Special Articles
The Spectrum of Histopathologic Findings in Lungs of
Patients With Fatal Coronavirus Disease 2019
(COVID-19) Infection
Anja C. Roden, MD; Melanie C. Bois, MD; Tucker F. Johnson, MD; Marie Christine Aubry, MD; Mariam P. Alexander, MD; Catherine
E. Hagen, MD; Peter T. Lin, MD; Reade A. Quinton, MD; Joseph J. Maleszewski, MD; Jennifer M. Boland, MD
 Context.—Respiratory failure appears to be the ultimate
mechanism of death in most patients with severe corona-
virus disease 2019 (COVID-19) infection. Studies of
postmortem COVID-19 lungs largely report diffuse alveo-
lar damage and capillary fibrin thrombi, but we have also
observed other patterns.
Objective.—To report demographic and radiographic
features along with macroscopic, microscopic, and micro-
biologic postmortem lung findings in patients with COVID-
19 infections.
Design.—Patients with confirmed COVID-19 infection
and postmortem examination (March 2020–May 2020)
were included. Clinical findings were abstracted from
medical records. Lungs were microscopically reviewed
independently by 4 thoracic pathologists. Imaging studies
were reviewed by a thoracic radiologist.
Results.—Eight patients (7 men, 87.5%; median age, 79
years; range, 69–96 years) died within a median of 17 days
(range, 6–100 days) from onset of symptoms. The median
lung weight was 1220 g (range, 960–1760 g); consolida-
A cute lung injury appears to be the most serious
complication of severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) infection and the subsequent
clinical disease, coronavirus disease 2019 (COVID-19),
resulting in respiratory failure and death in a subset of
patients. Epidemiologic studies show that 3.4% of COVID-19
patients develop acute respiratory distress syndrome
(ARDS).1 However, ARDS was found in 72% to 93% of
COVID-19 patients who died.2,3 In addition, many of these
patients have thromboembolic complications. Although it has
Accepted for publication August 17, 2020.
Published online August 21, 2020.
Supplemental digital content is available for this article at https://
meridian.allenpress.com/aplm in the January 2021 table of contents.
From the Departments of Laboratory Medicine and Pathology
(Roden, Bois, Aubry, Alexander, Hagen, Lin, Quinton, Maleszewski,
Boland) and Radiology (Johnson), Mayo Clinic, Rochester, Minne-
sota.
The authors have no relevant financial interest in the products or
companies described in this article.
Corresponding author: Anja C. Roden, MD, Department of
Laboratory Medicine and Pathology, Mayo Clinic Rochester, Hilton
11, 200 First St SW, Rochester, MN 55905 (email: roden.anja@mayo.
edu).
Arch Pathol Lab Med—Vol 145, January 2021
tions were found in 5 patients (62.5%) and gross
thromboemboli were noted in 1 patient (12.5%). Histo-
logically, all patients had acute bronchopneumonia; 6
patients (75%) also had diffuse alveolar damage. Two
patients (25%) had aspiration pneumonia in addition.
Thromboemboli, usually scattered and rare, were identi-
fied in 5 patients (62.5%) in small vessels and in 2 of these
patients also in pulmonary arteries. Four patients (50%)
had perivascular chronic inflammation. Postmortem bac-
terial lung cultures were positive in 4 patients (50%).
Imaging studies (available in 4 patients) were typical (n ¼
2, 50%), indeterminate (n ¼ 1, 25%), or negative (n ¼ 1,
25%) for COVID-19 infection.
Conclusions.—Our study shows that patients infected
with COVID-19 not only have diffuse alveolar damage but
also commonly have acute bronchopneumonia and aspi-
ration pneumonia. These findings are important for
management of these patients.
(Arch Pathol Lab Med. 2021;145:11–21; doi: 10.5858/
arpa.2020-0491-SA)
been shown that only 0.1% of all COVID-19 patients develop
disseminated intravascular coagulopathy,1 this presentation
was again much more common (8%) in COVID-19 patients
who died.2 Moreover, COVID-19 patients with ARDS had
thrombotic complications (11.7%) at more than double the
rate of patients with ARDS of other causes (4.8%), commonly
in the form of pulmonary thromboembolisms.4
Histopathologic studies have confirmed the increased
incidence of diffuse alveolar damage (DAD), the histomor-
phologic correlate of ARDS, and thromboembolic complica-
tions in COVID-19 patients. A few case series and reports of
postmortem studies have identified DAD in 67% to 100% of
COVID-19 patients.5–12 In addition, thromboembolic findings
were commonly observed, with one study5 reporting capillary
thrombi in all cases, arterial thrombi in 57%, and venous
thrombi in 71%. Another study reported fibrin thrombi in
small pulmonary arteries in 87% of cases.6 Only occasional
cases have been described to also show acute bronchopneu-
monia on postmortem examination.9,11,13 Furthermore, the
long-term consequences for patients who survive COVID-19
infection of the lungs are still unknown.14
Herein, we report the postmortem macroscopic, micro-
scopic, and microbiological pulmonary findings in 8 patients
who tested positive for COVID-19 antemortem. In addition,
Histopathology of Lungs in COVID-19—Roden et al 11
we reviewed the imaging studies that were available at the
time of COVID testing and thereafter.
MATERIALS AND METHODS
Patients
All autopsies performed at our institution (March 2020–May
2020) on patients who tested positive for SARS-CoV-2 by
antemortem nasopharyngeal or oropharyngeal swab were includ-
ed, with detailed examination of the lungs. All patients underwent
another nasopharyngeal or oropharyngeal swab, and, if indicated, a
serologic test for immunoglobulin (Ig) G SARS-CoV-2 antibodies
at time of autopsy. Viral swabs at autopsy were analyzed for SARS-
CoV-2 based on real-time polymerase chain reaction technique as
previously described.15 In a single case, postmortem serum was also
analyzed for SARS-CoV-2 IgG antibodies by enzyme-linked
immunosorbent assay as previously described.16 Clinical informa-
tion was abstracted from medical records. Immediate and
underlying causes of death were recorded from the death certificate
and autopsy reports.
Legal next of kin consented for all autopsies, providing permissions
that allowed for research and education. Because of the postmortem
