Fatal Hemorrhagic Complications of Disseminated Adenovirus Infection

Case Presentation

A middle-aged man with recurrent multiple myeloma after autologous stem cell transplant followed by allogeneic stem cell transplant presented to a local emergency department with abdominal pain and profuse nonbloody diarrhea. He was admitted due to concern for infection versus graft-versus-host disease (GVHD). An enteric panel was positive for Yersinia enterocolitica. Blood cultures were negative. Biopsy of the sigmoid colon showed histologic changes consistent with Grade 3 of 4 GVHD. He was treated with intravenous antibiotics and steroids.

Approximately two weeks after admission, the patient was transferred to the intensive care unit (ICU) due to new-onset atrial fibrillation and acute hypoxic respiratory failure. A chest X-ray showed new ground glass opacities in the lung bases concerning for atelectasis versus pulmonary infiltrates. Subsequent computed tomography (CT) of the chest showed bilateral airspace disease concerning for atypical pneumonia. A respiratory pathogen panel was positive for adenovirus. The patient developed fulminant multisystem organ failure requiring intubation, severe coagulopathy, and worsening pancytopenia, despite antiviral therapy with intravenous cidofovir. Repeat CT of the chest showed a right internal jugular vein hematoma associated with a vascular catheter, bilateral pleural effusions, and diffuse lung opacities concerning for acute respiratory distress syndrome versus pulmonary hemorrhage. Computed tomography of the abdomen and pelvis identified mild hepatomegaly and left hydroureteronephrosis. The patient’s condition progressively worsened, and he was pronounced dead approximately two weeks after being transferred to the ICU. An autopsy was requested by the clinical team, with family consent, due to suspicion for disseminated adenovirus infection.

External examination was notable for jaundice, extensive ecchymoses of the neck and chest, dried blood in the nostrils, and abundant dried blood in the oral cavity. Internal examination revealed bilateral serosanguineous pleural effusions and marked pulmonary congestion and edema (combined lung weight 1750 grams) with variably hemorrhagic pleura ( Figure 1 ). The upper and lower airways contained abundant liquid blood. There was multifocal hepatic hemorrhage ( Figure 2A and B ). The left ureter, calyces, and renal pelvis were distended by liquid blood ( Figure 3A and B ). There was also hemorrhage of the gallbladder mucosa, mediastinum, and soft tissue of the chest wall.

Figure 1:

Internal examination revealed bilateral serosanguineous pleural effusions, marked pulmonary congestion and edema with variably hemorrhagic pleura, and multifocal hepatic hemorrhage.

Figure 2:

Gross examination of the liver revealed multifocal hemorrhage (A and B).

Figure 3:

Gross examination of the left ureter, calyces, and renal pelvis revealed distension by liquid blood (A and B).

Examination of the lungs after formalin fixation showed diffuse pulmonary hemorrhage with large consolidations of clotted blood ( Figure 4A-C ). Microscopic examination of the lungs revealed diffuse alveolar damage with bronchocentric necrosis ( Figure 5A and B ). Smudgy basophilic intranuclear inclusions, consistent with adenovirus cytopathic effect, were identified in hematoxylin and eosin stained sections of the lungs, liver, and gallbladder ( Figure 5C and D ). Adenovirus immunohistochemistry was positive in the lungs, liver, spleen, kidney, urothelium, adrenal gland, epicardium, gallbladder mucosa, ileum, and colon ( Figure 6A and B ). Real-time polymerase chain reaction (RT-PCR) for adenovirus had been ordered antemortem and returned positive for >2,000,000 copies adenovirus DNA/mL peripheral blood and urine after the autopsy examination.

Figure 4:

Gross examination of the lungs before (B) and after formalin fixation (A and C) showed diffuse pulmonary hemorrhage with large consolidations of clotted blood.

Figure 5:

Histologic examination of the lungs showed intra-alveolar hemorrhage (A) with diffuse alveolar damage (B). Histologic examination of the liver showed hemorrhagic necrosis (C) and hepatocytes with smudgy basophilic intranuclear inclusions consistent with adenovirus cytopathic effect (D). (Hematoxylin and eosin, magnifications ×200 [A], ×400 [B], ×200 [C], ×400 [D]).

