The heterogeneity of lung involvement in vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome: a case of hypersensitivity pneumonitis-like pattern.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently characterized disease associated with somatic mutations in the UBA1 gene, which cause dysregulation of ubiquitin-mediated processes. This case describes a 71-year-old male patient with VEXAS syndrome who presented with refractory lung inflammation with a pattern similar to computed tomography hypersensitivity pneumonitis, a novel finding in VEXAS syndrome. The presented clinical case highlights the protean involvement of the lung in VEXAS syndrome and emphasizes the importance of considering interstitial lung disease in the differential diagnosis.

Clinical course of IPF in Italian patients during 12 months of observation: results from the FIBRONET observational study.

BACKGROUND: FIBRONET was an observational, multicentre, prospective cohort study investigating the baseline characteristics, clinical course of disease and use of antifibrotic treatment in Italian patients with idiopathic pulmonary fibrosis (IPF). METHODS: Patients aged ≥ 40 years diagnosed with IPF within the previous 3 months at 20 Italian centres were consecutively enrolled and followed up for 12 months, with evaluations at 3, 6, 9 and 12 months. The primary objective was to describe the clinical course of IPF over 12 months of follow-up, including changes in lung function measured by % predicted forced vital capacity (FVC% predicted). RESULTS: 209 patients (82.3% male, mean age 69.54 ± 7.43 years) were enrolled. Mean FVC% predicted was relatively preserved at baseline (80.01%). The mean time between IPF diagnosis and initiation of antifibrotic therapy was 6.38 weeks; 72.3% of patients received antifibrotic therapy within the first 3 months of follow-up, and 83.9% within 12 months of follow-up. Mean FVC% predicted was 80.0% at baseline and 82.2% at 12 months, and 47.4% of patients remained stable (i.e. had no disease progression) in terms of FVC% predicted during the study. CONCLUSIONS: FIBRONET is the first prospective, real-life, observational study of patients with IPF in Italy. The short time between diagnosis and initiation of antifibrotic therapy, and the stable lung function between baseline and 12 months, suggest that early diagnosis and prompt initiation of antifibrotic therapy may preserve lung function in patients with IPF. TRIAL REGISTRATION: NCT02803580.

TAPSE/SPAP ratio stratifies mortality risk in mild-to-moderate idiopathic pulmonary fibrosis.

BACKGROUND: Due to paucity of literature data, we aimed at evaluating the prognostic role of the ratio of tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (SPAP) in idiopathic pulmonary fibrosis (IPF) patients without severe pulmonary hypertension and at assessing its correlation with effective arterial elastance index (EaI). METHODS: Multi-instrumental data obtained in 60 IPF patients (73.2 ± 6.8 years) and 60 matched controls were retrospectively analysed. Primary endpoint was all-cause mortality, while secondary endpoint was the composite of all-cause mortality and re-hospitalisations for all-causes over medium-term follow-up. RESULTS: ;At baseline, TAPSE/SPAP was significantly lower in patients with IPF than in controls (0.36 ± 0.25 vs. 0.77 ± 0.18 mm/mmHg; P < 0.001). TAPSE/SPAP was inversely correlated with EaI (r = -0.96) in IPF patients. During follow-up (3.5 ± 1.5 years), 21 patients died and 25 were re-hospitalised due to cardiopulmonary causes. TAPSE/SPAP was independently associated with both primary (HR 0.79, 95%CI 0.65-0.97) and secondary (HR 0.94, 95%CI 0.92-0.97) endpoints. A TAPSE/SPAP ratio of <0.20 and <0.44 mm/mmHg showed the greatest sensitivity and specificity for predicting primary (AUC 0.98) and secondary (AUC 0.99) endpoints, respectively. CONCLUSIONS: TAPSE/SPAP is a strong predictor of adverse outcomes in mild-to-moderate IPF. The strong correlation between TAPSE/SPAP and EaI might be an expression of a systemic fibrotic process which involves the heart, lungs and circulation.

High-resolution CT in smoking-related interstitial lung diseases.