nature of the cases, the study was exempted by the Mayo Clinic
Rochester (Rochester, Minnesota) Institutional Review Board.
Autopsy
At autopsy, the lungs were removed from the heart and the
trachea and were individually weighed. Based on gross findings
and medical history, lung cultures were performed at the discretion
of the autopsy physician in a subset of patients. For lung cultures,
an approximately 1-cm3 piece of tissue was placed in a sterile
container and submitted for bacterial and fungal cultures. Cultures
were taken from areas of gross consolidation if present. Subse-
quently, both lungs were individually perfused with formalin. After
about 30 minutes to 1 hour, the lungs were serially sectioned,
parasagitally, at 1-cm thickness. Multiple (at least 5) sections were
taken for microscopy from both lungs, including areas of
consolidation and grossly fibrotic areas.
Imaging
Any available imaging studies of the chest from between
COVID-19 testing and death were reviewed by a thoracic
radiologist (T.F.J.) blinded to clinical information and histomor-
phologic findings. Patterns on computed tomography imaging
were categorized as typical, indeterminate, or negative related to
COVID-19 based on the recent expert consensus statement by the
Radiological Society of North America.17 Chest radiographs were
evaluated using a similar approach.
Pathology Evaluation
Gross findings of lung specimens were abstracted from the
autopsy report. All lung specimens were morphologically reviewed
by 4 thoracic pathologists (A.C.R., M.C.B., M.C.A., and J.M.B.)
independently and blinded to radiologic findings. Ancillary testing
including Grocott methenamine silver, Verhoeff–van Gieson,
sulfated Alcian blue, and Congo red stains was performed in
selected cases based on morphologic findings. Consensus mor-
phologic features were recorded.
Statistical Analysis
To summarize numerical data, a median was calculated and the
data range was provided.
RESULTS
Demographics and Clinical Findings of Patients With
COVID-19 Infection
Eight patients were included in the study. These patients
tested positive for COVID-19 by nasopharyngeal or
12 Arch Pathol Lab Med—Vol 145, January 2021
oropharyngeal swab, died within less than 1 to 10 weeks
after diagnosis, and had a complete autopsy. Demographics
of the study population are summarized in Table 1. The
majority of patients were men (7 of 8; 87.5%). All patients
were older than 69 years, with a median age of 79 years. The
majority of patients (5 of 8; 62.5%) were former smokers;
the remainder were never smokers. The time between onset
of symptoms and death was less than 4 weeks in most
patients (6 of 8; 75%). In 1 patient (12.5%), symptoms began
100 days before death. The exact date of onset of symptoms
was unknown in another patient. Three patients (37.5%)
were intubated prior to death for a median of 10 days
(range, 7–12 days). Four of 5 patients (80%) received
thrombolytics within a week prior to death, including
heparin (n ¼ 2, 50%), aspirin (n ¼ 1, 25%), and aspirin
followed by heparin (n ¼ 1, 25%); that information was
unknown in 3 patients.
All patients died from complications of COVID-19
infection (Table 1).
Six of 8 patients (75%) tested positive for COVID-19 by
nasopharyngeal or oropharyngeal swab at autopsy. For 1
patient (12.5%), the postmortem nasopharyngeal swab was
negative for COVID-19 but the SARS-CoV-2 IgG serum
enzyme-linked immunosorbent assay test was positive. In
another patient (12.5%), the postmortem oropharyngeal
and bronchial swabs were negative.
Most of the patients had other significant diseases, most
commonly cardiovascular disease (5 of 8; 62.5%) and/or
advanced dementia (4 of 8; 50%) (Table 1). One patient was
obese and 1 patient had diabetes mellitus type II. One
patient had a history of an esophageal stricture that had
been dilatated multiple times. At autopsy a slight stricture of
the esophagus was noted in that patient. Two patients had a
known underlying lung disease in the form of fibrosing
interstitial lung disease that was most consistent with
combined pulmonary fibrosis and emphysema at autopsy
and chronic obstructive pulmonary disease, respectively.
Another patient was clinically thought to have a fibrosing
interstitial lung disease possibly due to prior chemotherapy
for diffuse large B-cell lymphoma; however, extensive
sampling of the postmortem lungs revealed only very focal
fibrosis that could not be further classified, in part because
of the exuberant acute lung injury. A fourth patient was
found to have pulmonary arterial changes at autopsy that
were suggestive of pulmonary arterial hypertension.
Gross Findings in Patients With COVID-19 Infection
The gross findings of all lungs are summarized in Table 2.
With a median combined right and left lung weight of 1220
g (range, 960–1760 g), all lungs were heavier than the
expected weight of 650 to 850 g.18 Consolidation was found
in the majority of lungs (5 of 8; 62.5%), although, in general,
it was patchy and did not involve the entire lung (Figure 1,
A). Thromboemboli were noted only grossly in a single case
in distal pulmonary arteries (Figure 1, B and C). In 2 cases,
there appeared to be an underlying fibrosing process. In half
of the patients, pleural effusions were noted, which were
usually serous.
Histomorphologic Findings in Patients With COVID-19
Infections
A median of 9.5 (range, 5–15) sections were taken and
microscopically reviewed. The histomorphologic findings
are summarized in Table 2 and in more detail in
Supplemental Table 1 (see supplemental digital content at
Histopathology of Lungs in COVID-19—Roden et al
 Table 1. Clinicopathologic Findings and Cause of Death for Coronavirus Disease 2019 (COVID-19)–Infected Study Patients (N ¼ 8)
Time Between Time Between Time
COVID-19 Onset of Intubated Other Significant
Smoking Testing and Symptoms and Before Immediate Underlying Diseases
Case No. Age, y/Sex Status Death, d Death, d Death, d Cause of Death Cause of Death and Conditions
1 71.9/M Former 12 17 12 Complications of Coronary artery disease; None
COVID-19 status post recent
bypass grafting
2 86.7/M Never 6 6 0 Acute COVID-19 Advanced dementia

