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1.
Genome Med ; 13(1): 64, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879239

RESUMO

BACKGROUND: Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. METHODS: To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-ß) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. RESULTS: We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. CONCLUSIONS: Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.


Assuntos
/imunologia , Citocinas/imunologia , Macrófagos/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colo/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Pulmão/imunologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Fenótipo , RNA-Seq
2.
Anticancer Res ; 41(3): 1497-1506, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788742

RESUMO

BACKGROUND: No study has yet investigated the incidence of chemotherapy-induced acute exacerbation of interstitial pneumonia (AE-IP) in patients with autoantibody-positive IP and lung cancer. Herein, we retrospectively compared the incidence of chemotherapy-induced AE-IP in patients with lung cancer between those with autoantibody-positive and -negative IP. PATIENTS AND METHODS: Between October 2003 and December 2018, patients with lung cancer who received chemotherapy, underwent serological test of antinuclear antibody or rheumatoid factor, and were diagnosed with IP were enrolled. RESULTS: A total of 81 patients were enrolled; autoantibody-positive cases were observed in 23.5%. Autoantibody positivity was an independent risk factor for chemotherapy-induced AE-IP at 6 months after initiation of chemotherapy for lung cancer. The time to onset of AE-IP was significantly shorter in autoantibody-positive patients than in the seronegative patients. CONCLUSION: Chemotherapy-induced AE-IP developed earlier in patients with autoantibody than in those without. Therefore, the potential development of AE-IP in autoantibody-positive patients warrants monitoring.


Assuntos
Autoanticorpos/imunologia , Quimioterapia de Indução/efeitos adversos , Doenças Pulmonares Intersticiais/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Quimioterapia de Indução/métodos , Estimativa de Kaplan-Meier , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco
3.
Medicine (Baltimore) ; 100(4): e24260, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33530214

RESUMO

ABSTRACT: Interstitial pneumonia with autoimmune features (IPAF) is a special subtype of interstitial lung disease that has received worldwide attention. Krebs von den Lungen-6 (KL-6) and surfactant protein-A (SP-A) can be used as an important biomarker of interstitial lung disease, but its exact relationship with IPAF is poorly understood.A total of 65 IPAF patients were included in the study and were followed up for 52 weeks. The KL-6 and SP-A were evaluated by chemiluminescence enzyme immunoassay. The above indicators were tested at 2 time points, baseline (the first admission of patients) and 52 weeks. We also collected the indicators of antinuclear antibodies and rheumatoid factor. Based on high-resolution computed tomography evaluations, patients were divided into: aggravation, stable, and improvement group. At same time, 30 age-matched normal people as normal control were recruited, the same information was collected. Correlations among the groups were compared and analyzed.The KL-6 and SP-A level in IPAF patients were significantly higher than normal controls (fold increase = 11.35 and 1.39, both P < .001) and differed significantly at baseline and 52 weeks in IPAF (difference ratio = 37.7% and 21.3%, P < .05, both). There were significant differences at baseline and 52 weeks (r values of aggravation, improvement, and stable groups for KL-6 were 0.705, 0.770, and 0.344, P = .001, .001, and .163, and for SP-A the r value were 0.672, 0.375, and 0.316, P = .001, .126, and .152). In aggravation group, KL-6 and SP-A were correlated with CT scores (both P < .05). Diffusing capacity of the lung for carbon monoxide (DLCO) and forced vital capacity (FVC), % predicted showed a progressive downward trend, with a significant difference at baseline and 52 weeks in IPAF patients (difference ratio = 23.8% and 20.6%, both P < .05). There was a significant correlation between KL-6 and FVC % predicted and DLCO (both P < .05), SP-A showed negatively correlated with DLCO, but not significantly correlated with FVC % predicted (P < .05 and .47).This study demonstrated that KL-6 and SP-A can reflect disease progression, and both 2 play a key role at reflection of lung epithelial cell injury and fibrosis degree in IPAF.