In addition to chronic obstructive pulmonary disease (COPD) and bronchogenic carcinoma, smoking can also cause interstitial lung diseases (ILDs) such as respiratory bronchiolitis (RB), RB with ILD (RB-ILD), desquamative interstitial pneumonia (DIP), Langerhans cell granulomatosis (LCG) and idiopathic pulmonary fibrosis-usual interstitial pneumonia (IPF-UIP). However, smoking seems to have a protective effect against hypersensitivity pneumonitis (HP), sarcoidosis and organising pneumonia (OP). High-resolution computed tomography (HRCT) has a pivotal role in the differential diagnosis. RB is extremely frequent in smokers, and is considered a marker for smoking exposure. It has no clinical relevance in itself since most patients with RB are asymptomatic. It is frequent to observe the association of RB with other smoking-related diseases, such as LCG or pulmonary neoplasms. In RB-ILD, HRCT features are more conspicuous and diffuse than in RB, but there is no definite cut-off between the two entities and any distinction can only be made by integrating imaging and clinical data. RB, RB-ILD and DIP may represent different degrees of the same pathological process, consisting in a bronchiolar and alveolar inflammatory reaction to smoking. Smoking is also a well-known risk factor for pulmonary fibrosis. Multidisciplinary discussion and follow-up can generally solve even the most difficult cases.

Lung function predicts lung cancer risk in smokers: a tool for targeting screening programmes.

The relationship between smoking, lung cancer and airflow obstruction is recognised but it is unclear whether the presence of minimal lung function damage constitutes an independent risk factor for the development of lung cancer. In order to identify those individuals at higher risk of lung cancer on the basis of functional impairment, we evaluated baseline pulmonary function tests of 3,806 heavy smokers undergoing annual chest computed tomography screening, and compared the forced expiratory volume in 1 s (FEV(1)) % predicted of 57 lung cancer cases and that of 3,749 subjects without cancer. We obtained odds ratios (ORs) of lung cancer and the corresponding 95% confidence intervals (CIs) using unconditional logistic regression, adjusting for age, sex, study and smoking variables. Compared with subjects with FEV(1) >or=90% pred, the OR of lung cancer was 2.45 (95% CI 1.39-4.33) for subjects with FEV(1) <90% pred and 2.90 (95% CI 1.34-6.27) for subjects with FEV(1) <70% pred. These data show that even a relatively small reduction in FEV(1) % pred is a significant predictor of increased lung cancer risk. Test screening for lung cancer using airflow obstruction with FEV(1) <90% is a strategy worth future consideration.

IPF: new insight on pathogenesis and treatment.

Recent years have seen a robust influx of exciting new observations regarding the mechanisms that regulate the initiation and progression of pulmonary fibrosis but the pathogenesis remains poorly understood. The search for an alternative hypothesis to unremitting, chronic inflammation as the primary explanation for the pathophysiology of idiopathic pulmonary fibrosis (IPF) derives, in part, from the lack of therapeutic efficacy of high-dose immunosuppressive therapy in patients with IPF. The inflammatory hypothesis of IPF has since been challenged by the epithelial injury hypothesis, in which fibrosis is believed to result from epithelial injury, activation, and/or apoptosis with abnormal wound healing. This hypothesis suggests that recurrent unknown injury to distal pulmonary parenchyma causes repeated epithelial injury and apoptosis. The resultant loss of alveolar epithelium exposes the underlying basement membrane to oxidative damage and degradation. Emerging concepts suggest that IPF is the result of epithelial-mesenchymal interaction. The initiation of this fibrotic response may depend upon genetic factors and environmental triggers; the role of Th1 or Th2 cell-derived cytokines may also be important. This process appears to be unique to usual interstitial pneumonia/IPF. It is clear that IPF is a heterogeneous disease with variations in pathology, high-resolution computed tomography findings, and patterns of progression. Idiopathic pulmonary fibrosis is a complex disorder, and no unifying hypothesis has been identified at present that explains all the abnormalities.

Radiological diagnosis of fibrosing interstitial lung diseases: innovations and controversies.

