key: cord-0810692-9tu7993i
authors: Grosse, Claudia; Grosse, Alexandra; Salzer, Helmut J.F.; Dünser, Martin W.; Motz, Reinhard; Langer, Rupert
title: Analysis of cardiopulmonary findings in COVID-19 fatalities: High incidence of pulmonary artery thrombi and acute suppurative bronchopneumonia
date: 2020-07-16
journal: Cardiovasc Pathol
DOI: 10.1016/j.carpath.2020.107263
sha: 77c3ca2d245e33eb3a116d79dfded215c0216409
doc_id: 810692
cord_uid: 9tu7993i

Since its recognition in December 2019, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has rapidly spread globally causing a pandemic that represents the greatest medical challenge in decades. The aim of the study was to evaluate the spectrum of cardiopulmonary pathology of COVID-19 based on (non-minimal invasive) autopsies performed on 14 COVID-19 decedents. Bilateral diffuse alveolar damage (DAD) was found in all patients. Superimposed acute bronchopneumonia was present in 11 of 14 (78.6%) patients and was considered the major cause of death in 2 patients. A key finding was the presence of thrombotic/thromboembolic vascular occlusions. We classified 5 types of pulmonary thrombi: 1. capillary microthrombi (11/14, 78.6%); 2. partially organized thrombi in mid-sized pulmonary arteries with complete vessel occlusion; 3. non-organized thrombi in mid-sized pulmonary arteries that did not completely fill out the vessel lumen and probably represented thromboemboli rather than thrombosis; 4. bone marrow emboli (1/14, 7.1%); and 5. septic pulmonary thromboemboli (1/14, 7.1%). Pulmonary thrombi in mid-sized arteries were noted in 5 of 14 (35.7%) patients, causing pulmonary infarction and/or pulmonary hemorrhage. All patients had evidence of chronic cardiac disease, including myocardial hypertrophy (13/14, 92.9%), mild to marked coronary artery atherosclerosis (14/14, 100%) and focal myocardial fibrosis (3/14, 21.4%). Acute myocardial infarction was found as concurrent cause of death in 3 (21.4%) patients, and significant cardiac hypertrophy (heart weight 750 g) was present in 1 (7.1%) patient with ATTR-positive cardiac amyloidosis. The autopsy findings confirm that COVID-19 is a systemic disease, with major involvement of the lungs, that increases the risk of cardiac and vascular complications including acute myocardial injury and thrombotic/thromboembolic events. Secondary acute bronchopneumonia is a common complication in patients with COVID-19 and may be the major cause of death.

Italy and as a major draw for winter sports and après-ski events, was hit by the pandemic in early March 2020. However, due to strict public safety regulations the number of infections and deaths has been kept comparatively low, with 706 recorded deaths as of July 6, 2020 [3] . Despite relatively low mortality rates a large number of COVID-19 decedents are autopsied in Austria because Austrian law (Section 25 of the Federal Hospitals Act) authorizes pathologists to perform autopsies on deceased patients at public hospitals for the protection of public and scientific interests without formal consent of the next-kind. Most patients with COVID-19 are asymptomatic or have mild symptoms, including fever, dry cough, fatigue and shortness of breath. However, some individuals, especially those with advanced age and pre-existing comorbidities such as hypertension, diabetes mellitus and cardiovascular disease, develop acute respiratory distress syndrome (ARDS), systemic inflammation and multiorgan dysfunction, associated with high mortality. While previous studies mainly focused on the clinical manifestations, epidemiology and radiographic characteristics of COVID-19, data on the histopathologic findings of COVID-19 are scarce due to barely accessible autopsy or biopsy specimens. Initial reports based on postmortem biopsies have indicated that acute-phase or early organizing-phase diffuse alveolar damage (DAD) is a major histopathologic finding in decedents with COVID-19 pneumonia [4, 5] . Compared with postmortem biopsies or other minimal invasive techniques for tissue sampling, conventional (non-minimal invasive) autopsies offer the advantage of comprehensive tissue sampling, thereby allowing accurate determination of the cause of death and minimizing the risk of sampling error. The aim of the study was to investigate the cardiopulmonary histopathologic findings of COVID-19 based on conventional (non-minimal invasive) autopsies performed on SARS-CoV-2 infected individuals who died during the COVID-19 pandemic. Our findings may help to gain a better understanding of the pathogenic mechanisms underlying cardiopulmonary involvement by SARS-CoV-2. Knowledge of COVID-19 pathology may provide the basis for diagnostic and therapeutic strategies.

