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1.
Cytokine ; 138: 155389, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33348065

RESUMO

BACKGROUND: The infection caused by SARS CoV-2 has been postulated to induce a cytokine storm syndrome that results in organ failure and even death in a considerable number of patients. However, the inflammatory response in Corona virus disease-19 (Covid-19) and its potential to cause collateral organ damage has not been fully elucidated to date. This study aims to characterize the acute cytokine response in a cohort of critically ill Covid-19 patients. METHOD: 24 adults with PCR-confirmed Covid-19 were included at time of admission to intensive care a median of eleven days after initial symptoms. Eleven adult patients admitted for elective abdominal surgery with preoperative plasma samples served as controls. All patients were included after informed consent was obtained. 27 cytokines were quantified in plasma. The expression of inflammatory mediators was then related to routine inflammatory markers, SAPS3, SOFA score, organ failure and 30-day mortality. RESULTS: A general increase in cytokine expression was observed in all Covid-19 patients. A strong correlation between respiratory failure and IL-1ra, IL-4, IL-6, IL-8 and IP-10 expression was observed. Acute kidney injury development correlated well with increased levels of IL-1ra, IL-6, IL-8, IL-17a, IP-10 and MCP-1. Generally, the cohort demonstrated weaker correlations between cytokine expression and 30-day mortality out of which IL-8 showed the strongest signal in terms of mortality. CONCLUSION: The present study found that respiratory failure, acute kidney injury and 30-day mortality in critically ill Covid-19 patients are associated with moderate increases of a broad range of inflammatory mediators at time of admission.


Assuntos
Lesão Renal Aguda/patologia , Síndrome da Liberação de Citocina/mortalidade , Citocinas/sangue , Insuficiência Respiratória/patologia , Lesão Renal Aguda/virologia , Idoso , Biomarcadores/sangue , /mortalidade , Estado Terminal , Síndrome da Liberação de Citocina/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Respiratória/virologia , /imunologia
2.
Rev Mal Respir ; 37(9): 756-765, 2020 Nov.
Artigo em Francês | MEDLINE | ID: mdl-33169687

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, especially in cases of chronic hypercapnic respiratory failure. Following a prolonged debate, the indication and benefits of noninvasive ventilation (NIV) have been recently established. Although improved ventilation and reduction in hyperinflation appear to underlie the positive effect on NIV in COPD, only a few studies have focused on specific ventilatory algorithms for improving PaCO2. METHODS: The main objective of this study is to analyze the impact of Löwenstein's ventilatory algorithms, supposed to allow a better management of hyperinflation and its consequences on alveolar ventilation and blood gas parameters. This is an interventional study in routine care, prospective, single blind, randomized with cross over. The primary endpoint will be the transcutaneous partial pressure of nocturnal carbon dioxide. Secondary endpoints will be: abnormal respiratory events occurring during nocturnal NIV; the objective quality of sleep via polysomnography; the tolerance of ventilation and the subjective quality of sleep evaluated by auto questionnaires. EXPECTED RESULTS: The results of this study will clarify whether is it necessary to explore more the impact of the ventilatory modes developed by Löwenstein, dedicated to hypercapnic COPD patients, requiring a long-term NIV.


Assuntos
Algoritmos , Hipercapnia/terapia , Ventilação não Invasiva , Doença Pulmonar Obstrutiva Crônica/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Dióxido de Carbono/análise , Dióxido de Carbono/sangue , Estudos Cross-Over , Serviços de Assistência Domiciliar , Humanos , Hipercapnia/complicações , Hipercapnia/patologia , Monitorização Fisiológica/métodos , Monitorização Fisiológica/normas , Ventilação não Invasiva/métodos , Seleção de Pacientes , Polissonografia , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/patologia , Insuficiência Respiratória/terapia , Tamanho da Amostra , Índice de Gravidade de Doença , Método Simples-Cego , Sono/fisiologia
3.
Mol Med ; 26(1): 95, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054759

RESUMO

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.