Following the introduction of new effective antifibrotic drugs, interest in fibrosing interstitial lung diseases (FILD) has been renewed. In this context, radiological evaluation of FILD plays a cardinal role. Radiological diagnosis is possible in about 50% of the cases, which allows the initiation of effective therapy, thereby avoiding invasive procedures such as surgical lung biopsy. Usual interstitial pneumonia (UIP) pattern may be diagnosed based on clinical, radiological, and pathological data. High-resolution computed tomography features of UIP have been widely described in literature; however, interpreting them remains challenging, even with specific expertise on the subject. Diagnostic difficulties are understandable given the continuous evolution of FILD classifications and their complexity. Both early-stage diseases and advanced or combined patterns are not easily classifiable, and many end up being labelled 'indeterminate´ or 'unclassifiable´. Especially in these cases, optimal patient management involves collaboration and communication between different specialists. Here, we discuss the most critical aspects of radiological interpretation in FILD diagnosis based on the most recent classifications. We believe that the clinicians´ awareness of radiological diagnostic issues of FILD would improve comprehension and dialogue between physicians and radiologists, leading to better clinical practice.

Severe idiopathic pulmonary fibrosis: A clinical approach.

Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease associated with a high mortality rate. Novel antifibrotic therapies have been recently demonstrated to slow disease progression and improve survival. However, the management of IPF remains a difficult challenge, since lung complications can still occur, particularly in patients with advanced-stage disease. This paper highlights the most common complications and difficult tasks related to severe IPF such as acute exacerbation of the disease, development of lung cancer, rapid disease progression, and indication for lung transplantation.

Endocrine and metabolic assessment in adults with Langerhans cell histiocytosis.

CONTEXT: Diabetes insipidus (DI) is one of most common complications of Langerhans cell histiocytosis (LCH) but prevalence of anterior pituitary deficiencies and metabolic alterations have not been clearly defined yet. OBJECTIVES: Evaluate prevalence of endocrine and metabolic manifestations in a cohort of patients affected by Pulmonary LCH. METHODS: Observational cross-sectional study on 18 adults (7 M/11 F, 42±12years) studied for complete basal and dynamic endocrine lab tests and glucose metabolism. RESULTS: Hypothalamic-pituitary endocrine alterations were found in 9 patients: 9 had DI, 5 Growth Hormone Deficiency (GHD), 5 central hypogonadism, 3 central hypothyroidism and 1 central hypoadrenalism. Hyperprolactinemia and hypothalamic syndrome were found in 2 patients each. All these central endocrine alterations were always associated to DI. Five of the 10 MRI performed showed abnormalities. Prevalence of obesity and glucose alterations (either DM or IFG/IGT) were respectively 39% and 33%, higher than expected basing on epidemiological data on general Italian population. Multi-system-LCH without risk-organ involvement (LCH MS-RO-) seems to have slightly higher prevalence of insulin resistance, glucose alterations and metabolic syndrome than LCH with isolated lung involvement (LCH SS lung+). A papillary BRAFV600E positive thyroid carcinoma was diagnosed in one patient. CONCLUSIONS: The presence of anterior pituitary deficiencies should be systematically sought in all LCH patients with DI both at diagnosis and during the follow-up by basal and dynamic hormonal assessment. Patients with pulmonary LCH, particularly those with MS disease, have a worse metabolic profile than general population. Occurrence of papillary thyroid carcinoma has been reported.

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.

Current strategies in the treatment of invasive Aspergillus infections in immunocompromised patients.

Aspergillus infections have a very high mortality rate. Their incidence is growing because of the increasing number of immunocompromised patients. Treatment of Aspergillus infection is difficult, and the agents used have numerous adverse effects and toxicities. Recently, new and less nephrotoxic formulations of amphotericin B have come onto the market and other new drugs, such as voriconazole and terbinafine, are under evaluation for this infection. Restoration of host immune defences by tapering of immunosuppressive therapy in transplant patients or correction of granulocytopenia in haematological disease is the cornerstone of modern treatment of aspergillosis in immunocompromised patients. In patients with invasive aspergillosis it is very important to achieve therapeutic concentrations of antimycotic drugs as quickly as possible. Patients at high risk of developing aspergillosis (e.g. those with granulocytopenia) should be treated on the basis of clinical or radiological criteria alone if microbiological or histological diagnosis would significantly delay treatment. Conventional amphotericin B is still the first-line treatment for patients with invasive aspergillosis. In transplant patients receiving other nephrotoxic drugs, particularly cyclosporin, first-line therapy with one of the new amphotericin B formulations should be considered. If the emergence of renal toxicity in any patient precludes aggressive treatment, the patient should be switched to one of the new formulations of amphotericin B. For patients cured with amphotericin B, secondary prophylaxis is needed at the end of the intravenous therapy. Amphotericin B by aerosol or itraconazole are possible solutions. In non-invasive forms of aspergillosis, such as suppurative bronchitis, patients could be treated either with amphotericin B or itraconazole as first-line therapy.