Assuntos
Doenças Pulmonares Intersticiais/sangue , Mucina-1/sangue , Proteína A Associada a Surfactante Pulmonar/sangue , Adulto , Anticorpos Antinucleares/sangue , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Pulmão/imunologia , Pulmão/patologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/sangue
4.
BMC Pulm Med ; 21(1): 57, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579248

RESUMO

BACKGROUND: Anti-synthetase syndrome (ASSD) is a chronic autoimmune condition characterized by antibodies directed against an aminoacycl transfer RNA synthetase (ARS) along with a group of clinical features including the classical clinical triad: inflammatory myopathy, arthritis, and interstitial lung disease (ILD). ASSD is highly heterogenous due to different organ involvement, and ILD is the main cause of mortality and function loss, which presents as different patterns when diagnosed. We designed this retrospective cohort to describe the clinical features and disease behaviour of ASSD associated ILD. METHODS: Data of 108 cases of ASSD associated ILD were retrospectively collected in Beijing Chaoyang Hospital from December 2017 to March 2019. Data were obtained from the Electronic Medical Record system. Patients were divided into 5 groups according to distinct aminoacyl tRNA synthetase (ARS) antibodies. RESULTS: Overall, 108 consecutive patients were recruited. 33 were JO-1 positive, 30 were PL-7 positive, 23 were EJ positive, 13 were PL-12 positive and 9 were OJ positive. The JO-1 (+) group had a significant higher rate of mechanic's hand (57.6%) than other 4 groups. Polymyositis/dermatomyositis (PM/DM) was diagnosed in 25 (23.1%) patients and no difference was observed among the 5 groups. The PL-7 (+) group had a higher frequency of UIP pattern (13.3%) than the other 4 groups but the difference was not significant, and the EJ (+) group had the most frequent OP pattern (78.2%), which was significantly higher than the PL-7 (+) (P < 0.001) and PL-12 (+) groups (P = 0.025). The median follow-up time was 10.7 months, during which no patients died. All received prednisone treatment, with or without immunosuppressants. At the 6-month follow-up, 96.3% of all patients (104/108) had a positive response to therapy, the JO-1 (+) and EJ (+) groups had a significantly higher improvement of forced vital capacity than the other 3 groups (P < 0.05), and the PL-7 group had the lowest FVC improvement (P < 0.05). The JO-1 (+) group and EJ (+) group had significantly higher anti-Ro-52 positive occurrence than the other 3 groups (P < 0.05). CONCLUSION: Anti PL-7 antibody had the same frequency as anti-JO-1 in ASSD-ILD, in which the ILD pattern was different with distinct anti-ARS antibodies. Most ASSD-ILD had a positive response to steroid therapies, with or without immunosuppressants. The PL-7 (+) group had the highest occurrence of UIP pattern, and a significantly lower response to therapy.


Assuntos
Autoanticorpos/imunologia , Dermatomiosite/fisiopatologia , Doenças Pulmonares Intersticiais/fisiopatologia , Miosite/fisiopatologia , Adulto , Idoso , Alanina-tRNA Ligase/imunologia , Anticorpos Antinucleares/imunologia , China , Estudos de Coortes , Dermatomiosite/tratamento farmacológico , Dermatomiosite/imunologia , Feminino , Glucocorticoides/uso terapêutico , Glicina-tRNA Ligase/imunologia , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/fisiopatologia , Imunossupressores/uso terapêutico , Isoleucina-tRNA Ligase/imunologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/imunologia , Masculino , Pessoa de Meia-Idade , Miosite/tratamento farmacológico , Miosite/imunologia , Prednisona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Treonina-tRNA Ligase/imunologia , Resultado do Tratamento , Capacidade Vital
5.
Mod Rheumatol Case Rep ; 5(1): 101-107, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33019894

RESUMO

Anti-melanoma differentiation-associated gene 5 juvenile dermatomyositis (anti-MDA5 JDM) is associated with high risk of developing rapidly progressive interstitial lung disease (RP-ILD). Here we report an 11-year-old girl with anti-MDA5 JDM and RP-ILD which led to a fatal outcome, further aggravated by SARS-CoV-2 infection. She was referred to our hospital after being diagnosed with anti-MDA5 JDM and respiratory failure due to RP-ILD. On admission, fibrobronchoscopy with bronchoalveolar lavage (BAL) revealed Pneumocystis jirovecii infection so treatment with intravenous trimethoprim-sulfamethoxazole was initiated. Due to RP-ILD worsening, immunosuppressive therapy was intensified using methylprednisolone pulses, cyclophosphamide, tofacitinib and intravenous immunoglobulin without response. She developed severe hypoxemic respiratory failure, pneumomediastinum and pneumothorax, further complicated with severe RP-ILD and cervical subcutaneous emphysema. Three real-time RT-PCR for SARS-CoV-2 were made with a negative result. In addition, she was complicated with a secondary hemophagocytic lymphohistiocytosis and a fourth real-time PCR for SARS-CoV-2 performed in BAS sample was positive. Despite aggressive treatment of RP-ILD due to anti-MDA5 JDM, there was no improvement of respiratory failure in the following days and patient developed refractory septic shock and died. Anti-MDA5 JDM patients with RP-ILD have a poor prognosis with a high mortality rate. For this reason, intensive immunosuppressive therapy is essential including the use of promising drugs such as tofacitinib. COVID-19 in children with underlying health conditions like anti-MDA5 JDM may still be at risk for disease and severe complications.