Assuntos
Infecções por Coronavirus/imunologia , Epigênese Genética/imunologia , Fibrose Pulmonar Idiopática/imunologia , Mecanotransdução Celular/imunologia , Pneumonia Viral/imunologia , Embolia Pulmonar/imunologia , Insuficiência Respiratória/imunologia , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Fenômenos Biomecânicos , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/virologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/patologia , Mecanotransdução Celular/genética , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Embolia Pulmonar/genética , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Insuficiência Respiratória/virologia , Estresse Mecânico
4.
Sci Adv ; 6(31)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32937590

RESUMO

The outbreak of the highly contagious and deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), has posed a serious threat to public health across the globe, calling for the development of effective diagnostic markers and therapeutics. Here, we report a highly reliable severity diagnostic biomarker, acetylated 676th lysine transforming growth factor-beta-induced protein (TGFBIp K676Ac). TGFBIp K676Ac was consistently elevated in the blood of patients with SARS-CoV-2 pneumonia (n = 113), especially in patients in the intensive care unit (ICU) compared to non-ICU patients. Patients' blood samples showed increased cytokines and lymphopenia, which are exemplary indicators of SARS-CoV-2 pneumonia. Treatment with TGFBIp neutralizing antibodies suppressed the cytokine storm. The increased level of TGFBIp K676Ac in ICU patients suggests the promise of this protein as a reliable severity diagnostic biomarker for severe SARS-CoV-2 disease.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Síndrome da Liberação de Citocina/diagnóstico , Proteínas da Matriz Extracelular/imunologia , Leucócitos Mononucleares/imunologia , Pneumonia Viral/diagnóstico , Processamento de Proteína Pós-Traducional , Insuficiência Respiratória/diagnóstico , Fator de Crescimento Transformador beta/imunologia , Acetilação , Anticorpos Neutralizantes/farmacologia , Betacoronavirus/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Proteínas da Matriz Extracelular/antagonistas & inibidores , Proteínas da Matriz Extracelular/genética , Expressão Gênica , Humanos , Unidades de Terapia Intensiva , Contagem de Leucócitos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/virologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Lisina/metabolismo , NF-kappa B/genética , NF-kappa B/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Cultura Primária de Células , Prognóstico , Insuficiência Respiratória/sangue , Insuficiência Respiratória/imunologia , Insuficiência Respiratória/patologia , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/genética
5.
6.
Liver Int ; 40(9): 2110-2116, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32654359

RESUMO

SARS2-CoV-2 breakout in Italy caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection, very few information are available about liver involvement, possibly evocating a systemic disease. Post-mortem wedge liver biopsies from 48 patients died from severe pulmonary COVID-19 disease with respiratory failure were collected from two main hospitals in northern Italy. No patient had clinical symptoms of liver disease or signs of liver failure before and during hospitalization; for each of them liver function tests were available. All liver samples showed minimal inflammation features. Histological pictures compatible with vascular alterations were observed, characterized by increase in number of portal vein branches associated with lumen massive dilatation, partial or complete luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally markedly enlarged and fibrotic. SARS-CoV-2 was found in 15 of 22 samples tested by in situ hybridization method. Our preliminary results confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage. Histopathological findings are highly suggestive for marked derangement of intrahepatic blood vessel network secondary to systemic changes induced by virus that could target not only lung parenchyma but also cardiovascular system, coagulation cascade and endothelial layer of blood vessels. It still remains unclear if the mentioned changes are directly related to virus infection or if SARS-CoV-2 triggers a series of reactions leading to striking vascular alterations.