Arch Pathol Lab Med—Vol 145, January 2021

bronchopneumonia Cardiac amyloidosis, ATTR (transthyretin)
type, moderate–marked
Ischemic heart disease, with remote
myocardial infarction
3 80.6/M Never 7 7 0 Acute COVID-19 Atherosclerotic and hypertensive
bronchopneumonia cardiovascular disease
Advanced dementia
Colonic adenocarcinoma
4 74.0/M Never 25 27 7 Acute COVID-19 Possible fibrosing interstitial lung disease
bronchopneumonia Diffuse large B-cell
lymphoma
5 93.5/M Former 4 unknown 0 Acute COVID-19 Urosepsis
bronchopneumonia Congestive heart failure
Coronary artery disease
Advanced dementia
Slight esophageal stricture
6 77.3/M Former 13 15 0 Acute COVID-19 Advanced dementia
bronchopneumonia Hypertensive cardiovascular disease
Obesity
7 94.5/M Former 67 100 0 Acute COVID-19 Interstitial lung disease
bronchopneumonia Hypertensive and atherosclerotic
cardiovascular disease
Mild cognitive impairment
8 69.3/F Former 18 22 10 Acute COVID-19 Chronic obstructive pulmonary disease
bronchopneumonia Systemic hypertension
Diabetes mellitus type II
Median (range) 79.0 (69.3–94.5) 12.5 (4–67) 17.0 (6–100)

