Cystic lung in sarcoidosis: Clinico-radiologic characteristic and evolution.

BACKGROUND AND OBJECTIVE: Sarcoidosis can manifest with atypical findings on chest computed tomography (CT). Cysts are a rare manifestation of lung sarcoidosis. The aim of the study was to describe a series of patients with cystic sarcoidosis and their clinical-radiological characteristics and progression. METHODS: In this retrospective, bicentric study we recruited all patients affected by sarcoidosis with lung cystic lesions at chest CT. We collected clinical characteristics, pulmonary tests and tracked number, distribution and size of the cysts at diagnosis and at the last evaluation. RESULTS: Twelve patients (6 males, median age 53 years) were identified (prevalence: 1.9%; 95% Confidence Interval: 0.8%-2.9%). All patients presented multiple cystic lesions (median number: 14 [range: 2-216]) with a bilateral distribution in 10/12, micronodules and nodules in 11/12 and fibrotic lesions in 4/12. Seven patients had normal lung function test, three had an obstructive syndrome, one had a restrictive syndrome and one had coexistence of both. During follow-up (median: 10 years [range 1-16 years]), an increase of the number of cysts was observed in four patients. At last evaluation, 3/12 patients experienced a decline of forced vital capacity >10% and 3/12 patients a decline of diffusing capacity for carbon monoxide (DLCO) >10%. A lower DLCO at diagnosis, and the presence of nodules or fibrotic lesions on CT were associated with an increase in the number of cysts. CONCLUSION: Cystic lung lesions are rare in patients with sarcoidosis and do not influence long term prognosis.

European Respiratory Society guidelines for the Diagnosis and Management of Pulmonary Alveolar Proteinosis.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by several distinct diseases leading to progressive dyspnoea, hypoxemia, risk of respiratory failure and early death due to accumulation of proteinaceous material in the lungs. Diagnostic strategies may include computed tomography (CT) of the lungs, bronchoalveolar lavage, evaluation of antibodies against granulocyte macrophage colony stimulating factor (GM-CSF), genetic testing, and, eventually, lung biopsy. The management options are focused at removing the proteinaceous material by whole lung lavage (WLL), augmentation therapy with GM-CSF, rituximab, plasmapheresis, and lung transplantation. The presented diagnostic and management guideline aim to provide guidance to physicians managing patients with PAP. METHODS: A European Respiratory Society Task Force committee composed of clinicians, methodologists, and patients with experience in PAP developed recommendations in accordance with the ERS Handbook for Clinical Practice Guidelines and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. This included a systematic review of the literature and application of the GRADE approach to assess the certainty of the evidence and strength of recommendations. The committee formulated five PICO (Patients, Intervention, Comparison, Outcomes) questions, and two narrative questions to develop specific evidence-based recommendations. RESULTS: The Task Force committee developed recommendations for five PICOs. These included management of PAP with WLL, GM-CSF augmentation therapy, rituximab, plasmapheresis, and lung transplantation. Also, the committee made recommendations regarding the use of GM-CSF antibody testing, diagnostic bronchoalveolar lavage (BAL) and biopsy based on narrative questions.In addition to the recommendations, the committee provided information on the hierarchy of diagnostic interventions and therapy. CONCLUSIONS: The diagnosis of PAP is based on CT and BAL cytology or lung histology, whereas diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis. There are several therapies including WLL and augmentation therapy with GM-CSF available to treat PAP, but supporting evidence is still limited.

Alemtuzumab-based conditioning regimen before hematopoietic stem cell transplantation in patients with short telomere syndromes: a retrospective study of the SFGM-TC.

