Concurrent features of sarcoidosis and hypersensitivity pneumonitis in two patients exposed to fungal antigens.

BACKGROUND: Sarcoidosis and hypersensitivity pneumonitis (HP) are two distinct clinical entities that share granulomatous inflammation, although each of them has specific clinical, radiologic and pathologic profiles. Coexistence of the two diseases have been described, suggesting, at least in some cases, a common biologic background. CASE PRESENTATION: We describe two patients showing the concurrent diagnosis of sarcoidosis and hypersensitivity pneumonitis. Case 1: a 51-year old never smoker man had a history of occupational exposure, episodes of acute exacerbations and positive serum precipitins to Penicillium spp suggestive of HP, while the positivity of serum angiotensin converting enzyme (ACE) favored sarcoidosis. Case 2: a 42-year old non-smoker woman with occasional finding of enlarged mediastinal lymph nodes had a history of domestic exposure to molds and positive serum precipitins to Aspergillus spp suggestive of HP. In both cases high resolution computed tomography (HRCT) together with broncoscopy findings allowed to maintain both the diagnoses: HRCT showed both enlarged hilar/mediastinal limph nodes and intersitial lung involvement typical of HP; bronchoalveolar lavage presented marked lymphocytosis and granulomatous nodal lesions were observed at transbronchial needle aspiration. CONCLUSIONS: Sarcoidosis and HP share some clinical findings and the differential diagnosis may be difficult. Our cases suggest that a common trait may be responsible for the concurrent diagnosis of sarcoidosis and hypersensitivity pneumonitis in the same patient.

Molecular Biomarkers in Idiopathic Pulmonary Fibrosis: State of the Art and Future Directions.

Idiopathic pulmonary fibrosis (IPF), the most lethal form of interstitial pneumonia of unknown cause, is associated with a specific radiological and histopathological pattern (the so-called "usual interstitial pneumonia" pattern) and has a median survival estimated to be between 3 and 5 years after diagnosis. However, evidence shows that IPF has different clinical phenotypes, which are characterized by a variable disease course over time. At present, the natural history of IPF is unpredictable for individual patients, although some genetic factors and circulating biomarkers have been associated with different prognoses. Since in its early stages, IPF may be asymptomatic, leading to a delayed diagnosis. Two drugs, pirfenidone and nintedanib, have been shown to modify the disease course by slowing down the decline in lung function. It is also known that 5-10% of the IPF patients may be affected by episodes of acute and often fatal decline. The acute worsening of disease is sometimes attributed to identifiable conditions, such as pneumonia or heart failure; but many of these events occur without an identifiable cause. These idiopathic acute worsenings are termed acute exacerbations of IPF. To date, clinical biomarkers, diagnostic, prognostic, and theranostic, are not well characterized. However, they could become useful tools helping facilitate diagnoses, monitoring disease progression and treatment efficacy. The aim of this review is to cover molecular mechanisms underlying IPF and research into new clinical biomarkers, to be utilized in diagnosis and prognosis, even in patients treated with antifibrotic drugs.

History of lung volume reduction procedures.

Lung volume reduction (LVR) procedures for emphysematous patients were firstly introduced in the second half of the twentieth century. Over time, from the first invasive surgical procedures, new less invasive techniques have been conceived. In regards to the surgical approach, the adoption of VATS and the execution, in selected centers, of a non-resectional approach, with folding of less functional lung tissue, reduced mortality and adverse events risks. As regards to the bronchoscopic approach, endobronchial valves (EBV) and intrabronchial valves (IBV) were initially proposed in the early 2000s to obtain segmental or lobar atelectasis of the more compromised lung parenchyma. Despite showing promising results with respect to improvement of pulmonary function tests, particularly forced expiratory volume in 1st second (FEV1), and quality of life, and a good safety profile, valves showed disappointing results in presence of collateral ventilation, such as in cases of incomplete fissures. To overcome this technical issue, in the last 10 years, endobronchial coils have been designed and used. Having a compressive effect on the lung parenchyma where they are located, they are not affected by collateral ventilation. Randomized control trials (RCTs) on endobronchial coils showed a significant improvement in FEV1 and quality of life, however this technique was not immune to side effects, particularly low respiratory tract infections and pneumothoraces. Besides bronchial valves (BV) and coils, airway by-pass stents have also been evaluated in a RCT but without reaching the desired endpoints. Other innovative procedures recently considered and delivered through bronchoscopy regards thermal energy, with vapour therapy, to achieve a scarring reaction of the emphysematous lung parenchyma, and polymeric foams used as lung sealants to achieve absorptive atelectasis. In conclusion, LVR procedures may be considered in carefully selected patients with symptomatic emphysema and severe lung hyperinflation, and might be personalized according to the anatomical characteristics of emphysematous area.

