Multidisciplinary Approach to the Diagnosis of Idiopathic Interstitial Pneumonias: Focus on the Pathologist's Key Role.

Idiopathic Interstitial Pneumonias (IIPs) are a heterogeneous group of the broader category of Interstitial Lung Diseases (ILDs), pathologically characterized by the distortion of lung parenchyma by interstitial inflammation and/or fibrosis. The American Thoracic Society (ATS)/European Respiratory Society (ERS) international multidisciplinary consensus classification of the IIPs was published in 2002 and then updated in 2013, with the authors emphasizing the need for a multidisciplinary approach to the diagnosis of IIPs. The histological evaluation of IIPs is challenging, and different types of IIPs are classically associated with specific histopathological patterns. However, morphological overlaps can be observed, and the same histopathological features can be seen in totally different clinical settings. Therefore, the pathologist's aim is to recognize the pathologic-morphologic pattern of disease in this clinical setting, and only after multi-disciplinary evaluation, if there is concordance between clinical and radiological findings, a definitive diagnosis of specific IIP can be established, allowing the optimal clinical-therapeutic management of the patient.

Pathological Changes and Cause of Death Associated with the Global Novel Coronavirus Disease (COVID-19).

The coronavirus disease 2019 (COVID-19) has been a global epidemic for more than three years, causing more than 6.9 million deaths. COVID-19 has the clinical characteristics of strong infectivity and long incubation period, and can cause multi-system damage, mainly lung damage, clinical symptoms of acute respiratory distress syndrome (ARDS) and systemic multiple organ damage. The SARS-CoV-2 virus is still constantly mutating. At present, there is no global consensus on the pathological changes of COVID-19 associated deaths and even no consensus on the criteria for determining the cause of death. The investigation of the basic pathological changes and progression of the disease is helpful to guide the clinical treatment and the development of therapeutic drugs. This paper reviews the autopsy reports and related literature published worldwide from February 2020 to June 2023, with a clear number of autopsy cases and corresponding pathological changes of vital organs as the inclusion criteria. A total of 1 111 autopsy cases from 65 papers in 18 countries are included. Pathological manifestations and causes of death are classified and statistically analyzed, common pathological changes of COVID-19 are summarized, and analytical conclusions are drawn, suggesting that COVID-19 infection can cause life-threatening pathological changes in vital organs. On the basis of different health levels of infected groups, the direct cause of death is mainly severe lung damage and secondary systemic multiple organ failure.

Immune check-point inhibitor-related pneumonitis: acute lung injury with rapid progression and organising pneumonia with less severe clinical disease.

AIMS: To improve understanding of the pathology of immune check-point inhibitor (ICI)-related pneumonitis, clinical, radiographic and histopathological features and outcomes were investigated in a cohort of patients who were treatment-naive before receiving ICI inhibition, who underwent lung biopsy, and in whom other potential causes of lung injury were excluded. METHODS: Patients were retrospectively identified via searches of institutional pathology and clinical records. Patients treated with other modalities for cancer and patients with lung infections or other aetiologies that could cause pneumonitis were excluded. Clinical records were reviewed by pulmonologists. Imaging studies at presentation and follow-up were reviewed by a thoracic radiologist. Pathology was reviewed by thoracic pathologists. RESULTS: Six patients with ICI-related pneumonitis were identified. Two patients presented with respiratory failure requiring mechanical ventilation, diffuse ground glass opacities (GGOs) on chest computed tomography (CT) and acute lung injury (ALI) pattern on transbronchial lung biopsies and had fatal outcomes, despite treatment. The remaining four patients presented with less severe symptoms, predominantly consolidations and patchy ground glass and part solid opacities on chest CT, organising pneumonia (OP) or chronic interstitial inflammation histologically, and showed favourable responses to treatment and remission within months. CONCLUSIONS: This study highlights two radiological-pathological patterns of ICI-related pneumonitis with different behaviour: (1) severe respiratory symptoms and diffuse GGOs on imaging correlating with ALI pattern histologically and poor prognosis; and (2) mild respiratory symptoms and consolidations or patchy subsolid opacities on imaging correlating histologically with OP or chronic interstitial inflammation and good outcomes.

A new mouse unilateral model of diffuse alveolar damage of the lung.