Assuntos
Infecções por Coronavirus/patologia , Fígado/patologia , Pneumonia Viral/patologia , Veia Porta/patologia , Insuficiência Respiratória/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Infecções por Coronavirus/complicações , Feminino , Humanos , Fígado/irrigação sanguínea , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Insuficiência Respiratória/virologia
7.
Clin Immunol ; 220: 108545, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32710937

RESUMO

COVID-19 rapidly turned to a global pandemic posing lethal threats to overwhelming health care capabilities, despite its relatively low mortality rate. The clinical respiratory symptoms include dry cough, fever, anosmia, breathing difficulties, and subsequent respiratory failure. No known cure is available for COVID-19. Apart from the anti-viral strategy, the supports of immune effectors and modulation of immunosuppressive mechanisms is the rationale immunomodulation approach in COVID-19 management. Diet and nutrition are essential for healthy immunity. However, a group of micronutrients plays a dominant role in immunomodulation. The deficiency of most nutrients increases the individual susceptibility to virus infection with a tendency for severe clinical presentation. Despite a shred of evidence, the supplementation of a single nutrient is not promising in the general population. Individuals at high-risk for specific nutrient deficiencies likely benefit from supplementation. The individual dietary and nutritional status assessments are critical for determining the comprehensive actions in COVID-19.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/dietoterapia , Tosse/dietoterapia , Fatores Imunológicos/uso terapêutico , Micronutrientes/uso terapêutico , Pandemias , Pneumonia Viral/dietoterapia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Tosse/diagnóstico , Tosse/imunologia , Tosse/patologia , Gerenciamento Clínico , Febre/diagnóstico , Febre/dietoterapia , Febre/imunologia , Febre/patologia , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Transtornos do Olfato/diagnóstico , Transtornos do Olfato/dietoterapia , Transtornos do Olfato/imunologia , Transtornos do Olfato/patologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/dietoterapia , Insuficiência Respiratória/imunologia , Insuficiência Respiratória/patologia , Índice de Gravidade de Doença , Oligoelementos/uso terapêutico , Vitaminas/uso terapêutico
8.
PLoS One ; 15(7): e0235458, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645044

RESUMO

A recently developed pneumonia caused by SARS-CoV-2 bursting in Wuhan, China, has quickly spread across the world. We report the clinical characteristics of 82 cases of death from COVID-19 in a single center. Clinical data on 82 death cases laboratory-confirmed as SARS-CoV-2 infection were obtained from a Wuhan local hospital's electronic medical records according to previously designed standardized data collection forms. All patients were local residents of Wuhan, and a large proportion of them were diagnosed with severe illness when admitted. Due to the overwhelming of our system, a total of 14 patients (17.1%) were treated in the ICU, 83% of deaths never received Critical Care Support, only 40% had mechanical ventilation support despite 100% needing oxygen and the leading cause of death being pulmonary. Most of the patients who died were male (65.9%). More than half of the patients who died were older than 60 years (80.5%), and the median age was 72.5 years. The bulk of the patients who died had comorbidities (76.8%), including hypertension (56.1%), heart disease (20.7%), diabetes (18.3%), cerebrovascular disease (12.2%), and cancer (7.3%). Respiratory failure remained the leading cause of death (69.5%), followed by sepsis/MOF (28.0%), cardiac failure (14.6%), hemorrhage (6.1%), and renal failure (3.7%). Furthermore, respiratory, cardiac, hemorrhagic, hepatic, and renal damage were found in 100%, 89%, 80.5%, 78.0%, and 31.7% of patients, respectively. On admission, lymphopenia (89.2%), neutrophilia (74.3%), and thrombocytopenia (24.3%) were usually observed. Most patients had a high neutrophil-to-lymphocyte ratio of >5 (94.5%), high systemic immune-inflammation index of >500 (89.2%), and increased C-reactive protein (100%), lactate dehydrogenase (93.2%), and D-dimer (97.1%) levels. A high level of IL-6 (>10 pg/ml) was observed in all detected patients. The median time from initial symptoms to death was 15 days (IQR 11-20), and a significant association between aspartate aminotransferase (p = 0.002), alanine aminotransferase (p = 0.037) and time from initial symptoms to death was remarkably observed. Older males with comorbidities are more likely to develop severe disease and even die from SARS-CoV-2 infection. Respiratory failure is the main cause of COVID-19, but the virus itself and cytokine release syndrome-mediated damage to other organs, including cardiac, renal, hepatic, and hemorrhagic damage, should be taken seriously as well.