Assuntos
/complicações , Dermatomiosite/complicações , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/complicações , Linfo-Histiocitose Hemofagocítica/etiologia , Pneumonia por Pneumocystis/complicações , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Autoanticorpos/imunologia , Broncoscopia , Criança , Ciclofosfamida/uso terapêutico , Dermatomiosite/tratamento farmacológico , Dermatomiosite/imunologia , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Hospedeiro Imunocomprometido , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Helicase IFIH1 Induzida por Interferon/imunologia , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/terapia , Linfo-Histiocitose Hemofagocítica/imunologia , Enfisema Mediastínico/etiologia , Metilprednisolona/uso terapêutico , Piperidinas/uso terapêutico , Pneumonia por Pneumocystis/imunologia , Pneumotórax/etiologia , Pirimidinas/uso terapêutico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Choque Séptico/etiologia , Enfisema Subcutâneo/etiologia , Tomografia Computadorizada por Raios X , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
6.
Artigo em Inglês | MEDLINE | ID: mdl-33093767

RESUMO

Objective: To describe the clinical and serological patients characteristics with Microscopic Polyangiitis (MPA) and Interstitial lung disease (ILD). Methods: Of all the patients with AAV diagnosed between 2007-2017 at the Hospital Clinico Universidad de Chile, those with MPA and ILD were selected and studied retrospectively. Results: All patients were Hispanic; median age at diagnosis 65 years (32-84). 59% were female. All were positive for p-ANCA, 16 patients for MPO. Most common manifestations were constitutional symptoms, weight loss and fever. CT-Scans patterns were Usual Interstitial Pneumonia (UIP) in 10 patients, Nonspecific Interstitial Pneumonia (NSIP) in 6 and fibrosis not UIP or NSIP pattern in 1. In 6 cases, ILD was diagnosed 0.5-14 years before MPA and concomitantly in 11. Conclusions: Although infrequent, Microscopic Polyangiitis should be suspected in patients with ILD particularly if extra-pulmonary manifestations that rise the possibility of a systemic illness are present, regardless of the time elapsed between the latter and the diagnosis of this type of lung involvement. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 37-42).


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Doenças Pulmonares Intersticiais/sangue , Poliangiite Microscópica/sangue , Peroxidase/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Chile , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/imunologia , Masculino , Poliangiite Microscópica/diagnóstico , Poliangiite Microscópica/imunologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Testes Sorológicos , Tomografia Computadorizada por Raios X
7.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 136-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093777

RESUMO

Background: Interstitial lung disease (ILD) is a common complication of primary Sjögren's syndrome (pSS). Because there is a paucity of literature on the management of pSS-associated ILD (pSS-ILD), this retrospective cohort study assessed the efficacy of azathioprine and mycophenolate therapy in adult patients with pSS-ILD. Methods: A retrospective cohort study was performed using electronic health records to identify adults meeting the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for pSS. The presence of pSS-ILD was confirmed by characteristic high-resolution computed tomography and/or histopathology findings. Sociodemographic, clinical, and pulmonary function test (PFT) data were abstracted for patients meeting the criteria and followed longitudinally from the date of their ILD diagnosis. PFT values were anchored on time of treatment start, and linear mixed-effects modeling was used to analyze changes in diffusion capacity for carbon monoxide (DLCO) and forced vital capacity (FVC) before and after treatment initiation. Results: We identified 19 subjects who had pSS-ILD, of whom seven were treated with azathioprine and seven were treated with mycophenolate. Within the azathioprine treated group, FVC% slope change trended toward improvement from a rate of -9.8% per month pre-treatment to 2.1% per month post-treatment (p = 0.13). Within the mycophenolate treated group, FVC% slope change improved from a rate of 1.5% per month pre-treatment to 4.3% per month post-treatment (p = 0.02) and DLCO% slope changed from a rate of -3.8% to -1.3% per month (p = 0.01) after therapy start. Conclusions: Mycophenolate treatment was associated with significant improvement in PFTs of pSS-ILD patients over time, and azathioprine treatment followed a similar non-significanttrend. Additional prospective studies are needed to further evaluate these findings. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 136-147).