OBJECTIVE AND DESIGN: The existing biological models of diffuse alveolar damage (DAD) in mice have many shortcomings. To offset these shortcomings, we have proposed a simple, nonsurgical, and reproducible method of unilateral total damage of the left lung in ICR mice. This model is based on the intrabronchial administration of a mixture of bacterial lipopolysaccharide (LPS) from the cell wall of S. enterica and α-galactosylceramide (inducing substances) to the left lung. METHODS: Using computer tomography of the lungs with endobronchial administration of contrast material, we have been able to perform an operative intravital verification of the targeted delivery of the inducer. The model presented is characterized by more serious and homogeneous damage of the affected lung compared to the existing models of focal pneumonia; at the same time, our model is characterized by longer animal survival since the right lung remains intact. RESULTS: The model is also characterized by diffuse alveolar damage of the left lung, animal survival of 100%, abrupt increases in plasma levels of TNFa, INFg, and IL-6, and significant myocardial overload in the right heart. It can be used to assess the efficacy of innovative drugs for the treatment of DAD and ARDS as the clinical manifestations that are developed in patients infected with SARS-CoV-2. Morphological patterns of lungs in the noninfectious ("sterile") model of DAD induced by LPS simultaneously with α-galactosylceramide (presented here) and in the infectious model of DAD induced by SARS-CoV-2 have been compared. CONCLUSION: The DAD model we have proposed can be widely used for studying the efficacy of candidate molecules for the treatment of infectious respiratory diseases, such as viral pneumonias of different etiology, including SARS-CoV-2.

COVID-19: immunopathology, pathophysiological mechanisms, and treatment options.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID-19 cases are characterised by a mild, self-limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Progression of COVID-19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS-CoV-2 infection and contribute to organ-specific tissue damage. In this respect, dissecting currently available knowledge of COVID-19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune-mediated pathways during SARS-CoV-2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID-19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence-based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID-19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID-19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID-19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Recent Advances in Pathology: the 2021 Annual Review Issue of The Journal of Pathology.

The 2021 Annual Review Issue of The Journal of Pathology contains 14 invited reviews on current research areas of particular importance in pathology. The subjects included here reflect the broad range of interests covered by the journal, including both basic and applied research fields but always with the aim of improving our understanding of human disease. This year, our reviews encompass the huge impact of the COVID-19 pandemic, the development and application of biomarkers for immune checkpoint inhibitors, recent advances in multiplexing antigen/nucleic acid detection in situ, the use of genomics to aid drug discovery, organoid methodologies in research, the microbiome in cancer, the role of macrophage-stroma interactions in fibrosis, and TGF-ß as a driver of fibrosis in multiple pathologies. Other reviews revisit the p53 field and its lack of clinical impact to date, dissect the genetics of mitochondrial diseases, summarise the cells of origin and genetics of sarcomagenesis, provide new data on the role of TRIM28 in tumour predisposition, review our current understanding of cancer stem cell niches, and the function and regulation of p63. The reviews are authored by experts in their field from academia and industry, and provide comprehensive updates of the chosen areas, in which there has been considerable recent progress. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Pathological findings in COVID-19: A conventional autopsy-based study from India.

Background & objectives: Autopsy study has been considered the gold standard method for studying the effects of any disease on the body. Since COVID-19 is a novel disease, autopsy is crucial to understand its pathophysiology. This study was conducted to analyze the microscopic and macroscopic findings of various organs in COVID-19 and to associate those findings with clinical observations and laboratory findings. Methods: Conventional invasive autopsies were performed on 33 patients with COVID-19 from September 7, 2020 to December 23, 2020. All the organs were removed by routine dissection techniques and preserved in 10 per cent formalin. The tissues were processed and stained according to standard practices using haematoxylin-eosin (H & E) and periodic acid-schiff (PAS) stain. Results: The study included 28 males and 5 females with a median age of 61 yr (range 30-90 yr). Massive pulmonary oedema and thrombi in the lungs were the characteristic features macroscopically. On microscopic examination, diffuse alveolar damage in the exudative/proliferative phase was found in 29 (87.88%) cases. Among the other notable microscopic findings were bronchopneumonia and lung abscesses due to secondary bacterial infection (n=17, 51.52%), acute tubular injury (n=21, 63.64%) and thrombi in the lungs, heart, and kidneys. Interpretation & conclusions: COVID-19 primarily affected the respiratory and the renal systems in the vast majority of severely affected patients in our study. We also found signs of hypercoagulability, as evidenced by widespread thrombi in multiple organs, along with a raised d-dimer level and a hyperinflammatory state manifested by elevated inflammatory markers. Our autopsy findings and altered laboratory investigations support the role of immune-mediated cellular injury along with direct virus-mediated cellular damage.

