The impact of nintedanib and pirfenidone on lung function and survival in patients with idiopathic pulmonary fibrosis in real-life setting.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial pneumonia of unknown cause that is associated with radiological and/or histological features of usual interstitial pneumonia (UIP). A mean survival of 2-5 years was reported previously to the advent of antifibrotics. According to clinical trials, nintedanib and pirfenidone induce a significant delay in functional decline, with a favorable impact on survival. METHODS: A real-life retrospective and longitudinal study was conducted to assess the efficacy and tolerability of antifibrotics in IPF patients, between January 2014 and December 2020. Two groups (under nintedanib or pirfenidone) were analyzed at diagnosis through their clinical features and radiological patterns. Lung function was assessed at diagnosis (time 0) and after 6, 12 and 24 months of treatment. We also compared this antifibrotic cohort with an older naïve antifibrotic cohort, mainly treated with immunosuppressive drugs and/or N- acetylcysteine. Survival was analyzed and prognostic features were also studied. Statistical analysis was performed with IBM® SPSS®. RESULTS: A cohort of 108 patients under antifibrotics (nintedanib n = 54; pirfenidone n = 54) was assessed. Lung function analysis showed an overall stabilization in FVC and DLCO mean predicted percentages at 6, 12 and 24 months of treatment. The mean decline in FVC and DLCO, at 12 months, was -40.95 ± 438.26 mL and -0.626 ± 1.31 mL/min/mmHg, respectively. However, during this period, 34.2% of the patients died mostly due to acute exacerbation associated with a poorer lung function at diagnosis. Mean survival in the naïve antifibrotic cohort was significantly lower than in the antifibrotic cohort (39.9 months versus 58.2 months; p < 0.005). Regarding lung function evolution and survival, we found no differences between definitive or probable UIP radiological patterns, both on patients under nintedanib and pirfenidone (p = 0.656). CONCLUSIONS: In this real-life observational study, the positive impact of antifibrotic therapy on the IPF clinical course and on survival was corroborated. Regarding efficacy, there was no difference between patients taking nintedanib or pirfenidone. The need for an early treatment was also demonstrated, since a worse outcome is clearly associated with lower lung volumes and lower diffusing capacity at diagnosis.

Predictive value of common genetic variants in idiopathic pulmonary fibrosis survival.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown etiology. The role of genetic risk factors has been the focus of numerous studies probing for associations of genetic variants with IPF. We aimed to determine whether single-nucleotide polymorphisms (SNPs) of four candidate genes are associated with IPF susceptibility and survival in a Portuguese population. A retrospective case-control study was performed with 64 IPF patients and 74 healthy controls. Ten single-nucleotide variants residing in the MUC5B, TOLLIP, SERPINB1, and PLAU genes were analyzed. Single- and multi-locus analyses were performed to investigate the predictive potential of specific variants in IPF susceptibility and survival. Multifactor dimensionality reduction (MDR) was employed to uncover predictive multi-locus interactions underlying IPF susceptibility. The MUC5B rs35705950 SNP was significantly associated with IPF: T allele carriers were significantly more frequent among IPF patients (75.0% vs 20.3%, P < 1.0 × 10-6). Genotypic and allelic distributions of TOLLIP, PLAU, and SERPINB1 SNPs did not differ significantly between groups. However, the MUC5B-TOLLIP T-C-T-C haplotype, defined by the rs35705950-rs111521887-rs5743894-rs5743854 block, emerged as an independent protective factor in IPF survival (HR = 0.37, 95% CI 0.17-0.78, P = 0.009, after adjustment for FVC). No significant multi-locus interactions correlating with disease susceptibility were detected. MUC5B rs35705950 was linked to an increased risk for IPF, as reported for other populations, but not to disease survival. A haplotype incorporating SNPs of the MUC5B-TOLLIP locus at 11p15.5 seems to predict better survival and could prove useful for prognostic purposes and IPF patient stratification. KEY MESSAGES : The MUC5B rs35705950 minor allele is associated with IPF risk in the Portuguese. No predictive multi-locus interactions of IPF susceptibility were identified by MDR. A haplotype defined by MUC5B and TOLLIP SNPs is a protective factor in IPF survival. The haplotype may be used as a prognostic tool for IPF patient stratification.

