Gastrointestinal Pathology in Samples From
Coronavirus Disease 2019 (COVID-19)–Positive Patients
Maria Westerhoff, MD; Dan Jones, MD, PhD; Steven M. Hrycaj, PhD; May P. Chan, MD; Liron Pantanowitz, MD, MHA; Huolin Tu, PhD; Karen Choi, MD; Joel Greenson, MD; Laura Lamps, MD
Context.—Although primarily considered a respiratory illness, coronavirus disease 2019 (COVID-19) can cause gastrointestinal manifestations.Objective.—To evaluate histopathology and in situ hybridization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in gastrointestinal samples from patients with recent and remote COVID-19.
Design.—Patients with positive SARS-CoV-2 nasopha-ryngeal tests and a gastrointestinal tissue specimen were included. SARS-CoV-2 in situ hybridization (ISH) was performed on each sample. A subset had SARS-CoV-2 next-generation sequencing (NGS) performed.
Results.—Twenty-five patients met inclusion criteria. Five had positive SARS-CoV-2 nasopharyngeal tests within 7 days of their gastrointestinal procedure. Two were ulcerative colitis patients on steroid therapy who lacked typical COVID-19 symptoms. Their colectomies showed severe ulcerative colitis; one demonstrated SARS-CoV-2 by NGS but a negative ISH. Another had an ischemic colon
resected as a complication of the COVID-19 course; however, both ISH and NGS were negative. A fourth had a normal-appearing terminal ileum but positive ISH and NGS. The fifth patient had ileal ulcers with SARS-CoV-2 negativity by both modalities. The remaining 20 patients had positive nasopharyngeal tests an average of 53 days prior to procedure. None of their samples demonstrated SARS-CoV-2 ISH positivity, but one was positive on NGS despite a negative nasopharyngeal test.
Conclusions.—Gastrointestinal findings from SARS-CoV-2–infected patients ranged from normal with virus detected by ISH and NGS to bowel ischemia secondary to systemic viral effects without evidence of virus in the tissue. No distinct histologic finding was identified in those with gastrointestinal tissue specimens demonstrating SARS-CoV-2 positivity in this cohort.
(Arch Pathol Lab Med. 2021;145:1062–1068; doi: 10.5858/arpa.2021-0137-SA)
C
oronavirus disease 2019 (COVID-19) is the cause of the current worldwide pandemic and continues to be a considerable global public health threat. Up to half of patients affected by COVID-19 are described as having gastrointestinal (GI) symptoms such as diarrhea, nausea, and abdominal pain.1 Severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) RNA has been detected in stool for up to a month in patients with mild infection.2
Moreover, a subset of these patients reportedly continue to have positive stool SARS-CoV-2 RNA after negative respiratory samples.3,4 Such studies raise public health
concerns given the potential for fecal-oral or fecal-respira-tory virus transmission.5
Little is known regarding the manifestations of COVID-19 in the GI tract. Absorptive enterocytes in the ileum express angiotensin-converting enzyme 2 (ACE2) and transmem-brane serine protease 2 (TMPRSS2), which mediate SARS-CoV-2 entry by binding the viral spike (S) protein.6Hence,
COVID-19 may manifest in GI specimens obtained from SARS-CoV-2–infected patients. COVID-19 has also been linked to hypercoagulability, a cause for GI ischemia in at-risk patients.7 For these reasons, it would be helpful to
understand the effects of COVID-19 on the GI tract.8
We identified 25 patients who had SARS-CoV-2 poly-merase chain reaction (PCR) positivity in nasopharyngeal samples and had undergone digestive disease–related procedures. Our aim was to describe the histopathologic findings of GI specimens from these patients. Secondly, we applied SARS-CoV-2 in situ hybridization (ISH) to these GI tract specimens in order to assess the degree of positivity in both recently and remotely infected patients.
MATERIALS AND METHODS
Our laboratory information system was queried for all patients who tested positive for SARS-CoV-2 reverse transcription PCR by nasopharyngeal swab and who had undergone a biopsy or resection of the GI tract between March and August 2020. Clinical data were gathered from the electronic medical record. This
Accepted for publication May 3, 2021.
Supplemental digital content is available for this article at https:// meridian.allenpress.com/aplm in the September 2021 table of contents.
From the Department of Pathology, University of Michigan, Ann Arbor (Westerhoff, Hrycaj, Chan, Pantanowitz, Choi, Greenson, Lamps); and the Department of Pathology, The Ohio State University Wexner Medical Center, Columbus (Jones, Tu).