Assuntos
Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Adulto , Fatores Etários , Idoso , Betacoronavirus , Causas de Morte , China/epidemiologia , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Insuficiência Respiratória/patologia , Estudos Retrospectivos
9.
Int J Mol Sci ; 21(13)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32629817

RESUMO

By attaching to the angiotensin converting enzyme 2 (ACE2) protein on lung and intestinal cells, Sudden Acute Respiratory Syndrome (SARS-CoV-2) can cause respiratory and homeostatic difficulties leading to sepsis. The progression from acute respiratory failure to sepsis has been correlated with the release of high-mobility group box 1 protein (HMGB1). Lack of effective conventional treatment of this septic state has spiked an interest in alternative medicine. This review of herbal extracts has identified multiple candidates which can target the release of HMGB1 and potentially reduce mortality by preventing progression from respiratory distress to sepsis. Some of the identified mixtures have also been shown to interfere with viral attachment. Due to the wide variability in chemical superstructure of the components of assorted herbal extracts, common motifs have been identified. Looking at the most active compounds in each extract it becomes evident that as a group, phenolic compounds have a broad enzyme inhibiting function. They have been shown to act against the priming of SARS-CoV-2 attachment proteins by host and viral enzymes, and the release of HMGB1 by host immune cells. An argument for the value in a nonspecific inhibitory action has been drawn. Hopefully these findings can drive future drug development and clinical procedures.


Assuntos
Betacoronavirus/fisiologia , Proteína HMGB1/metabolismo , Insuficiência Respiratória/patologia , Sepse/patologia , Proteína HMGB1/antagonistas & inibidores , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/virologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Exsudatos de Plantas/química , Exsudatos de Plantas/farmacologia , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Insuficiência Respiratória/metabolismo , Insuficiência Respiratória/prevenção & controle , Sepse/metabolismo , Sepse/prevenção & controle , Internalização do Vírus/efeitos dos fármacos
10.
Tunis Med ; 98(5): 378-395, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32548841

RESUMO

OBJECTIVE: The objective of this literature review is to gather all the LFT norms available for the Tunisian population, as well as QDV questionnaires specific to chronic respiratory patients that have been validated in Tunisia. METHODS: This review included a literature search using the PubMed and Sciencedirect databases. The reference lists of the retrieved English/French articles were searched for any additional reference. Specific research has been carried out for each stage of the natural evolution of chronic diseases. For LFT used in the exploration of deficiency, the key-words were ("respiratory function test" OR "spirometry" OR "plethysmography" OR "exhaled fraction of oxide nitric" OR "lung diffusion" OR "peak nasal inspiratory flow" OR "Lung age") AND ("Tunisia" OR "North Africa") AND ("reference equation" OR "reference value" OR "standard reference"). For LFT used in the exploration of incapacity, the key-words were ("exercise test" OR "maximal oxygen uptake" OR "cardiorespiratory test" OR "six minute walk distance" OR "six-minute walk distance" OR "6-minute walk distance" OR "six-min walk distance" OR "6-min walk distance" OR "six minute walking distance" OR "six-minute walking distance" OR "6MWD") AND ("Tunisia" OR "North Africa") AND ("reference equation" OR "reference value" OR "standard reference"). For the QOL questionnaires used in pneumology, the key-words were: ("quality of life" OR "QOL") AND ("respiratory" OR "pulmonology") AND ("Tunisia" OR "North Africa"). RESULTS: As part of deficiency exploration, 11 Tunisian norms are available. As part of incapacity exploration, three Tunisian norms are available for the 6-minute walk test. Only one QOL questionnaire specific to chronic respiratory patients has been validated in Tunisia. CONCLUSION: Despite its richness, the Tunisian "bank" of norms for LFT and QOL questionnaires has yet to be enriched.