Interstitial pneumonia and diffuse alveolar damage in domestic animals.

Classification of pneumonia in animals has been controversial, and the most problematic pattern is interstitial pneumonia. This is true from the gross and histologic perspectives, and also from a mechanistic point of view. Multiple infectious and noninfectious diseases are associated with interstitial pneumonia, all of them converging in the release of inflammatory mediators that generate local damage and attract inflammatory cells that inevitably trigger a second wave of damage. Diffuse alveolar damage is one of the more frequently identified histologic types of interstitial pneumonia and involves injury to alveolar epithelial and/or endothelial cells, with 3 distinct stages. The first is the "exudative" stage, with alveolar edema and hyaline membranes. The second is the "proliferative" stage, with hyperplasia and reactive atypia of type II pneumocytes, infiltration of lymphocytes, plasma cells, and macrophages in the interstitium and early proliferation of fibroblasts. These stages are reversible and often nonfatal. If damage persists, there is a third "fibrosing" stage, characterized by fibrosis of the interstitium due to proliferation of fibroblasts/myofibroblasts, persistence of type II pneumocytes, segments of squamous metaplasia of alveolar epithelium, plus inflammation. Understanding the lesion patterns associated with interstitial pneumonias, their causes, and the underlying mechanisms aid in accurate diagnosis that involves an interdisciplinary collaborative approach involving pathologists, clinicians, and radiologists.

Histologic pulmonary lesions of SARS-CoV-2 in 4 nonhuman primate species: An institutional comparative review.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an emergent, amphixenotic infection that resulted in a pandemic declaration in March 2020. A rapid search for appropriate animal models of this newly emergent viral respiratory disease focused initially on traditional nonhuman primate research species. Nonhuman primate models have previously been shown to be valuable in evaluation of emerging respiratory coronaviruses with pandemic potential (ie, SARS-CoV and Middle East respiratory syndrome coronavirus). In this article, we review the pulmonary histopathologic characteristics and immunohistochemical evaluation of experimental SARS-CoV-2 infection in the rhesus macaque, pigtail macaque, African green monkey, and squirrel monkey. Our results indicate that all evaluated nonhuman primate species developed variably severe histopathologic changes typical of coronavirus respiratory disease characterized by interstitial pneumonia with or without syncytial cell formation, alveolar fibrin, and pulmonary edema that progressed to type II pneumocyte hyperplasia. Lesion distribution was multifocal, frequently subpleural, and often more severe in lower lung lobes. However, squirrel monkeys showed the least severe and least consistent lesions of the evaluated nonhuman primates. Additionally, our results highlight the disparate physical relationship between viral antigen and foci of pulmonary lesions. While classic respiratory coronaviral lesions were observed in the lungs of all nonhuman primates evaluated, none of the primates exhibited severe lesions or evidence of diffuse alveolar damage and therefore are unlikely to represent the severe form of SARS-CoV-2 infection observed in fatal human cases.

Simultaneous occurrence of accelerated nodulosis in lungs, liver, and kidneys, and acute exacerbation of interstitial pneumonia in a patient with rheumatoid arthritis: an autopsy case report.

BACKGROUND: Accelerated nodulosis (ARN) is a rare variant of rheumatoid nodules (RNs) that is characterized by a rapid onset or the worsening of RNs. It generally develops at the fingers in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX). Few case reports have described ARN at an extracutaneous location. CASE PRESENTATION: An elderly patient with long-standing RA was admitted to our hospital with acute respiratory failure. Computed tomography upon admission showed diffuse ground-glass opacities superimposed with subpleural reticular shadowing and honeycombing and multiple nodules in the lungs and liver. Despite the discontinuation of MTX and introduction of an immunosuppressive regimen with pulse methylprednisolone followed by a tapering dose of prednisolone and intravenous cyclophosphamide, the patient died due to the acute exacerbation (AE) of RA-related interstitial lung disease (ILD) following the parallel waxing and waning of a diffuse interstitial shadow and pulmonary and liver nodules. At autopsy, RNs were scattered throughout both lung fields in addition to extensive interstitial changes. RNs were also detected in the liver and kidneys. The foci of cryptococcosis were mainly identified in alveolar spaces. Based on the clinical and pathological findings, these nodules were most consistent with ARN because of acute increases in the size and number of previously detected pulmonary nodules. CONCLUSION: The present case is noteworthy because ARN was concurrently detected in multiple internal organs and may be associated with the AE of RA-related ILD.