Characterizing Non-Tuberculous Mycobacteria Infection in Bronchiectasis.

Chronic airway infection is a key aspect of the pathogenesis of bronchiectasis. A growing interest has been raised on non-tuberculous mycobacteria (NTM) infection. We aimed at describing the clinical characteristics, diagnostic process, therapeutic options and outcomes of bronchiectasis patients with pulmonary NTM (pNTM) disease. This was a prospective, observational study enrolling 261 adult bronchiectasis patients during the stable state at the San Gerardo Hospital, Monza, Italy, from 2012 to 2015. Three groups were identified: pNTM disease; chronic P. aeruginosa infection; chronic infection due to bacteria other than P. aeruginosa. NTM were isolated in 32 (12%) patients, and among them, a diagnosis of pNTM disease was reached in 23 cases. When compared to chronic P. aeruginosa infection, patients with pNTM were more likely to have cylindrical bronchiectasis and a "tree-in-bud" pattern, a history of weight loss, a lower disease severity and a lower number of pulmonary exacerbations. Among pNTM patients who started treatment, 68% showed a radiological improvement, and 37% achieved culture conversion without recurrence, while 21% showed NTM isolation recurrence. NTM isolation seems to be a frequent event in bronchiectasis patients, and few parameters might help to suspect NTM infection. Treatment indications and monitoring still remain an important area for future research.

Nontuberculous Mycobacteria in Noncystic Fibrosis Bronchiectasis.

During the past decades, a growing interest has been raised in evaluating nontuberculous mycobacteria (NTM) in patients with noncystic fibrosis bronchiectasis (NCFBE). This paper reviews several aspects of the correlations between NTM and NCFBE, including pathogenesis, radiological features, diagnosis, and management. Bronchiectasis and NTM lung disease are connected, but which one comes first is still an unresolved question. The rate of NTM lung disease in NCFBE varies through the studies, from 5% to 30%. The most frequent species isolated is MAC. NCFBE patients affected by NTM infection frequently present coinfections, including both other different NTM species and microorganisms, such as P. aeruginosa. Once a diagnosis of NTM disease has been reached, the initiation of therapy is not always mandatory. NTM species isolated, patients' conditions, and disease severity and its evolution should be considered. Risk factors for disease progression in NCFBE patients with NTM are low body mass index, cavitary disease, consolidations, and macrolide resistance at presentation.

A case of pulmonary tuberculosis presenting as diffuse alveolar haemorrhage: is there a role for anticardiolipin antibodies?

BACKGROUND: Diffuse alveolar haemorrhage (DAH) has been rarely reported in association with pulmonary infections. CASE PRESENTATION: We report the case of a 43 year old immunocompetent man presenting with dyspnoea, fever and haemoptysis. Chest imaging showed bilateral ground glass opacities. Microbiological and molecular tests were positive for Mycobacterium tuberculosis and treatment with isoniazid, rifampicin, ethambutol and pyrazinamide was successful. In this case the diagnosis of DAH relies on clinical, radiological and endoscopic findings. Routine blood tests documented the presence of anticardiolipin antibodies. In the reported case the diagnostic criteria of antiphospholipid syndrome were not fulfilled. CONCLUSIONS: The transient presence of anticardiolipin antibodies in association with an unusual clinical presentation of pulmonary tuberculosis is intriguing although a causal relationship cannot be established.

New tools for detecting latent tuberculosis infection: evaluation of RD1-specific long-term response.