Assuntos
Doença Pulmonar Obstrutiva Crônica/diagnóstico , Qualidade de Vida , Testes de Função Respiratória/normas , Insuficiência Respiratória/diagnóstico , Inquéritos e Questionários/normas , Doença Crônica , Pessoas com Deficiência , Progressão da Doença , Teste de Esforço/métodos , Teste de Esforço/normas , Humanos , Doença Pulmonar Obstrutiva Crônica/patologia , Valores de Referência , Testes de Função Respiratória/métodos , Insuficiência Respiratória/patologia , Índice de Gravidade de Doença , Tunísia , Estudos de Validação como Assunto
11.
Immunotherapy ; 12(15): 1121-1126, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32546029

RESUMO

Background: Coronavirus disease 2019 (COVID-19) is a novel disease associated with a cytokine-mediated, severe, acute respiratory syndrome. Tocilizumab and lenzilumab are recombinant monoclonal antibodies against IL-6 and granulocyte macrophage colony-stimulating factor, respectively, and have been proposed as a potential treatment for acute, hypoxic respiratory failure associated with COVID-19. Results & methodology: We present the case of a 68-year-old man with COVID-19 who was initially treated with hydroxychloroquine and lenzilumab, but continued to develop hypoxemia, requiring an increase in respiratory support with an associated rise in serum inflammatory markers. He was subsequently treated with tocilizumab with marked clinical improvement and a decrease in acute phase reactants within 48 h. Discussion & conclusion: This case demonstrates the effective use of tocilizumab in the treatment of COVID-19 and suggests the superiority of tocilizumab over lenzilumab in the management of this cytokine-mediated syndrome.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Idoso , Betacoronavirus , Terapia Combinada , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/terapia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Humanos , Masculino , Pandemias , Pneumonia Viral/patologia , Receptores de Interleucina-6/antagonistas & inibidores , Insuficiência Respiratória/patologia , Insuficiência Respiratória/terapia , Resultado do Tratamento
12.
Transl Res ; 220: 1-13, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32299776

RESUMO

Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention.


Assuntos
Betacoronavirus , Proteínas do Sistema Complemento/metabolismo , Infecções por Coronavirus/complicações , Microvasos/patologia , Pneumonia Viral/complicações , Insuficiência Respiratória/etiologia , Trombose/etiologia , Adulto , Idoso , Ativação do Complemento/fisiologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Masculino , Microvasos/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Púrpura/etiologia , Púrpura/patologia , Púrpura/virologia , Insuficiência Respiratória/patologia , Trombose/patologia
13.
Rinsho Shinkeigaku ; 60(5): 334-339, 2020 May 26.
Artigo em Japonês | MEDLINE | ID: mdl-32307395

RESUMO

Hereditary myopathy with early respiratory failure (HMERF) with heterozygous mutations in the titin gene (TTN) is characterized by respiratory failure developing from the early phase of limb weakness or gait disturbance. Here, we describe a characteristic distribution of muscle involvement in three members of a HMERF family with a TTN mutation. Despite the differences in severity exhibited among the father, daughter and son, the systemic imaging studies showed a similar pattern among these individuals. The semitendinosus and fibularis longus muscles were selectively affected, as described previously. In addition, we found marked atrophy in the sternocleidomastoid and psoas major muscles, regardless of the disease severity. The atrophy in selective trunk muscles observed in routine CT scans can be useful for the differential diagnosis of hereditary myopathies with heart and respiratory failure.


Assuntos
Conectina/genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Músculo Esquelético/patologia , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Adulto , Idoso , Atrofia , Diagnóstico Diferencial , Feminino , Doenças Genéticas Inatas/diagnóstico por imagem , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Doenças Musculares/diagnóstico por imagem , Insuficiência Respiratória/diagnóstico por imagem , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
14.
Crit Care ; 24(1): 85, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164784