Enlightening clinical and therapeutic heterogeneity in thoracic actinomycosis: A review in bronchiectasis and non-bronchiectasis patients.

Actinomycosis is a rare chronic infection triggered by species of Actinomyces. Although thoracic involvement represents about 15% of human actinomycosis, its true incidence may be underestimated, not only because of its challenging diagnosis, but also because it can be treated unintentionally with antibiotics for other diseases. In this sense, this work aims at providing an up-to-date literature review on thoracic actinomycoses, with particular emphasis on presentation, diagnostic and therapeutic approaches, also paving upcoming clinical interventions from findings obtained of a presentation of a case series. Data discussed here clearly denote the rarity, non-specificity and heterogeneity of clinical presentations of the disease, reinforcing the need for individualized therapeutic approaches.

Insights on chronic hypersensitivity pneumonitis' treatment: Factors associated with a favourable response to azathioprine.

BACKGROUND: The use of immunosuppressive and antifibrotic agents for the treatment of chronic hypersensitivity pneumonitis (CHP) appears promising, but there is still no evidence supporting the clinical decision regarding the implementation of each specific pharmacological strategy. METHODS: Patients diagnosed with CHP and treated with azathioprine (AZA) were retrospectively selected from a single centre for Interstitial Lung Diseases. Baseline clinical data, as well as functional, imaging, bronchoalveolar lavage (BAL) and histology features were assessed. Longitudinal data on functional parameters were collected and comparatively analysed with patients' characteristics. RESULTS: In this cohort of 80 patients, of those who reached 12 months of treatment, 78.3% presented a preserved forced vital capacity, with 59 being eligible to be classified as AZA responders (n = 36) or non-responders (n = 23). BAL lymphocytosis was associated with a favourable response to AZA treatment (OR 1.051; 95% CI 1.015-1.089), although it didn't identify all responders. CONCLUSIONS: AZA revealed to be effective in disease stabilisation in most patients, while ineffective for a subset. BAL lymphocytosis appears as a potentially valuable strategy to identify AZA responders, although with limited accuracy. Further studies are needed to clarify other response markers to immunosuppressive agents, in order to optimize the therapeutic options for this condition.

Pulmonary sarcoidosis: prognostic factors at diagnosis in patients from North of Portugal / Sarcoidosis pulmonar: factores pronósticos en el diagnóstico en enfermos del norte de Portugal

BACKGROUND: Sarcoidosis is a multisystemic granulomatous disease that affects the lungs in more than 90% of the patients. It is associated with a variable clinical course and considering all the different forms of disease presentation, there are an absence of reliable clinical prognostic markers that can predict the outcome at diagnosis. OBJECTIVE: The aim of our study was to investigate prognostic factors at diagnosis in a population of sarcoidosis patients from Northern Portugal. METHODS: A group of 110 patients with chronic evolution was compared with 129 patients with disease resolution regarding their clinical, radiologic and laboratorial features. RESULTS: We found a positive association between the chronic forms and lung function impairment, radiologic stage II, lower lymphocyte CD4/CD8 and extrapulmonary disease. Löfgren syndrome and asthenia instead had a protective significant association to chronicity. Our final logistic regression model found a significant independent association between age (adjusted OR=1.06), extrapulmonary involvement (adjusted OR=2.68), Löfgren's syndrome (adjusted OR=0.15) with outcome toward chronicity. CONCLUSIONS: In this first study searching for prognostic factors at diagnosis in a Northern Portuguese population, we found clinical prognosis factors that have been described in other populations that should be considered whenever sarcoidosis is identified