Histopathology of Lungs in COVID-19—Roden et al 13

 Table 2. Postmortem Pulmonary Gross and Histomorphologic Features and Culture Results From Coronavirus Disease 2019 (COVID-19) Patients (N ¼ 8)
Case No.
1 2 3 4 5 6 7 8
Gross findings
Lung weight, combined, g 1280 1160 960 1380 1000 1760 1120 1350
Consolidation Bilateral upper Bilateral lower N Patchy all lobes Bilateral lower lobes N N Bilateral lower
and lower and right lobes and right
lobes middle lobe middle lobe
PA thromboemboli N N N N Unilateral upper and N N N
lower distal
Other N N N Areas suspicious for Ill-defined induration Bronchi with Marked N
fibrosis with in right upper lobe nonobstructive interstitial
calcification mucopurulent fibrosis and
bilateral bases and exudate cobblestoning
right middle lobe of pleura, all
Bronchi with lobes

14 Arch Pathol Lab Med—Vol 145, January 2021

nonobstructive
mucopurulent
exudate
Pleural effusion N Unilateral, 600 N Bilateral, 250 mL N Unilateral, 45 mL, N Bilateral, 100 mL
mL, serous each, serous serosanguineous each, serous
Microscopic findings
DAD Y Y N Y Y Y Y N
Acute bronchopneumonia Y Y Y Y Y Y Y Y
OP N N N Y N N Y Y
CIP N N Y N Y N N N
MNGC Y N N Y N Y Y Y
Thromboemboli, small vessels Y N Y N Y Y Y N
Thromboemboli, PA N N Y N Y N N N
Perivascular chronic inflammation Y N N N N Y Y Y
Marked squamous metaplasia, focal Y N Y Y N Y N N
Chronic bronchiolitis N N N N Y Y Y Y
Chronic inflammation of bronchi N Y Y Y N Y Y N
Acute inflammation of bronchi N Y Y N Y Y N N
Others N Diffuse N Early collagen in OP Aspiration Aspiration Mucostasis; Acute
parenchymal pneumonia pneumonia mature necrotizing
amyloid Centrilobular Centrilobular interstitial epiglottitis
emphysema emphysema fibrosis Acute ulcerating
Marked intimal Emphysema tracheitis
fibrosis of
pulmonary arteries
Results of lung cultures Candida NP NP Lactobacillus Staphylococcus Usual flora S aureus 4þ S aureus 1þ
nivariensis, rhamnosus 4þ aureus 4þ
few Yeast 2þ Enterococcus
Candida krusei many faecium 4þ
Enterobacter cloacae
complex 3þ
Abbreviations: CIP, chronic interstitial pneumonia; DAD, diffuse alveolar damage; MNGC, multinucleated giant cells; N, not identified; NP, not performed; OP, organizing pneumonia; PA, pulmonary

Histopathology of Lungs in COVID-19—Roden et al

artery; Y, yes present.
 Figure 2. Acute bronchopneumonia. A and B, Alveoli are diffusely
filled by cells, mostly neutrophils, consistent with acute bronchopneu-
monia (hematoxylin-eosin, original magnifications 340 [A] and 3600
[B]).

https://meridian.allenpress.com/aplm in the January 2021

table of contents). All patients had an acute bronchopneu-
monia either superimposed on DAD (6 of 8 cases; 75%) or
as sole finding (2 cases; 25%) (Figure 2, A and B). Diffuse
alveolar damage was identified as acute (ie, hyaline
membranes present; n ¼ 3; Figure 3, A through C),
organizing (ie, interstitial fibroblast proliferation; n ¼ 1), or
acute and organizing (ie, hyaline membranes and interstitial
fibroblast proliferation; n ¼ 2; Figure 3, D and E). In 2
patients (25%), at least some of the acute lung injury was
attributable to aspiration pneumonia (Figure 3, F). Both of
these patients suffered from advanced dementia; one also
had recurrent esophageal strictures. In one case, organizing
pneumonia was focally associated with early fibrosis.
Thromboemboli were seen in 5 patients (62.5%) in small
vessels, with pulmonary arterial involvement in 2 of these
patients (Figure 4, A and B). However, in most patients,