RESUMO

BACKGROUND: Diaphragm atrophy and dysfunction are consequences of mechanical ventilation and are determinants of clinical outcomes. We hypothesize that partial preservation of diaphragm function, such as during assisted modes of ventilation, will restore diaphragm thickness. We also aim to correlate the changes in diaphragm thickness and function to outcomes and clinical factors. METHODS: This is a prospective, multicentre, observational study. Patients mechanically ventilated for more than 48 h in controlled mode and eventually switched to assisted ventilation were enrolled. Diaphragm ultrasound and clinical data collection were performed every 48 h until discharge or death. A threshold of 10% was used to define thinning during controlled and recovery of thickness during assisted ventilation. Patients were also classified based on the level of diaphragm activity during assisted ventilation. We evaluated the association between changes in diaphragm thickness and activity and clinical outcomes and data, such as ventilation parameters. RESULTS: Sixty-two patients ventilated in controlled mode and then switched to the assisted mode of ventilation were enrolled. Diaphragm thickness significantly decreased during controlled ventilation (1.84 ± 0.44 to 1.49 ± 0.37 mm, p < 0.001) and was partially restored during assisted ventilation (1.49 ± 0.37 to 1.75 ± 0.43 mm, p < 0.001). A diaphragm thinning of more than 10% was associated with longer duration of controlled ventilation (10 [5, 15] versus 5 [4, 8.5] days, p = 0.004) and higher PEEP levels (12.6 ± 4 versus 10.4 ± 4 cmH2O, p = 0.034). An increase in diaphragm thickness of more than 10% during assisted ventilation was not associated with any clinical outcome but with lower respiratory rate (16.7 ± 3.2 versus 19.2 ± 4 bpm, p = 0.019) and Rapid Shallow Breathing Index (37 ± 11 versus 44 ± 13, p = 0.029) and with higher Pressure Muscle Index (2 [0.5, 3] versus 0.4 [0, 1.9], p = 0.024). Change in diaphragm thickness was not related to diaphragm function expressed as diaphragm thickening fraction. CONCLUSION: Mode of ventilation affects diaphragm thickness, and preservation of diaphragmatic contraction, as during assisted modes, can partially reverse the muscle atrophy process. Avoiding a strenuous inspiratory work, as measured by Rapid Shallow Breathing Index and Pressure Muscle Index, may help diaphragm thickness restoration.


Assuntos
Diafragma/diagnóstico por imagem , Respiração Artificial/efeitos adversos , Insuficiência Respiratória/terapia , Ultrassonografia/métodos , Trabalho Respiratório , Estado Terminal , Diafragma/patologia , Diafragma/fisiopatologia , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Contração Muscular/fisiologia , Debilidade Muscular/diagnóstico por imagem , Estudos Prospectivos , Insuficiência Respiratória/patologia
15.
Fetal Pediatr Pathol ; 39(1): 85-89, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31286806

RESUMO

Introduction: Endobronchial granular cell tumors are uncommon in the pediatric population. Case report: A 9-year-old female presented with respiratory failure due to an endobronchial tumor. After debulking and diagnosis, she underwent thoracotomy with right upper lobe resection and bronchoplasty. Pathology demonstrated an endobronchial S-100 negative granular cell tumor, which to our knowledge, is the first such report in the literature. Conclusion: Endobronchial granular cell tumors may cause obstructive respiratory failure, are amenable to surgery, and may be S-100 negative.


Assuntos
Brônquios/patologia , Tumor de Células Granulares/patologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/patologia , Broncoscopia/métodos , Criança , Feminino , Tumor de Células Granulares/diagnóstico , Humanos
16.
Cell Death Dis ; 10(11): 838, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685810

RESUMO

We reported previously that adult (HRAS-/-; NRAS-/-) double knockout (DKO) mice showed no obvious external phenotype although lower-than-expected numbers of weaned DKO animals were consistently tallied after crossing NRAS-KO and HRAS-KO mice kept on mixed genetic backgrounds. Using mouse strains kept on pure C57Bl/6 background, here we performed an extensive analysis of the offspring from crosses between HRAS-KO and NRAS-KO mice and uncovered the occurrence of very high rates of perinatal mortality of the resulting DKO littermates due to respiratory failure during the first postnatal 24-48 h. The lungs of newborn DKO mice showed normal organ structure and branching but displayed marked defects of maturation including much-reduced alveolar space with thick separating septa and significant alterations of differentiation of alveolar (AT1, AT2 pneumocytes) and bronchiolar (ciliated, Clara cells) cell lineages. We also observed the retention of significantly increased numbers of undifferentiated progenitor precursor cells in distal lung epithelia and the presence of substantial accumulations of periodic acid-Schiff-positive (PAS+) material and ceramide in the lung airways of newborn DKO mice. Interestingly, antenatal dexamethasone treatment partially mitigated the defective lung maturation phenotypes and extended the lifespan of the DKO animals up to 6 days, but was not sufficient to abrogate lethality in these mice. RNA microarray hybridization analyses of the lungs of dexamethasone-treated and untreated mice uncovered transcriptional changes pointing to functional and metabolic alterations that may be mechanistically relevant for the defective lung phenotypes observed in DKO mice. Our data suggest that delayed alveolar differentiation, altered sphingolipid metabolism and ceramide accumulation are primary contributors to the respiratory stress and neonatal lethality shown by DKO mice and uncover specific, critical roles of HRAS and NRAS for correct lung differentiation that are essential for neonatal survival and cannot be substituted by the remaining KRAS function in this organ.


