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.

Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis.

Rationale: Sarcoidosis is a multisystemic inflammatory disease characterized by the formation of granulomas in response to persistent stimuli. The long pentraxin PTX3 (pentraxin 3) has emerged as a component of humoral innate immunity with essential functions in the resolution of inflammation, but its role during granuloma formation is unknown. Objectives: To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis. Methods: Peripheral blood mononuclear cells obtained from patients with sarcoidosis harboring loss-of-function genetic variants and gene-deleted mice were used to assess the role of PTX3 in experimental models of granuloma formation in vitro and in vivo. The identified mechanisms of granulomatous inflammation were further evaluated in tissue and BAL samples and correlated with the disease course. Measurements and Main Results: We have identified a molecular link between PTX3 deficiency and the pathogenic amplification of complement activation to promote granuloma formation. Mechanistically, PTX3 deficiency licensed the complement component C5a-mediated activation of the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) and the reprogramming of macrophages toward increased glycolysis to foster their proliferation and aggregation. This process sustained the further recruitment of granuloma-promoting immune cells and the associated proinflammatory microenvironment and influenced the clinical course of the disease. Conclusions: Our results identify PTX3 as a pivotal molecule that regulates complement-mediated signaling cues in macrophages to restrain granulomatous inflammation and highlight the therapeutic potential of this signaling axis in targeting granuloma formation in sarcoidosis.

The Role of Ultrasonography in the Diagnosis and Decision Algorithm for the Management of Pneumothorax after Transbronchial Lung Cryobiopsy.

BACKGROUND: Pneumothorax is one of the main complications of transbronchial lung cryobiopsy (TBLC). Chest ultrasound (CUS) is a radiation-free alternative method for pneumothorax detection. OBJECTIVE: We tested CUS diagnostic accuracy for pneumothorax and assessed its role in the decision algorithm for pneumothorax management. Secondary objectives were to evaluate the post-procedure pneumothorax occurrence and risk factors. METHODS: Eligible patients underwent TBLC, followed by chest X-ray (CXR) evaluation 2 h after the procedure, as our standard protocol. Bedside CUS was performed within 30 min and 2 h after TBLC. Pneumothorax by CUS was defined by the absence of lung sliding and comet-tail artefacts and confirmed with the stratosphere sign on M-mode. Pneumothorax size was determined through lung point projection on CUS and interpleural distance on CXR and properly managed according to clinical status. RESULTS: Sixty-seven patients were included. Nineteen pneumothoraces were detected at 2 h after the procedure, of which 8 (42.1%) were already present at the first CUS evaluation. All CXR-detected pneumothoraces had a positive CUS detection. There were 3 discordant cases (κ = 0.88, 95% CI: 0.76-1.00, p < 0.001), which were detected by CUS but not by inspiration CXR. We calculated a specificity of 97.5% (95% CI: 86.8-99.9) and a sensitivity of 100% (95% CI: 87.2-100) for CUS. Pneumothorax rate was higher when biopsies were taken in 2 lobes and if histology had pleural representation. Final diagnosis was achieved in 79.1% of patients, with the most frequent diagnosis being hypersensitivity pneumonitis. Regarding patients with large-volume pneumothorax needing drainage, the rate of detection was similar between CUS and CRX. CONCLUSION: CUS can replace CXR in detecting the presence of pneumothorax after TBLC, and the lung point site can reliably indicate its size. This useful method optimizes time spent at the bronchology unit and allows immediate response in symptomatic patients, helping to choose optimal treatment strategies, while preventing ionizing radiation exposure.

Resistance Profile of Osimertinib in Pre-treated Patients With EGFR T790M-Mutated Non-small Cell Lung Cancer.