Figure 6:

Adenovirus immunohistochemistry of the lungs (A) and liver (B) was positive (magnifications ×400 [A and B]).

Additional autopsy findings included multifocal severe atherosclerotic disease of the coronary arteries, mild cardiomegaly, and arterionephrosclerosis. The bone marrow was hypocellular with trilineage hematopoiesis and no evidence of recurrent multiple myeloma. Histologic changes consistent with at least Grade 2 to 3 GVHD were identified in the small intestine and colon.

The cause of death was disseminated adenovirus infection complicating immunosuppression due to allogeneic stem cell transplant due to multiple myeloma. Atherosclerotic and hypertensive cardiovascular disease was considered a significant condition that also contributed to death. The manner of death was natural.

Discussion

Adenoviruses are ubiquitous, nonenveloped, double-stranded DNA viruses that typically cause asymptomatic to mild, self-limited upper respiratory infections (1). However, severe and potentially fatal infections can occur particularly in immunocompromised patients and neonates. Severe adenovirus infection can present as pneumonia, pulmonary hemorrhage, meningoencephalitis, hemorrhagic cystitis, necrotizing hepatitis, and/or enterocolitis (1 -4). Patients with a history of stem cell or solid organ transplantation, GVHD, or immunodeficiency are at particular risk of disseminated disease, which is defined as involvement of two or more organs (3, 4). Disseminated adenovirus infection is frequently fatal, with mortality rates of 61% and 83% reported in immunocompromised adult and pediatric patients, respectively (1, 3 -5, 6).

Fatal adenovirus pneumonia with and without pulmonary hemorrhage is well-documented, although depictions and/or descriptions of the gross pulmonary pathology are relatively uncommon (7, 8, 10). In addition, hemorrhagic complications of adenovirus including hemorrhagic cystitis, hepatitis, pancreatitis, enterocolitis, epicardial hemorrhage, and disseminated intravascular coagulation (DIC) have been described (1, 5, 6, 9, 11). However, the spectrum of hemorrhagic complications in disseminated adenovirus infection has been infrequently described in the autopsy literature. This case demonstrates the hemorrhagic pathology of disseminated adenovirus infection, with an emphasis on the gross pathology. To our knowledge, gallbladder, ureteral, and soft tissues hemorrhage, as seen in this case, have not been previously described.

Adenovirus directly infects epithelial and endothelial cells, leading to vascular endothelial injury with risk of life-threatening hemorrhage, thrombosis, and DIC (12). This property is not unique to adenovirus, as many other viruses including cytomegalovirus (CMV), herpes simplex virus, parainfluenza virus, human immunodeficiency virus (HIV), Ebola virus, and dengue virus also infect endothelial cells (12). The development of vasculitis may also play a role in the pathogenesis of some viral infections including adenovirus, CMV, HIV, and Parvovirus B-19 (12).

The differential diagnosis for a fatal, nontraumatic hemorrhagic process in an immunocompromised patient is broad, with an emphasis on atypical infections. Atypical infections to consider include viral infections such as adenovirus and CMV, fungal infections such as mucormycosis, and mycobacterial infections.

Conclusion

This case demonstrates the gross and microscopic pathology characteristic of disseminated adenovirus infection with an emphasis on hemorrhagic complications. Forensic and autopsy pathologists should maintain a high degree of suspicion for atypical infections in this patient population and consider collection of additional specimens for culture, serologic studies, or PCR to aid in the postmortem diagnosis.

Authors

Tracy S. Halvorson MD, Department of Pathology, University of Iowa Hospitals and Clinics

Roles: A, C, E, 1—Performed the autopsy examination, wrote the manuscript.

Timothy N. Maxwell MD, Department of Pathology, University of Iowa Hospitals and Clinics

Roles: C—Wrote the manuscript.

Joseph M. Laakman MD, Department of Pathology, University of Iowa Hospitals and Clinics

Roles: A, C—Performed the autopsy examination, wrote the manuscript.

Marina Ivanovic MD, Department of Pathology, University of Iowa Hospitals and Clinics

Roles: D, 4—Reviewed and edited the manuscript.