Stefania Cerri

Performance of tests for latent tuberculosis in different groups of immunocompromised patients.

BACKGROUND Immunocompromised persons infected with Mycobacterium tuberculosis (MTB) have increased risk of tuberculosis (TB) reactivation, but their management is hampered by the occurrence of false-negative results of the tuberculin skin test (TST). The T-cell interferon (IFN)-gamma release blood assays T-SPOT.TB (TS.TB) [Oxford Immunotec; Abingdon, UK] and QuantiFERON-TB Gold In-Tube (QFT-IT) [Cellestis Ltd; Carnegie, VIC, Australia] might improve diagnostic accuracy for latent TB infection (LTBI) in high-risk persons, although their performance in different groups of immunocompromised patients is largely unknown. METHODS AND RESULTS Over a 1-year period, we prospectively enrolled patients in three different immunosuppressed groups, as follows: 120 liver transplantation candidates (LTCs); 116 chronically HIV-infected persons; and 95 patients with hematologic malignancies (HMs). TST, TS.TB, and QFT-IT were simultaneously performed, their results were compared, and intertest agreement was evaluated. Overall, TST provided fewer positive results (10.9%) than TS.TB (18.4%; p < 0.001) and QFT-IT (15.1%; p = 0.033). Significantly fewer HIV-infected individuals had at least one positive test (9.5%) compared with LTCs (35.8%; p < 0.001) and patients with HMs (29.5%; p < 0.001). Diagnostic agreement between tests was moderate (kappa = 0.40 to 0.65) and decreased in the HIV-infected group when the results of the TS.TB were compared with either TST (kappa = 0.16) or QFT-IT (kappa = 0.19). Indeterminate blood test results due to low positive control values were significantly more frequent with QFT-IT (7.2%) than with TS.TB (0.6%; p < 0.001). CONCLUSIONS Blood tests identified significantly more patients as being infected with MTB than TST, although diagnostic agreement varied across groups. Based on these results, we recommend tailoring application of the new blood IFN-gamma assays for LTBI in different high-risk groups and advise caution in their current use in immunosuppressed patients.

Efficacy of pirfenidone for idiopathic pulmonary fibrosis: An Italian real life study

BACKGROUND In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. METHODS We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. RESULTS At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. CONCLUSIONS In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease.

Sarcoidosis: challenging diagnostic aspects of an old disease

Over the past few years, there have been substantial advances in our understanding of sarcoidosis immunopathogenesis. Conversely, the etiology of the disease remains obscure for a number of reasons, including heterogeneity of clinical manifestations, often overlapping with other disorders, and insensitive and nonspecific diagnostic tests. While no cause has been definitely confirmed, there is increasing evidence that one or more infectious agents may cause the disease, although the organism may no longer be viable. Here we present 2 cases, in which sarcoidosis preceded tuberculosis and non-Hodgkin lymphoma. Development of new lesions in a patient with chronic/remitting sarcoidosis should be looked at with suspicion and promptly investigated in order to rule out an alternative/concomitant diagnosis. In such cases, tissue confirmation from the most accessible site, and bone marrow biopsy-if lymphoma is in the differential diagnosis-should be performed. In conclusion, we strongly advise that physicians be ready to reconsider the diagnosis of sarcoidosis in the presence of atypical manifestations or persistent/progressive disease despite conventional therapy.

Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease: Our interdisciplinary rheumatology-pneumology experience, and review of the literature.