Figure 1. Gross findings. A, The lung shows patchy consolidations in

the upper and lower lobes. B and C, Pulmonary emboli are present in
mid to peripheral pulmonary arteries (arrows).
Arch Pathol Lab Med—Vol 145, January 2021 Histopathology of Lungs in COVID-19—Roden et al 15
Figure 3. Diffuse alveolar damage and aspiration pneumonia. A through C, Early/acute diffuse alveolar damage. Eosinophilic hyaline membranes
(arrows) line slightly thickened interalveolar septa. There are no septal fibroblasts. D and E, Acute and organizing diffuse alveolar damage. D, Thick
hyaline membranes (arrows) line slightly thickened interalveolar septa consistent with acute diffuse alveolar damage. E, Proliferating fibroblasts
focally expand the interstitium, consistent with the organizing phase of diffuse alveolar damage. F, Aspiration pneumonia. Focally there is foreign
body material (arrow) associated with the neutrophilic infiltrate. The foreign body material is birefringent under polarized light (F, inset)
(hematoxylin-eosin, original magnifications 3100 [A and E], 3400 [B, C, F, and F inset] and 3200 [D]).

16 Arch Pathol Lab Med—Vol 145, January 2021 Histopathology of Lungs in COVID-19—Roden et al
Figure 4. Fibrin thromboemboli. A, Fibrin thromboemboli in small vessels. B, Fibrin thromboembolus in pulmonary artery. C, Nonoccluding fibrin
thromboembolus in a small vessel (arrow). D, Fibrin thromboemboli within submucosal small vessels in trachea (arrows); note cartilage on left-hand
side and submucosal glands (hematoxylin-eosin, original magnifications 3400 [A and C], 320 [B], and 3100 [D]).

these fibrin thromboemboli were scattered and rare rather
than a diffuse finding (Figure 4, C). Only 1 patient (12.5%)
had thromboemboli identified diffusely in pulmonary
arteries of all calibers, and also in pulmonary veins. In this
patient, gross examination also revealed pulmonary arterial
thromboemboli. Scattered thromboemboli were identified
in small vessels in the submucosa of the trachea (Figure 4,
D) and bronchi of another patient; however, the pulmonary
interstitium showed only scattered fibrin thromboemboli in
small vessels.
In 4 cases (50%) there was perivascular chronic inflam-
mation (Figure 5, A and B). Chronic inflammation was also
observed around large airways (3 patients; 37.5%), small
airways (2 patients; 25%), or around both large and small
airways (2 patients; 25%) (Figure 5, C and D).
Postmortem lung cultures were performed in 6 cases and
are detailed in Table 2. In 3 of 6 cases (50%), the culture
results indicated definite bacterial infection (4þ), mostly due
to Staphylococcus aureus, whereas cultures in the 3 other
cases (50%) resulted in inconclusive findings because of
possible contamination.
Arch Pathol Lab Med—Vol 145, January 2021
In addition, the lung parenchyma showed alveolar septal
amyloid in a patient who also was found to have cardiac
amyloidosis of ATTR (transthyretin) type. In one patient an
underlying interstitial fibrosing lung disease was morpho-
logically most consistent with combined pulmonary fibrosis
and emphysema. Additional morphologic findings are
detailed in Supplemental Table 1.
Radiologic Findings in Patients With COVID-19 Infection
Imaging studies performed between the day of positive
COVID-19 testing and death were available in only half (4
of 8) of the patients and mostly included chest radiographs.
All imaging findings are summarized in Table 3. Two cases
had imaging findings that were regarded as typical for
COVID-19 infection. The computed tomography case
showed extensive mixed ground-glass opacities and con-
solidation involving both lungs essentially throughout the
left lung and peripherally in the right upper lobe. The chest
radiograph case showed patchy peripheral and basilar-
predominant airspace opacities with subsequent develop-
ment of consolidation within areas of airspace opacities
(Figure 6, A and B). In another case the pattern was
Histopathology of Lungs in COVID-19—Roden et al 17
Figure 5. Perivascular inflammation and inflammation around airways. A and B, Perivascular chronic inflammation. C, Marked chronic
inflammation in the submucosa of a bronchus extending into areas of submucosal glands (note that mucosa is sloughed off). D, Chronic inflammation
in the submucosa of a bronchiole (hematoxylin-eosin, original magnifications 3400 [A], 3200 [B], and 3100 [C and D]).