While HSCT is the only curative option for patients with short telomere syndromes (STSs) and severe bone marrow failure (BMF) or myeloid malignancies (MM), their increase sensitivity to conditioning regimen strongly affect outcomes. To minimize HSCT related mortality, alemtuzumab-based conditioning regimens have been proposed, but the number of patients transplanted with those regimens reported in the literature remains very low. We retrospectively analyzed outcome of adults and adolescents with STSs transplanted after an alemtuzumab, fludarabine and cyclophosphamide based regimen registered by the SFGM-TC. Seven patients were transplanted for a BMF and 5 for a MM (median age 34 years, (IQR [22-45])). The 2-year GRFS for patients with MM was 20% (95% CI [3;100]), and 57% (95% CI [30;100]) in others. In univariate (hazard ratio, HR = 6, 95% CI [1;31]) and multivariate analysis (HR = 26, 95% CI [2;414]) stem cell source was a predictive factor for GRFS. Three of the 5 patients with pre-transplant MM relapsed and 2 of them died at last follow up. The 2-year OS was 66% (95% CI [43;99]) in the whole cohort with a median follow up of 32 months (IQR [13-56]). In conclusion, Alemtuzumab-based conditioning regimen with bone marrow is an option for patients with STSs and BMF, but others modalities have to be explored for patients with MM.

Epidemiology of childhood interstitial lung disease in France: the RespiRare cohort.

INTRODUCTION: Interstitial lung disease in children (chILD) are rare and mostly severe lung diseases. Very few epidemiological data are available in limited series of patients. The aim of this study was to assess the prevalence and incidence of chILD in France. METHODS: We performed within the RespiRare network a multicentre retrospective observational study in patients with chILD from 2000 to 2022 and a prospective evaluation of chILD's incidence between February 2022 and 2023. RESULTS: chILD was reported in 790 patients in 42 centres. The estimated 2022 prevalence in France was 44 /million children (95% CI 40.76 to 47.46) and the computed incidence was 4.4 /million children (95% CI 3.44 to 5.56). The median age at diagnosis was 3 months with 16.9% of familial forms. Lung biopsy and genetic analyses were performed in 23.4% and 76.9%, respectively. The most frequent chILD aetiologies in the <2 years group were surfactant metabolism disorders (16.3%) and neuroendocrine cell hyperplasia of infancy (11.8%), and in the 2-18 years group diffuse alveolar haemorrhage (12.2%), connective tissue diseases (11.4%), hypersensitivity pneumonitis (8.8%) and sarcoidosis (8.8%). The management included mainly oxygen therapy (52%), corticosteroid pulses (56%), oral corticosteroids (44%), azithromycin (27.2%), enteral nutrition (26.9%), immunosuppressants (20.3%) and hydroxychloroquine (15.9%). The 5-year survival rate was 57.3% for the patients diagnosed before 2 years and 86% between 2 and 18 years. CONCLUSION: This large and systematic epidemiological study confirms a higher incidence and prevalence of chILD than previously described. In order to develop international studies, efforts are still needed to optimise the case collection and to harmonise diagnostic and management practices.

An underrecognized phenotype of pulmonary emphysema with marked pulmonary gas exchange but with mild or moderate airway obstruction.

In patients with pulmonary emphysema and mild to moderate airflow limitation, one does not expect the features marked exertional dyspnea and hypoxemia as well as a profound decrease in diffusing capacity of the lung for carbon monoxide (DLCO). Here we describe this phenotype and its prognosis. From our database, we retrospectively selected cases associating emphysema, exertional breathlessness, O2 requirement at least upon exercise, forced expiratory volume in 1 sec (FEV1) ≥ 50% predicted, and DLCO ≤ 50% predicted, without associated combined pulmonary fibrosis and emphysema, right-to-left shunt, or severe pulmonary hypertension. Over a 12-year period, we identified 16 patients with emphysema and the above presentation. At the initial evaluation, the median age was 62 years (interquartile range 53.8-68.9). The median FEV1 and DLCO% predicted and mean pulmonary artery pressure were 86 (65-95)%, 38 (31-41)%, and 20 (17-25) mm Hg, respectively. On room air, the median arterial partial pressure of oxygen and partial pressure of carbon dioxide in arterial blood were 63.5 (55.8-69) mm Hg and 34.5 (31-36) mm Hg with increased median alveolar-arterial oxygen difference (46 [39-51] mm Hg). After the initial evaluation, the respiratory condition worsened in 13 of 14 (92.8%) patients with one or more re-evaluations (median follow-up 2.6 [0.9-5.8] years). In 12, lung transplantation was considered. Four patients died after 5.8, 5.7, 7.1, and 0.8 years of follow-up, respectively. We describe an underrecognized phenotype of pulmonary emphysema featuring a particular profile characterized by marked exertional dyspnea, impaired pulmonary gas exchange with low DLCO and marked oxygen desaturation at least on exercise but with mild or moderate airway obstruction.