Immunocytochemical detection of progesterone receptors. A study in a patient with primary pulmonary hypertension.

Primary pulmonary plexogenic arteriopathy (PPPA) is one of the principal conditions in which pulmonary hypertension may be clinically unexpected. It occurs in the lung vessels in the absence of any demonstrable cause. Its high incidence in women of childbearing age combined with reports of disease following delivery of a child or assumption of oral contraceptives suggest that hormonal factors may play a role in the pathogenesis of PPPA. The suspicion that the pulmonary vascular lesions occurring in PPPA could represent the effect of a hormonal mediated vascular hyperreactivity prompted the evaluation of the steroid hormone receptor status on lung tissue obtained from a women suffering from this disease who had a double-lung transplantation. By the immunocytochemical method performed on formalin fixed, paraffin-embedded lung tissue, we showed the presence of progesterone receptors (PR) in the nuclei of the myofibroblasts forming the arterial obstructive intimal proliferations and of the spindle cells present in the walls of the plexiform lesions. To enhance the staining and to facilitate the observation, we used a microwave-based antigen unmasking technique. The lack of estrogen receptors and the presence of PR could have increased, in the case, the sensitivity of the pulmonary muscular arteries to vasoconstrictory compounds. We hypothesize that on this substrate of a presumptive steroid-mediated vasoconstriction the sequence of the histologic lesions characteristic of pulmonary vascular hypertensive disease could have developed.

Prognostic value of pulmonary hypertension in patients with chronic interstitial lung disease referred for lung or heart-lung transplantation.

BACKGROUND: The purpose of this study was to identify precise and reliable prognostic parameters in patients affected by serious chronic interstitial lung disease, who were undergoing screening for lung or heart-lung transplantation. METHODS: Hemodynamic and respiratory function parameters of 67 patients (43 with idiopathic pulmonary fibrosis, 18 with histiocytosis X, and 6 with lymphangioleiomyomatosis) undergoing clinical screening for lung transplantation. RESULTS: Statistical analysis showed that hemodynamic and respiratory function parameters in patients affected by histiocytosis X and idiopathic pulmonary fibrosis were not related to survival time. Moreover, the degree of pulmonary hypertension showed no correlation between respiratory function parameters in all the groups of diseases examined. Patients affected with histiocytosis X, even with higher degrees of pulmonary hypertension, had a better survival rate (p < 0.0005) compared with patients with idiopathic pulmonary fibrosis. CONCLUSIONS: Hemodynamic and respiratory parameters obtained during the clinical screening for lung transplantation do not predict survival and cannot be used as prognostic indicators.

Pulmonary Langerhans cell Histiocytosis.

Pulmonary Langerhans cell Histiocytosis is a rare granulomatous disease affecting both sexes, with greater incidence in the second and third decades of life; smoking appears to be the most important risk factor. Its etiology is unknown, although there are data indicating an uncontrolled immune response as possible cause, sustained by the Langerhans cells, antigen presenting cells for T lymphocytes, and their accumulation in the distal bronchioles; these cells express on their surface the CD1a and CD1c antigens, and the B7 molecule, essential for activating quiescent T lymphocytes. In its evolution the granuloma is characterized by the progressive reduction in the LC number, with the increase of fibrosis, surrounding and destroying the bronchiolar lumen; the remaining of the lumen, or the traction exerted by fibrous tissue on the adjacent alveolar spaces leads to the cyst development. Vascular involvement occurs frequently, and may explain the onset of pulmonary hypertension in advanced cases of the disease. The disease may be asymptomatic, or it may present with aspecific respiratory signs and symptoms, and has characteristic radiological findings, being included in the group of cysticaerial parenchymal alterations. The diagnosis could be suggested by the finding of a number of LC in BAL greater than 5%. Different therapies have been proposed, but it seems that the most important measure is smoking cessation.