Diffuse alveolar damage patterns reflect the immunological and molecular heterogeneity in fatal COVID-19.

BACKGROUND: Severe COVID-19 lung disease exhibits a high degree of spatial and temporal heterogeneity, with different histological features coexisting within a single individual. It is important to capture the disease complexity to support patient management and treatment strategies. We provide spatially decoded analyses on the immunopathology of diffuse alveolar damage (DAD) patterns and factors that modulate immune and structural changes in fatal COVID-19. METHODS: We spatially quantified the immune and structural cells in exudative, intermediate, and advanced DAD through multiplex immunohistochemistry in autopsy lung tissue of 18 COVID-19 patients. Cytokine profiling, viral, bacteria, and fungi detection, and transcriptome analyses were performed. FINDINGS: Spatial DAD progression was associated with expansion of immune cells, macrophages, CD8+ T cells, fibroblasts, and (lymph)angiogenesis. Viral load correlated positively with exudative DAD and negatively with disease/hospital length. In all cases, enteric bacteria were isolated, and Candida parapsilosis in eight cases. Cytokines correlated mainly with macrophages and CD8+T cells. Pro-coagulation and acute repair were enriched pathways in exudative DAD whereas intermediate/advanced DAD had a molecular profile of elevated humoral and innate immune responses and extracellular matrix production. INTERPRETATION: Unraveling the spatial and molecular immunopathology of COVID-19 cases exposes the responses to SARS-CoV-2-induced exudative DAD and subsequent immune-modulatory and remodeling changes in proliferative/advanced DAD that occur side-by-side together with secondary infections in the lungs. These complex features have important implications for disease management and the development of novel treatments. FUNDING: CNPq, Bill and Melinda Gates Foundation, HC-Convida, FAPESP, Regeneron Pharmaceuticals, and the Swedish Heart & Lung Foundation.

Ultrasound assessment of pulmonary fibroproliferative changes in severe COVID-19: a quantitative correlation study with histopathological findings.

PURPOSE: This study was designed to evaluate the usefulness of lung ultrasound (LUS) imaging to characterize the progression and severity of lung damage in cases of COVID-19. METHODS: We employed a set of combined ultrasound parameters and histopathological images obtained simultaneously in 28 patients (15 women, 0.6-83 years) with fatal COVID-19 submitted to minimally invasive autopsies, with different times of disease evolution from initial symptoms to death (3-37 days, median 18 days). For each patient, we analysed eight post-mortem LUS parameters and the proportion of three histological patterns (normal lung, exudative diffuse alveolar damage [DAD] and fibroproliferative DAD) in eight different lung regions. The relationship between histopathological and post-mortem ultrasonographic findings was assessed using various statistical approaches. RESULTS: Statistically significant positive correlations were observed between fibroproliferative DAD and peripheral consolidation (coefficient 0.43, p = 0.02) and pulmonary consolidation (coefficient 0.51, p = 0.005). A model combining age, time of evolution, sex and ultrasound score predicted reasonably well (r = 0.66) the proportion of pulmonary parenchyma with fibroproliferative DAD. CONCLUSION: The present study adds information to previous studies related to the use of LUS as a tool to assess the severity of acute pulmonary damage. We provide a histological background that supports the concept that LUS can be used to characterize the progression and severity of lung damage in severe COVID-19.

Tracking the time course of pathological patterns of lung injury in severe COVID-19.