Funded by anatomic pathology departmental research funding at University of Michigan. The authors have no relevant financial interest in the products or companies described in this article.
Corresponding author: Maria Westerhoff, MD, Michigan Medi-cine, University of Michigan, Department of Pathology, 2800 Plymouth Rd, Bldg 35, Ann Arbor, MI 48109 (email: mwesterh@ med.umich.edu).
included information regarding patient age, sex, symptoms, indications for biopsy/resection, body mass index, comorbidities, dates of SARS-CoV-2 testing, inpatient length of stay (days), follow-up, and clinical outcomes. Endoscopic or gross findings and available laboratory values at the time of positive PCR, such as D-dimer, prothrombin time, partial thromboplastin time, white blood cell count, and anti–SARS-CoV-2 serum antibody status, were also reviewed. The project received institutional review board approval.
Pathologic Examination
Gastrointestinal biopsies and resections were retrieved after diagnosis by GI pathologists (M.W., K.C., J.G., L.L.) and underwent central review by one author (M.W.). All samples were routinely processed with 10% buffered formalin. Formalin-fixed, paraffin-embedded sections were cut at 5 lm and stained with hematoxylin and eosin. Gross pathology descriptions and histology slides were reviewed. Histologic features such as ischemia, vasculitis, fibrin thrombi, active inflammation, viral inclusions, crypt apoptosis, and lymphocytosis were noted along with any other additional pathology.
In Situ Hybridization
SARS-CoV-2 RNA ISH was performed on 4-lm-thick formalin-fixed, paraffin-embedded sections of all specimens using RNA-scope 2.5 LS probe V-nCoV2019-S (Advanced Cell Diagnostics, Hayward, California) on the fully automated Ventana Discover Ultra platform. This included colorectum (n ¼ 13), ileum (n ¼ 10), stomach (n ¼ 8), duodenum (n ¼ 6), esophagus (n ¼ 4), liver (n ¼ 3), pancreas (n ¼ 1), and gallbladder (n ¼ 1) samples. Briefly, deparaffinized sections were subjected to target retrieval for 24 minutes at 978C in RNAScope VS Universal Target Retrieval v2 solution (Advanced Cell Diagnostics). Slides were subsequently incubated with the ready-to-use SARS-CoV-2 RNA probe mixture for 2 hours at 438C and the signal was amplified using amplifiers (Amp1–6) according to the manufacturer’s recommendation. The signal was detected using an mRNA DAB kit (Ventana, Oro Valley, Arizona). The probe targets the mRNA transcript for the S protein of SARS-CoV-2. Appropriate positive and negative RNA controls and a positive SARS-CoV-2 control were also performed.
Next-Generation Sequencing
SARS-CoV-2 was detected in GI tissue by next-generation sequencing (NGS) using a clinical assay in the James Molecular Laboratory at the The Ohio State University (Columbus). Testing was performed on 11 GI specimens from 7 patients (including all patients with positive SARS-CoV-2 nasopharyngeal PCR within a week of their procedure). This included colon (n ¼ 5; 3 resections and 2 biopsies), terminal ileum (n ¼ 5; 3 resections and 2 biopsies), and stomach (n ¼ 1). RNA quality was excellent in all tissue blocks. Briefly, formalin-fixed, paraffin-embedded sections were deparaffi-nized and RNA extracted with the PureLink FFPE Total RNA Isolation Kit (Invitrogen, Carlsbad, California). Next-generation sequencing was performed using primer sets covering the entire SARS-CoV-2 genome (Ion AmpliSeq SARS-CoV-2 Research Panel, ThermoFisher, Waltham, Massachusetts), with reverse transcription/library preparation and sequencing performed on Ion Chef and S5, respectively (Ion Torrent, Life Technologies, Carlsbad, California). Coamplified human housekeeping gene sequences were used to ensure RNA quality. Analysis was performed in the Ion Browser with COVID-19 annotation plug-ins and strain typing was performed with a set of phylogeny tools including a local install of NextStrain (nextstrain.org).
RESULTS
Overall, 830 COVID-19–positive patients were discharged from our institution during the study period, including those who died. Twenty-five patients met the criteria of having nasopharyngeal swab PCR positivity for SARS-CoV-2 as well as a digestive tract–related tissue pathology specimen.