Assuntos
Brônquios , Diferenciação Celular , Proteínas Monoméricas de Ligação ao GTP/deficiência , Proteínas Proto-Oncogênicas p21(ras)/deficiência , Alvéolos Pulmonares , Insuficiência Respiratória , Animais , Brônquios/crescimento & desenvolvimento , Brônquios/patologia , Camundongos , Camundongos Knockout , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Alvéolos Pulmonares/crescimento & desenvolvimento , Alvéolos Pulmonares/patologia , Insuficiência Respiratória/genética , Insuficiência Respiratória/metabolismo , Insuficiência Respiratória/patologia
17.
Sci Rep ; 9(1): 17190, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748613

RESUMO

The study aimed to evaluate the clinical and imaging features of critically ill patients with interstitial lung disease (ILD) treated in respiratory intensive care unit (RICU) and assess the prognostic effects of these factors. A total of 160 severe ILD patients admitted to the RICU were finally enrolled in this study. The clinical, imaging and follow-up data of them were studied retrospectively. The in-hospital mortality and total mortality were 43.1% and 63.8% respectively. By multivariate cox regression analysis, shock (OR = 2.39, P = 0.004), pulmonary fibrosis on CT (OR = 2.85, P = 0.002) and non-invasive ventilation (OR = 1.86, P = 0.037) were harmful factors to survivals of critically ill patients with ILD. In contrast, oxygenation index (OR = 0.99, P = 0.028), conventional oxygen therapy (OR = 0.59, P = 0.048) and ß-lactam antibiotics use (OR = 0.51, P = 0.004) were protective factors. There is significant difference of survivals between patients with and without fibrosing ILD on CT (Log-rank, p = 0.001). The prognosis of critically ill patients with ILD was poor. Shock, respiratory failure and fibrosing signs on chest CT affected the prognosis. Chest CT was considered as a valuable tool to indicate the prognosis.


Assuntos
Estado Terminal , Mortalidade Hospitalar/tendências , Unidades de Terapia Intensiva/estatística & dados numéricos , Doenças Pulmonares Intersticiais/patologia , Insuficiência Respiratória/patologia , Tomografia Computadorizada por Raios X/métodos , Idoso , Gasometria , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/terapia , Masculino , Prognóstico , Insuficiência Respiratória/diagnóstico por imagem , Insuficiência Respiratória/terapia , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
18.
J Cardiovasc Pharmacol ; 74(5): 389-399, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31730560