BACKGROUND: Pulmonary involvement in COVID-19 is characterized pathologically by diffuse alveolar damage (DAD) and thrombosis, leading to the clinical picture of Acute Respiratory Distress Syndrome. The direct action of SARS-CoV-2 in lung cells and the dysregulated immuno-coagulative pathways activated in ARDS influence pulmonary involvement in severe COVID, that might be modulated by disease duration and individual factors. In this study we assessed the proportions of different lung pathology patterns in severe COVID-19 patients along the disease evolution and individual characteristics. METHODS: We analysed lung tissue from 41 COVID-19 patients that died in the period March-June 2020 and were submitted to a minimally invasive autopsy. Eight pulmonary regions were sampled. Pulmonary pathologists analysed the H&E stained slides, performing semiquantitative scores on the following parameters: exudative, intermediate or advanced DAD, bronchopneumonia, alveolar haemorrhage, infarct (%), arteriolar (number) or capillary thrombosis (yes/no). Histopathological data were correlated with demographic-clinical variables and periods of symptoms-hospital stay. RESULTS: Patient´s age varied from 22 to 88 years (18f/23 m), with hospital admission varying from 0 to 40 days. All patients had different proportions of DAD in their biopsies. Ninety percent of the patients presented pulmonary microthrombosis. The proportion of exudative DAD was higher in the period 0-8 days of hospital admission till death, whereas advanced DAD was higher after 17 days of hospital admission. In the group of patients that died within eight days of hospital admission, elderly patients had less proportion of the exudative pattern and increased proportions of the intermediate patterns. Obese patients had lower proportion of advanced DAD pattern in their biopsies, and lower than patients with overweight. Clustering analysis showed that patterns of vascular lesions (microthrombosis, infarction) clustered together, but not the other patterns. The vascular pattern was not influenced by demographic or clinical parameters, including time of disease progression. CONCLUSION: Patients with severe COVID-19 present different proportions of DAD patterns over time, with advanced DAD being more prevalent after 17 days, which seems to be influenced by age and weight. Vascular involvement is present in a large proportion of patients, occurs early in disease progression, and does not change over time.

Palliative care in pulmonary medicine.

Palliative care was initially developed for patients with advanced cancer. The concept has evolved and now encompasses any life-threatening chronic disease. Studies carried out to compare end-of-life symptoms have shown that although symptoms such as pain and dyspnea are as prevalent in patients with lung disease as in patients with cancer, the former receive less palliative treatment than do the latter. There is a need to refute the idea that palliative care should be adopted only when curative treatment is no longer possible. Palliative care should be provided in conjunction with curative treatment at the time of diagnosis, by means of a joint decision-making process; that is, the patient and the physician should work together to plan the therapy, seeking to improve quality of life while reducing physical, psychological, and spiritual suffering.

Thrombolysis in acute pulmonary embolism.

OBJECTIVES: Acute pulmonary embolism (APE) is an important cause of cardiovascular mortality, due mainly to hemodynamic instability. In these cases, the recommendation is to perform some reperfusion procedure, with systemic thrombolysis being the main therapy used. However, national data evaluating the efficacy and safety of thrombolysis are scarce. METHODS: Retrospective analysis of a case series. We included 13 patients diagnosed with high-risk APE and 4 patients with intermediate-high risk from a single-center, who were treated with alteplase 100mg. RESULTS: The mean age of the patients was 55 years, most of them female (76.4%). Among the risk factors for VTE were immobilization (41.17%), contraceptive use (35.29%), cancer (17.63%), and previous history of DVT (11.76%). The most frequent clinical manifestations of APE were dyspnea (88.23%), hypoxia (82.35%), hypotension (82.35%), and tachycardia (64.70%). 82.35% of the patients had echocardiographic signs of right ventricular dysfunction, and 52.94% had increased troponin and BNP. Severe bleeding associated with thrombolysis occurred in 17.54% of cases. No patient died due to bleeding. There were 8 deaths from right ventricular failure (47%), 6 in the cases of patients presenting as high-risk APE (35.3%), and 2 in the cases of intermediate-high risk (11.8%). CONCLUSION: Thrombolysis in patients with high-risk APE or intermediate-high risk had a severe bleeding rate of 17.6%. However, the high mortality of this population (47%) due to right ventricular failure justifies the use of this therapeutic modality.

Thrombolysis in acute pulmonary embolism

SUMMARY OBJECTIVES Acute pulmonary embolism (APE) is an important cause of cardiovascular mortality, due mainly to hemodynamic instability. In these cases, the recommendation is to perform some reperfusion procedure, with systemic thrombolysis being the main therapy used. However, national data evaluating the efficacy and safety of thrombolysis are scarce. METHODS Retrospective analysis of a case series. We included 13 patients diagnosed with high-risk APE and 4 patients with intermediate-high risk from a single-center, who were treated with alteplase 100mg. RESULTS The mean age of the patients was 55 years, most of them female (76.4%). Among the risk factors for VTE were immobilization (41.17%), contraceptive use (35.29%), cancer (17.63%), and previous history of DVT (11.76%). The most frequent clinical manifestations of APE were dyspnea (88.23%), hypoxia (82.35%), hypotension (82.35%), and tachycardia (64.70%). 82.35% of the patients had echocardiographic signs of right ventricular dysfunction, and 52.94% had increased troponin and BNP. Severe bleeding associated with thrombolysis occurred in 17.54% of cases. No patient died due to bleeding. There were 8 deaths from right ventricular failure (47%), 6 in the cases of patients presenting as high-risk APE (35.3%), and 2 in the cases of intermediate-high risk (11.8%). CONCLUSION Thrombolysis in patients with high-risk APE or intermediate-high risk had a severe bleeding rate of 17.6%. However, the high mortality of this population (47%) due to right ventricular failure justifies the use of this therapeutic modality.

