic. Given the favorable location of one big lesion at the superior left lobe, a CT-FNAB was proposed instead of a more invasive SLB. At histology examination a diagnosis of pulmonary nodular AL kappa amyloidosis in the context of SS was established. In conclusion, CT-FNAB might represent an alternative and less invasive diagnostic procedure than SLB in the differential diagnosis of CLD, even if further research is needed. Moreover, this case presents an unusual association between SS and pulmonary nodular AL kappa amyloidosis, with pulmonary nodules and cysts without systemic manifestations.

Peripheral CD19+CD24highCD38high B-regulatory cells in lung transplant recipients.

BACKGROUND: The role of CD19+CD24highCD38high B-regulatory cells in solid-organ Transplant (Tx) in acceptance are still scarce. In previous studies on kidney transplant recipients may suggest a protective role of this cell subtype in graft tolerance and the existence of a cross talk between B-and T-regulatory clones. In lung transplantation, the role of B-regulatory cells has never been investigated. In a murine tracheal transplantation model, this subset seems able to prevent tracheal obliteration when in combination with rapamycin. Aim of this study is to analyze peripheral CD19+CD24highCD38high B-reg cells counts in a cohort of lung recipients, their association with several clinical and pharmacological variables and their possible association with T regulatory cell. METHODS: From Jan 2009 to Dec 2014, 117 lung Tx recipients were submitted to an immunological follow up I-FU(median: 108.7 months (6.7-310.5)). Immunological follow up consisted of a complete blood peripheral immuno-phenotype, inclusive of CD19+CD24highCD38high B-cells (globally 1106 determinations). We tested the association between B-reg and relevant variables by linear or regression models for repeated measures, adjusting for time from Tx. RESULTS: Among all variables analyzed at multivariate analysis: chronic rejection (OR - 0.19, p = .039), use of Mycophenolate (OR - 0.38, p < .001) and the presence of a concomitant pulmonary infection of S. aureus (OR 0.66, p = .002) and A. fumigatus (OR 0.50, p = .009) were significantly associated to B-reg cell. No significant correlation between CD19+CD24highCD38high B-reg cells and T-reg cells counts was found in our cohort. CONCLUSIONS: Our present data highlight, for the first time, that this cell subset might participate in long-term lung graft acceptance mechanisms.

The earlier, the better: Impact of early diagnosis on clinical outcome in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a complex disease with a highly variable clinical course and generally poor prognosis. Classified as a rare disease, significant increases in incidence have been recorded worldwide in recent years. Left untreated IPF is extremely debilitating with substantial personal, social and economic implications. OBJECTIVES: To discuss how IPF is diagnosed and managed in real life clinical practice with particular reference to Italy and to determine how new and effective therapies can be incorporated into a patient-centred management approach in order to improve the lives of patients with IPF. OUTCOMES: Barriers to early diagnosis are discussed. Cited reasons for delays in diagnosing IPF in Italy include: inherent difficulties in diagnosis; lack of knowledge/awareness of the condition among point-of-contact healthcare professionals; delays in referral to centres of excellence and underestimation of symptoms by both patients and healthcare workers. Valid therapeutic options with demonstrated efficacy in slowing the decline in lung function are now available for patients with IPF. The ASCEND trial confirmed the effects of pirfenidone, approved for the treatment of IPF on the basis of the four phase III trials. Nintedanib, a tyrosine kinase inhibitor that targets the PDGF receptors α/ß, FGF receptors 1 to 3, and VEGF receptors 1-3, is approved in the USA and the EU for the treatment of IPF. The TOMORROW and the INPULSIS placebo controlled trials in patients with IPF confirm the efficacy and safety of nintedanib and recent interim analyses endorse its long-term effects in slowing disease progression. CONCLUSIONS: The importance of early and accurate diagnosis of IPF cannot be underestimated and it is the duty of all healthcare professionals to be vigilant to the symptoms of IPF and to involve a multidisciplinary team in diagnosing and managing IPF early in the course of disease.

Clinical utility of CD4+ function assessment (ViraCor-IBT ImmuKnow test) in lung recipients.

The ImmuKnow assay measures cell-mediated immunity, quantifying ATP production from peripheral blood CD4+T-cells in solid-organ transplant patients who undergo immunosuppressive therapy. We aimed to measure functional immunity in lung transplant recipients and correlate Immuknow values with immunosuppression levels, presence of chronic lung allograft dysfunction (CLAD) and infections. We evaluated 61 lung recipients who underwent follow-up for lung transplantation between 2010 and 2014. Rejection and infection were retrospectively analyzed. The association between over-immunosuppression and a number of predictors was assessed by means of univariate and multivariate logistic regression models. 71 out of 127 samples (56%) showed an over-immunosuppression with an ImmuKnow assay mean level of 112.92ng/ml (SD±58.2), vs. 406.14ng/ml (SD±167.7) of the rest of our cohort. In the over-immunosuppression group we found 51 episodes of infection (71%) (OR 2.754, 95% CI 1.40-5.39; P-value 0.003). In the other group, only 25 samples (44%) were taken during an infectious episode. The mean absolute ATP level was significantly different between patients with or without infection (202.38±139.06ng/ml vs. 315.51±221.60ng/ml; P<0.001). RAS (Restrictive allograft syndrome) was associated to low ImmuKnow level (P<0.001). These results were confirmed by the multivariate analysis. The ImmuKnow assay levels were significantly lower in infected lung transplant recipients compared with non-infected recipients and in RAS patients.