Fourteen consecutive patients with COVID-19 who died at Kepler University Hospital in Linz, Austria, between March 17, 2020, and May 14, 2020, were included in the study. The diagnosis of COVID-19 was confirmed by ante-mortem positive testing for SARS-CoV-2 RNA in nasopharyngeal and oropharyngeal swabs using real-time reverse transcription polymerase chain reaction (RT-PCR). Postmortem external and internal examinations were performed in accordance with recently published biosafety recommendations for autopsies of COVID-19 patients [6] . The deceased were transported from the COVID-19 ward or intensive care unit to the autopsy room in special safety plastic bags. During the autopsy procedure the deceased remained in these plastic bags to reduce contamination. External and internal examination of the body was performed by an experienced pathologist using personal protective equipment including FFP2/3 masks, surgical protection gear, eye protection and 3 layers of gloves, plastic sleeve and two aprons. Tissue samples were collected from the lungs and heart and processed using standard histochemical methods (hematoxylin and eosin staining and additional stains [i.e., Congo red, Prussian blue] where necessary). Elastica van Gieson-and hematoxylin and eosinstained slides of lung tissue were reviewed on each patient (range, 5 to 15 slides per patient; mean, 10 slides per patient) for the presence or absence of multiple histopathologic features (Table 2) . When present, these features were semi-quantitatively assessed by three pathologists in consensus as mild (+), moderate (++) or marked (+++), based on severity of involvement and extent of affected lung tissue. In all patients, representative sections of lung tissue were stained with gram stain, Ziehl Neelsen, periodic acid-Schiff and Grocott methenamine silver stain.

Immunohistochemical stainings were performed for CD3, CD20, CD68, thyroid transcription factor (TTF-1) and pancytokeratin using standard protocols. Tissue specimens were also obtained from the liver, spleen, kidneys, intestine and colorectum. Patient demographic characteristics and clinical presentation were recorded. The study was approved by the Ethics Committee of the Medical Faculty of Johannes Kepler University Linz (EK-Nr.78/2020) and conducted in accordance with the regulations issued by the 1964 Helsinki Declaration and its later amendments.

Patient demographic and clinical characteristics are shown in Table 1 . The study comprised 9 males and 5 females with a median age of 82 years (range, 55-94 years). Survival duration from symptom onset to death ranged from 6 to 50 days (median, 20 days). The median duration from admission to death was 25 days (range, 2-71 days). The longest disease duration was 50 days in a patient who was tested positive for SARS-CoV-2 RNA throughout a period of 50 days. Seven (50.0%) patients (cases 2, 4, 6, 9, 11, 13 and 14) were admitted to hospital for reasons unrelated to COVID-19 (treatment of dementia: n = 3, hip surgery: n = 1, dehydration: n = 1, treatment for gastric cancer: n = 1) and acquired COVID-19 during hospitalization. Seven (50.0%) patients were infected outside the hospital. Presenting symptoms included fever in 11 (78.6%) patients, shortness of breath in 13 (92.9%), fatigue in 10 (71.4%), cough in 7 (50.0%) and diarrhea in 1 (7.1%). One (7.1%) patient died within 36 hours after admission, and 7 (50.0%) patients required intensive care unit support with mechanical ventilation. Each patient had at least one underlying disease. The most common comorbidity was heart disease, including coronary heart disease in 14 (100%), cardiomyopathy in 5 (35.7%), and a history of myocardial infarction in 2 (14.3%).