Of these, 5 had positive nasopharyngeal swab PCR tests within 7 days of their biopsy or resection procedures. The remaining 20 patients had positive nasopharyngeal swab testing on an average of 53 days before their GI procedure (range, 17–121 days). The average age of the patients was 52 years (range, 19–87 years). Eleven were female and 14 were male. The average body mass index was 27.7 (range, 16.6– 42.9; normal is 18.5–24.9). Comorbid conditions included obesity (body mass index .30; n ¼ 7), diabetes (n ¼ 8), hypertension (n ¼ 8), history of organ transplant (n ¼ 4), and past histories of cancer (n ¼ 3; breast, prostate, acute leukemia). Two patients died (both 2 months after admission) and the remaining patients had an average of 5.2 months follow-up (range, 1–9 months). See supple-mental digital content at https://meridian.allenpress.com/ aplm in the September 2021 table of contents for additional detailed clinical and laboratory information.
COVID-19–Related Symptoms
Sixteen of the 25 patients (64%) experienced COVID-19– related symptoms including fever, cough, malaise, shortness of breath, or loss of taste. Of the 9 without typical COVID-19 symptoms, 7 were incidentally found to be positive on their preprocedural nasopharyngeal PCR testing and had to defer their GI procedure. The remaining 2 patients were incidentally found to be positive for SARS-CoV-2 during their admission for abdominal discomfort related to ulcerative colitis.
Gastrointestinal Symptoms.—Gastrointestinal symp-toms were documented in 16 of the 25 patients (64%). In the 5 patients with positive SARS-CoV-2 nasopharyngeal swab tests within 7 days of their procedure, GI bleeding (n ¼ 2), ulcerative colitis flare (n ¼ 2), and diarrhea (n ¼ 1) were the main GI symptoms requiring gastroenterologic inter-vention. Three of this group also had typical COVID-19 symptoms such as shortness of breath, fever, and cough prior to their GI symptoms, whereas the 2 ulcerative colitis patients had only severe abdominal pain and an acute increase in bloody diarrhea related to their flares.
The remaining 11 of 16 patients with GI symptoms had more remote histories of SARS-CoV-2 nasopharyngeal swab PCR positivity. Their GI symptoms included nausea, vomiting, diarrhea, abdominal pain, weight loss, and blood in stool. Three of this group had only GI symptoms without other typical COVID-19 symptoms.
Histopathologic Findings
Patients With Positive COVID-19 Testing Within 7 Days of Their GI Procedure.—Pathology findings for the 5 patients with positive SARS-CoV-2 PCR tests on nasopha-ryngeal samples within 7 days of their GI procedure are listed in Table 1. Three had colectomies and 2 underwent biopsies.
Of the 3 bowel resections, 1 showed ischemic complica-tions deemed secondary to COVID-19–associated coagu-lopathy, whereas the other 2 were likely due to severe ulcerative colitis. The ischemic case was taken from a patient who developed diarrhea, abdominal pain, and severe abdominal tenderness a few days after established COVID-19 with respiratory manifestations. A stool GI PCR panel for infectious organisms including Clostridioides difficile was negative. D-dimer levels were markedly elevated at 30.34 mg/L (reference range, ,0.59 mg/L). The gross findings included a thickened sigmoid colon wall with serosal
petechiae as well as necrotic-appearing splenic flexure and distal transverse colon. The mucosa was hemorrhagic, necrotic, and sharply demarcated from the background of viable tissue. Microscopic evaluation revealed diffuse muco-sal necrosis with areas typical of colonic ischemia, such as attenuated, dying crypt epithelium and lamina propria hemorrhage (Figure 1, A through D). Mesenteric vessels were not thrombosed and thrombi were only seen in submucosal veins. Other areas of the bowel displayed small mucosal abscesses and features resembling pseudomembra-nous colitis. In situ hybridization and NGS for SARS-CoV-2 were negative.