RESUMO OBJETIVOS A embolia pulmonar aguda (EAP) é uma causa importante de mortalidade cardiovascular ao causar instabilidade hemodinâmica. Nesses casos, a recomendação é a realização de algum procedimento de reperfusão, sendo a trombólise sistêmica a principal terapia utilizada. No entanto, dados nacionais avaliando a eficácia e a segurança da trombólise são escassos. MÉTODO Análise retrospectiva de uma série de casos. Foram incluídos 13 pacientes com o diagnóstico de EAP de alto risco e quatro pacientes de risco intermediário-alto, de um único centro, e que foram tratados com alteplase 100 mg. RESULTADOS A média de idade dos pacientes foi 55 anos, sendo a maioria do gênero feminino (76,4%). Dos fatores de risco para TEV, estavam presentes a imobilização (41,17%), o uso de anticonceptivos (35,29%), câncer (17,63%) e história prévia de TVP (11,76%). As manifestações clínicas mais frequentes da EAP foram dispneia (88,23%), hipóxia (82,35%), hipotensão (82,35%) e taquicardia (64,70%); 82,35% dos pacientes apresentaram sinais ecocardiográficos de disfunção ventricular direita e 52,94% apresentaram aumento da troponina e BNP. Sangramento grave associado à trombólise ocorreu em 17,54% dos casos. Nenhum paciente faleceu em decorrência de sangramento. Houve oito mortes por insuficiência ventricular direita (47%): seis nos casos de paciente que se apresentaram como EAP de alto risco (35,3%) e duas nos casos de risco intermediário-alto (11,8%). CONCLUSÃO A trombólise nos pacientes com EAP de alto risco ou risco intermediário-alto apresentou uma taxa de sangramento grave de 17,6%. No entanto, a alta mortalidade dessa população (47%) por insuficiência ventricular direita justifica o uso desta modalidade terapêutica.

Lung Cavities in Chronic Thromboembolic Pulmonary Hypertension.

OBJECTIVES: Chronic thromboembolic pulmonary hypertension (CTEPH) is a unique form of pulmonary hypertension (PH) that arises from obstruction of the pulmonary vessels by recanalized thromboembolic material. CTEPH has a wide range of radiologic presentations. Commonly, it presents as main pulmonary artery enlargement, peripheral vascular obstructions, bronchial artery dilations, and mosaic attenuation patterns. Nevertheless, other uncommon presentations have been described, such as lung cavities. These lesions may be solely related to chronic lung parenchyma ischemia but may also be a consequence of concomitant chronic infectious conditions. The objective of this study was to evaluate the different etiologies that cause lung cavities in CTEPH patients. METHODS: A retrospective data analysis of the medical records of CTEPH patients in a single reference PH center that contained or mentioned lung cavities was conducted between 2013 and 2016. RESULTS: Seven CTEPH patients with lung cavities were identified. The cavities had different sizes, locations, and wall thicknesses. In two patients, the cavities were attributed to pulmonary infarction; in 5 patients, an infectious etiology was identified. CONCLUSION: Despite the possibility of being solely associated with chronic lung parenchyma ischemia, most cases of lung cavities in CTEPH patients were associated with chronic granulomatous diseases, reinforcing the need for active investigation of infectious agents in this setting.