Arterial hypertension was present in 8 (57.1%) patients, neurologic disease including dementia (n = 5) and/or a history of cerebral infarction (n = 2) in 7 (50.0%), renal disease in 7 (50.0%), 

Macroscopically, the lungs were heavy and firm in all patients (390 g to 1340 g for the right lung; 350 g to 1100 g for the left lung), with pronounced pulmonary edema, massive bilateral vascular congestion and patchy to homogeneous dark red to grayish-red appearance of the lung parenchyma in the lower lobes and basal segments of the upper lobes. Two (14.3%) patients had mild serous pleural effusions (50ml/80 ml), and 1 (7.1%) patient had mild fibrinous pleuritis.

The histopathologic findings of lung tissue are summarized in Table 2 . All (100%) patients displayed histologic patterns of bilateral DAD. The dominant picture was that of organizingphase/proliferative DAD, while histologic features of acute-phase/exudative DAD were only mild to moderate. Acute-phase DAD was characterized by hyaline membranes, congestion of alveolar septal capillaries, interstitial edema, mild interstitial lymphocytic inflammation, alveolar exudate and alveolar epithelial desquamation (Figures 1 and 2A) . Organizing DAD was seen with varying degree and extent in the majority (13/14, 92.9%) of patients. Moderate to marked organizing DAD was the predominant finding in 11 (78.6%) patients with more than 10 days illness duration. A mixed pattern of coexistent moderate acuteand chronic-phase DAD was present in 1 (7.1%) patient with illness duration of 10 days ( Figure   4A ). Two (14.3%) patients with less than 10 days disease duration showed mild and focal acutephase DAD, one with concomitant minor changes of organizing DAD and both with severe superimposed bacterial bronchopneumonia. Overall, secondary acute bronchopneumonia was seen in 11 of 14 (78.6%) patients, including 2 patients with less than 10 days illness duration and patient showed partially organized thrombi with complete vessel occlusion, 1 patient showed both partially organized and non-organized thrombi, and 2 patients showed exclusively non-organized fibrinous thrombi that did not completely fill out the vessel lumen. Bone marrow emboli, likely shock-related, were present in 1 (7.1%) patient with cytokine storm (Figure 5F ), and septic pulmonary thromboemboli with entrapment of neutrophils and fungal structures were identified in 1 (7.1%) patient with a history of deep vein thrombosis. This patient had undergone treatment for gastric cancer before acquiring COVID-19 during hospitalization and had been tested positive for SARS-CoV-2 RNA for a remarkably long period of 50 days prior to his death ( Figure 6 ). Deep vein thrombosis in the lower extremities was noted in 4 (28.6%) patients, including the patient with septic pulmonary thromboemboli, the 2 patients with exclusively nonorganized pulmonary thrombi in mid-sized arteries and the patient with both partially organized and non-organized pulmonary thrombi in mid-sized arteries. Thrombi were not apparent in the central pulmonary arteries or in any other organs examined, including heart, kidney, liver, spleen and brain. Histopathologic findings associated with thrombotic/thromboembolic vascular occlusions in lung sections included pulmonary infarction, superimposed infection of infarcted lung tissue and pulmonary hemorrhage. Pulmonary hemorrhage, ranging from mild to marked, was seen in all (100%) patients, pulmonary infarction in 2 (14.3%) (Figure 5G) , and secondary infection of the infarcted lung parenchyma in 1 (7.1%) ( Figure 5H ).