Background: Osimertinib efficacy in pre-treated patients with epidermal growth factor receptor (EGFR) T790M-mutated non-small cell lung cancer (NSCLC) has been demonstrated in clinical trials, but real-world data, particularly regarding resistance profile, remains limited. This study aims to analyze the resistance mechanisms acquired after treatment with Osimertinib. Methods: Clinical outcomes and molecular results from re-biopsies at the time of osimertinib progression of EGFR T790M-mutated NSCLC patient were analyzed. Results: Twenty-one patients with stage IV adenocarcinoma were included [median 69 years; 57.1% female; 85.7% never-smokers; 23.8% ECOG performance status (PS) ≥2]. Median PFS and OS were 13.4 (95% CI: 8.0-18.9) and 26.4 (95% IC: 8.9-43.8) months, respectively. At the time of analysis, 10 patients had tumor progression (47.6%). T790M loss occurred in 50%, being associated with earlier progression (median PFS 8.1 vs. 21.4 months, p = 0.011). Diverse molecular alterations were identified, including C797S mutation (n = 1), PIK3CA mutation (n = 2), MET amplification (n = 1), CTNNB1 mutation (n = 1), and DCTN1-ALK fusion (n = 1). Histological transformation into small cell carcinoma occurred in one patient. Conclusions: This real-world life study highlights the relevance of re-biopsy at the time of disease progression, contributing to understand resistance mechanisms and to guide treatment strategies.

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.

Pleuroparenchymal Fibroelastosis as Another Potential Lung Toxicity Pattern Induced by Amiodarone / Fibroelastosis pleuroparenquimal como posible patrón de toxicidad pulmonar inducido por amiodarona

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Targeted Gene Next-Generation Sequencing Panel in Patients with Advanced Lung Adenocarcinoma: Paving the Way for Clinical Implementation.

Identification of targetable molecular changes is essential for selecting appropriate treatment in patients with advanced lung adenocarcinoma. Methods: In this study, a Sanger sequencing plus Fluorescence In Situ Hybridization (FISH) sequential approach was compared with a Next-Generation Sequencing (NGS)-based approach for the detection of actionable genomic mutations in an experimental cohort (EC) of 117 patients with advanced lung adenocarcinoma. Its applicability was assessed in small biopsies and cytology specimens previously tested for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational status, comparing the molecular changes identified and the impact on clinical outcomes. Subsequently, an NGS-based approach was applied and tested in an implementation cohort (IC) in clinical practice. Using Sanger and FISH, patients were classified as EGFR-mutated (n = 22, 18.8%), ALK-mutated (n = 9, 7.7%), and unclassifiable (UC) (n = 86, 73.5%). Retesting the EC with NGS led to the identification of at least one gene variant in 56 (47.9%) patients, totaling 68 variants among all samples. Still, in the EC, combining NGS plus FISH for ALK, patients were classified as 23 (19.7%) EGFR; 20 (17.1%) KRAS; five (4.3%) B-Raf proto-oncogene (BRAF); one (0.9%) Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2); one (0.9%) STK11; one (0.9%) TP53, and nine (7.7%) ALK mutated. Only 57 (48.7%) remained genomically UC, reducing the UC rate by 24.8%. Fourteen (12.0%) patients presented synchronous alterations. Concordance between NGS and Sanger for EGFR status was very high (κ = 0.972; 99.1%). In the IC, a combined DNA and RNA NGS panel was used in 123 patients. Genomic variants were found in 79 (64.2%). In addition, eight (6.3%) EML4-ALK, four (3.1%), KIF5B-RET, four (3.1%) CD74-ROS1, one (0.8%) TPM3-NTRK translocations and three (2.4%) exon 14 skipping MET Proto-Oncogene (MET) mutations were detected, and 36% were treatable alterations. Conclusions: This study supports the use of NGS as the first-line test for genomic profiling of patients with advanced lung adenocarcinoma.

Diffuse smoking-related lung diseases: insights from a radiologic-pathologic correlation.