The 2 ulcerative colitis resections were from patients with incidentally positive SARS-CoV-2 nasopharyngeal PCR tests. Both presented as having worsening ulcerative colitis flares and had been taking prednisone. No viral inclusions, increased lymphocytes, or any other features unrelated to ulcerative colitis were seen in their colectomies. The bowel resection of 1 patient showed numerous perforations and severe colitis. Pathologic findings included severe ulcerative pancolitis with deep ulcers and pseudopolyps typical of the disease. Neither ISH nor NGS identified any SARS-CoV-2 in tissue sections including small bowel and colon. The second ulcerative colitis patient had worsening abdominal symptoms after the prednisone dose was lowered. The steroid therapy had been decreased specifically because of the patient’s SARS-CoV-2 result. The patient’s D-dimer levels also became elevated at 1.40 mg/L. The pathologic findings, however, showed active ulcerative pancolitis with cecal sparing and inflammatory pseudopolyps typical of the disease. No distinctive vascular, thrombotic, or
inflamma-tory findings unrelated to ulcerative colitis were seen. Although SARS-CoV-2 ISH was negative in small bowel and colon samples, NGS revealed virus in both samples. The small bowel demonstrated 290 reads and the cecum revealed 119, which is low and may be below the detection limit of ISH. It demonstrated the common G strain with the S D614G and ORF3 Q57H variants.
Both biopsy cases from patients with concurrently positive SARS-CoV-2 RNA included terminal ileum samples. One was endoscopically and histologically normal, whereas the other showed active enteritis. Interestingly, the patient with normal-appearing small bowel exhibited strong cytoplasmic and dotlike expression by ISH for SARS-CoV-2 RNA in the epithelium overlying a Peyer patch (Figure 2, A through D). The patient’s accompanying colon biopsies were negative by ISH; however, both terminal ileum and colon biopsies were positive using NGS. This testing showed a common G strain with the S D614G and ORF3 Q57H variants, which was the most common virus type in the midwestern United States at the time of biopsy. The terminal ileum specimen showed a depth of 5600 reads; the right colon showed 75 reads.
The other case with biopsies exhibited active ileitis with evidence of chronic injury. The small bowel showed abnormally villous architecture with lymphocytosis, in-creased numbers of goblet cells lining the villi, and crypt hyperplasia. Thrombi, vasculitis, and viral inclusions were not identified. The patient had 2 separate sets of ileal biopsies, neither of which showed evidence of SARS-CoV-2 by ISH or NGS. This was despite the fact that the patient was still PCR positive on nasopharyngeal swab.
Table 1. Pathologic Findings in the 5 Patients Who Were Positive for Coronavirus Disease 2019 (COVID-19) Within 1 Week of Procedure
Patient No.
Site of Resection/Biopsy
Endoscopic/Gross
Findings Pathologic Findings
SARS-CoV-2 In Situ
Hybridization Result NGS Result 1 Colon resection Diffusely hemorrhagic
mucosa sharply demarcated from viable mucosa, submucosal hemorrhage, edema Acute ischemic mucosal necrosis with submucosal venous thrombi Negative Negative 2 Terminal ileum, right colon, biopsies Normal No significant abnormalities Positive in terminal ileum epithelium, intense cytoplasmic and dotlike staining
Positive in terminal ileum (depth of 5600 reads); positive in right colon (depth of 75 reads) 3 Terminal ileum, biopsy; separate additional procedure 4 days later biopsying 2 sites of terminal ileum (proximal and distal) Procedure 1: ulcer in jejunum and petechiae, and congestion in proximal ileum
No significant abnormalities in first biopsy set; active ileitis with evidence of chronic injury in second set
Negative Negative
Procedure 2: large ulcers, up to 2 cm, taking up 30% of terminal ileum 4 Total abdominal colectomy Diffusely nodular, hemorrhagic, dusky, necrotic mucosa, multiple perforations involving cecum and transverse colon
Severe ulcerative pancolitis with deep ulcers and inflammatory pseudopolyps Negative Negative 5 Total abdominal colectomy Numerous pseudopolyps and ulcers affecting ascending colon to rectum, sparing cecum. Thickened sigmoid colon
Active ulcerative pancolitis with cecal sparing, normal terminal ileum
Negative Positive in the terminal ileum (depth of 290 reads) and cecum (depth of 119 reads) Abbreviations: NGS, next-generation sequencing; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Patients With Remote History of COVID-19 and GI Procedures.—The findings of the 20 patients with COVID-19 testing beyond a week from their procedure are listed in Table 2. They had a range of GI pathologic findings, including no significant abnormalities (n ¼ 8), active inflammation with apoptotic bodies attributed to nonste-roidal anti-inflammatory drug use (n ¼ 1), adenomas or hyperplastic polyp (n ¼ 4), adenocarcinoma (n ¼ 1), graft-versus-host disease (n ¼ 1), microscopic colitis (n ¼ 2), erosion (n ¼ 2), and well-differentiated neuroendocrine tumor (n ¼ 1). All were negative for SARS-CoV-2 ISH.