Cardiovascular and myocardial findings included myocardial hypertrophy (heart weight ranging from 385 g to 750 g) in 13 (92.9%) patients, acute myocardial infarction in 3 (21.4%), focal myocardial fibrosis caused by previous myocardial infarction in 6 (42.9%), amyloidogenic transthyretin (ATTR)-positive cardiac amyloidosis in 1 (7.1%), and mild to severe coronary artery atherosclerosis in 14 (100%). Among patients with coronary artery atherosclerosis, 2 had mild 1-vessel coronary artery disease with 25% lumen stenosis, 6 had 2-vessel coronary artery disease (25% lumen stenosis: n = 1; 25-50% lumen stenosis: n = 4; > 75% lumen stenosis: n = 1), and 6 had moderate to severe 3-vessel coronary artery disease (25-50% lumen stenosis: n = 1; 50% lumen stenosis: n = 1; > 75% lumen stenosis: n = 4). All (100%) patients showed at least some mononuclear inflammatory cells in the myocardial interstitium, mainly consisting of CD3positive T-lymphocytes and ranging in density from average 2 lymphocytes/HPF to 4 lymphocytes/HPF (Figure 7A ).

Other pathologic findings (Figure 7B-D) , likely related to comorbidities such as arterial hypertension and diabetes mellitus or attributed to shock, included acute renal tubular injury 

This paper provides detailed information on the histopathologic spectrum of cardiopulmonary findings of COVID-19 decedents from a major referral center in Austria, Central Europe. We performed conventional (non-minimal invasive) autopsies on 14 deceased patients with confirmed SARS-CoV-2 infection and systematically investigated the histopathologic cardiopulmonary findings. The main pathologic changes in the lungs consisted of different stages of bilateral DAD. The histopathologic patterns of acute-and chronic-phase DAD were similar to those described in previous studies on COVID-19 pathology [4, 5, [7] [8] [9] [10] [11] [12] as well as in autopsy series of patients who died from SARS-CoV-1 during the SARS outbreak in 2002 [13] [14] [15] [16] .

Although patients with longer disease duration outnumbered those with shorter illness duration in the current study, we were able to show a correlation between histologic patterns of DAD and disease duration, with cases of more than 10 days illness duration showing predominantly organizing DAD and cases of 10 or fewer days illness duration showing exudative DAD, with or without minor features of organizing DAD. Chronic-phase DAD was commonly associated with squamous metaplasia, type II pneumocyte hyperplasia and multinucleated cells. Squamous metaplasia was seen in the distal bronchioles and alveoli and seems to reflect a reparative response to epithelial lung injury. Hyperplastic pneumocytes may show marked cytological atypia, including enlarged nuclei, cytomegaly, clearing of nuclear chromatin, prominent nucleoli, and multinucleation [13] . The occurrence of multinucleated cells has previously been reported in lung specimens from patients with COVID-19 [4, 5, 8] and SARS-CoV-1 infection [13] [14] [15] [16] .

While histiocytic multinucleated cells likely represent nonspecific reactive lung changes, it has been proposed that multinucleated epithelial cells could reflect viral-induced cytopathic effect [13] [14] [15] . Yet, the presence of these cells is not unique to SARS-CoV-2, and similar cytological changes can be seen in non-viral cases of DAD and other viral pneumonias like measles, mumps and respiratory syncytial virus [16] .