Elevated plasma levels of Krebs von den Lungen-6 and geographic appearance on high-resolution computed tomography are associated with diffuse alveolar damage in autopsy cases of acute respiratory distress syndrome: a retrospective study.

BACKGROUND: Although diffuse alveolar damage (DAD) is a histopathological hallmark of acute respiratory distress syndrome (ARDS), its detection without lung biopsy is challenging. In patients with ARDS, the specificity of the Berlin definition to diagnose DAD as a reference standard is not adequately high, making it difficult to adequately diagnose DAD. The purpose of this study was to investigate the relationship between DAD and clinical findings, including KL-6 and geographic appearance, in ARDS patients and to identify more specific diagnostic criteria for DAD. METHODS: Among all adult autopsy cases at a tertiary hospital in Japan between January 2006 and March 2021, patients with ARDS who met the Berlin definition criteria were included. The patients' conditions were classified according to histopathological patterns as DAD or non-DAD, and clinical characteristics, laboratory data, and high-resolution computed tomography (HRCT) findings were compared between the two groups. RESULTS: During the study period, 27 met the Berlin definition (median age: 79 years, 19 men), of whom 18 (67%) had DAD and 9 (33%) did not. In the non-DAD group, histopathologic findings revealed organizing pneumonia in seven patients and pulmonary hemorrhage in two patients. On HRCT at onset, patients with DAD had more geographic appearance than those without DAD (89% vs. 44%). In patients with geographic appearance and elevated KL-6 (> 500 U/mL), the sensitivity and specificity for DAD diagnosis were 56% and 100%, respectively. All three patients with no geographic appearance and normal KL-6 did not have DAD. CONCLUSIONS: Geographic appearance on HRCT combined with KL-6 levels may predict the presence of DAD in patients with ARDS.

Broad Severe Acute Respiratory Syndrome Coronavirus 2 Cell Tropism and Immunopathology in Lung Tissues From Fatal Coronavirus Disease 2019.

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients manifest with pulmonary symptoms reflected by diffuse alveolar damage (DAD), excessive inflammation, and thromboembolism. The mechanisms mediating these processes remain unclear. METHODS: We performed multicolor staining for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins and lineage markers to define viral tropism and lung pathobiology in 5 autopsy cases. RESULTS: Lung parenchyma showed severe DAD with thromboemboli. Viral infection was found in an extensive range of cells including pneumocyte type II, ciliated, goblet, club-like, and endothelial cells. More than 90% of infiltrating immune cells were positive for viral proteins including macrophages, monocytes, neutrophils, natural killer (NK) cells, B cells, and T cells. Most but not all infected cells were angiotensin-converting enzyme 2 (ACE2) positive. The numbers of infected and ACE2-positive cells are associated with extensive tissue damage. Infected tissues exhibited high levels of inflammatory cells including macrophages, monocytes, neutrophils, and NK cells, and low levels of B cells but abundant T cells consisting of mainly T helper cells, few cytotoxic T cells, and no regulatory T cells. Robust interleukin-6 expression was present in most cells, with or without infection. CONCLUSIONS: In fatal COVID-19 lungs, there are broad SARS-CoV-2 cell tropisms, extensive infiltrated innate immune cells, and activation and depletion of adaptive immune cells, contributing to severe tissue damage, thromboemboli, excess inflammation, and compromised immune responses.

[Features of the cell composition of inflammatory infiltrate in different phases of diffuse alveolar lung damage with COVID-19]. / Osobennosti kletochnogo sostava vospalitel'nogo infil'trata v raznye fazy diffuznogo al'veolyarnogo povrezhdeniya legkikh pri COVID-19.