INTRODUCCIÓN: La sarcoidosis es una enfermedad granulomatosa multisistémica que afecta a los pulmones en más del 90% de los enfermos. Está asociada a un curso clínico variable y, considerando todas las formas diferentes de presentación de la enfermedad, hay una ausencia de marcadores de pronóstico clínico confiables que puedan predecir el resultado en el momento del diagnóstico. OBJETIVO: El objetivo de nuestro estudio fue investigar los factores pronósticos en el momento del diagnóstico en una población de enfermos con sarcoidosis del norte de Portugal. MÉTODOS: Se comparó un grupo de 110 enfermos con evolución crónica con 129 enfermos con resolución de la enfermedad teniendo en cuenta sus características clínicas, radiológicas y de laboratorio. RESULTADOS: Se encontró una asociación positiva entre las formas crónicas y el deterioro de la función pulmonar, el estadio radiológico II, la relación CD4/CD8 más baja y la enfermedad extrapulmonar. Ya el síndrome de Löfgren y la astenia tuvieron una asociación protectora significativa con la cronicidad. Nuestro modelo de regresión logística final encontró una asociación independiente significativa entre la edad (OR ajustada=1,06), la afectación extrapulmonar (OR ajustada=2,68), el síndrome de Löfgren (OR ajustada=0,15) y el resultado hacia la cronicidad. CONCLUSIONES: En este primer estudio de búsqueda de factores pronósticos en el momento del diagnóstico en una población del norte de Portugal, fueron encontrados predictores clínicos, que se han descrito en otras poblaciones que se deben considerar cada vez que se hace el diagnóstico de una sarcoidosis

Diagnostic yield and safety of transbronchial cryobiopsy in sarcoidosis.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) is an endoscopic technique proven to be useful in diagnostic approach to interstitial lung disease (ILD), but its role in sarcoidosis is not fully established. The aim of the present study was to assess the diagnostic yield of TBLC in sarcoidosis and its safety profile. METHODS: Retrospective analysis of patients, evaluated in a tertiary hospital ILD outpatient clinic, who underwent TBLC in the diagnostic work-up. TBLC was performed in accordance with the 2018 expert statement from the Cryobiopsy Working Group. RESULTS: 32 patients were included (mean±sd age 47.7±12.6 years, 59.4% male) and divided into three groups: highly likely sarcoidosis (n=21), possible sarcoidosis (n=6) and unlikely sarcoidosis (n=5). A mean of 2.8±0.8 TBLCs were performed. The definitive diagnosis was established by TBLC in 20 out of 27 patients with suspected sarcoidosis. Two patients were diagnosed with sarcoidosis by other methods performed afterwards. TBLC leaded to other diagnosis as well, such as fungal infection (n=1), hypersensitivity pneumonitis (n=1) and silicosis (n=3), making the diagnostic yield for suspected sarcoidosis of TBLC of 92.6%. TBLC was also able to show compatible histological features in five patients whom sarcoidosis was not previously considered. The complications reported overall were pneumothorax in five (15.6%) patients and moderate bleeding in one (3.1%) case. CONCLUSION: In this cohort, TBLC was a safe, reliable and useful procedure in sarcoidosis diagnosis. These results suggest that TBLC can be used successfully in those cases where a definitive diagnosis could not be reached with the usual and less-invasive diagnostic tools.

NK and NKT cells in the diagnosis of diffuse lung diseases presenting with a lymphocytic alveolitis.