BACKGROUND: Interferon-gamma (IFN-gamma) release assays (IGRAs) were designed to detect latent tuberculosis infection (LTBI). However, discrepancies were found between the tuberculin skin test (TST) and IGRAs results that cannot be attributed to prior Bacille Calmètte Guerin vaccinations. The aim of this study was to evaluate tools for improving LTBI diagnosis by analyzing the IFN-gamma response to RD1 proteins in prolonged (long-term response) whole blood tests in those subjects resulting negative to assays such as QuantiFERON-TB Gold In tube (QFT-IT). METHODS: The study population included 106 healthy TST+ individuals with suspected LTBI (recent contact of smear-positive TB and homeless) consecutively enrolled. As controls, 13 healthy subjects unexposed to M. tuberculosis (TST-, QFT-IT-) and 29 subjects with cured pulmonary TB were enrolled. IFN-gamma whole blood response to RD1 proteins and QFT-IT were evaluated at day 1 post-culture. A prolonged test evaluating long-term IFN-gamma response (7-day) to RD1 proteins in diluted whole blood was performed. RESULTS: Among the enrolled TST+ subjects with suspected LTBI, 70/106 (66.0%) responded to QFT-IT and 64/106 (60.3%) to RD1 proteins at day 1. To evaluate whether a prolonged test could improve the detection of LTBI, we set up the test using cured TB patients (with a microbiologically diagnosed past pulmonary disease) who resulted QFT-IT-negative and healthy controls as comparator groups. Using this assay, a statistically significant difference was found between IFN-gamma levels in cured TB patients compared to healthy controls (p < 0.006). Based on these data, we constructed a receiver operating characteristic (ROC) curve and we calculated a cut-off. Based on the cut-off value, we found that among the 36 enrolled TST+ subjects with suspected LTBI not responding to QFT-IT, a long term response to RD1 proteins was detected in 11 subjects (30.6%). CONCLUSION: These results indicate that IFN-gamma long-term response to M. tuberculosis RD1 antigens may be used to detect past infection with M. tuberculosis and may help to identify additional individuals with LTBI who resulted negative in the short-term tests. These data may provide useful information for improving immunodiagnostic tests for tuberculosis infection, especially in individuals at high risk for active TB.

Molecular diagnosis of fatal Nocardia farcinica pneumonia in an HIV-negative patient.

Nocardiosis is a rare and potentially life-threatening infection caused by several species of the Nocardia genus. Most cases occur in immunocompromised patients, and a delay in establishing the diagnosis is common due to the non-specific clinical presentations and the difficulty in cultivating Nocardia. Although the majority of pulmonary nocardiosis cases are caused by Nocardia asteroides, cases of human infection due to N. farcinica are increasingly diagnosed due to recent developments in taxonomy and diagnostic methods. N. farcinica is a separate species from N. asteroides and appears to be more virulent and resistant to antibiotics. Herein, we describe the case of a 65-year-old HIV-negative immunocompromised patient with a fulminant bilateral pulmonary nocardiosis while on empirical treatment with trimethoprim/sulfamethoxazole and imipenem. Post-mortem diagnosis of N. farcinica infection was performed by means of DNA amplification and sequencing of the 65-kDa bacterial heat shock protein.

Transcriptional profile of the immune response in the lungs of patients with active tuberculosis.

Despite advances in diagnosis and treatment, Mycobacterium tuberculosis causes active disease in about 8 million people worldwide annually. The study of the interplay between the host and the pathogen at the site of infection in human TB may contribute to elucidate the pathogenesis of the disease. In this work, using macroarray technology and real-time PCR, we analyzed the modulation of 847 genes encoding immune-inflammatory mediators in BALF samples of patients affected by active pulmonary TB (PTB) and control patients affected by non-TB diseases. The data show that the PTB milieu contains a complex network of gene activation. Different genes with adhesive properties and involved in tissue repair and fibrosis were modulated. In TB patients, we observed the up-regulation of cytokines, including IFN-gamma and IFN-gamma pathway genes, of several apoptotic genes, and of potent transcriptional activators. These findings can contribute to elucidate the mechanisms of MTB pathogenicity in humans.

Immunogenetics of severe respiratory infections: models for the development of new therapeutic strategies.

Innate and adaptive immunity plays a critical role in the defence of the lung and other mucosal surfaces exposed to micro-organisms. Anti-microbial peptides and proteins, cytokines and chemokines are important immune weapons as they build up the protective front for the respiratory tract. The notion that susceptibility to infectious diseases may be inherited is widely accepted and, as it is the failure to activate adaptive immunity that may allow infection to become established and progress toward invasion and dissemination, the recognition of specific gene defects affecting the ability of the immune system to overcome invading pathogens may shed light upon those mechanisms of immune regulation that are playing the most critical roles. The aim of the present review is to discuss some of the advances in infection immunogenetics that may lead to identify new strategies in the development of new anti-infectious and anti-inflammatory drugs.

Bleomycin-induced upper lobe fibrosis: a case report.

We report a case of late-onset pulmonary fibrosis involving the upper lobes that occurred in a young man treated with bleomycin for mediastinal germ-cell carcinoma. The parenchymal lesions became clinically apparent about two years after chemotherapy had been completed, with a slowly progressive course and sparing the lower lung fields during follow-up. Other possible diagnoses could be excluded on the basis of the patient's clinical history, laboratory tests and pathological findings.