BACKGROUND: Acute respiratory distress syndrome (ARDS) with COVID-19 has a worse prognosis than ARDS with other diseases. Mortality from ARDS with COVID-19 is 26.0 - 61.5%, and due to other causes - 35.3-37.2%. OBJECTIVE: To find of the correlation between polymorphonuclear leukocytes (PMNs), lymphocytes, and macrophages in the cellular composition of the inflammatory infiltrate at different stages and phases of diffuse alveolar damage (DAD) with COVID-19, analyzing the autopsy material. MATERIAL AND METHODS: The lung tissue of 25 patients who died from ARDS with COVID-19 without a secondary bacterial or mycotic infection, another thanatologically significant pathology of the lungs, was studied. To study the cellular composition of the inflammatory infiltrate and the dynamics of its changes a double immunohistochemical analysis of the expression of antibodies to CD15, CD3, and CD68 was used. RESULTS: The inflammatory infiltrate and intraalveolar exudate in the exudative phase of DAD was represented by 56.8% of PMNs (CD15-positive cells; hereinafter - the average value of the percentage of positive cells to the total number of cells of the inflammatory infiltrate), 6.9% - lymphocytes (CD3-positive cells) and 19.5% macrophages (CD68-positive cells). In the early stage of the proliferative phase: 14.1% PMNs, 38.7% lymphocytes and 13.5% macrophages. In the late stage of the proliferative phase: 11.3% PMNs, 14.5% lymphocytes and 39.3% macrophages. CONCLUSIONS: In the exudative phase of DAD a statistically significant predominance of PMN was revealed, which could determine the main volume of lung damage and the severity of ARDS with COVID-19. In the early stage of the proliferative phase of DAD, a statistically significant change in the composition of the inflammatory infiltrate was revealed to compare with the exudative phase: a significant decrease in the content of PMNs relative to the total number of cells in the inflammatory infiltrate; an increase in the number of lymphocytes, which is probably associated with the start of organization and repair processes. In the late stage of the proliferative phase of DAD, compared with its early stage, was revealed a statistically significant increase in the number of macrophages in ratio.

Pathological Lung Patterns of COVID-19 and its Clinical Correlation to Disease Severity.

Introduction: Coronavirus disease-2019 (COVID-19) infection can result in pulmonary complications ranging from mild illness to severe life-threatening disease. There are limited studies correlating the association between the clinical course of COVID-19 and histopathological findings. This study aimed to examine the postmortem histopathological changes in lung tissue of COVID-19-positive patients and to correlate those changes with disease severity. Materials and methods: This prospective observational study was conducted in adult COVID-19-positive patients. Postmortem core needle biopsy (CNB) of the lung was done using ultrasonography guidance within 1 hour of death. Histopathological analyses were performed by two expert pulmonary pathologists. The demographic and clinical data of the patients were recorded to correlate them with histopathological findings. Results: In total, 48 patients were assessed for inclusion, and 21 patient relatives consented for the study. The median duration of illness was 21 (range 9-38) days, the predominant histopathological finding was diffuse alveolar damage (DAD) in most patients (19/21), followed by pneumonia (13/21). Exudative, intermediate, and advanced DAD patterns were seen in 9.5%, 52.4%, and 28.6% of cases, respectively. Advanced DAD was associated with a longer duration of disease. The pneumonia findings were associated with positive respiratory and blood cultures. The microvascular thrombus was seen only in one patient. Conclusion: The predominant pathological findings in our patients were DAD and pneumonia. The DAD type correlated with the duration of illness, and we attributed pneumonia findings to secondary infection. The incidence of microvascular thrombi was low, and it might reflect the effect of treatment with anticoagulation. How to cite this article: Maddani SS, Rao R, Deepa HC, Noronha AK, Chaudhuri S, Vishwas P. Pathological Lung Patterns of COVID-19 and its Clinical Correlation to Disease Severity. Indian J Crit Care Med 2022;26(12):1285-1292.

Anatomical and Pathological Observation and Analysis of SARS and COVID-19: Microthrombosis Is the Main Cause of Death.