Assuntos
Azatioprina/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pulmão/efeitos dos fármacos , Ácido Micofenólico/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Azatioprina/efeitos adversos , Registros Eletrônicos de Saúde , Feminino , Humanos , Imunossupressores/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia , Fatores de Tempo , Resultado do Tratamento
8.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 231-233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093788

RESUMO

Background: A subgroup of patients with fibrotic ILD experience progression and several risk factors for ILD progression have been reported, such as male sex, older age, lower baseline pulmonary function, and a radiological or pathological pattern of usual interstitial pneumonia. Objective: To describe a possible new phenotype of rapidly non IPF progressive fibrosing with an IPF-like outcome. Methods: Three previously fit and well patients who developed a rapidly progressive ILD and died within 6 to 7 months from the initial development of respiratory symptoms. Results: Unlike what is currently known, our patients developed a severe fibrosing ILD with an IPF-like outcome despite a) being younger than the average patient with IPF, b) having received a non-IPF MDT diagnosis, c) having a non-UIP pattern on HRCT. Moreover and similarly to IPF, they failed to respond to immunosuppressive treatment which is the preferred treatment option in these cases. Conclusion: We believe that patients who present with similar characteristics should be considered as likely to develop a phenotype of rapidly progressive ILD and be treated with antifibrotic medications instead of immunosuppressive ones according to the favourable treatment response to antifibrotic therapy observed in clinical trials of patients with progressive fibrosing ILDs. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 231-233).


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Pulmão/diagnóstico por imagem , Fibrose Pulmonar/diagnóstico , Tomografia Computadorizada por Raios X , Adulto , Antibacterianos/uso terapêutico , Progressão da Doença , Evolução Fatal , Volume Expiratório Forçado , Humanos , Imunossupressores/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/fisiopatologia , Índice de Gravidade de Doença , Fatores de Tempo , Falha de Tratamento , Capacidade Vital
9.
Front Immunol ; 11: 587517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123171

RESUMO

Background and Objectives: Understanding the pathophysiology of respiratory failure in coronavirus disease 2019 (COVID-19) is indispensable for development of therapeutic strategies. Since we observed similarities between COVID-19 and interstitial lung disease in connective tissue disease (CTD-ILD), we investigated features of autoimmunity in SARS-CoV-2-associated respiratory failure. Methods: We prospectively enrolled 22 patients with RT-PCR-confirmed SARS-CoV-2 infection and 10 patients with non-COVID-19-associated pneumonia. Full laboratory testing was performed including autoantibody (AAB; ANA/ENA) screening using indirect immunofluorescence and immunoblot. Fifteen COVID-19 patients underwent high-resolution computed tomography. Transbronchial biopsies/autopsy tissue samples for histopathology and ultrastructural analyses were obtained from 4/3 cases, respectively. Results: Thirteen (59.1%) patients developed acute respiratory distress syndrome (ARDS), and five patients (22.7%) died from the disease. ANA titers ≥1:320 and/or positive ENA immunoblots were detected in 11/13 (84.6%) COVID-19 patients with ARDS, in 1/9 (11.1%) COVID-19 patients without ARDS (p = 0.002) and in 4/10 (40%) patients with non-COVID-19-associated pneumonias (p = 0.039). Detection of AABs was significantly associated with a need for intensive care treatment (83.3 vs. 10%; p = 0.002) and occurrence of severe complications (75 vs. 20%, p = 0.03). Radiological and histopathological findings were highly heterogeneous including patterns reminiscent of exacerbating CTD-ILD, while ultrastructural analyses revealed interstitial thickening, fibroblast activation, and deposition of collagen fibrils. Conclusions: We are the first to report overlapping clinical, serological, and imaging features between severe COVID-19 and acute exacerbation of CTD-ILD. Our findings indicate that autoimmune mechanisms determine both clinical course and long-term sequelae after SARS-CoV-2 infection, and the presence of autoantibodies might predict adverse clinical course in COVID-19 patients.