Cigarettes are well-recognized risk factors responsible for the emergence of a variety of pathologic conditions affecting both the airways and the lungs. Smoking-related lung diseases can be classified as chronic obstructive pulmonary disease (COPD) and several types of interstitial diseases, such as pulmonary Langerhans cell histiocytosis, bronchiolitis, desquamative interstitial pneumonitis, acute eosinophilic pneumonia, and interstitial fibrosing lung diseases. The evidence of combined lower lung fibrosis and predominant upper lung emphysema is renowned as a distinct clinical entity, named combined pulmonary fibrosis and emphysema. Although computerized tomography permits an adequate classification and distinction of these diseases, the clinical, imaging, and histological features often overlap and coexist in a single patient. Therefore, a combined radiologic and pathologic approach, in the appropriate clinical setting, is useful for best comprehension and distinction of these entities. Our goals are to describe the imaging features in smoking-related lung diseases and how the pathological manifestations translate on high-resolution computerized tomography.

Interstitial lung disease and pre-capillary pulmonary hypertension in neurofibromatosis type 1.

Although previously reported, the existence of a neurofibromatosis (NF)-associated diffuse lung disease (DLD) still lacks solid evidence. We report a case of a 68-year-old non-smoking female with NF1, pre-capillary pulmonary hypertension (PH) and an interstitial lung pattern. Initial findings included progressive dyspnea, hypoxemia and sparse centrilobular ground-glass micronodules on high-resolution computed tomography (HRCT). Further study demonstrated a severe defect in diffusing capacity for carbon monoxide (DLCO), macrophages on bronchoalveolar lavage and pre-capillary PH on right cardiac catheterization. Surgical biopsy revealed macrophage accumulation along bronchovascular bundles and alveolar spaces and type II pneumocytes hyperplasia. Given the absence of environmental exposure or new drugs, a NF-DLD was hypothesized. Pre-capillary PH was disproportionate to interstitial findings, so it was attributed to a NF1-vasculopathy. Treatment with triple sequential combined therapy was unsuccessful culminating in death 18 months later. This case adds HRCT and anatomopathological data suggesting NF-DLD as a distinct manifestation of the disease.

Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study.

BACKGROUND: Diffuse parenchymal lung disease represents a diverse and challenging group of pulmonary disorders. A consistent diagnostic approach to diffuse parenchymal lung disease is crucial if clinical trial data are to be applied to individual patients. We aimed to evaluate inter-multidisciplinary team agreement for the diagnosis of diffuse parenchymal lung disease. METHODS: We did a multicentre evaluation of clinical data of patients who presented to the interstitial lung disease unit of the Royal Brompton and Harefield NHS Foundation Trust (London, UK; host institution) and required multidisciplinary team meeting (MDTM) characterisation between March 1, 2010, and Aug 31, 2010. Only patients whose baseline clinical, radiological, and, if biopsy was taken, pathological data were undertaken at the host institution were included. Seven MDTMs, consisting of at least one clinician, radiologist, and pathologist, from seven countries (Denmark, France, Italy, Japan, Netherlands, Portugal, and the UK) evaluated cases of diffuse parenchymal lung disease in a two-stage process between Jan 1, and Oct 15, 2015. First, the clinician, radiologist, and pathologist (if lung biopsy was completed) independently evaluated each case, selected up to five differential diagnoses from a choice of diffuse lung diseases, and chose likelihoods (censored at 5% and summing to 100% in each case) for each of their differential diagnoses, without inter-disciplinary consultation. Second, these specialists convened at an MDTM and reviewed all data, selected up to five differential diagnoses, and chose diagnosis likelihoods. We compared inter-observer and inter-MDTM agreements on patient first-choice diagnoses using Cohen's kappa coefficient (κ). We then estimated inter-observer and inter-MDTM agreement on the probability of diagnosis using weighted kappa coefficient (κw). We compared inter-observer and inter-MDTM confidence of patient first-choice diagnosis. Finally, we evaluated the prognostic significance of a first-choice diagnosis of idiopathic pulmonary fibrosis (IPF) versus not IPF for MDTMs, clinicians, and radiologists, using univariate Cox regression analysis. FINDINGS: 70 patients were included in the final study cohort. Clinicians, radiologists, pathologists, and the MDTMs assigned their patient diagnoses between Jan 1, and Oct 15, 2015. IPF made up 88 (18%) of all 490 MDTM first-choice diagnoses. Inter-MDTM agreement for first-choice diagnoses overall was moderate (κ=0·50). Inter-MDTM agreement on diagnostic likelihoods was good for IPF (κw=0·71 [IQR 0·64-0·77]) and connective tissue disease-related interstitial lung disease (κw=0·73 [0·68-0·78]); moderate for non-specific interstitial pneumonia (NSIP; κw=0·42 [0·37-0·49]); and fair for hypersensitivity pneumonitis (κw=0·29 [0·24-0·40]). High-confidence diagnoses (>65% likelihood) of IPF were given in 68 (77%) of 88 cases by MDTMs, 62 (65%) of 96 cases by clinicians, and in 57 (66%) of 86 cases by radiologists. Greater prognostic separation was shown for an MDTM diagnosis of IPF than compared with individual clinician's diagnosis of this disease in five of seven MDTMs, and radiologist's diagnosis of IPF in four of seven MDTMs. INTERPRETATION: Agreement between MDTMs for diagnosis in diffuse lung disease is acceptable and good for a diagnosis of IPF, as validated by the non-significant greater prognostic separation of an IPF diagnosis made by MDTMs than the separation of a diagnosis made by individual clinicians or radiologists. Furthermore, MDTMs made the diagnosis of IPF with higher confidence and more frequently than did clinicians or radiologists. This difference is of particular importance, because accurate and consistent diagnoses of IPF are needed if clinical outcomes are to be optimised. Inter-multidisciplinary team agreement for a diagnosis of hypersensitivity pneumonitis is low, highlighting an urgent need for standardised diagnostic guidelines for this disease. FUNDING: National Institute of Health Research, Imperial College London.