RPA3-UMAD1 rs12702634 and rheumatoid arthritis-associated interstitial lung disease in European ancestry.

Objective: Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950. Methods: In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin. Results: Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 × 10-11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70). Conclusion: Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.

Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study.

BACKGROUND: A usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors. METHODS: We used two-sample bidirectional Mendelian randomisation (MR) to test the hypothesis of a causal effect of RA on UIP and of UIP on RA, using variants from genome-wide association studies (GWAS) of RA (separately for seropositive (18 019 cases and 991 604 controls) and seronegative (8515 cases and 1 015 471 controls) RA) and of IPF (4125 cases and 20 464 controls) as genetic instruments. Sensitivity analyses were conducted to assess the robustness of the results to violations of the MR assumptions. FINDINGS: IPF showed a significant causal effect on seropositive RA, with developing IPF increasing the risk of seropositive RA (OR=1.06, 95% CI: 1.04 to 1.08, p<0.001) which was robust under all models. For the MR in the other direction, seropositive RA showed a significant protective effect on IPF (OR=0.93; 95% CI: 0.87 to 0.99; p=0.032), but the effect was not significant when sensitivity analyses were applied. This was likely because of bias due to exclusion of patients with RA from among the cases in the IPF GWAS, or possibly because our genetic instruments did not fully capture the effect of the complex human leucocyte antigen region, the strongest RA genetic risk factor. INTERPRETATION: Our findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between UIP and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The significant causal effect of IPF on seropositive RA suggests that pathomechanisms involved in the development of UIP may promote RA, and this may help inform future guidelines on screening for ILD in patients with RA.

High risk of lung cancer in surfactant-related gene variant carriers.

BACKGROUND: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers. METHODS: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers. RESULTS: We identified 99 SRG adult variant carriers (SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer (SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1/SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7). CONCLUSIONS: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated.

Successful lung transplantation in genetic methionyl-tRNA synthetase-related alveolar proteinosis/lung fibrosis without recurrence under methionine supplementation: Medium-term outcome in 4 cases.

Pulmonary alveolar proteinosis (PAP) results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages, and can be associated with pulmonary fibrosis, with a need for lung transplantation (LTx). Causes of PAP are autoimmune (90%-95%), secondary (5%), or hereditary (<1%). Patients with hereditary PAP are generally not considered for isolated LTx, due to the high probability of recurrence after LTx, and only a challenging scenario with sequential LTx followed by hematopoietic stem cell transplantation (HSCT) was reported as successful. Recently, a new genetic cause of PAP linked to mutations in the methionyl-tRNA synthetase (MARS) gene has been reported, with a highly variable clinical presentation. Because clinical correction of the defective MARS activity with methionine supplementation has been reported in nontransplanted children, we reassessed the feasibility of LTx for candidates with MARS-related PAP/fibrosis. We report 3 cases of LTx performed for MARS-related pulmonary alveolar proteinosis-pulmonary fibrosis without recurrence under methionine supplementation, whereas another fourth case transplanted without supplementation had fatal PAP recurrence. These results suggest the effectiveness of methionine in correcting defective MARS activity and also looking for this very rare diagnosis in case of unclassified PAP/fibrosis. It argues for not excluding the feasibility of isolated LTx in patients with MARS mutation.

Similarities and differences of interstitial lung disease associated with pathogenic variants in SFTPC and ABCA3 in adults.

BACKGROUND AND OBJECTIVE: Variants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults. METHODS: We conducted a multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed. RESULTS: We included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% ([52-72]) and DLco was 44% ([35-50]). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground-glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DLCO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DLCO , p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow-up in the ABCA3 group. CONCLUSION: SFTPC and ABCA3-associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground-glass opacities and/or cysts is frequently found in these rare conditions.

Anti-mutated citrullinated vimentin antibodies are increased in IPF patients.