Assuntos
Doenças do Tecido Conjuntivo/patologia , Infecções por Coronavirus/patologia , Doenças Pulmonares Intersticiais/patologia , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Betacoronavirus/imunologia , Doenças do Tecido Conjuntivo/imunologia , Infecções por Coronavirus/imunologia , Feminino , Humanos , Pulmão/patologia , Doenças Pulmonares Intersticiais/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Estudos Prospectivos , Síndrome Respiratória Aguda Grave/imunologia
10.
Clin Rheumatol ; 39(11): 3171-3175, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32844364

RESUMO

We treated two patients with severe respiratory failure due to coronavirus disease 2019 (COVID-19). Case 1 was a 73-year-old woman, and Case 2 was a 65-year-old-man. Neither of them had a history of autoimmune disease. Chest computed tomography scans before the antiviral therapy showed bilateral multiple patchy ground-glass opacities (GGO) consistent with COVID-19 pneumonia. The GGO regressed over the course of the antiviral treatment; however, new non-segmental patchy consolidations emerged, which resembled those of interstitial lung disease (ILD), specifically collagen vascular disease-associated ILD. We tested the patients' sera for autoantibodies and discovered that both patients had high anti-SSA/Ro antibody titers. In Case 1, the patient recovered with antiviral therapy alone. However, in Case 2, the patient did not improve with antiviral therapy alone but responded well to corticosteroid therapy (methylprednisolone) and made a full recovery. The relationship between some immunological responses and COVID-19 pneumonia exacerbation has been discussed previously; our discovery of the elevation of anti-SSA/Ro antibodies suggests a contribution from autoimmunity functions of the immune system. Although it is unclear whether the elevation of anti-SSA/Ro antibodies was a cause or an outcome of aggravated COVID-19 pneumonia, we hypothesize that both patients developed aggravated the COVID-19 pneumonia due to an autoimmune response. In COVID-19 lung injury, there may be a presence of autoimmunity factors in addition to the known effects of cytokine storms. In patients with COVID-19, a high level of anti-SSA/Ro52 antibodies may be a surrogate marker of pneumonia severity and poor prognosis.


Assuntos
Anticorpos Antinucleares/imunologia , Infecções por Coronavirus/imunologia , Doenças Pulmonares Intersticiais/imunologia , Pneumonia Viral/imunologia , Insuficiência Respiratória/imunologia , Idoso , Amidas/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/tratamento farmacológico , Feminino , Glucocorticoides/uso terapêutico , Guanidinas/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Masculino , Metilprednisolona/uso terapêutico , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/tratamento farmacológico , Pregnenodionas/uso terapêutico , Pirazinas/uso terapêutico , Recuperação de Função Fisiológica , /imunologia , Insuficiência Respiratória/etiologia , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
11.
Am J Respir Crit Care Med ; 202(10): 1430-1444, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32602730

RESUMO

Rationale: Chronic hypersensitivity pneumonitis (CHP) is caused by an immune response to antigen inhalation and is characterized by variable histopathological and clinical features. A subset of subjects with CHP have usual interstitial pneumonia and appear to be clinically similar to subjects with idiopathic pulmonary fibrosis (IPF).Objectives: To determine the common and unique molecular features of CHP and IPF.Methods: Transcriptome analysis of lung samples from CHP (n = 82), IPF (n = 103), and unaffected controls (n = 103) was conducted. Differential gene expression was determined adjusting for sex, race, age, and smoking history and using false discovery rate to control for multiple comparisons.Measurements and Main Results: When compared with controls, we identified 413 upregulated and 317 downregulated genes in CHP and 861 upregulated and 322 downregulated genes in IPF. Concordantly upregulated or downregulated genes in CHP and IPF were related to collagen catabolic processes and epithelial development, whereas genes specific to CHP (differentially expressed in CHP when compared with control and not differentially expressed in IPF) were related to chemokine-mediated signaling and immune responsiveness. Using weighted gene coexpression network analysis, we found that among subjects with CHP, genes involved in adaptive immunity or epithelial cell development were associated with improved or reduced lung function, respectively, and that MUC5B expression was associated with epithelial cell development. MUC5B expression was also associated with lung fibrosis and honeycombing.Conclusions: Gene expression analysis of CHP and IPF identified signatures common to CHP and IPF, as well as genes uniquely expressed in CHP. Select modules of gene expression are characterized by distinct clinical and pathological features of CHP.


