Pathomorphological Features of Acute Respiratory Distress Syndrome in Competing Lung Diseases: Covid-19 and Sarcoidosis

The COVID-19 pandemic is a worldwide problem. The clinical spectrum of SARS-CoV-2 infection varies from asymptomatic or paucity-symptomatic forms to conditions such as pneumonia, acute respiratory distress syndrome and multiple organ failure. Objective was to describe a clinical case of SARS-CoV-2 infection in the patient with sarcoidosis and cardiovascular pathology developing acute respiratory syndrome and lung edema. Material and methods. There were analyzed accompanying medical documentation (outpatient chart, medical history), clinical and morphological histol-ogy data (description of macro-and micro-preparations) using hematoxylin and eosin staining. Results. Lung histological examination revealed signs of diffuse alveolar damage such as hyaline membranes lining and following the contours of the alveolar walls. Areas of necrosis and desquamation of the alveolar epithelium in the form of scattered cells or layers, areas of hemorrhages and hemosiderophages are detected in the alveolar walls. In the lumen of the alveoli, a sloughed epithe-lium with a hemorrhagic component, few multinucleated cells, macrophages, protein masses, and accumulated edema-tous fluid were determined. Pulmonary vessels are moderately full-blooded, surrounded by perivascular infiltrates. Signs of lung sarcoidosis were revealed. Histological examination found epithelioid cell granulomas consisting of mononuclear phagocytes and lymphocytes, without signs of necrosis. Granulomas with a proliferative component and hemorrhage sites were determined. Giant cells with cytoplasmic inclusions were detected - asteroid corpuscles and Schauman corpuscles. Non-caseous granulomas consisting of clusters of epithelioid histiocytes and giant Langhans cells surrounded by lympho-cytes were detected in the lymph nodes of the lung roots. Hamazaki-Wesenberg corpuscles inside giant cells were found in the zones of peripheral sinuses of lymph nodes. In the lumen of the bronchi, there was found fully exfoliated epithelium, mucus. Granulomas are mainly observed subendothelially on the mucous membrane, without caseous necrosis. Histo-logical examination of the cardiovascular system revealed fragmentation of some cardiomyocytes, cardiomyocyte focal hypertrophy along with moderate interstitial edema, erythrocyte sludge. Zones of small focal sclerosis were determined. The vessels of the microcirculatory bed are anemic, with hypertrophy of the walls in small arteries and arterioles. Virologi-cal examination of the sectional material in the lungs revealed SARS-CoV-2 RNA. Conclusion. Based on the data of medi-cal documentation and the results of a post-mortem examination, it follows that the cause of death of the patient R.A., 50 years old, was a new coronavirus infection COVID-19 that resulted in bilateral total viral pneumonia. Co-morbidity with competing diseases such as lung sarcoidosis and cardiovascular diseases aggravated the disease course, led to the development of early ARDS and affected the lethal outcome.

Results From a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Repository Corticotropin Injection for the Treatment of Pulmonary Sarcoidosis.

INTRODUCTION: Long-term treatment of pulmonary sarcoidosis with glucocorticoids has been associated with toxicity and other adverse events, highlighting the need for alternative therapies. The goal of this study was to evaluate the efficacy and safety of repository corticotropin injection (RCI, Acthar® Gel) in patients with pulmonary sarcoidosis and to validate endpoints for use in future clinical trials. METHODS: In this multicenter, randomized, placebo-controlled trial, subjects received subcutaneous RCI (80 U) twice weekly or matching placebo through 24 weeks in a double-blind treatment phase, followed by an optional 24-week open-label extension. Efficacy was measured by glucocorticoid tapering, pulmonary function tests, chest imaging, patient-reported outcomes, and a novel sarcoidosis treatment score (STS). Safety was assessed by adverse events, physical examinations, vital signs, clinical laboratory abnormalities, and imaging. The study was terminated early due to low enrollment caused by the COVID-19 pandemic, thereby precluding statistical analysis. RESULTS: Fifty-five subjects were randomized to receive either RCI (n = 27) or placebo (n = 28). Mean STS at week 24 showed greater improvement with RCI (1.4) compared with placebo (0.7). At week 48, those who remained on RCI had an STS of 1.8 compared with 0.9 in those who switched from placebo to RCI. More subjects in the RCI group discontinued glucocorticoids at week 24 compared to the placebo group. Glucocorticoid discontinuation was comparable at week 48 for those who switched from placebo to RCI and those who continued RCI. Similar trends in favor of RCI over placebo were observed with the other efficacy endpoints. No new or unexpected safety signals were identified. CONCLUSIONS: RCI was safe and well tolerated, with trends in efficacy data suggesting greater improvement with RCI compared to placebo in patients receiving standard-of-care therapy for pulmonary sarcoidosis. The study also provided validation of efficacy endpoints that may be used in larger trials for pulmonary sarcoidosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03320070.