indeterminate. In that case, although there were airspace
opacities in mid and lower lungs, these were superimposed
on interstitial fibrosis. This case did show acute broncho-
pneumonia and DAD on microscopic examination. A fourth
case did not show any abnormalities on chest radiograph.
Gross examination of the lungs of that case also did not
show any consolidation. Microscopy revealed focal acute
bronchopneumonia. This patient had underlying athero-
sclerotic and hypertensive cardiovascular disease, which
might have contributed to his death.
DISCUSSION
Our study of postmortem lungs from patients who died
after testing positive for SARS-CoV-2 by nasopharyngeal or
oropharyngeal swab found that all lungs had morphologic
findings of an acute lung injury. However, the extent and
spectrum of morphologic patterns of acute lung injury were
quite variable. All cases showed acute bronchopneumonia
and most cases also showed a pattern of DAD. In 2 cases, at
least some of the acute lung injury was attributable to
aspiration pneumonia. That was further highlighted by the
results of lung cultures that confirmed bacterial infections in
18 Arch Pathol Lab Med—Vol 145, January 2021
at least half of these cases, most of which grew S aureus. Not
surprisingly, acute bronchopneumonia was considered the
immediate cause of death in 87.5% of these cases.
Interestingly, in contrast to other reports, thromboembolism
was not a uniform finding in our study population, and, if
present, was usually not a diffuse or marked feature. In cases
with available imaging studies, radiologic and histopatho-
logic findings appeared to correlate in most cases. In 1 case,
a chest radiograph 7 days before death did not reveal any
parenchymal abnormalities, whereas the lungs did show
focal acute bronchopneumonia at autopsy. This discrepancy
might be due to the interval of 7 days between the imaging
study and the death of the patient, in addition to the acute
bronchopneumonia being a focal finding.
Although our results confirmed earlier reports of DAD
being a common finding in postmortem lungs of COVID-
19–infected patients,5–7 the high percentage of acute
bronchopneumonia that we observed has not been previ-
ously described. Only occasional cases of acute broncho-
pneumonia at autopsy have been reported, including 25% to
33% in small autopsy series9,11 and a single case report.13
However, the common finding of acute bronchopneumonia
Histopathology of Lungs in COVID-19—Roden et al
 Table 3. Radiologic Findings of the Lungs of Coronavirus Disease 2019 (COVID-19) Patients (N ¼ 4)a
Case Time Before
No. Examination Death, d Pattern Radiologic Findings
1 PE study 12 Typical Extensive mixed ground-glass opacities and consolidation involving the left lung and
right upper lobe, with the right upper lobe opacities being peripheral
predominant and the left lung opacities being both central and peripheral in
distribution
Small left pleural effusion
3 Chest x-ray 7 Negative No parenchymal opacities
4 Chest x-ray 26 Indeterminate Multifocal airspace opacities in both lungs compatible with multifocal pneumonia
with background lower lung fibrosis
Follow-up examination at day of death (chest x-ray): pattern: indeterminate.
Development of airspace opacities in mid and lower lungs superimposed on
pulmonary fibrosis in lung bases
Pre–COVID-19 infection chest x-ray (63 d prior to death): pattern: negative. Mild to
moderate pulmonary fibrosis in the lung base
8 Chest x-ray 13 Typical Patchy peripheral and basilar predominant airspace opacities
Cardiomegaly
Follow up chest x-ray 1 d prior to death. Pattern: typical. Development of
consolidation among areas of peripheral and basilar predominant airspace
opacities. Persistent cardiomegaly
Abbreviation: PE, pulmonary embolism.
a
Cases 2 and 5 through 7 did not have any recent imaging studies available for review.