One case in this group was noteworthy: virus was detected in the terminal ileum by NGS, despite the patient having a negative nasopharyngeal PCR sample. The patient’s procedure was performed 17 days after having a positive SARS-CoV-2 nasopharyngeal test and COVID-19 respiratory symptoms. At the time of colonoscopy, however, the nasopharyngeal PCR sample was negative and the patient was asymptomatic for respiratory symptoms. The indication for the procedure was to identify the cause of abdominal pain of 2 months’ duration. Pertinent endoscopic findings showed a cobblestoned appearance to the stomach, normal duodenum, and a single ulcer and stenosis at the ileocecal valve. Nodular mucosa was seen in the transverse colon. Microscopically, the terminal ileum and transverse colon both showed apoptotic cells involving the crypt bases and mild architectural distortion. Additionally, active enteritis with erosion and ulcer edge changes were seen in the ileum. Despite the architectural distortion, the density of chronic lamina propria inflammation was not in the range typical of a chronic idiopathic inflammatory bowel disease
(IBD) diagnosis. No vascular abnormalities or viral inclu-sions were seen. Clinically, long-standing nonsteroidal anti-inflammatory drug use was deemed the cause for the endoscopic and pathologic findings. Although ISH studies were negative in all 4 sites, the terminal ileum was positive for SARS-CoV-2 by NGS. Sequencing gaps precluded full clade/strain typing.
DISCUSSION
SARS-CoV-2 is known to involve the GI tract. Ileal epithelium, in particular, exhibits high expression of ACE2 and TMPRSS2, which are important in the entry of this novel coronavirus into cells. The S protein of SARS-CoV-2 binds to the ACE2 receptor and is then cleaved by the host’s protease TMPRSS2, exposing the S protein’s subunit that allows virus and cell fusion. Gastrointestinal involve-ment by SARS-CoV-2 is frequently associated with symptoms of diarrhea, nausea, and vomiting. Highly persistent viral particle shedding in feces has also been documented, even after respiratory infection subsides.9–12
One systematic review with meta-analysis found that up to 43% of COVID-19 patients were positive for SARS-CoV-2 RNA in stool specimens. Twenty-seven percent continued to show fecal positivity for viral RNA after pharyngeal swabs turned negative, for approximately a week longer.9
The infectivity and viability of fecal viral isolates have been questioned, however. Several studies have attempted to culture the virus in fecal samples, and few11,12 have been
reportedly successful. The ability of virus gleaned from stool samples to cause viral invasion into a cell line or result in positive nasal washes in inoculated animals has
Figure 1. Ischemic colon in the setting of coronavirus disease 2019 (COVID-19) infection. (A) Gross specimen of the bowel revealed large regions of necrosis sharply demarcated from background viable colon (left aspect of bowel). B, Microscopy revealed ischemia with hemorrhagic, hyalinized lamina propria, as well as attenuation of crypt epithelium. C and D, Additional regions showed epithelial injury with mild acute inflammation. Distinctive features due to the COVID-19–related coagulopathy were not identified (hematoxylin-eosin, original magnifications320 [B and C] and
been reported, but in small numbers.5,11As such, although
the presence of SARS-CoV-2 in GI specimens is certainly concerning for the potential for fecal-oral spread, the clinical significance of finding evidence of virus in the GI tissue itself is not completely elucidated.
In this study, our goals were to (1) elucidate the possible pathologic effects of SARS-CoV-2 on the digestive tract and (2) assess whether or not SARS-CoV-2 ISH would detect virus in patients’ GI biopsies, whether concurrent with or weeks after their infection. Firstly, we described the GI specimens of 5 patients who were positive for COVID-19 during the time of their GI procedure. These patients displayed a variety of findings, but no specific histologic feature indicative of COVID-19 was identified. Moreover, the expression of SARS-CoV-2 via both ISH and NGS did not correlate with histopathologic findings. The case yielding the highest viral reads by NGS—and also the only single positive ISH result—was histologically unremarkable. The other cases reflected features indistinguishable from their underlying disease despite the GI tissues being positive for virus on NGS. Nevertheless, we found it useful to learn the effects of COVID-19–induced coagulopathy and
subse-quent ischemic consequences in the bowel, and to learn that we may not be able to diagnose COVID-19 in a bowel biopsy even if it is harboring virus. For our second objective, we applied ISH to all of the GI specimens, but only 1 was positive, despite the fact that multiple cases showed evidence of virus by NGS. In terms of using SARS-CoV-2 ISH for routine practice, it is useful to know that even if GI tissues are harboring virus, the viral burden may be below the detection limit of ISH. Hence, we cannot rely on a negative result.