INTRO: An increased prevalence of serum anti-MCV antibody is observed in the serum of patients with idiopathic pulmonary fibrosis (IPF) but the clinical relevance of these antibodies is unknown. METHODS: Patients from our center with a diagnosis of IPF according to the 2018 ATS/ERS/JRS/ALAT guidelines and at least one anti-MCV assay available were selected. All patients were part of the prospective cohort European IPF registry and selected between 03/2010 and 03/2018. We constituted two groups of patients according to the anti-MCV status at baseline to compare their characteristics at baseline and the evolution of lung function, survival and/or transplantation status. RESULTS: Anti-MCV data were available for 101 patients, of whom 86 had complete clinical data available. Twenty-nine (34 %) patients had a positive anti-MCV assay (MCV+), at a low level in most patients (29 UI/mL [IQR 25-40]), and 57 (66 %) patients a negative assay (MCV-). MCV+ patients were 20 men and 9 women, with a median age of 73 years [IQR 67-78]. MCV- patients were 49 men and 8 women with a median age of 72 years [IQR 64-77]. Sixty-two (75 %) patients were ex-smokers and 5 (6 %) were active smokers. Median cumulative tobacco smoke exposure was 22.5 (15.0-38.6) and was similar in both groups. Lung function test results and HRCT pattern distribution was similar in both groups at baseline. The median duration of follow-up was 3.5 years [IQR 2.1-5.0]. Lung function decline was similar in both groups. During the study period, 31 (36 %) patients died or have been transplanted with no difference in transplant-free survival status between the two groups. CONCLUSION: Low level anti-MCV autoimmunity was prevalent in IPF patients.

Effect of antifibrotic agents on postoperative complications after lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Antifibrotic agents (AFAs) are now standard-of-care for idiopathic pulmonary fibrosis (IPF). Concerns have arisen about the safety of these drugs in patients undergoing lung transplantation (LTx). METHODS: We performed a multi-centre, nationwide, retrospective, observational study of French IPF patients undergoing LTx between 2011 and 2018 to determine whether maintaining AFAs in the peri-operative period leads to increased bronchial anastomoses issues, delay in skin healing and haemorrhagic complications. We compared the incidence of post-operative complications and the survival of patients according to AFA exposure. RESULTS: Among 205 patients who underwent LTx for IPF during the study period, 58 (28%) had received AFAs within 4 weeks before LTx (AFA group): pirfenidone in 37 (18.0%) and nintedanib in 21 (10.2%). The median duration of AFA treatment before LTx was 13.8 (5.6-24) months. The AFA and control groups did not significantly differ in airway, bleeding or skin healing complications (p = 0.91, p = 0.12 and p = 0.70, respectively). Primary graft dysfunction was less frequent in the AFA than control group (26% vs. 43%, p = 0.02), and the 90-day mortality was lower (7% vs. 18%, p = 0.046). CONCLUSIONS: AFA therapy did not increase airway, bleeding or wound post-operative complications after LTx and could be associated with reduced rates of primary graft dysfunction and 90-day mortality.

CSF2RB mutation-related hereditary pulmonary alveolar proteinosis: the "long and winding road" into adulthood.

Genetic analysis pre-lung transplantation diagnosed a case of hereditary pulmonary alveolar proteinosis (PAP) complicated by fibrosis in adulthood. The need for genetic testing in GM-CSF autoantibody negative and unclassifiable PAP is highlighted. https://bit.ly/3QcsYwM.

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.

BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. APPROACH AND RESULTS: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001). CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial.

Outcome of lung transplantation for adults with interstitial lung disease associated with genetic disorders of the surfactant system.

Background: Interstitial lung disease associated with genetic disorders of the surfactant system is a rare entity in adults that can lead to lung transplantation. Our objective was to describe the outcome of these patients after lung transplantation. Methods: We conducted a retrospective, multicentre study, on adults who underwent lung transplantation for such disease in the French lung transplant centres network, from 1997 to 2018. Results: 20 patients carrying mutations in SFTPA1 (n=5), SFTPA2 (n=7) or SFTPC (n=8) were included. Median interquartile range (IQR) age at diagnosis was 45 (40-48) years, and median (IQR) age at lung transplantation was 51 (45-54) years. Median overall survival after transplantation was 8.6 years. Two patients had a pre-transplant history of lung cancer, and two developed post-transplant lung cancer. Female gender and a body mass index <25 kg·m-2 were significantly associated with a better prognosis, whereas transplantation in high emergency was associated with a worst prognosis. Conclusions: Lung transplantation in adults with interstitial lung disease associated with genetic disorders of surfactant system may be a valid therapeutic option. Our data suggest that these patients may have a good prognosis. Immunosuppressive protocol was not changed for these patients, and close lung cancer screening is needed before and after transplantation.