Lung cavities in chronic thromboembolic pulmonary hypertension

OBJECTIVES: Chronic thromboembolic pulmonary hypertension (CTEPH) is a unique form of pulmonary hypertension (PH) that arises from obstruction of the pulmonary vessels by recanalized thromboembolic material. CTEPH has a wide range of radiologic presentations. Commonly, it presents as main pulmonary artery enlargement, peripheral vascular obstructions, bronchial artery dilations, and mosaic attenuation patterns. Nevertheless, other uncommon presentations have been described, such as lung cavities. These lesions may be solely related to chronic lung parenchyma ischemia but may also be a consequence of concomitant chronic infectious conditions. The objective of this study was to evaluate the different etiologies that cause lung cavities in CTEPH patients. METHODS: A retrospective data analysis of the medical records of CTEPH patients in a single reference PH center that contained or mentioned lung cavities was conducted between 2013 and 2016. RESULTS: Seven CTEPH patients with lung cavities were identified. The cavities had different sizes, locations, and wall thicknesses. In two patients, the cavities were attributed to pulmonary infarction; in 5 patients, an infectious etiology was identified. CONCLUSION: Despite the possibility of being solely associated with chronic lung parenchyma ischemia, most cases of lung cavities in CTEPH patients were associated with chronic granulomatous diseases, reinforcing the need for active investigation of infectious agents in this setting.

Pulmonary arteriovenous malformations: diagnostic and treatment characteristics.

OBJECTIVE: To present a case series of pulmonary arteriovenous malformations (PAVMs), describing the main clinical findings, the number/location of pulmonary vascular abnormalities, the clinical complications, and the treatment administered. METHODS: This was a retrospective observational study evaluating patients with PAVM divided into two groups: hereditary hemorrhagic telangiectasia (HHT); and idiopathic PAVM (iPAVM). RESULTS: A total of 41 patients were selected for inclusion, but only 33 had PAVMs. After clinical evaluation, 27 and 6 were diagnosed with HHT and iPAVM, respectively. In the HHT group, the mean age was 49.6 years and 88.9% were female. In that group, 4 patients had an SpO2 of < 90% and the most common clinical finding was epistaxis. In the iPAVM group, the mean age was 48.1 years and 83.3% were female. In that group, 3 patients had an SpO2 of < 90%. Computed tomographic pulmonary angiography showed that most of the PAVMs were in the lower lobes: 56.4% in the HHT group and 85.7% in the iPAVM group. Embolization was performed in 23 patients (in both groups). At this writing, 10 patients are scheduled to undergo the procedure. One of the patients who underwent embolization was subsequently referred for pulmonary resection. CONCLUSIONS: In both of the PAVM groups, there was a predominance of women and of fistulas located in the lower lobes. Few of the patients had respiratory symptoms, and most had an SpO2 > 90%. The treatment chosen for all patients was percutaneous transcatheter embolization.

Pulmonary arteriovenous malformations: diagnostic and treatment characteristics / Malformações arteriovenosas pulmonares: características diagnósticas e de tratamento

ABSTRACT Objective: To present a case series of pulmonary arteriovenous malformations (PAVMs), describing the main clinical findings, the number/location of pulmonary vascular abnormalities, the clinical complications, and the treatment administered. Methods: This was a retrospective observational study evaluating patients with PAVM divided into two groups: hereditary hemorrhagic telangiectasia (HHT); and idiopathic PAVM (iPAVM). Results: A total of 41 patients were selected for inclusion, but only 33 had PAVMs. After clinical evaluation, 27 and 6 were diagnosed with HHT and iPAVM, respectively. In the HHT group, the mean age was 49.6 years and 88.9% were female. In that group, 4 patients had an SpO2 of < 90% and the most common clinical finding was epistaxis. In the iPAVM group, the mean age was 48.1 years and 83.3% were female. In that group, 3 patients had an SpO2 of < 90%. Computed tomographic pulmonary angiography showed that most of the PAVMs were in the lower lobes: 56.4% in the HHT group and 85.7% in the iPAVM group. Embolization was performed in 23 patients (in both groups). At this writing, 10 patients are scheduled to undergo the procedure. One of the patients who underwent embolization was subsequently referred for pulmonary resection. Conclusions: In both of the PAVM groups, there was a predominance of women and of fistulas located in the lower lobes. Few of the patients had respiratory symptoms, and most had an SpO2 > 90%. The treatment chosen for all patients was percutaneous transcatheter embolization.