It is challenging to explain the relationship between COVID-19 and what we found in our patients’ GI tracts. Does the bowel act as a secondary site for viral entry alone or cause actual viral infection–induced pathology? In argument for the former, one report of 73 patients who tested positive for SARS-CoV-2 RNA in their stool indicated that endoscopic findings were in fact normal in infected patients. Their biopsies of GI sites such as stomach, duodenum, and rectum exhibited nonspecific changes described by the authors3 as
having plasma cells, lymphocytes, and interstitial edema in the lamina propria. Our patient with a histologically normal terminal ileum that demonstrated high tissue viral reads by
Figure 2. Terminal ileum biopsy in a patient with coronavirus disease 2019 (COVID-19). A and B, This patient’s terminal ileum was endoscopically and histologically uninflamed. No active inflammation, lymphocytosis, or viral inclusions were identified. C and D, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in situ hybridization revealed positive epithelial expression in epithelium with cytoplasmic and dotlike staining. Next-generation sequencing also revealed high levels of viral reads (hematoxylin-eosin, original magnifications3100 [A] and3400 [B]; SARS-CoV-2 in situ hybridization, original magnifications3100 [C] and3400 [D]).
NGS may have represented one whose bowel was a site of viral entry without evidence of viral-induced GI disease. Although the patient was biopsied a few days before respiratory symptoms manifested, this patient never devel-oped GI symptoms.
On the other hand, another study13 of 95 COVID-19
patients concluded that the presence of SARS-CoV-2 in GI tissue was indicative of severe symptoms. The study
included 6 patients with worsening GI symptoms who underwent endoscopy, of whom 4 were considered to have nonsevere and 2 to have severe infection. Only the patients with severe COVID-19 had SARS-CoV-2 RNA detected in their GI tissues and/or any abnormal findings on endoscopy. A recent systematic review also supports that GI manifes-tations are higher in patients with severe infection requiring intensive care.14Indeed, patient 1 in this study had a severe
Table 2. Pathologic Findings in the 20 Patients Who Were Coronavirus Disease 2019 (COVID-19) Positive More Than 7 Days From Gastrointestinal Procedure
Patient No.
Site of Resection/Biopsy
Endoscopic/Gross
Findings Pathologic Findings
SARS-CoV-2 In Situ Hybridization
Result NGS Result 6 Right and left colon,
biopsy
Normal Collagenous colitis Negative Negative 7 Stomach, duodenum,
ileum, transverse colon, biopsies
Normal esophagus, cobblestoning appearance to gastric body and antrum; normal duodenum, ulcer and stenosis at ileocecal valve, nodular mucosa in transverse colon
Stomach and duodenum with no significant abnormalities; active enteritis in ileum and scattered apoptotic crypt epithelial cells in transverse colon
Negative Positive in the terminal ileum
8 Colon biopsies (2 sites) Polyps Adenomas Negative Not performed 9 Gallbladder resection Cholelithiasis Acute cholecystitis Negative Not performed 10 Pancreas biopsy NA Neuroendocrine tumor (G1) Negative Not performed 11 Esophagus, stomach, biopsy Food substance in esophagus, nonbleeding gastric ulcers No significant abnormalities
Negative Not performed
12 Colon, biopsy Polyp Hyperplastic polyp Negative Not performed 13 Liver, stomach, duodenum,
left colon, biopsies
Duodenal bulb erythema, otherwise normal
Graft-versus-host disease in all sites
Negative Not performed 14 Stomach, biopsy Normal No significant
abnormalities
Negative Not performed 15 Liver, biopsy NA Nonspecific mild portal
inflammation with eosinophils
Negative Not performed
16 Colon, biopsy Polyps Adenoma Negative Not performed
17 Colon, biopsy Polyp Adenoma Negative Not performed
18 Esophagus, stomach, duodenum, biopsies
Esophageal erosion, varices, normal stomach and duodenum
Esophageal erosion; stomach and duodenum without significant abnormalities
Negative Not performed
19 Stomach, biopsy Erythematous stomach Helicobacter pylorigastritis Negative Not performed 20 Duodenum, biopsy Submucosal mass Only mucosa sampled; no
significant abnormality
Negative Not performed 21 Terminal ileum, right
colon, transverse colon, descending colon, sigmoid colon, rectum, biopsies
Involvement of terminal ileum by Crohn disease, normal colon
Active Crohn ileitis, normal colon
Negative Not performed
22 Esophagus, stomach, duodenum, biopsies
Normal No significant abnormalities