Disruption of BASIGIN decreases lactic acid export and sensitizes non-small cell lung cancer to biguanides independently of the LKB1 status.

Most cancers rely on aerobic glycolysis to generate energy and metabolic intermediates. To maintain a high glycolytic rate, cells must efficiently export lactic acid through the proton-coupled monocarboxylate transporters (MCT1/4). These transporters require a chaperone, CD147/BASIGIN (BSG) for trafficking to the plasma membrane and function.To validate the key role of these transporters in lung cancer, we first analysed the expression of MCT1/4 and BSG in 50 non-small lung cancer (NSCLC) cases. These proteins were specifically upregulated in tumour tissues. We then disrupted BSG in three NSCLC cell lines (A549, H1975 and H292) via 'Zinc-Finger Nucleases'. The three homozygous BSG-/- cell lines displayed a low MCT activity (10- to 5-fold reduction, for MCT1 and MCT4, respectively) compared to wild-type cells. Consequently, the rate of glycolysis, compared to the wild-type counterpart, was reduced by 2.0- to 3.5-fold, whereas the rate of respiration was stimulated in BSG-/- cell lines. Both wild-type and BSG-null cells were extremely sensitive to the mitochondria inhibitor metformin/phenformin in normoxia. However, only BSG-null cells, independently of their LKB1 status, remained sensitive to biguanides in hypoxia in vitro and tumour growth in nude mice. Our results demonstrate that inhibiting glycolysis by targeting lactic acid export sensitizes NSCLC to phenformin.

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.

Wegener's granulomatosis and alveolar hemorrhage - case report.

The authors present a clinical case of 55 years old female patient with limited form of Wegener's granulomatosis (WG), which first manifestation was non-erosive polyarthritis with rheumatoid factor positive that antedates one decade the pulmonary manifestations. She had acute episodes with purulent expectoration, fever and hemoptysis, with resolution in a week. The chest x-rays demonstrated migratory bilateral pulmonary infiltrates. Transthoracic lung biopsy was performed and revealed capilaritis and signs of old and recent hemorrhage. At that time, autoimmunity study was repeated and showed positive for rheumatoid factor, negative anti-cyclic citrullinated peptide antibodies (anti-CCP) and high sustained PR3 anti-neutrophil cytoplasmic antibodies. The diagnosis of WG was established and cyclophosphamide started. This patient had a less common presentation and a less common histological pattern compared to the typical necrotizing granulomatous inflammation. She was treated with immunosuppression therapy which could have contributed to a mild clinical expression and a lower diagnostic yield. In suspicious cases, repeat the autoimmunity study, when facing new findings, could confirm the correct diagnosis.