RESUMO

Levosimendan is a calcium sensitizer that promotes myocyte contractility through its calcium-dependent interaction with cardiac troponin C. Administered intravenously, it has been used for nearly 2 decades to treat acute and advanced heart failure and to support the heart function in various therapy settings characterized by low cardiac output. Effects of levosimendan on noncardiac muscle suggest a possible new application in the treatment of people with amyotrophic lateral sclerosis (ALS), a neuromuscular disorder characterized by progressive weakness, and eventual paralysis. Previous attempts to improve the muscle response in ALS patients and thereby maintain respiratory function and delay progression of disability have produced some mixed results. Continuing this line of investigation, levosimendan has been shown to enhance in vitro the contractility of the diaphragm muscle fibers of non-ALS patients and to improve in vivo diaphragm neuromuscular efficiency in healthy subjects. Possible positive effects on respiratory function in people with ALS were seen in an exploratory phase 2 study, and a phase 3 clinical trial is now underway to evaluate the potential benefit of an oral form of levosimendan on both respiratory and overall functions in patients with ALS. Here, we will review the various known pharmacologic effects of levosimendan, considering their relevance to people living with ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Diafragma/inervação , Neurônios Motores/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Fármacos Neuromusculares/uso terapêutico , Respiração/efeitos dos fármacos , Insuficiência Respiratória/tratamento farmacológico , Simendana/uso terapêutico , Esclerose Amiotrófica Lateral/patologia , Esclerose Amiotrófica Lateral/fisiopatologia , Animais , Progressão da Doença , Humanos , Neurônios Motores/patologia , Recuperação de Função Fisiológica , Insuficiência Respiratória/patologia , Insuficiência Respiratória/fisiopatologia , Resultado do Tratamento
19.
Nat Commun ; 10(1): 3422, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366921

RESUMO

Severe influenza infection has no effective treatment available. One of the key barriers to developing host-directed therapy is a lack of reliable prognostic factors needed to guide such therapy. Here, we use a network analysis approach to identify host factors associated with severe influenza and fatal outcome. In influenza patients with moderate-to-severe diseases, we uncover a complex landscape of immunological pathways, with the main changes occurring in pathways related to circulating neutrophils. Patients with severe disease display excessive neutrophil extracellular traps formation, neutrophil-inflammation and delayed apoptosis, all of which have been associated with fatal outcome in animal models. Excessive neutrophil activation correlates with worsening oxygenation impairment and predicted fatal outcome (AUROC 0.817-0.898). These findings provide new evidence that neutrophil-dominated host response is associated with poor outcomes. Measuring neutrophil-related changes may improve risk stratification and patient selection, a critical first step in developing host-directed immune therapy.


Assuntos
Armadilhas Extracelulares/imunologia , Influenza Humana/imunologia , Influenza Humana/patologia , Ativação de Neutrófilo/imunologia , Neutrófilos/imunologia , Ciclo Celular/imunologia , Feminino , Expressão Gênica/genética , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Vírus da Influenza B/imunologia , Vírus da Influenza B/isolamento & purificação , Influenza Humana/mortalidade , Pulmão/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Respiração Artificial , Insuficiência Respiratória/mortalidade , Insuficiência Respiratória/patologia , Insuficiência Respiratória/virologia
20.
BMJ Case Rep ; 12(7)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31300601

RESUMO

This is a rare case of sporadic lymphangioleiomyomatosis (S-LAM) manifesting as refractory chylothorax and chyloperitoneum. A middle-aged woman with unremarkable medical history presented with respiratory failure, abdominal distension and anasarca. She was found to have high-output chylous effusion that required chest tube drainage, as well as chylous ascites. Notably initial chest and abdominal CT did not reveal characteristic pulmonary cysts or the presence of angiomyolipomas suggestive of LAM. An extensive oncologic and infectious work-up was undertaken with negative findings. The chylous effusion was persistent and refractory to thoracic duct embolization, total parenteral nutrition with octreotide, and talc pleurodesis. Diagnosis of S-LAM was confirmed after repeat chest CT showed subtle pulmonary cystic changes, and serum vascular endothelial growth factor-D level was found to be elevated at 834 pg/mL. Patient was started on sirolimus therapy, but lost to follow-up after hospital discharge. Patient died approximately 1 year later.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Quilotórax/diagnóstico , Linfangioleiomiomatose/diagnóstico , Insuficiência Respiratória/patologia , Sirolimo/uso terapêutico , Ducto Torácico/patologia , Tubos Torácicos , Quilotórax/fisiopatologia , Quilotórax/terapia , Drenagem , Edema , Evolução Fatal , Feminino , Humanos , Linfangioleiomiomatose/fisiopatologia , Linfangioleiomiomatose/terapia , Pessoa de Meia-Idade , Nutrição Parenteral Total , Insuficiência Respiratória/diagnóstico por imagem
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