Negative Not performed 23 Esophagus, stomach,
duodenum, terminal ileum, colon, biopsies
Normal esophagus, erythema in stomach, normal duodenum, terminal ileum, and colon
No significant abnormalities
Negative Negative
24 Terminal ileum resection as part of stoma
NA Ostomy site changes Negative Not performed 25 Terminal ileum, rectum,
resection; liver, biopsy
Terminal ileum serosal masses, perirectal soft tissue masses, liver mass
Metastatic adenocarcinoma from known prior appendiceal primary
Negative Not performed
COVID-19 course and hypercoagulability. COVID-19 has been linked to hypercoagulability, a known cause for GI ischemia in at-risk patients.7It is thought that endothelial
dysfunction caused by infection results in excess thrombin generation and halting of fibrinolysis. Moreover, increased blood viscosity and hypoxia-inducible transcription factor– dependent signaling pathway may also contribute to the hypoxia in severe COVID-19.15Hence, COVID-19 patients
are at risk for ischemic bowel.8Patient 1’s D-dimer level was
markedly elevated, which has been associated with throm-bosis and worse COVID-19 outcomes in some studies.16
Although the patient did not have virus demonstrated in the bowel, the bowel pathology was a secondary consequence of the systemic effects of COVID-19 infection.
Ulcerative colitis is certainly a condition in which COVID-19 susceptibility has raised heightened concern in the gastroenterology literature. Many patients are on therapies that increase their risk of contracting certain infections. One report17 showed that age, inflammation, and location of
disease were important in determining expression of ACE2 and TMPRSS2 in chronic idiopathic IBD patients. It raised the possibility that enhanced viral production and uptake in the colon can occur during active IBD given the increased expression of colonic ACE2 with inflammation. Another group of authors18reported that IBD patients did not have
higher expression of ACE2 and TMPRSS2. A meta-analysis study19 finally indicated that IBD patients are not more
prone to COVID-19 infection than the general population, but that ulcerative colitis patients are overall at higher risk of hospitalization and mortality. Inflammatory bowel disease patients on steroid therapy did have higher risk of adverse COVID-19 outcomes, but biological agent use seemed protective. Both of the COVID-19–positive ulcerative colitis patients in our cohort had been taking steroids. One had evidence of virus in the colon by sequencing. Neither showed specific histologic evidence of infection or suffered COVID-19–related complications. As reports of severe IBD flares while SARS-CoV-2 positive are few, it may be useful for pathologists to know that ulcerative colitis patients may not necessarily have respiratory symptoms despite severe IBD symptoms resulting in colectomy.20 As only one
requisition form submitted to our pathology laboratory indicated that the patient had COVID-19, universal precautions with fresh specimen handling should be taken. Of the group with distant histories of SARS-CoV-2 positivity, 6 had SARS-CoV-2 incidentally detected when tested specifically for their GI procedure and required postponement of the procedure for an average of 41 days. Although most of these patients were simply undergoing screening or surveillance colonoscopies, 2 had specific management deferred, including a patient with metastatic appendiceal carcinoma needing tumor debulking and a patient with a prolapsed ileostomy. Additionally, a bone marrow transplant patient with suspected graft-versus-host disease had her confirmatory endoscopic procedures de-ferred for 26 days after being found to be positive for SARS-CoV-2. None in this group showed evidence of virus by ISH, but we could not test all the specimens with NGS. One did have evidence of SARS-CoV-2 in the bowel specimen by
NGS despite having a negative nasopharyngeal PCR test 17 days after documented infection; this has potential implica-tions regarding risk of exposure for endoscopy staff who perform procedures on cleared patients.
In summary, GI tract specimens from COVID-19 patients in our study did not show unique histologic features of viral infection; however, it is important for pathologists to know that sequelae secondary to the systemic effects of the virus, such as ischemia, may be encountered. SARS-CoV-2 ISH detected only 1 of the cases positive for virus on NGS, and a negative result may not exclude the presence of virus in a GI specimen.
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