The spread of the coronavirus (SARS-CoV-2, COVID-19 for short) has caused a large number of deaths around the world. We summarized the data reported in the past few months and emphasized that the main causes of death of COVID-19 patients are DAD (Diffuse Alveolar Damage) and DIC (Disseminated intravascular coagulation). Microthrombosis is a prominent clinical feature of COVID-19, and 91.3% of dead patients had microthrombosis.Endothelial damage caused by SARS-CoV-2 cell invasion and subsequent host response disorders involving inflammation and coagulation pathways play a key role in the progression of severe COVID-19. Microvascular thrombosis may lead to microcirculation disorders and multiple organ failure lead to death.The characteristic pathological changes of DAD include alveolar epithelial and vascular endothelial injury, increased alveolar membrane permeability, large numbers of neutrophil infiltration, alveolar hyaline membrane formation, and hypoxemia and respiratory distress as the main clinical manifestations. DAD leads to ARDS in COVID-19 patients. DIC is a syndrome characterized by the activation of systemic intravascular coagulation, which leads to extensive fibrin deposition in the blood. Its occurrence and development begin with the expression of tissue factor and interact with physiological anticoagulation pathways. The down-regulation of fibrin and the impaired fibrinolysis together lead to extensive fibrin deposition.DIC is described as a decrease in the number of platelets and an increase in fibrin degradation products, such as D-dimer and low fibrinogen. The formation of microthrombus leads to the disturbance of microcirculation, which in turn leads to the death of the patient. However, the best prevention and treatment of COVID-19 microthrombosis is still uncertain.This review discusses the latest findings of basic and clinical research on COVID-19-related microthrombosis, and then we proposed the theory of microcirculation perfusion bundle therapy to explore effective methods for preventing and treating COVID-19-related microthrombosis. Further research is urgently needed to clarify how SARS-CoV-2 infection causes thrombotic complications, and how it affects the course and severity of the disease. To cultivate a more comprehensive understanding of the underlying mechanism of this disease. Raise awareness of the importance of preventing and treating microthrombosis in patients with COVID-19.

Progression to fibrosing diffuse alveolar damage in a series of 30 minimally invasive autopsies with COVID-19 pneumonia in Wuhan, China.

AIMS: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), infection has been deemed as a global pandemic by the World Health Organisation. While diffuse alveolar damage (DAD) is recognised to be the primary manifestation of COVID-19 pneumonia, there has been little emphasis on the progression to the fibrosing phase of DAD. This topic is of great interest, due to growing concerns regarding the potential long-term complications in prolonged survivors. METHODS AND RESULTS: Here we report a detailed histopathological study of 30 autopsy cases with COVID-19 virus infection, based on minimally invasive autopsies performed between February and March, 2020. The mean age was 69 years, with 20 (67%) males and 10 (33%) females and frequent (70.0%) underlying comorbidities. The duration of illness ranged from 16 to 82 (median = 42) days. Histologically, the most common manifestation was diffuse alveolar damage (DAD) in 28 (93.3%) cases which showed predominantly acute (32%), organising (25%) and/or fibrosing (43%) patterns. Patients with fibrosing DAD were one decade younger (P = 0.034) and they had a longer duration of illness (P = 0.033), hospitalisation (P = 0.037) and mechanical ventilation (P = 0.014) compared to those with acute DAD. Patients with organising DAD had a longer duration of illness (P = 0.032) and hospitalisation (P = 0.023) compared to those with acute DAD. CONCLUSIONS: COVID-19 pneumonia patients who develop DAD can progress to the fibrosing pattern. While we observed fibrosing DAD in fatal cases, whether or not surviving patients are at risk for developing pulmonary fibrosis and the frequency of this complication will require further clinical and radiological follow-up studies.

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.

COVID-19 Autopsies: A Case Series from Poland.

This paper presents autopsy findings of 3 COVID-19 patients randomly selected for post-mortem from two tertiary referral Polish hospitals. Analysis of macroscopic, histopathological findings with clinical features was performed. All 3 deceased patients were Caucasian males (average age 61 years, range from 56 to 68 years). Using real-time polymerase chain reaction assay, the patients were confirmed (antemortem) to have severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Two patients were obese, and 1 patient had type 2 diabetes mellitus. The medical history of 1 patient included hemorrhagic pancreatitis, gangrenous cholecystitis, Acinetobacter baumanii sepsis, and cholecystectomy. Pulmonary embolism was diagnosed in 2 patients. At autopsy, in 1 case, the lungs showed bilateral interstitial pneumonia with diffuse alveolar damage (DAD), while in another case, interstitial pulmonary lymphoid infiltrates and enlarged atypical pneumocytes were present but without DAD. Microthrombi in lung vessels and capillaries were observed in 2 cases. This study revealed thrombotic complications of COVID-19 and interstitial pneumonia with DAD presence as the main autopsy findings in patients with SARS-CoV-2 infection that was confirmed antemortem with molecular tests. Autopsy studies using tissue sections handled in accordance with SARS-CoV-2 biosafety guidelines are urgently needed, especially in the case of subjects who were below the age of 60.