BACKGROUND: Diffuse lung diseases (DLD) are characterized by different immunophenotypes in the bronchoalveolar lavage fluid (BALF). We aimed to evaluate the diagnostic value of BALF NK and NKT cell counts of patients with DLD and lymphocytic alveolitis. METHODS: We assessed 202 patients with DLD, who underwent BALF immunophenotyping. Samples were routinely processed by flow cytometry and lymphocyte subsets were compared between patients with sarcoidosis (n = 106), hypersensitivity pneumonitis (HP; n = 53), and other DLDs (n = 43). We compared absolute counts and percentages of NK and NKT cells between patients with HP versus the remaining DLD patients. To assess the accuracy of BALF lymphocyte subsets in the diagnosis of HP, we calculated the respective areas under the receiver operating characteristic curves (AUC-ROC). RESULTS: Patients with HP had significantly higher numbers of BALF NK cells, and its percentage was significantly associated with a higher odds of HP, even after adjustment for the NKT and CD8+ cells. For the absolute number of BALF NK cells, we found an AUC-ROC of 0.76 (95%CI = 0.68-0.84) when comparing patients with HP versus the remaining DLD. The cut-offs of 2000 NK cells/mL and of 2.4% NK cells in the BALF had a specificity and a negative predictive value over 80% for the diagnosis of HP. BALF NK cells absolute counts were significantly higher in HP patients with a restrictive pattern. No such differences were observed for NKT cells. CONCLUSIONS: BALF NK immunophenotyping may be a helpful adjunct to the diagnostic work-up of DLD, particularly in the differential diagnosis of HP.

Obstructive sleep apnoea in patients with fibrotic diffuse parenchymal lung disease-characterization and treatment compliance assessment.

INTRODUCTION: Recent studies have reported a high prevalence of obstructive sleep apnoea (OSA) among patients with diffuse parenchymal lung disease (DPLD), mainly idiopathic pulmonary fibrosis (IPF). Effective OSA treatment appears to have a positive impact on morbidity and mortality in these patients. However, poor compliance to positive airway pressure (PAP) treatment in fibrotic DPLD patients has been reported. The aims of our study were to characterize patients with fibrotic DPLD and OSA and to assess their compliance to PAP treatment. METHODS: Forty-nine patients with fibrotic DPLD underwent level III polysomnography. Auto-adjusting PAP (APAP) treatment was proposed for those patients with moderate-to-severe OSA and those with mild OSA with daytime sleepiness and/or cardiovascular disease. The APAP treatment compliance was assessed after 1 month of therapy. RESULTS: The distribution of the 49 fibrotic DPLD patients included was as follows: 21 with chronic hypersensitivity pneumonitis, 12 with IPF, 10 with connective-tissue associated DPLD, 4 with stage IV sarcoidosis, 1 with idiopathic pleuropulmonary fibroelastosis, and 1 with DPLD-associated vasculitis. Thirty-four (69.4%) of the patients presented with OSA; 22 had mild OSA, and 12 had moderate-to-severe OSA. APAP treatment was prescribed in 17 of the patients. After 1 month of therapy, all patients used APAP more than 70% of the nights for more than 4 h per night. CONCLUSION: We found a high prevalence of OSA among all of the patients with fibrotic DPLD (not only IPF). Despite certain difficulties, it was possible to achieve good APAP compliance in these patients.

WITHDRAWN: Idiopathic pleuroparenchymal fibroelastosis: A rare but increasingly recognized entity.

This article has been withdrawn for editorial reasons because the journal will be published only in English. In order to avoid duplicated records, this article can be found at http://dx.doi.org/10.1016/j.rppnen.2014.04.008. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Hypersensitivity reaction and tolerance induction to ethambutol.

Tuberculosis remains the leading cause of death worldwide from any infectious agent and the alarming increase in the annual incidence of new cases has been described as a global emergency. Mycobacterium infection requires simultaneous administration of multiple drugs. Although the majority of treatment courses progress with minor side effects, adverse reactions to antituberculosis drugs occur in about 5% of treated patients and can be responsible for cessation or switching the therapy. Both nonimmediate (mostly maculopapular rash) and immediate reactions (urticarial reactions) have been described with these drugs. The main problem is the occurrence of reactions while the patient is on treatment with multiple drugs. The diagnosis of the culprit drug is mostly based on stopping all medication, followed by the reintroduction of each drug with a time interval of four to five days. An alternative drug should be the first approach if it is equally effective. Most of the times, none of the alternative drugs are as effective as the culprit. If this is the case, a desensitization procedure should be performed. The authors describe a case of a woman with Mycobacterium avium complex (MAC) infection, to whom treatment with ethambutol was crucial to recovery, and present a modified desensitization protocol to this drug.