RESUMO Objetivo: Apresentar uma série de casos de malformações arteriovenosas pulmonares (MAVP) e descrever os principais achados clínicos, a quantidade e localização das MAVP, as complicações clínicas e os tratamentos realizados. Métodos: Estudo retrospectivo observacional que avaliou pacientes com MAVP divididos em dois grupos: telangiectasia hemorrágica hereditária (THH) e MAVP idiopática (MAVPi). Resultados: Foram avaliados 41 pacientes, sendo 33 pacientes portadores de MAVP. Após a avaliação clínica, 27 e 6 foram diagnosticados com THH e MAVPi, respectivamente. No grupo THH a média de idade foi de 49,6 anos e 88,9% eram do sexo feminino. Desses pacientes, 4 tinham SpO2 < 90% e o achado clínico mais frequente era epistaxe. No grupo MAVPi a média de idade foi de 48,1 anos, sendo que 83,3% eram do sexo feminino. Desses, 3 tinham SpO2 < 90%. Após a realização de angiotomografia de tórax observou-se que a maior parte das MAVP se situava nos lobos inferiores, totalizando 56,4% e 85,7% nos grupos THH e MAVPi, respectivamente. O tratamento por embolização foi realizado em 23 pacientes nos dois grupos, enquanto 10 aguardavam o procedimento até o momento da escrita deste estudo. Um paciente submetido à embolização foi encaminhado para ressecção pulmonar. Conclusões: Em ambos os grupos de pacientes com MAVP observou-se uma predominância de mulheres e de fístulas localizadas nos lobos inferiores. A maioria era assintomático respiratório com SpO2 > 90%. O tratamento de escolha para todos foi a embolização percutânea por cateter.

A rodent model of NASH with cirrhosis, oval cell proliferation and hepatocellular carcinoma.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a well recognized complication of advanced NASH (non-alcoholic steatohepatitis). We sought to produce a rat model of NASH, cirrhosis and HCC. METHODS: Adult Sprague-Dawley rats, weighing 250-300g, were fed a choline-deficient, high trans-fat diet and exposed to DEN in drinking water. After 16 weeks, the animals underwent liver ultrasound (US), sacrifice and assessment by microscopy, immunohistochemistry and transmission electron microscopy (TEM). RESULTS: US revealed steatosis and focal lesions in 6 of 7. All had steatohepatitis defined as inflammation, advanced fibrosis and ballooning with Mallory-Denk bodies (MDB) with frank cirrhosis in 6. Areas of more severe injury were associated with anti-CK19 positive ductular reaction. HCC, present in all, were macro-trabecullar or solid with polyhedral cells with foci of steatosis and ballooned cells. CK19 was positive in single or solid nests of oval cells and in neoplastic hepatocytes. TEM showed ballooning with small droplet fat, dilated endoplasmic reticulum and MDB in non-neoplastic hepatocytes and small droplet steatosis in some cancer cells. CONCLUSIONS: This model replicated many features of NASH including steatohepatitis with ballooning, fibrosis, cirrhosis and hepatocellular carcinoma. Oval cell proliferation was evident and the presence anti-CK 19 positivity in the cancer suggests oval cell origin of the malignancy.

Nonalcoholic steatohepatitis (NASH) in ob/ob mice treated with yo jyo hen shi ko (YHK): effects on peroxisome proliferator-activated receptors (PPARs) and microsomal triglyceride transfer protein (MTP).

YHK has antioxidant properties, has a hypoglycemic effect, and may reduce plasma lipid levels. In this study, we examined the hepatic expression of PPAR-alpha and -gamma and MTP in ob/ob mice receiving or not receiving YHK. Ob/ob mice were assigned to receive oral YHK (20 mg/kg/day) fed solution (methionine/choline-deficient [MCD] diet+YHK group) or vehicle (MCD group) by gavage for 4 weeks. Liver fragments were collected for histologic examination and mRNA isolation. PPAR-alpha and -gamma and MTP gene expression was examined by RT-qPCR. YHK treatment was associated with NASH prevention, weight loss, and reduction of visceral fat and of serum concentrations of aminotransferases in comparison to the MCD group. YHK promoted an increment in PPAR-alpha and MTP and a decrement in PPAR-gamma mRNA contents. These findings suggest that modulation of PPAR-alpha and -gamma and MTP RNA expression may be implicated in the protective effect of YHK in experimental NASH, limiting hepatocyte lipid accumulation.