Assuntos
Alveolite Alérgica Extrínseca/genética , Alveolite Alérgica Extrínseca/imunologia , Perfilação da Expressão Gênica , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/imunologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alveolite Alérgica Extrínseca/fisiopatologia , Feminino , Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade
12.
Science ; 369(6505): 818-823, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32616673

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. It is unclear whether convalescing patients have a risk of reinfection. We generated a rhesus macaque model of SARS-CoV-2 infection that was characterized by interstitial pneumonia and systemic viral dissemination mainly in the respiratory and gastrointestinal tracts. Rhesus macaques reinfected with the identical SARS-CoV-2 strain during the early recovery phase of the initial SARS-CoV-2 infection did not show detectable viral dissemination, clinical manifestations of viral disease, or histopathological changes. Comparing the humoral and cellular immunity between primary infection and rechallenge revealed notably enhanced neutralizing antibody and immune responses. Our results suggest that primary SARS-CoV-2 exposure protects against subsequent reinfection in rhesus macaques.


Assuntos
Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Canal Anal/virologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Subpopulações de Linfócitos B/imunologia , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Modelos Animais de Doenças , Interações entre Hospedeiro e Microrganismos , Imunidade Celular , Imunidade Humoral , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/virologia , Macaca mulatta , Nasofaringe/virologia , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Recidiva , Subpopulações de Linfócitos T/imunologia , Carga Viral , Replicação Viral
15.
PLoS One ; 15(6): e0234523, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32525903

RESUMO

OBJECTIVE: Surfactant protein D (SP-D) is considered a serum biomarker of various forms of interstitial lung disease (ILD). In this study, we examined the utility of SP-D as a predictive biomarker for mortality in patients with ILD associated with polymyositis/dermatomyositis (PM/DM) using large-scale multicentre cohort data. METHODS: We enrolled 381 patients with incident PM/DM-associated ILD in a multicentre retrospective cohort based on the availability of serum SP-D at the baseline. Demographic and clinical characteristics as well as the presence of autoantibodies to melanoma differentiation-associated gene 5 (MDA5) and aminoacyl tRNA synthetase were measured at the time of diagnosis, and follow-up survival data were collected prospectively. RESULTS: Seventy-eight patients died during the median observation period of 18 months, and the majority of patients died of ILD. The SP-D levels at baseline were significantly lower (P = 0.02) in a non-survivor subset than in a survivor subset among the entire enrolled patients. However, the SP-D levels were higher in the non-survivor subset than in the survivor subset based on the stratification by anti-MDA5-positive, anti-ARS-positive and, double-negativity, although there was an only statistically significant difference (P = 0.01) in the double-negative group. Surprisingly, the SP-D levels were within the upper limit of normal, 110 ng/mL, in 54 (87%) of 62 anti-MDA5-positive patients who died. In the double-negative group, the mortality rates were significantly higher (P = 0.002) in a subset with SP-D ≥127.6 ng/mL, the cut-off value for mortality calculated by the receiver operating characteristic curve, than the other subset. All of patients with SP-D <127.6 ng/mL survived. CONCLUSION: Serum SP-D levels behave differently among patients with stratified by anti-MDA5 antibody, anti-ARS antibody and both negativity in PM/DM-associated ILD. Its use in clinical practice should be applied with caution on the basis of the presence or absence of anti-MDA5 antibody or anti-ARS antibody.