is not particularly surprising, as our patients were elderly,

Figure 6. Computed tomography. A and B, Pulmonary embolism
study revealed patchy consolidations and ground-glass opacities
throughout both lungs (A, upper lung; B, lower lung).
Arch Pathol Lab Med—Vol 145, January 2021
with a median age of 79 years. Moreover, many of our
patients had advanced dementia and lived in an assisted-
care facility, features that predisposed them to a higher
likelihood of acute bronchopneumonia and aspiration
pneumonia. Furthermore, one of our patients had a slight
esophageal stricture and another patient was obese, features
that might also have contributed to aspiration. Indeed, the
acute lung injury in 2 of our patients was, at least in part,
attributed to aspiration pneumonia.
There are myriad potential explanations for the common
finding of acute bronchopneumonia. One hypothesis for the
high percentage of acute bronchopneumonia in these
patients might be that COVID-19 infection of the lungs
increases susceptibility to acute bacterial superinfection,
possibly by further weakening the immune system and
altering the defense mechanisms of the respiratory tract.
Alternatively, it could be that an occult acute bacterial
bronchopneumonia and/or aspiration pneumonia preceded
SARS-CoV-2 infection in at least some of our patients, which
then led to an exacerbation of a preexisting acute lung injury.
It was surprising to us that other studies5,6 did not find higher
numbers of acute bronchopneumonia even though their
populations comprised patients of similar ages, with mean
and median ages of 69 and 78 years (range, 32–96 years).
Furthermore, although in all studies5,6,8 patients were found
to have various comorbidities, including hypertension (58%–
100%), cardiovascular disorders (35%), diabetes mellitus
(29%–43%), immunosuppression (14%), and mild chronic
obstructive pulmonary disorders (10%), none of the studies
reported dementia in any patients. One reported case13 of
acute bronchopneumonia at autopsy in the context of
COVID-19 infection was a 42-year-old man with myotonic
dystrophy who also had aspiration pneumonia.
A third possibility might center on increased time
between first symptoms of COVID-19 infection and death.
However, in our study, the median time between onset of
symptoms and death was 17 days, ranging from 6 to 100
days, which was only slightly longer than in the study by
Histopathology of Lungs in COVID-19—Roden et al 19
Carsana et al6 (mean time, 16 days; range, 5–31 days) and
longer than in the study by Fox et al8 (median, 10.5 days;
range, 1–32 days).
A fourth hypothesis could be that the COVID-19 virus is
eliciting acute bronchopneumonia. Although acute bron-
chopneumonia is usually caused by bacterial infections, it
might be that this particular virus elicits an acute broncho-
pneumonia pattern, especially in cases that are negative by
culture. Similarly, a combination of DAD and acute
bronchopneumonia (with and without positive cultures)
has been described in postmortem lungs from patients who
died because of H1N1 influenza.19 However, negative
cultures in cases of acute bronchopneumonia might also
be due to sampling, as cultures were taken from the
periphery of the lungs before they were perfused with
formalin and sectioned.
In the study by Ackermann et al,5 all lung specimens from
the COVID-19 group had DAD with necrosis of alveolar
lining cells, type II pneumocyte hyperplasia, and linear
intra-alveolar fibrin deposition (ie, hyaline membranes).
Similarly, in the study of Carsana et al,6 87% of lungs had
hyaline membranes. Although the majority of lungs
examined in our study (6 of 8; 75%) also showed DAD, in
1 case DAD was exclusively of the organizing phase without
hyaline membranes, and 2 other cases did not show definite
findings of DAD. In 3 cases in our study there was a
combination of acute and organizing DAD.
Evidence suggests that SARS-CoV-2 infections are
associated with frequent activation of the coagulation
system, and COVID-19 disease has been associated with
high rates of venous thromboembolism and particularly
acute pulmonary embolism.20–22 Moreover, autopsy studies
have proposed that the inflammatory process in the
microcirculation of the lung may cause in situ immuno-
thrombi, providing an alternative explanation to the
conventional thromboembolic mechanism of pulmonary
embolism. One study5 suggested that lungs from COVID-19
patients show severe endothelial injury associated with
intracellular virus and disrupted cell membranes, and that
alveolar capillary microthrombi are 9 times as prevalent in
COVID-19 patients as in patients with influenza. In
addition, it has been shown that lungs from COVID-19
patients have a larger amount of new vessel growth,
predominantly through a mechanism of intussusceptive
angiogenesis, when compared with patients with influenza.5
Another study20 suggested that the phenotype of pulmonary
embolism in COVID-19–infected patients might differ from
the phenotype in non–COVID-19 patients. Indeed, imaging
studies revealed that pulmonary embolism in COVID-19
patients predominantly affected segmental (70%) and
subsegmental pulmonary arteries (13%), in contrast to
pulmonary embolism in non–COVID-19 patients, in whom
embolism to the main/lobar pulmonary arteries (38%) and
segmental pulmonary arteries (41%) more commonly
occured.20 In addition, D-dimer was reported to be higher
in COVID-19 patients (median, 7551 ng/mL) when com-
pared with non–COVID-19 patients (median, 2637 ng/
mL).20 Although the reason for these findings is not entirely