Pulmonary sarcoidosis is a disease characterized by inflammation of the lungs. Standard treatments include glucocorticoids, which may have harmful side effects. This clinical trial investigated whether repository corticotropin injection (RCI, Acthar^® Gel) was safe and effective in patients who were already taking glucocorticoids to treat pulmonary sarcoidosis. Patients were randomly assigned to be in one of two treatment groups: RCI or placebo. In the first 24 weeks of the study, 27 patients were injected with RCI twice weekly, while 28 patients were injected with an inactive substance (placebo). Forty-seven patients continued into an optional phase of the study for an additional 24 weeks in which all patients received RCI twice weekly. A sarcoidosis treatment score and assessments of lung health, general health, and fatigue were used to determine whether RCI was effective. These assessments showed greater improvements with RCI compared to placebo. Patients who switched from placebo to RCI showed similar improvements to those who remained on RCI throughout the entire study. Patients receiving RCI were able to discontinue their use of glucocorticoids more quickly than those taking placebo, thus helping them to avoid the harmful side effects of the glucocorticoids. Side effects for RCI were mostly mild or moderate, and no new or unexpected safety concerns for RCI were seen throughout the study.

PATHOMORPHOLOGICAL FEATURES OF ACUTE RESPIRATORY DISTRESS SYNDROME IN COMPETING LUNG DISEASES: COVID-19 AND SARCOIDOSIS

The COVID-19 pandemic is a worldwide problem. The clinical spectrum of SARS-CoV-2 infection varies from asymptomatic or paucity-symptomatic forms to conditions such as pneumonia, acute respiratory distress syndrome and multiple organ failure. Objective was to describe a clinical case of SARS-CoV-2 infection in the patient with sarcoidosis and cardiovascular pathology developing acute respiratory syndrome and lung edema. Material and methods. There were analyzed accompanying medical documentation (outpatient chart, medical history), clinical and morphological histology data (description of macro- and micro-preparations) using hematoxylin and eosin staining. Results. Lung histological examination revealed signs of diffuse alveolar damage such as hyaline membranes lining and following the contours of the alveolar walls. Areas of necrosis and desquamation of the alveolar epithelium in the form of scattered cells or layers, areas of hemorrhages and hemosiderophages are detected in the alveolar walls. In the lumen of the alveoli, a sloughed epithelium with a hemorrhagic component, few multinucleated cells, macrophages, protein masses, and accumulated edematous fluid were determined. Pulmonary vessels are moderately full-blooded, surrounded by perivascular infiltrates. Signs of lung sarcoidosis were revealed. Histological examination found epithelioid cell granulomas consisting of mononuclear phagocytes and lymphocytes, without signs of necrosis. Granulomas with a proliferative component and hemorrhage sites were determined. Giant cells with cytoplasmic inclusions were detected — asteroid corpuscles and Schauman corpuscles. Non-caseous granulomas consisting of clusters of epithelioid histiocytes and giant Langhans cells surrounded by lymphocytes were detected in the lymph nodes of the lung roots. Hamazaki–Wesenberg corpuscles inside giant cells were found in the zones of peripheral sinuses of lymph nodes. In the lumen of the bronchi, there was found fully exfoliated epithelium, mucus. Granulomas are mainly observed subendothelially on the mucous membrane, without caseous necrosis. Histological examination of the cardiovascular system revealed fragmentation of some cardiomyocytes, cardiomyocyte focal hypertrophy along with moderate interstitial edema, erythrocyte sludge. Zones of small focal sclerosis were determined. The vessels of the microcirculatory bed are anemic, with hypertrophy of the walls in small arteries and arterioles. Virological examination of the sectional material in the lungs revealed SARS-CoV-2 RNA. Conclusion. Based on the data of medical documentation and the results of a post-mortem examination, it follows that the cause of death of the patient R.A., 50 years old, was a new coronavirus infection COVID-19 that resulted in bilateral total viral pneumonia. Сo-morbidity with competing diseases such as lung sarcoidosis and cardiovascular diseases aggravated the disease course, led to the development of early ARDS and affected the lethal outcome. © 2022 Saint Petersburg Pasteur Institute. All rights reserved.

PATHOMORPHOLOGICAL FEATURES OF ACUTE RESPIRATORY DISTRESS SYNDROME IN COMPETING LUNG DISEASES: COVID-19 AND SARCOIDOSIS.