Assuntos
Autoanticorpos/sangue , Dermatomiosite/complicações , Doenças Pulmonares Intersticiais/mortalidade , Proteína D Associada a Surfactante Pulmonar/sangue , Adulto , Idoso , Aminoacil-tRNA Sintetases/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Biomarcadores/sangue , Dermatomiosite/sangue , Dermatomiosite/imunologia , Dermatomiosite/mortalidade , Estudos de Viabilidade , Feminino , Humanos , Helicase IFIH1 Induzida por Interferon/imunologia , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Valores de Referência , Estudos Retrospectivos , Análise de Sobrevida
16.
Ann Rheum Dis ; 79(6): 724-726, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32349982

RESUMO

Due to the frequent presence of interstitial lung disease and widespread use of immunosuppressive treatment, systemic sclerosis (SSc) patients may be considered at risk for a more severe disease course and higher mortality when they develop Severe Acute Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) virus infection. Therefore, with World Scleroderma Foundation endorsement, experts from different specialties including rheumatology, virology and clinical immunology gathered virtually to answer to the main practical clinical questions regarding SARS-CoV-2 infection coming from both patients and physicians. This preliminary advice is aligned with other national and international recommendations, adapted for SSc patients.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Escleroderma Sistêmico/terapia , Escleroderma Sistêmico/virologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/virologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , /virologia , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia
17.
Science ; 369(6505): 812-817, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32434946

RESUMO

An understanding of protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for vaccine and public health strategies aimed at ending the global coronavirus disease 2019 (COVID-19) pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against reexposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. After the initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with after the primary infection. Anamnestic immune responses after rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against reexposure in nonhuman primates.


Assuntos
Betacoronavirus , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Betacoronavirus/imunologia , Betacoronavirus/fisiologia , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Feminino , Imunidade Celular , Imunidade Humoral , Memória Imunológica , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/virologia , Macaca mulatta , Masculino , Mucosa Nasal/virologia , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Recidiva , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral , Replicação Viral
18.
Am J Surg Pathol ; 44(8): 1073-1081, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32235152

RESUMO

Common variable immunodeficiency (CVID) and selective immunoglobulin A deficiency (IgAD) often cause chronic lung disease, but the pulmonary pathologic features of these systemic diseases are poorly recognized by pathologists. It has been claimed that CVID cases show a characteristic combination of noncaseating granulomas-lymphoid proliferations termed granulomatous-lymphocytic interstitial lung disease (GLILD). We present 34 surgical lung biopsy cases of CVID and 4 of IgAD. Noncaseating granulomas were seen in 23/34 (68%) CVID and 2/4 (50%) IgAD cases. A statistically identical pattern of benign lymphoid proliferation was found in CVID and IgAD whether or not granulomas were present. Organizing pneumonia, sometimes considered a part of GLILD, was seen in 25/34 (74%) CVID and 2/4 (50%) IgAD cases and did not correlate with the presence of granulomas. On follow-up, 3 CVID patients died (only 1 of pulmonary disease), while 21 others are alive at 1 to 300 months with no difference by presence or absence of granulomas. Three IgAD patients with follow-up are alive. We conclude that CVID and IgAD are indistinguishable in surgical lung biopsies and a subset of both show patterns that would qualify as GLILD, while other cases lack granulomas but have identical patterns of lymphoid infiltration and organizing pneumonia. We suggest that GLILD is neither a specific nor a useful entity, and biopsies from CVID and IgAD patients should be diagnosed simply by microscopic pattern(s) observed. The prognosis of CVID with lymphoid infiltrates with or without granulomas in this series was good, contrary to claims in the literature about GLILD.


Assuntos
Imunodeficiência de Variável Comum/patologia , Granuloma do Sistema Respiratório/patologia , Deficiência de IgA/patologia , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Linfócitos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Proliferação de Células , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/mortalidade , Imunodeficiência de Variável Comum/terapia , Feminino , Granuloma do Sistema Respiratório/imunologia , Granuloma do Sistema Respiratório/mortalidade , Granuloma do Sistema Respiratório/terapia , Humanos , Deficiência de IgA/imunologia , Deficiência de IgA/mortalidade , Deficiência de IgA/terapia , Pulmão/imunologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/terapia , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , América do Norte , Valor Preditivo dos Testes , Prognóstico , Adulto Jovem
19.
Nat Rev Rheumatol ; 16(6): 301-315, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341463