BACKGROUND Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lungs, varying from idiopathic interstitial pneumonias to secondary variants, including the ILDs associated to connective tissue diseases (CTDs). In addition, a number of patients are recognized as unclassifiable ILD (U-ILD), because of the inability to reach a definite diagnosis; some of them show autoimmune manifestations not fulfilling the classification criteria of a given CTD. The term interstitial pneumonia with autoimmune features (IPAF) has been recently proposed for this particular ILD subset. METHODS Here, we report our experience resulting from the integrated - pneumology/rheumatology - approach to patients with suspected ILDs or CTDs referred to our university-based Center for the Rare Pulmonary Diseases and Rheumatology Unit, from January 2009 to June 2015, with particular attention to the above-mentioned U-ILD, IPAF, and undifferentiated connective tissue disease (UCTD). The comparative analysis of these clinical variants was carried out; moreover, the observed findings were compared with the results of the updated review of the literature. RESULTS After the first clinical assessment, the U-ILD were identified in 50 patients; afterwards, on the basis of clinico-serological and radiological findings U-ILD group was subdivided into 2 subgroups, namely U-ILD without any clinical extra-thoracic manifestations and/or immunological alterations (15 pts) and IPAF according to the above-mentioned classification criteria (35 pts). Patients with either IPAF or U-ILD were compared with a series of 52 stable UCTD (disease duration ≥3 years), followed at our Rheumatology Unit. Some important differences were evidenced among the 3 series of U-ILD, IPAF, and UCTD: firstly, female gender was more frequent in patients with UCTD (86%) or IPAF (69%) compared with U-ILD (60%) or idiopathic pulmonary fibrosis (24%; p=0.001). In addition, UCTD patients were younger and showed longer disease duration. More interestingly, both UCTD and IPAF series show a comparable prevalence of various clinical manifestations, with the exception of the interstitial lung involvement detectable in a very small percentage of UCTD patients. Concordantly, the review of the literature evidenced two main subsets of U-ILD, one is characterized by isolated unclassifiable interstitial pneumonia and another one composed by subjects with clinically prevalent lung involvement in the setting of not definite CTD, the recently proposed IPAF. CONCLUSION We hypothesize that IPAF and UCTD might represent two clinical variants of the same systemic autoimmune disorders. The marked difference regarding the prevalence of ILD, which is the clinical hallmark of IPAF but very rare in UCTD, may at least in part reflect a selection bias of patients generally referred to different specialist centers, i.e. pneumology or rheumatology, according to the presence/absence of clinically dominant ILD, respectively. Well-integrated, interdisciplinary teams are recommended for the assessment and management of these patients in the clinical practice. Finally, the cooperation between multidisciplinary groups with different experiences may be advisable for a validation study of the proposed nomenclature and classification criteria of these indefinable ILD/CTD variants.

Diagnosis of occult tuberculosis in hematological malignancy by enumeration of antigen-specific T cells.

Diagnosis of occult tuberculosis in hematological malignancy by enumeration of antigen-specific T cells

The big clinical trials in idiopathic pulmonary fibrosis

Purpose of reviewSince the late 1990 s, when a more uniform definition of idiopathic pulmonary fibrosis (IPF) was proposed, more than 3000 patients have been enrolled in clinical studies exploring novel therapies. Some of the most relevant trials have been published only recently. Recent findingsThis review describes and comments on the randomized clinical trials in IPF published within the past 18 months, with emphasis on the studies evaluating pirfenidone, which at present is the only drug approved for IPF (at least in Europe and Japan), and bosentan. This latter represents the largest single trial performed in IPF so far. SummaryDespite multiple clinical trials, there is no strong, definitive evidence in favor of any agent to treat IPF. On the other hand, the placebo arms of these large trials have provided us with important critical information on the natural history of this disease. Clinical heterogeneity represents a critical issue to be taken into account in designing future clinical trials. The limited effectiveness of current treatment regimes has fuelled the search for a variety of new therapeutic approaches.

Emerging drugs for idiopathic pulmonary fibrosis

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal lung disorder of unknown etiology. The disease is characterized by alveolar epithelial cell injury, formation of activated fibroblasts/myofibroblasts foci and finally by the exaggerated accumulation of extracellular matrix with the subsequent destruction of the lung architecture. The long-term survival is distinctly poor, with only a 20 – 30% survival 5 years after the time of diagnosis. Actually, regardless of extensive research, no current therapy has been shown to either reverse or stop the progression of this disease. Areas covered: The authors searched the Medline database from January 1990 to December 2010 using search terms ‘pulmonary fibrosis’, ‘fibrosing alveolitis’ and ‘usual interstitial pneumonia’. Several subsets were included: definition and epidemiology, risk factors, clinical behavior, pathogenesis and therapy. For the section of IPF treatment, the authors examined all relevant studies including randomized controlled trials, cohort studies, case-control studies and cross-sectional studies. In this review, the authors describe the current therapeutic approaches, the ongoing clinical trials and some future options based on stem cells, lung bioengineering and microRNAs. Expert opinion: The treatment of IPF represents one of the greatest challenges confronting respiratory medicine and, currently, there is no effective therapeutic option for IPF. Perhaps some of the drugs that are under evaluation in clinical trials will slow the decline of the pulmonary function tests or hopefully stabilize some patients. Nonetheless, it appears clear that new therapeutic approaches are urgently needed.