Pulmonary rehabilitation in patients with bronchiectasis: pulmonary function, arterial blood gases, and the 6-minute walk test.

BACKGROUND: Information regarding the effects of pulmonary rehabilitation (PR) on pulmonary function (PF), arterial blood gases (ABG), and 6-minute walk distance (6MWD) in patients with bronchiectasis is scant in the literature. METHODS: To evaluate the effects of PR on these indices in this population, a retrospective evaluation of those who attended PR from 2007 to 2010, was made. Pulmonary rehabilitation lasted a mean of 12 weeks and included cycle ergometer exercise for 30 minutes, 3 times per week, with additional upper limbs and quadriceps training. PF, ABG, and 6MWD were evaluated before and after PR to determine the potential influence of gender, exacerbations, underlying cause of bronchiectasis, severity of obstruction, and colonization with bacteria. RESULTS: Forty-one patients (48.8% males; median age, 54 years) were included; 25 had severe obstruction and 19 were colonized with bacteria. Following PR, no significant changes were detected in PF or ABG. Median 6MWD before PR was 425 m and post-PR was 450 m (P = .431). Outcomes did not show any interaction with gender, colonization, or exacerbations. However, patients with idiopathic bronchiectasis did show a significant improvement in forced vital capacity in percent of predicted and residual volume after PR (P = .016 and .048, respectively). Patients with severe obstruction showed a statistically significant decrease in percent of predicted residual volume (P = .025). CONCLUSION: There appears to be a beneficial impact of PR on PF in certain groups of patients with bronchiectasis. In addition, PR indications and protocols for patients with bronchiectasis may need to be adapted to accommodate specific patients, so that expressive exercise capacity improvement can be achieved.

Diagnostic value of CD103 expression in bronchoalveolar lymphocytes in sarcoidosis.

BACKGROUND: Pulmonary sarcoidosis is frequently characterized by a CD4(+)/CD8(+) ratio ≥3.5 in bronchoalveolar lavage fluid (BALF), although up to 40% of the cases present a normal or even decreased ratio, pointing out its variability and limitation as a diagnostic marker for sarcoidosis. Lung lymphocytes within the bronchial epithelium, the alveolar walls, and BALF express the integrin CD103. Our aim was to compare the expression of CD103 in BALF T-lymphocytes between sarcoidosis and other interstitial lung diseases (ILD) and to evaluate its relevance as a BALF diagnostic marker for sarcoidosis. METHODS: A total of 86 patients with ILD (mean age ± standard deviation, 42.6 ± 16.6 years; 60.5% female), who underwent BALF as part of their initial diagnostic work-up, were enrolled into 2 groups: sarcoidosis (n = 41) and other ILD (n = 45). Area under the receiver operating characteristic (ROC) curve (AUC) was used to describe the performance of CD103 for sarcoidosis diagnosis. RESULTS: Sarcoidosis patients presented a significantly reduced CD103 expression in BALF T-lymphocytes, more pronounced in the CD4(+) subset. The BALF CD103(+)CD4(+)/CD4(+) ratio for a cutoff point of 0.45 was associated with a better diagnostic performance for sarcoidosis (AUC: 0.86 [95% confidence interval (95% CI): 0.78-0.94]; sensitivity: 81%; specificity: 78%), even for those with a CD4(+)/CD8(+) ratio <3.5 (AUC: 0.79 [95% CI: 0.64-0.93]; sensitivity: 75%; specificity: 78%). CONCLUSIONS: Assessment of CD103 expression in BALF CD4(+) T-lymphocytes may be a reliable tool for sarcoidosis diagnosis, independently of CD4(+)/CD8(+) ratio, pointing out the relevance of evaluating the CD103(+)CD4(+)/CD4(+) ratio in the ILD diagnostic work-up.

