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Tracking the Time Course of Pathological Patterns of Lung Injury in Severe COVID-19

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Tracking the Time Course of Pathological Patterns of Lung Injury in Severe COVID-19 Mauad et al. Respir Res (2021) 22:32 https://doi.org/10.1186/s12931-021-01628-9 RESEARCH Open Access Tracking the time course of pathological patterns of lung injury in severe COVID-19 Thais Mauad1* , Amaro Nunes Duarte‑Neto1, Luiz Fernando Ferraz da Silva1,2, Ellen Pierre de Oliveira3, Jose Mara de Brito1, Ellen Caroline Toledo do Nascimento1, Renata Aparecida de Almeida Monteiro1, Juliana Carvalho Ferreira3, Carlos Roberto Ribeiro de Carvalho3, Paulo Hilário do Nascimento Saldiva1 and Marisa Dolhnikof1 Abstract Background: Pulmonary involvement in COVID‑19 is characterized pathologically by difuse 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 infuence pulmonary involvement in severe COVID, that might be modulated by disease duration and individual factors. In this study we assessed the proportions of diferent lung pathology patterns in severe COVID‑19 patients along the disease evolu‑ tion 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‑hospi‑ tal 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 diferent 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 infuenced by demographic or clinical parameters, including time of disease progression. Conclusion: Patients with severe COVID‑19 present diferent proportions of DAD patterns over time, with advanced DAD being more prevalent after 17 days, which seems to be infuenced 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. Keywords: COVID‑19, Lung pathology, Minimally invasive autopsy, Difuse alveolar damage, Pulmonary thrombosis Introduction *Correspondence: [email protected] 1 Departamento de Patologia, Faculdade de Medicina da Universidade de Several autopsy studies have described lung pathology in São Paulo, Av. Dr. Arnaldo, 455, sala 1155, Cerqueira Cesar, São Paulo, Brazil patients that died due to SARS-CoV-2 infection, show- Full list of author information is available at the end of the article ing that most of the patients presented diferent stages © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mauad et al. Respir Res (2021) 22:32 Page 2 of 11 of difuse alveolar damage (DAD) and a high frequency for the treatment of severe cases of COVID-19 in São of macro and microvascular thrombosis, leading to the Paulo and responded to such challenges by allocating 900 clinical picture of Acute Respiratory Distress Syndrome hospital beds (300 intensive care beds) exclusively dedi- (ARDS) [1–3]. Te direct action of SARS-CoV-2 in lung cated to COVID-19 patients from March to August 2020. cells and the dysregulated immuno-coagulative pathways We investigated the pathology of severe fatal COVID-19 activated in ARDS may infuence patterns and extension by implementing a protocol of ultrasound-guided mini- of pulmonary involvement in severe COVID-19, that are mally invasive autopsies (MIA/US) which was conceived modulated by disease duration and individual factors. to reduce the risk of obtaining post-mortem tissue sam- ARDS is a severe pulmonary condition caused by dif- ples in a disease with high contagiousness [3]. ferent noxious stimuli, which have in common the In this study, we present the results of a quantitative capacity of damaging the alveolar-capillary barrier. Te histopathological study designed to describe the pro- alteration of permeability promoted by the aggression portions of diferent lung pathology patterns in severe to the air/blood interface causes signifcant exudation of COVID-19 patients along the disease evolution, with plasma components and infammatory cells into alveolar emphasis on its vascular and fbrotic alterations. We fur- space, altering gas difusion and disrupting alveolar sta- ther attempted to identify whether demographic-clinical bility by surfactant dysfunction. If injury progresses, the characteristics would infuence the frequency/distribu- infammatory condition elicits a progressive organiza- tion of histopathological patterns. tion of the intra-alveolar exudate and permanent fbrosis and distortion of the distal pulmonary parenchyma [4]. Autopsy studies confrmed that pulmonary fbrosis is not Methods an uncommon fnding in COVID-19 and anti-fbrotic Population therapeutic measures have been proposed to minimize Tis study was approved by the National Ethical Com- pulmonary fbrotic remodelling in afected patients mittee Board (CAAE # 3 30364720.0.0000.0068), and [5–8]. Polak et al. performed a systematic review of 69 autopsies were performed after written informed con- COVID-19 autopsies, showing changes compatible with sent by the next-of-kin. Te procedures were performed acute DAD, fbroproliferative DAD and vascular pathol- at the Image Platform in the Autopsy Room, a research ogy in the lungs. Such patterns seemed to occur simulta- centre in the University of Sao Paulo Medical School, neously in the lungs along time, but with a predominance located next to the Autopsy Service of Sao Paulo Uni- of the fbrotic pattern after three weeks of disease [9]. versity (https ://pisa.hc.fm.usp.br/). During the study COVID-19 is also associated with pulmonary throm- period there were 4507 admissions due to COVID-19 botic events that may be observed in diferent segments in the hospitals linked to the Medical School, with 1184 of pulmonary circulation, from capillaries to the large deaths. Our group performed 54 MIA/US in patients arterial branches. Te vascular thrombotic events may suspected or confrmed of having COVID-19 during the signifcantly contribute to the respiratory insufciency period. For this study, we included 41 adult patients that of COVID-19 [3, 10]. Tere is a lot of ongoing discussion died due to confrmed acute pulmonary disease related to on the pathogenic mechanisms of the vascular disease in COVID-19. COVID-19. Whereas endothelial dysfunction in COVID- 19 is certainly caused by disruption of coagulation and fbrinolytic pathways associated with ARDS, Sars-CoV-2 Autopsy protocol directly infects the endothelial cells [11]. It is possible MIA/US protocol was described previously [13] and was that a multitude of sequential injuries to endothelium adapted for COVID-19 for safety reasons [3]. Briefy, occurs in COVID-19, leading to the disproportional bodies were kept in the supine position and lung tis- larger number of systemic and pulmonary thrombotic sue was sampled from eight regions, in a combination events when compared to other causes of ARDS [12]. A of upper and lower chest (lateral and medial, 4 sites) predominance of direct efects of infection by the virus and right and left lungs (2 sides). In each sampling site, would cause immediate disease, whereas the indirect six samples were collected. Such protocol resulted in 48 efects of endothelial activation linked to the develop- tissue samples collected from eight pulmonary regions ment of ARDS would theoretically appear after some for each case. Immediately after sampling, pulmonary time of disease evolution. samples were immersed in 10% formalin solution for COVID-19 signifcantly impacted
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