clear, the authors20 suggested that COVID-19–associated
pulmonary embolism more likely represents a combination
of thromboembolic disease and in situ immunothrombosis.
Supporting this literature, our patient who was found to
have macroscopic pulmonary embolism demonstrated
thromboemboli in distal pulmonary arteries.
20 Arch Pathol Lab Med—Vol 145, January 2021
Previous reports5,6 showed that most, if not all, autopsy
lungs of COVID-19 patients (87%–100%) had fibrin thrombi
within alveolar capillaries. Pulmonary embolism and/or
microthrombi were identified in at least 58% of patients in
another autopsy study9 of COVID-19–infected patients,
although it was stated that microthrombi were regularly
found in capillaries of the lungs and 33.3% of the cases had
pulmonary embolism in the setting of deep vein thrombosis.
Moreover, in the study by Ackermann et al,5 57% of cases
had pulmonary arteries with a diameter of 1 to 2 mm that
harbored thrombi without complete luminal obstruction.
Our experience was somewhat different. We encountered
only a single case with rather diffuse pulmonary arterial
thromboemboli in variously sized pulmonary arteries.
Another case showed a single fibrinous pulmonary arterial
thromboembolus. Although we did identify fibrin throm-
boemboli in small vessels, this finding was apparent in only
62.5% of the cases and was in general only a focal finding,
not diffuse.
Arguably, fibrin thromboemboli are challenging to iden-
tify even under the microscope. However, in our study, 4
pulmonary pathologists independently evaluated all slides
with special emphasis on these previously described
findings. Therefore, failure to recognize fibrin thromboem-
boli might be unlikely to explain the lower number of cases
with capillary thromboemboli in our study. Furthermore, it
is very difficult to determine the significance of small
vascular thromboemboli in the setting of DAD. It is well
known that thromboemboli in the small pulmonary
vasculature frequently occur in the setting of DAD because
of any number of etiologies, presumably because of in situ
thrombosis secondary to endothelial damage and possible
hypercoagulable microenvironment in the setting of acute
lung injury.23 Therefore, it is difficult to attribute any special
COVID-19–related significance to small vessel thromboem-
boli in the lung when DAD pattern is present.
In addition, we noted a recurrent and often rather
prominent chronic inflammation around airways, including
bronchi and bronchioles. Indeed, chronic inflammation
around airways was identified in 87.5% of cases. Chronic
inflammation around airways has been described in other
postmortem histopathologic reports of lungs of COVID-19
patients; however, its prevalence is difficult to estimate
based on the available studies. For instance, Barton et al13
reported mild chronic inflammation within bronchi and
bronchioles in 1 of 2 autopsy cases. Carsana et al6
mentioned mild transmural lymphocytic and monocytic
infiltrates of main bronchi and bronchioles; however, it is
not clear how common this finding was. Fox et al8 described
an inflammatory cell infiltrate composed of a mixture of
CD4-positive and CD8-positive lymphocytes around larger
bronchioles in 2 of 10 patients with early alveolar damage.
In the study by Wichmann et al,9 chronic bronchitis was
described as a histologic finding in 2 of 12 patients;
however, the authors also stated that lymphocytic infiltra-
tion of the bronchi was often visible as a preexisting
condition. Other autopsy reports10,24 of COVID-19–infected
patients do not comment on chronic inflammation of
airways. The etiology of the chronic airways-centered
inflammation is not clear. Although the transmission of
SARS-CoV-2 is not fully understood, it is thought that the
virus is predominantly transmitted by droplet inhalation or
direct contact and that the virus can be inhaled and exhaled
from the lungs.25,26 Therefore, the chronic inflammation
around airways might be elicited by the virus itself or might
Histopathology of Lungs in COVID-19—Roden et al
be the result of an immunologic reaction to other changes
elicited by the virus or the aerosol droplets that contain the
virus.
Similar to the descriptions by Ackermann et al5 and
Konopka et al,11 we found patchy chronic inflammation
around small vessels in 50% of our cases, which were
identified as T-cell inflammation by Ackermann et al.5
Perivascular inflammation has been identified in previous
studies in association with other viral infections such as
cytomegalovirus or fungal infection such as Pneumocystis
jirovecii,27 although the exact mechanism for that finding is
not entirely clear.
Limitations of our study included the small number of
cases and the lack of virus-confirmatory studies such as
ultrastructural, immunohistochemical, or molecular studies.
These studies are still under development in our institution
and therefore were not available to us at the time of this
study. Furthermore, detailed imaging studies were lacking
from many of our patients. For instance, except for a single
computed tomography scan that was done as chest
computed tomography with pulmonary embolism protocol,
all other available imaging was chest radiographs.
In conclusion, our study shows that patients infected with
COVID-19 might die because of respiratory failure due to
conditions other than DAD. These conditions include acute
bronchopneumonia and aspiration pneumonia, and possibly
pulmonary embolism. These findings are important for
treatment and management of these patients.
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