Activation of oncogenic pathways in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause. The most recent hypotheses on IPF pathogenesis suggest a central role of epithelial cell damage, followed by a dysregulated molecular cross talk between epithelial cells and fibroblasts. Thus, IPF progression has often been assimilated to that of cancer, and several signaling patterns appear to be disrupted in both diseases. Here, we analyze the expression in an IPF series of a panel of molecules, which are known to play a role in tumorigenic process. Our findings, although preliminary, reveal that IPF landscape is enriched in neoplastic potential expressed in a context of complex genomic polyclonality and cellular heterogeneity. These results provide a rationale for further investigations aimed to exploit-in a similar fashion to cancer-targeted therapies for a "precision medicine" approach to IPF.

Post-transplant lymphoproliferative disorders and Epstein-Barr virus DNAemia in a cohort of lung transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) are serious complications in lung transplant recipients. No consensus on EBV DNAemia levels predictive of PTLD has been reached. In addition, in many instances EBV DNAemia is determined in patients with suggestive symptoms only. METHODS: The characteristics of five patients with PTLD as well as the prevalence of EBV DNAmia in a cohort of 137 consecutive patients receiving lung transplantation are described. RESULTS: Twenty-six out of 137 patients (18.9%) were excluded from the analysis because lost at follow-up or dead from PTLD-independent reasons within three months of transplantation. EBV DNA in peripheral blood mononuclear cells (PBMC) was determined in 83/111 patients (74.8%) because of potential PTLD-related symptoms, while 28 patients (25.2%) showed no symptoms and were not examined. EBV DNAemia was positive in 53/83 patients (63.8%), and negative in 30/83 patients (36.2%). PTLD was diagnosed in five (4.5%) patients at a median time of 270 (range 120-870) days following transplantation. All five PTLD (three large B-cell lymphomas, one Hodgkin lymphoma and one possible pre-neoplastic lesion) were potentially associated with EBV infection. However, only 3/5 patients with PTLD had detectable EBV DNAemia: < 1,000 copies EBV DNA/1 × 105 PBMC in one patient and > 1,000 copies EBV DNA/1 × 105 PBMC in two patients. CONCLUSION: A systematic multidisciplinary (clinical, radiologic, virologic and histologic) approach is mandatory for the diagnosis and management of PTLD in lung transplant recipients, while monitoring of symptomatic patients only may provide an incomplete or late picture of the clinical problem. In addition, staining for EBV antigens and quantification of EBV DNA in biopsy specimens should always be performed to understand the role of EBV infection in the pathogenesis of PTLD.

Incomplete expression of epithelial-mesenchymal transition markers in idiopathic pulmonary fibrosis.

The hypothesis that epithelial-mesenchymal transition (EMT) contributes to the formation of fibroblast foci (FF), which are the histological hallmark and the site of active disease progression of Idiopathic Pulmonary Fibrosis (IPF), has not yet received a conclusive demonstration. Cells undergoing EMT lose epithelial features and acquire mesenchymal markers and morphology. Cadherin expression switch (from E to N) is one of the first events in EMT. We investigated the immunohistochemical expression of E- and N-cadherin, vimentin, fibronectin, laminin-5-γ2, α-smooth muscle actin, and fibroblast-specific protein-1 involved in EMT in 20 IPF lung biopsies, focusing on metaplastic squamous cells of bronchial basal origin, positive for laminin-5-γ2 and ΔNp63/p40, that cover FF. The results were compared with organizing pneumonia, reactive squamous cell metaplasia of bronchiolar epithelia, and squamous cell carcinoma. Bronchiolar basal metaplastic cells in IPF partially lost E-cadherin and expressed vimentin and fibronectin. Hyperplastic pneumocytes in IPF and controls coexpressed E-cadherin and N-cadherin, and were weakly positive for lam5-γ2. Reactive squamous cell metaplasia did not show any mesenchymal markers. Squamous cell carcinoma only expressed lam5-γ2. In IPF lungs, we observed two epithelial cell populations with a different expression profile of markers involved in EMT. Although neither hyperplastic pneumocytes nor bronchial basal cells showed evidence of complete EMT, only the latter seem to be specific for UIP and might have a role in its development.