Lung cancer: atypical brain metastases mimicking neurocysticercosis.

The authors describe a case of a 47-year-old male smoker with a 3-month history of hearing loss, tinnitus and dizziness. Physical examination revealed neurosensory hearing loss. Small rounded hypodensities without mass effect were evident in a computed tomography scan of the head, confirmed by brain magnetic resonance imaging as multiple cystic lesions in both cerebral and cerebellar hemispheres, without perilesional edema or gadolinium enhancement, suggestive of neurocysticercosis. Extraparenchymal involvement was also noted. Albendazole and dexamethasone were started. As a chest radiograph showed a bilateral reticulonodular pattern, a bronchoscopy was performed showing normal results. However, transbronchial biopsy revealed lung adenocarcinoma. Thoracoabdominopelvic computed tomography scan showed secondary lung and bone lesions. Since brain lesions were not suggestive of secondary tumor lesions, a brain biopsy was performed confirming metastatic disease. This case illustrates some peculiar imagiological features of brain metastases in lung cancer, indicating that sometimes invasive procedures are required to establish a definitive diagnosis.

APAP impact on metabolic syndrome in obstructive sleep apnea patients.

PURPOSE: Prevalence of metabolic syndrome (MS) in obstructive sleep apnea (OSA) patients is high. The effect of autoadjusting positive airway pressure (APAP) on MS remains unclear. This study aimed to determine the prevalence of MS in OSA patients before and 6 months after APAP, and to identify potential determinants of metabolic status change. METHODS: Seventy-four male patients with moderate to severe OSA were enrolled. MS diagnosis was established according to the National Cholesterol Education Program/Adult Treatment Panel III. APAP was prescribed to all patients. RESULTS: In the studied population, mean age was 55.9 years (SD 10.7 years), median body mass index (BMI), Epworth sleepiness scale (ESS), and respiratory disturbance index (RDI) were 33.4 kg/m(2) (interquartile range (IQR) 8.4 kg/m(2)), 12.0 (IQR 8.0), and 46.9/h (IQR 33.6/h), respectively. Prevalence of MS before and 6 months after APAP was 63.5% and 47.3%, respectively, and this difference was statistically significant (p = 0.004). In the subgroup of patients with MS at baseline (n = 47), 14 did not present MS after APAP. In these patients, a significant negative association with RDI (p = 0.016) and a positive association with percent of total days of usage (p = 0.014) were found. Blood pressure (p = 0.018) and serum triglycerides (p = 0.001) had a statistically significant reduction during this period. In patients that still had MS, 22.2% presented a reduction of the number of MS criteria. CONCLUSIONS: After 6 months, APAP reduced the prevalence of MS, mainly in patients with less severe OSA and with a better therapeutic compliance. Blood pressure and serum triglycerides reduction contributed to this metabolic status change.

Extrapulmonary tuberculosis: importance of differential diagnosis.

Patients with tuberculosis (TB) typically present with pulmonary TB, but extrapulmonary TB is also an important clinical problem. In particular, osteoarticular TB has a great morbidity and its diagnosis gold-standard includes culture and histopathology of the infected area. The present case study describes a 53-year-old female Portuguese farmer who had initial clinical and imaging features suggestive of tuberculous osteomyelitis. However, she denied any TB contacts and the tuberculin skin-test and interferon-γ release assay result were negative. Brucella melitensis was isolated from a tissue biopsy cultural examination, and treatment for brucellosis was started, yielding a favourable outcome. In similar circumstances, a precise diagnosis, that considers the epidemiological context, is crucially important for adequate treatment and reduction of morbidity.