While COVID-19 is known to affect primarily the lungs, it also involves multiple organs, infecting human cells using the angiotensin-converting enzyme-2 (ACE-2) receptor, which is expressed by alveolar epithelium, hepatocytes, biliary epithelium, renal tubular epithelium, enterocytes, and endothelial cells. For pathologists it may be difficult to distinguish COVID-19 related pathologic changes from superimposed infectious processes or underlying illnesses (potentially predisposing to fatal courses). A significant number of patients in our series presented with superimposed acute bronchopneumonia, which could be linked to COVID-19 related lymphopenia, predisposing infected individuals to bacterial or fungal superinfection. Two patients with clinical courses of less than 10 days showed extensive acute suppurative bronchopneumonia with only mild and focal exudative DAD. Because acute bronchopneumonia was the predominant finding in these two cases, we assumed that the patients died from bacterial bronchopneumonia rather than from direct SARS-CoV-2 induced lung injury. Furthermore, all patients in the current study had pre-existing cardiovascular disease and increased NT-proBNP and troponin levels indicative of cardiac injury on preterminal laboratory tests. Studies have shown that in patients with COVID-19 elevated troponin is consistently associated with worse outcomes [17] [18] [19] [20] [21] , and patients with pre-existing cardiovascular disease are at increased risk of developing complications including myocarditis, acute myocardial infarction, cardiomyopathy, cardiogenic shock, cardiac arrthythmia, and thrombotic or thromboembolic events [22] [23] [24] [25] [26] [27] [28] . The mechanisms leading to myocardial injury are not yet completely understood. In the setting of COVID-19, myocardial injury, defined by an elevated troponin level, may be due to unmasking of underlying cardiovascular disease, exacerbated in the setting of physiological stress response, or acute coronary syndrome, triggered by coronary plaque destabilization, demand ischemia or vasospasm in the setting of hemodynamic changes, prothrombotic endothelial dysfunction and exaggerated inflammatory response frequently seen with COVID-19 [17, 18] . Other potential mechanisms of myocardial injury include non-ischemic myocardial processes such as severe respiratory infection with hypoxia, sepsis, systemic inflammation, pulmonary thrombosis and thromboembolism, cardiac adrenergic hyperstimulation during cytokine release syndrome, myocarditis, and stress cardiomyopathy triggered by increased sympathetic stimulation, microcirculatory dysfunction, high catecholamine states, vasospasm and proinflammatory states [17, 18, 28] . In the current study, we found acute myocardial infarction as concurrent cause of death alongside histologically confirmed DAD in 3 patients. One patient presented with a heart weight of 750 g due to massive cardiac amyloidosis (a finding reportedly present in a significant number of COVID-19 decedents [9] ). We assumed that this patients died from cardiac decompensation in the context of extensive organizing DAD and pulmonary thrombi, causing pulmonary infarction with superimposed Candida sp. pneumonia. Early reports have indicated that fulminant myocarditis may occur in SARS-CoV-2 infection, contributing significantly to morbidity of COVID-19 [29] [30] [31] [32] [33] [34] . In addition, acute lymphocytic myocarditis has been demonstrated in endomyocardial biopsies of patients with clinically suspected SARS-CoV-2 associated myocarditis [35, 36] . In the current study, we found only scant T-lymphocytes in the myocardial interstitium on histologic sections of heart tissue. This is consistent with the results of previous autopsy studies [4, 7-9, 11, 37] , and we consider this findings of uncertain etiology. We cannot exclude that this observation represents early virus-related inflammatory changes in the myocardium. However, there were no significant lymphocytic inflammatory infiltrates with associated cardiomyocyte damage suggestive of viral myocarditis, and no obvious viral cytopathic effect was observed at light microscopy in the histologic sections of heart tissue; electron microscopic examination was not performed. Further pathologic studies, including ultrastructural analysis, are needed to investigate the effect of SARS-CoV-2 infection on heart vessels and myocardial tissue and to characterize acute myocardial injury in COVID-19 patients.

Emerging evidence shows that SARS-CoV-2 infected individuals are at increased risk of thrombotic/thromboembolic events due to a baseline hypercoagulable state.

Thrombotic/thromboembolic complications were seen in a significant number of patients in the current series. All patients with pulmonary artery thrombi had elevated D-dimer levels greater than 3.00 mg/L, and the majority of patients had an illness duration of more than 10 days. Based on our histopathologic findings we classified 5 types of pulmonary thrombi. One patient with prolonged clinical course and mild interstitial lung fibrosis showed multiple dilated small to midsized pulmonary arteries with intraluminal thrombi infiltrated by numerous neutrophil granulocytes admixed with fungal structures, corresponding to septic pulmonary thromboemboli.