Bronchoalveolar lavage fluid proteome in bronchiolitis obliterans syndrome: possible role for surfactant protein A in disease onset.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) affects long-term survival of lung transplant (Tx) recipients (LTRs), with no consistently effective treatment strategy. Identifying early markers of BOS is of paramount importance for improving graft survival. METHODS: We used 2-dimensional gel electrophoresis and protein identification by mass spectrometry to compare the protein profile of bronchoalveolar lavage fluid (BALf) in two groups of LTRs: one composed of patients with BOS and the other composed of patients with good graft function at >5 years post-surgery (stable LTRs). Based on the hypothesis that only proteins of lung origin could represent reliable BOS markers, we also evaluated paired plasma samples. Proteins of interest were also assessed in the BALf of control subjects and results confirmed by dot- blot analysis. RESULTS: Among 11 differentially expressed proteins, we identified 2 locally produced factors: peroxiredoxin II (PRXII), exclusively expressed in BOS; and surfactant protein A (SP-A), expressed consistently less in BOS patients than in stable LTRs. PRXII expression was never observed in BALf from control subjects, whereas SP-A was present in higher amounts compared with stable LTRs and BOS patients. Finally, the time course of SP-A was studied in 5 LTRs who subsequently developed BOS. A reduction in BALf SP-A content was detectable early after Tx, preceding BOS onset in 4 of 5 patients. CONCLUSIONS: Our results suggest that testing SP-A levels in BALf could predict LTR patients who are at higher risk of BOS development.

Risk factors for chronic renal dysfunction in lung transplant recipients.

Several factors predispose to renal dysfunction (RD), a common complication of solid organ transplants. We evaluated the impact of clinical and laboratory parameters on the decline of renal function in lung and heart-lung transplant recipients. We enrolled 45 patients who survived more than 6 months after transplantation, had normal renal function and urinalysis before the surgery. The prognostic value of variables for the occurrence of RD was calculated by univariate analysis. Thirty patients developed RD, defined as doubling of serum creatinine or creatinine steadily >1.5 mg/dL after a median time of 12 months. Serum creatinine above 0.9 mg/dL during the month preceding lung transplant, systolic blood pressure above 130 mmHg, and pretransplant idiopathic pulmonary hypertension were significantly associated with the development of RD. Our findings indicate that increased systolic blood pressure, reduced glomerular filtration rate, and idiopathic pulmonary hypertension are risk factors for chronic RD in lung transplant recipients.

The Italian register for diffuse infiltrative lung disorders (RIPID): a four-year report.

INTRODUCTION: RIPID (Italian register for diffuse infiltrative lung disorders) is a register aimed to create a national database of diffuse infiltrative lung disorders, also known as interstitial lung diseases. MATERIAL AND METHODS: The RIPID register collected prevalent data on patients affected by infiltrative diffuse lung disorders. The data form contains socio-demographic information (sex, age, years of education), existence in life, smoking habits, clinical data, diagnostic procedures (chest high resolution computed tomography (HRCT), bronchoalveolar lavage (BAL), transbronchial biopsies (TBB), surgical biopsies) and respiratory function tests at the time of diagnosis. RESULTS: Up to 18/01/2005 a total of 3152 patients had been included in the register. Seventy-nine centers and 138 physicians in all 20 regions of Italy contributed to patient enrolment. The vast majority of cases were from Northern Italy (2343 cases, 75%). The most frequently reported diagnoses were Sarcoidosis (1063 patients) and Idiopathic Pulmonary Fibrosis (IPF, 864 patients). DISCUSSION: The data in the RIPID confirm that epidemiological registries can be useful tools to investigate rare or relatively rare disorders (e.g. Sarcoidosis and IPF), in order to design multicentric clinical studies of adequate sample size, aimed at providing standardized diagnostic, management and follow up criteria with a particular regard to outcome.

Efficacy of tacrolimus rescue therapy in refractory acute rejection after lung transplantation.

BACKGROUND: Encouraging results in transplantation of other solid organs led to investigation of the use of tacrolimus in lung transplantation as a salvage immunosuppressant in persistent acute rejection. METHODS: The incidence and severity of acute rejection and the number of steroid pulses were analyzed in 20 lung recipients who were converted from a cyclosporine- to a tacrolimus-based immunosuppressive regimen because of refractory biopsy-proven acute rejection. RESULTS: Tacrolimus was started 12.0 +/- 13.0 months after transplantation, and the mean follow-up was 25.0 +/- 13.7 months. After shifting to tacrolimus, a significant decline was observed in both the number of acute rejections per patient (3.0 +/- 1.56 to 0.85 +/- 1.14, p < 0.0001), and the incidence of acute rejection per 100 patient-days (1.52 +/- 0.99 to 0.14 +/- 0.21, p < 0.0001). Furthermore, the average histologic grade of rejection decreased from 1.9 +/- 0.8 to 0.4 +/- 0.5 (p < 0.0001). Methylprednisolone pulses similarly decreased from 1.9 +/- 1.3/patient to 0.3 +/- 0.7/patient (p < 0.0001). During cyclosporine immunosuppression, the mean forced expiratory volume in 1 second decreased to 84.4% +/- 13.3% of individual best value. The average lung function parameters were stable 3 months after the change of medication, and then began to improve. After an average follow-up of 36.5 +/- 19.2 months, 2 patients have developed bronchiolitis obliterans syndrome (one has Stage 1 and one has Stage 3). CONCLUSION: Conversion to a tacrolimus-based immunosuppressive regimen for refractory acute lung rejection is associated with reduced incidence and severity of acute rejection episodes, steroid sparing, and stabilization or improvement of pulmonary function.