[Descamative interstitial pneumonia in a patient with undifferentiated connective-tissue disease]. / Pneumonia Intersticial Descamativa em doente com Conectivite Indeferenciada.

A 49 year-old Caucasian male, smoker (15 pack-year), had at the beginning of his disease an additive, symmetric polyarthritis, affecting predominantly the small joints of the hands, wrists, shoulders and tibiotarsal joints. The autoimmune study revealed ANA and anti-ribosomal P protein antibodies positivity. An undifferentiated connective tissue disease was diagnosed and treatment with deflazacort, naproxen and hydroxychloroquine was begun. Two years later, he starts exertional dyspnea, without other respiratory symptoms. A chest high-resolution computerized tomography scan was performed, evidencing diffuse "ground-glass" opacities. Respiratory functional study showed low diffusion capacity. The bronchoalveolar lavage (BAL) revealed a neutrophilic and eosinophilic (20%) alveolitis, which was not associated with peripheral blood eosinophilia. The definitive diagnosis was obtained by a surgical lung biopsy, which showed features consistent with Descamative Interstitial Pneumonia (DIP). This rare entity is referred as a smoke-related disease. The debate about an eventual association of DIP with autoimmune diseases and BAL eosinophilia is discussed by the authors based on the present clinical case features.

[Congenital lobar emphysema of the newborn. Report of four clinical cases]. / Enfisema lobar congénito com apresentação neonatal. Revisão de quatro casos clínicos.

INTRODUCTION: Congenital lobar emphysema (CLE) is a rare anomaly of lung development that presents in the neonatal period in about 50% of the cases. The authors report four clinical cases of congenital lobar emphysema in the newborn. CLINICAL CASES: Four term newborns, 3M/ 1F, were admitted for respiratory distress starting between 20 hours of life and 18 days. The chest x -ray at admission was suggestive of CLE and the diagnosis was confirmed by computorized tomography. The CLE affected the right upper lobe in three cases and the medium lobe in one case. All patients were treated with lobectomy. The pathological study of the surgical specimens confirmed the diagnosis in the four cases, and revealed hypoplasia of the bronquiolar tree cartilage in three. CONCLUSIONS: Our series is according to literature regarding to male gender preponderance, clinical presentation, different time to diagnosis, unilobar involvement and no identification of an evident aetiology in one case. Surgical treatment was universal.

Henoch-Schönlein purpura: a clinical case with dramatic presentation.

A case study involving a 55-year-old Caucasian male with end-stage glomerulosclerosis is presented here. Kidney biopsies showed no deposits on imunofluorescent microscopy. Relapsing massive haemoptysis and suspected bronchovascular malformation required lung lobectomy which revealed malformative and tortuous small blood vessels, with no vasculitis. Blood antinuclear antibodies, antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies were undetectable. Seric immunoglobulins and complement levels were normal. Three months later, arthralgia and joint oedema first appeared. Skin biopsy revealed vasculitis immune-reactive to immunoglobulin A. Systemic corticotherapy was then started. Two weeks later, the patient presented with abdominal pain melena and rectal bleeding (haematoquesia). Endoscopic study showed diffuse gastrointestinal haemorrhage. Angiographic study revealed diffuse lesions compatible with vasculitis and haemorrhage from multiple spots. Cyclophosphamide and then intravenous immunoglobulin were associated to treatment without response. Increasing blood loss occurred, with massive gastrointestinal haemorrhage and haemorrhagic ascitis. Death occurred due to uncontrolled diffuse bleeding. Necropsy findings showed generalised small vessels vasculitis compatible with Henoch-Schönlein purpura.