Because organizing DAD was only a minor finding in this case, fungal sepsis rather than respiratory failure due to COVID-19 related DAD was considered the cause of death in this patient. Microthrombi in small pulmonary arterioles were a frequent finding, present in 11 (78.6%) patients, and thrombi in mid-sized pulmonary arteries were found in 5 (35.7%) patients.

When the vascular lumen was not completely occluded by thrombotic material, we considered this finding to reflect an embolus rather than pulmonary thrombosis. When the affected vessel was completely occluded by partially organized thrombotic material, we assumed that this finding could reflect either pulmonary artery thrombosis or organized pulmonary thromboemboli.

Pulmonary artery thrombi in COVID-19 may be attributed to inflammatory and reparatory mechanisms triggered by alveolar and endothelial damage as a result of DAD. Endothelial damage may be related to host reponse or direct viral infection of endothelial cells, as recently proposed [38] . Furthermore, alvolar fibrin deposition in the event of exudative DAD may affect the delicate local balance of fibrinolysis and coagulation. A combination of alveolar and endothelial damage could lead to microvascular pulmonary thrombosis which then extends to larger-sized pulmonary vessels, contributing to fatal outcomes in SARS-CoV-2 infected individuals [11] . Thrombotic/thromboembolic complications have been reported in autopsy studies of COVID-19 [9-11, 37, 39, 40] as well as in the context of SARS-CoV-1 [13] . [11] . Because the affected pulmonary arteries were completely occluded by thrombotic material, the authors considered their findings to reflect pulmonary thrombosis rather than pulmonary thromboembolism. In another autopsy series, Menter et al. described pulmonary microthrombi in 45%, pulmonary embolism in 19% and fibrin thrombi in glomerular capillaries in 18% of COVID-19 autopsy cases [9] . As the authors suggested, the frequent findings of pulmonary capillarostasis and microthrombi in the lungs and kidneys could imply an impaired microcirculation. Hence, COVID-19 related coagulopathy, with features of both disseminated intravascular coagulation and thrombotic microangiopathy, may play an important role in disease progression and lethality [9] .

Our study shows that secondary acute bronchopneumonia can be found in a substantial number of patients with COVID-19 and may be the major cause of death. Furthermore, a high incidence of thrombotic/thromboembolic events is seen in COVID-19 decedents. We classified 5 types of thrombotic/thromboembolic vascular occlusions in lung specimens from COVID-19 decedents:

microthrombi; non-organized thrombi in mid-sized pulmonary arteries with incomplete occlusion of the vessel lumen, likely representing pulmonary thromboemboli; partially organized thrombi in mid-sized pulmonary arteries completely occluding the vessel lumen; bone marrow emboli, likely shock-related; and septic pulmonary thromboemboli. Our findings support the concept that COVID-19 is a systemic disease, with major involvement of the lungs, that increases the risk of thrombotic/thromboembolic events and cardiac complications, contributing to fatal outcomes in SARS-CoV-2 infected individuals.

The datasets supporting the conclusions of this article are available from the corresponding author on reasonable request.

CG, AG, and RL were responsible for the conceptualization of this study and the project administration. CG, AG, HS, MD and RM were responsible for data collection and literature analysis. AG and CG were responsible for analysis and data interpretation. CG and AG wrote the manuscript. All authors critically revised the manuscript and approved the final version.

The study was approved by the Ethics Committee of the Medical Faculty of Johannes Kepler University Linz (EK-Nr. 78/2020). Underlying illness on admission 

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marginal zone (splenitis). (C) Spleen with white pulp atrophy. (D) Liver with mild portal lymphocytic infiltration

The authors wish to thank Marion Almeder, PMBA, for assistance in dissection and all members of the histology team for histological sections and slide scanning.

The authors received no specific funding for this work.

The authors declare that they have no competing interests.