Infections in autoimmune pulmonary alveolar proteinosis: a large retrospective cohort.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease, predisposing to an increased risk of infection. A complete picture of these infections is lacking. RESEARCH QUESTION: Describe the characteristics and clinical outcomes of patients diagnosed with aPAP, and to identify risk factors associated with opportunistic infections. METHODS: We conducted a retrospective cohort including all patients diagnosed with aPAP between 2008 and 2018 in France and Belgium. Data were collected using a standardised questionnaire including demographics, comorbidities, imaging features, outcomes and microbiological data. RESULTS: We included 104 patients, 2/3 were men and median age at diagnosis was 45 years. With a median follow-up of 3.4 years (IQR 1.7-6.6 years), 60 patients (58%), developed at least one infection, including 23 (22%) with opportunistic infections. Nocardia spp was the main pathogen identified (n=10). Thirty-five (34%) patients were hospitalised due to infection. In univariate analysis, male gender was associated with opportunistic infections (p=0.04, OR=3.88; 95% CI (1.02 to 22.06)). Anti-granulocyte macrophage colony-stimulating factor antibody titre at diagnosis was significantly higher among patients who developed nocardiosis (1058 (316-1591) vs 580 (200-1190), p=0.01). Nine patients had died (9%), but only one death was related to infection. INTERPRETATION: Patients with aPAP often presented with opportunistic infections, especially nocardiosis, which highlights the importance of systematic search for slow-growing bacteria in bronchoalveolar lavage or whole lung lavage.

A 24-Year-Old Woman With Cough, Arthralgia, and Skin Ulcerations.

CASE PRESENTATION: A 24-year-old Senegalese woman without remarkable history except anemia and iron deficiency related to excessive menstrual bleeding and sickle cell trait was admitted to our internal medicine department with 4-month fever, weight loss (-13 kg), dyspnea for limited efforts, intermittent productive cough, and bilateral metacarpophalangeal (MCP) and interphalangeal arthralgia. She was born and lived in France. She traveled previously to Senegal in 2015. She had no history of tobacco, alcohol, or drug use nor proximity with animals. She was taking no medication.

Paraneoplastic pemphigus uncovers distinct clinical and biological phenotypes of western unicentric Castleman disease.

Unicentric Castleman disease (UCD) is a lymphoproliferative disease of unknown cause. Paraneoplastic pemphigus (PNP) is a major complication shown to be associated with a poor prognosis, with particular severity in patients with bronchiolitis obliterans (BO). This study describes the clinical and biological characteristics of UCD-PNP patients in a large Western cohort. A total of 148 patients diagnosed with UCD were identified, including 14 patients with a defined PNP. PNP was significantly associated with myasthenia gravis (MG) and FDC sarcoma during follow-up (FDCS). PNP was also significantly associated with reduced survival. These data, together with a multivariate analysis by principal components, led to the identification of UCD-PNP as a group at risk of MG, FDCS and death. PDGFRB sequencing performed on UCD lesions from six patients found the gain-of-function p.N666S variant in two. Interestingly, both patients had hyaline-vascular UCD subtype, were in the UCD-PNP subgroup and had FDCS. Sera from 25 UCD-PNP patients and 6 PNP patients without UCD were tested for PNP-associated autoantibodies. Sera from UCD-PNP patients had a strong reactivity against the N-terminal domain of recombinant periplakin (rPPL, 82%) and showed reactivity against at least two domains of rPPL. These features were not found in patients with UCD alone or in the PNP group without UCD. These data indicate that UCD-PNP patients belong to a subgroup sharing strong clinical and biological identity that might help to decipher the different dynamics of UCD natural history.