The COVID-19 pandemic is a worldwide problem. The clinical spectrum of SARS-CoV-2 infection varies from asymptomatic or paucity-symptomatic forms to conditions such as pneumonia, acute respiratory distress syndrome and multiple organ failure. Objective was to describe a clinical case of SARS-CoV-2 infection in the patient with sarcoidosis and cardiovascular pathology developing acute respiratory syndrome and lung edema. Material and methods. There were analyzed accompanying medical documentation (outpatient chart, medical history), clinical and morphological histology data (description of macro- and micro-preparations) using hematoxylin and eosin staining. Results. Lung histological examination revealed signs of diffuse alveolar damage such as hyaline membranes lining and following the contours of the alveolar walls. Areas of necrosis and desquamation of the alveolar epithelium in the form of scattered cells or layers, areas of hemorrhages and hemosiderophages are detected in the alveolar walls. In the lumen of the alveoli, a sloughed epithelium with a hemorrhagic component, few multinucleated cells, macrophages, protein masses, and accumulated edematous fluid were determined. Pulmonary vessels are moderately full-blooded, surrounded by perivascular infiltrates. Signs of lung sarcoidosis were revealed. Histological examination found epithelioid cell granulomas consisting of mononuclear phagocytes and lymphocytes, without signs of necrosis. Granulomas with a proliferative component and hemorrhage sites were determined. Giant cells with cytoplasmic inclusions were detected - asteroid corpuscles and Schauman corpuscles. Non-caseous granulomas consisting of clusters of epithelioid histiocytes and giant Langhans cells surrounded by lymphocytes were detected in the lymph nodes of the lung roots. Hamazaki-Wesenberg corpuscles inside giant cells were found in the zones of peripheral sinuses of lymph nodes. In the lumen of the bronchi, there was found fully exfoliated epithelium, mucus. Granulomas are mainly observed subendothelially on the mucous membrane, without caseous necrosis. Histological examination of the cardiovascular system revealed fragmentation of some cardiomyocytes, cardiomyocyte focal hypertrophy along with moderate interstitial edema, erythrocyte sludge. Zones of small focal sclerosis were determined. The vessels of the microcirculatory bed are anemic, with hypertrophy of the walls in small arteries and arterioles. Virological examination of the sectional material in the lungs revealed SARS-CoV-2 RNA. Conclusion. Based on the data of medical documentation and the results of a post-mortem examination, it follows that the cause of death of the patient R.A., 50 years old, was a new coronavirus infection COVID-19 that resulted in bilateral total viral pneumonia. So-morbidity with competing diseases such as lung sarcoidosis and cardiovascular diseases aggravated the disease course, led to the development of early ARDS and affected the lethal outcome. Copyright © 2022 Saint Petersburg Pasteur Institute. All rights reserved.

Management of Advanced Pulmonary Sarcoidosis.

The term "advanced sarcoidosis" is used for forms of sarcoidosis with a significant risk of loss of organ function or death. Advanced sarcoidosis often involves the lung and is described as "advanced pulmonary sarcoidosis" (APS), which includes advanced pulmonary fibrosis, associated complications such as bronchiectasis and infections, and pulmonary hypertension. Although APS affects a small proportion of patients with sarcoidosis, it is the leading cause of poor outcomes, including death. Here we review the major patterns of APS with a focus on the current management as well as potential approaches for improved outcomes for this most serious sarcoidosis phenotype.

The Impact of ACE and ACE2 Gene Polymorphisms in Pulmonary Diseases Including COVID-19.

Chronic and acute respiratory diseases pose a major problem for public health worldwide due to the high morbidity and mortality rates, while treatment options remain mostly symptomatic. The renin-angiotensin system (RAS) plays an important role in lung tissue, regulating pulmonary circulation and blood pressure, but also contributing to normal pulmonary function and development. Angiotensin-converting enzyme (ACE) and its homologous angiotensin-converting enzyme 2 (ACE2) are considered to be amongst the main RAS regulators and are highly expressed in the pulmonary vascular endothelium. This review discusses the impact of ACE and ACE2 functional gene polymorphisms on seven major pulmonary diseases, in terms of predisposition, course, and outcome, revealing their potential utility as both genetic markers and biomarkers. The discussed conditions include chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), asthma, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), lung cancer and pulmonary sarcoidosis (PS), as well as SARS-CoV-2 viral infection and COVID-19 disease.

Moderate or Severe Impairment in Pulmonary Function is Associated with Mortality in Sarcoidosis Patients Infected with SARS­CoV­2.

PURPOSE: To investigate whether sarcoidosis patients infected with SARS-CoV-2 are at risk for adverse disease outcomes. STUDY DESIGN AND METHODS: This retrospective study was conducted in five hospitals within the Mount Sinai Health System during March 1, 2020 to July 29, 2020. All patients diagnosed with COVID-19 were included in the study. We identified sarcoidosis patients who met diagnostic criteria for sarcoidosis according to accepted guidelines. An adverse disease outcome was defined as the presence of intubation and mechanical ventilation or in-hospital mortality. In sarcoidosis patients, we reported (when available) the results of pulmonary function testing measured within 3 years prior to the time of SARS­CoV­2 infection. A multivariable logistic regression model was used to generate an adjusted odds ratio (aOR) to evaluate sarcoidosis as a risk factor for an adverse outcome. The same model was used to analyze sarcoidosis patients with moderate and/or severe impairment in pulmonary function. RESULTS: The study included 7337 patients, 37 of whom (0.5%) had sarcoidosis. The crude rate of developing an adverse outcome was significantly higher in patients with moderately and/or severely impaired pulmonary function (9/14 vs. 3/23, p = 0.003). While the diagnosis of sarcoidosis was not independently associated with risk of an adverse event, (aOR 1.8, 95% CI 0.9-3.6), the diagnosis of sarcoidosis in patients with moderately and/or severely impaired pulmonary function was associated with an adverse outcome (aOR 7.8, 95% CI 2.4-25.8). CONCLUSION: Moderate or severe impairment in pulmonary function is associated with mortality in sarcoidosis patients infected with SARS­CoV­2.