RESUMO

Peptidylarginine deiminases (PADs) have an important role in the pathogenesis of rheumatoid arthritis (RA) owing to their ability to generate citrullinated proteins - the hallmark autoantigens of RA. Of the five PAD enzyme isoforms, PAD2 and PAD4 are the most strongly implicated in RA at both genetic and cellular levels, and PAD inhibitors have shown therapeutic efficacy in mouse models of inflammatory arthritis. PAD2 and PAD4 are additionally targeted by autoantibodies in distinct clinical subsets of patients with RA, suggesting anti-PAD antibodies as possible biomarkers for RA diagnosis and prognosis. This Review weighs the evidence that supports a pathogenic role for PAD enzymes in RA as both promoters and targets of the autoimmune response, as well as discussing the mechanistic and therapeutic implications of these findings in the wider context of RA pathogenesis. Understanding the origin and consequences of dysregulated PAD enzyme activity and immune responses against PAD enzymes will be important to fully comprehend the pathogenic mechanisms involved in this disease and for the development of novel strategies to treat and prevent RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Proteína-Arginina Desiminase do Tipo 2/metabolismo , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Artrite Reumatoide/enzimologia , Artrite Reumatoide/genética , Autoanticorpos/imunologia , Autoantígenos/imunologia , Autoantígenos/metabolismo , Citrulinação , Reações Cruzadas , Predisposição Genética para Doença , Humanos , Doenças Pulmonares Intersticiais/imunologia , Proteína-Arginina Desiminase do Tipo 2/genética , Proteína-Arginina Desiminase do Tipo 2/imunologia , Proteína-Arginina Desiminase do Tipo 3/imunologia , Proteína-Arginina Desiminase do Tipo 4/genética , Proteína-Arginina Desiminase do Tipo 4/imunologia , Desiminases de Arginina em Proteínas/genética , Desiminases de Arginina em Proteínas/imunologia , Desiminases de Arginina em Proteínas/metabolismo , Índice de Gravidade de Doença
20.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(4): 362-368, 2020 Apr 12.
Artigo em Chinês | MEDLINE | ID: mdl-32294819

RESUMO

Objective: To investigate the clinical features and prognosis of interstitial lung disease patients with positive anti-neutrophil cytoplasmic antibody. Methods: The patients with interstitial lung disease who visited Peking Union Medical College Hospital from March 2006 to March 2016 were divided into three groups: interstitial lung disease with ANCA-positive(ANCA-ILD), connective tissue disease associated interstitial lung disease and interstitial pneumonia with autoimmune features (CTD-ILD/IPAF) and idiopathic interstitial pneumonia (IIP). The three groups were analyzed in terms of clinical manifestations, serology, lung function, imaging, survival and recurrence. Results: Two hundred and seventy four patients were enrolled and 38 (14%) were ANCA-positive of whom 16 were male and 22 were female. The age of 38 ANCA-positive patients was (59±10) years and the follow-up time was (52±31) months. Seven among the 38 ANCA-positive patients died and the death rate is 18.42%. The ANCA-positive patients with interstitial lung disease have higher onset age (ANCA-ILD:59±10,CTD-ILD/IPAF:52±10,IIP:53±11,H=19.29, P<0.001), lower hemoglobin (ANCA-ILD: 129±21, CTD-ILD/IPAF: 138±15, IIP: 140±19, H=8.17, P=0.017), higher erythrocyte sedimentation rate (ANCA-ILD:45±35, CTD-ILD/IPAF:26±24,IIP:19±22,H=19.73, P<0.001), lower lung function improvement rate after treatment (ANCA-ILD:31%,CTD-ILD/IPAF:59%,IIP: 39%,χ(2)=11.74,P=0.003), lower absorption rate of CT lesion (ANCA-ILD:61%,CTD-ILD/IPAF:82%,IIP:67%, χ(2)=9.23,P=0.010) and higher death rate(ANCA-ILD:18%,CTD-ILD/IPAF:6%,IIP:12%, χ(2)=7.16,P=0.028). Conclusions: There are significant differences in clinical characteristics between ANCA-positive patients and other types of pulmonary interstitial disease. And both the treatment effect and the prognosis is poor for the ANCA-positive patients.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Doenças do Tecido Conjuntivo/diagnóstico , Pneumonias Intersticiais Idiopáticas/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico , Biomarcadores/sangue , Doenças do Tecido Conjuntivo/sangue , Doenças do Tecido Conjuntivo/imunologia , Doenças do Tecido Conjuntivo/mortalidade , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/imunologia , Pneumonias Intersticiais Idiopáticas/mortalidade , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Prognóstico , Tomografia Computadorizada por Raios X
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