A quantitative proteomic approach to identify significantly altered protein networks in the serum of patients with lymphangioleiomyomatosis (LAM)

Lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung condition affecting approximately 3.4–7.5/million women, with an average lag time between symptom onset and diagnosis of upwards of 4 years. The aim of this work was to identify altered proteins in LAM serum which may be potential biomarkers of disease. Serum from LAM patient volunteers and healthy control volunteers were pooled and analysis carried out using quantitative 4-plex iTRAQ technology. Differentially expressed proteins were validated using ELISAs and pathway analysis was carried out using Ingenuity Pathway Analysis. Fourteen proteins were differentially expressed in LAM serum compared to control serum (p<0.05). Further screening validated the observed differences in extracellular matrix remodelling proteins including fibronectin (30% decrease in LAM, p = 0.03), von Willebrand Factor (40% reduction in LAM, p = 0.03) and Kallikrein III (25% increase in LAM, p = 0.03). Pathway networks elucidated the relationships between the ECM and cell trafficking in LAM. This study was the first to highlight an imbalance in networks important for remodelling in LAM, providing a set of novel potential biomarkers. These understandings may lead to a new effective treatment for LAM in the future.

Fibulin-1 Predicts Disease Progression in Patients With Idiopathic Pulmonary Fibrosis

BACKGROUND The underlying mechanisms of idiopathic pulmonary fibrosis (IPF) are unknown. This progressive disease has high mortality rates, and current models for prediction of mortality have limited value in identifying which patients will progress. We previously showed that the glycoprotein fibulin-1 is involved in enhanced proliferation and wound repair by mesenchymal cells and, thus, may contribute to lung fibrosis in IPF. METHODS Serum, lung tissue, and lung function values were obtained from four independent locations (Sydney, NSW, and Perth, WA, Australia; San Francisco, CA; and Modena, Italy). Patients with IPF were followed for a minimum of 1 year and progression was defined as a significant decline in lung function or death. Primary parenchymal lung fibroblasts of 15 patients with and without IPF were cultured under nonstimulatory conditions. Fibulin-1 levels in serum, and secreted or deposited by fibroblasts, were measured by western blot and in lung tissue by immunohistochemistry. RESULTS Serum fibulin-1 levels were increased in patients with IPF compared with subjects without lung disease (P = .006). Furthermore, tissue fibulin-1 levels were increased in patients with IPF (P = .02) and correlated negatively with lung function (r = -0.9, P < .05). Primary parenchymal fibroblasts from patients with IPF produced more fibulin-1 than those from subjects without IPF (P < .05). Finally, serum fibulin-1 levels at first blood draw predicted disease progression in IPF within 1 year (area under the curve , 0.71; 95% CI, 0.57-0.86; P = .012). CONCLUSIONS Fibulin-1 is a novel potential biomarker for disease progression in IPF and raises the possibility that it could be used as a target for the development of new treatments.

Using ELISpot technology to improve the diagnosis of tuberculosis infection: from the bench to the T-SPOT.TB assay

Accurate detection and adequate treatment of latent tuberculosis infection represent a fundamental cornerstone to reduce the incidence of tuberculosis, in particular in low-incidence countries and among high-risk (i.e., immunosuppressed) individuals. Until recently, however, only the century-old tuberculin skin test was available as a diagnostic tool; its poor specificity and low sensitivity among immunosuppressed individuals has been a major limit to the implementation of effective tuberculosis control strategies. In the last years, the achievements of basic research on the genetics and immunology of Mycobacterium tuberculosis infection rapidly translated into clinical practice two elements of the vast amounts of knowledge acquired. First, the identification and use of specific antigens, which are absent in the tuberculosis vaccine and in most nontuberculous mycobacteria; and second, the identification of IFN-γ as the main fundamental cytokine implicated in the effective immune response against M. tuberculosis. In an incredibly powerful combination, this new knowledge has been applied to enzyme-linked immunospot (ELISpot) technology, the most sensitive technique to quantify an in vitro antigen-specific cellular immune response. In only a few years, a new commercial, regulatory-approved, diagnostic assay has entered clinical practice as a substitute to the tuberculin skin test. The T-SPOT.TB test has already been applied to several hundreds of patients in the context of controlled clinical trials in different countries and prevalence areas, showing improved specificity and sensitivity in the diagnosis of latent tuberculosis infection over the skin test, in particular in those settings where the diagnosis is most needed.