Retrospective Post-mortem SARS-CoV-2 RT-PCR of Autopsies with COVID-19-Suggestive Pathology Supports the Absence of Lethal Community Spread in Basel, Switzerland, before February 2020.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the world. While the first case was recorded in Hubei in December 2019, the extent of early community spread in Central Europe before this period is unknown. A high proportion of asymptomatic cases and undocumented infections, high transmissibility, and phylogenetic genomic diversity have engendered the controversial possibility of early international community spread of SARS-CoV-2 before its emergence in China. METHODS: To assess the early presence of lethal COVID-19 in Switzerland, we retrospectively performed an analysis of deaths at University Hospital Basel between October 2019 and February 2020 (n = 310), comparing the incidence of clinical causes of death with March 2020 (n = 72), the month during which the first lethal COVID-19 cases in Basel were reported. Trends of COVID-19-suggestive sequelae, such as bronchopneumonia with organization, acute respiratory distress syndrome (ARDS), or pulmonary embolisms (PE) were evaluated. In cases where autopsy was performed (n = 71), analogous analyses were conducted on the cause of death and pulmonary histological findings. Eight cases with a COVID-19-suggestive clinical history and histopathology between October 2019 and February 2020, and 3 cases before October 2019, were selected for SARS-CoV-2 RT-PCR. RESULTS: A statistically significant rise in pulmonary causes of death was observed in March 2020 (p = 0.03), consistent with the reported emergence of lethal COVID-19 in Switzerland. A rise in lethal bronchopneumonia was observed between December 2019 and January 2020, which was likely seasonal. The incidence of lethal ARDS and PE was uniformly low between October 2019 and February 2020. All autopsy cases analyzed by means of SARS-CoV-2 RT-PCR yielded negative results. CONCLUSION: Our data suggest the absence of early lethal community spread of COVID-19 in Basel before its initial reported emergence in Switzerland in March 2020.

Utilization of extracorporeal life support for diffuse alveolar damage and diffuse alveolar hemorrhage: A systematic review.

Modern extracorporeal life-support (ECLS) technology has been successfully utilized to treat patients with diffuse alveolar damage (DAD) and diffuse alveolar hemorrhage (DAH); however, reports in the literature remain scarce. We sought to pool existing evidence to better characterize ECLS use in these patients. An electronic search was conducted to identify all studies in the English literature reporting the use of ECLS for DAD/DAH. Thirty-two articles consisting of 38 patients were selected, and patient-level data were extracted and pooled for analysis. Median patient age was 36 [IQR: 27, 48] years, and the majority (63.2%) were female. Most common etiological factors included granulomatosis with polyangiitis (8/38, 21.1%), systemic lupus erythematosus (8/38, 21.1%), Goodpasture's syndrome (4/38, 10.5%), and microscopic polyangiitis (4/38, 10.5%). Immunologic markers included anti-neutrophil cytoplasmic antibody (ANCA) in 15/38 (39.5%), anti-nuclear antibody (ANA) in 6/38 (15.8%), and anti-glomerular basement membrane (anti-GBM) antibodies in 4/38 (10.5%). DAH was present in 32/38 (84.2%) of cases and DAD without evidence of DAH was present in 6/38 (15.8%) of cases. ECLS strategies included extracorporeal membrane oxygenation of veno-venous type (VV-ECMO) in 28/38 (73.7%), veno-arterial type (VA-ECMO) in 5/38 (13.2%), and one case of right ventricular assist device with oxygenator (RVAD-ECMO). Heparin was utilized in 18/38 (47.4%) of cases with no difference in use between DAH versus no DAH (P = .46) or VA- versus VV-ECLS (P = 1). Median duration of ECLS was 10 [5, 14] days. Pre- versus post-ECLS comparison of blood gases showed improvement in median PaO2 (49 [45, 59] mm Hg vs. 80 [70, 99] mm Hg, P < .001), PaO2:FiO2 ratio (48.2 [41.4, 54.8] vs. 182.0 [149.4, 212.2], P < .01), and pulse oximetry values (76% [72, 80] vs. 96% [94, 97], P = .086). Overall, 94.7% (36/38) of patients survived to decannulation while 30-day mortality was 10.5% (4/38) with no differences between VA- and VV-ECMO (P = 1 and P = .94, respectively). DAD/DAH occurs in a younger, predominantly female population, and tends to be associated with systemic autoimmune processes. ECLS, independent of its type, appears to result in favorable short-term survival.