—  SPECIALTY CONFERENCE  —

Infectious Disease Pathology

Case 4 - Disseminated Lymphocytic Choriomeningitis Virus Infection

Christopher D. Paddock
Centers for Disease Control and Prevention
Atlanta, GA


Click on each slide thumbnail image for an enlarged view
Chest 1983; 83: 82-86.

Clinical History
A 40 year-old-woman with alcoholic cirrhosis complicated by encephalopathy and hepatopulmonary syndrome was admitted to a Wisconsin hospital and an orthoptopic liver transplant was performed. On postoperative day 5 the patient developed fever. On day 8 she developed elevated hepatic transaminase levels and leukopenia. Liver biopsies showed focal centrilobular necrosis and changes consistent with mild rejection but no evidence of viral cytopathic changes. Immunohistochemical stains of the biopsy specimens were negative for herpes simplex virus, adenovirus, and cytomegalovirus. The patient's condition deteriorated and she developed mental status changes and a focal petechial rash around the surgical incision on day 14. The patient subsequently developed multiple bleeding diatheses around indwelling lines and incisional and biopsy sites. She died on postoperative day 18. An autopsy was performed. Histopathologic findings included multiple foci of necrosis, hemorrhage, and mild mononuclear cell infiltrates in the liver, diffuse alveolar damage of the lungs, and necrosis and hemorrhage of the adrenal glands. No specific etiologic diagnosis was obtained; however, 3 additional organ recipients who received kidneys and lungs from the same donor died 9-76 days following transplantation.


Case 4 - Figure 1 - Liver with multiple foci of necrosis and hemorrhage.
Case 4 - Figure 2 - Liver with a mild mononuclear infiltrate



Case 4 - Figure 3 - Lungs with classic diffuse alveolar damage.
Case 4 - Figure 4 - The adrenal glands had necrosis and hemorrhage.


Selected biopsy or autopsy tissues from the donor and each of the 4 recipients were sent to the Centers for Disease Control and Prevention for evaluation. Available tissues and histopathologic findings varied considerably among each of the other patients, but included focal necrosis of tubular epithelial cells with no significant inflammation in a renal biopsy of one kidney recipient, rare necrotic keratinocytes with no significant inflammation in a segment of skin excised from the other kidney recipient, and diffuse alveolar damage in the lung recipient.

Included in the diagnosis of viral infections in liver allograft recipients [1, 2, 3, 4] :

Human herpesvirus 5
Adenoviruses
Human herpesviruses 1 and 2
Human herpesvirus 3
Hepatitis B virus
Hepatitis C virus

Final Diagnosis: Disseminated lymphocytic choriomeningitis virus infection

Comment
During November 2003-January 2004, four recipients who received lungs, liver, or kidneys from a common donor died within 2-11 weeks following transplant. Clinical suspicion of a common infectious etiology prompted a multidisciplinary laboratory investigation by the Centers for Disease Control and Prevention that subsequently identified disseminated infection with lymphocytic choriomeningitis virus (LCMV) in 3 of the recipients.

Formalin-fixed, paraffin-embedded tissue specimens of the organ donor and the recipients were evaluated by routine histopathological and special stains, and by various immunohistochemical (IHC) stains for viral agents, including flaviviruses, adenoviruses, herpesviruses, and New and Old World arenaviruses. Cerebrospinal fluid specimens from several of these patients were inoculated into Vero E6 cells and cultures were evaluated and characterized by electron microscopy (EM), indirect fluorescent antibody (IFA) staining, and RT-PCR.

Histopathology varied among transplant recipients, but was most notable for necrosis without significant inflammation in transplanted organs. Available donor tissues, including CNS, were unremarkable other than for atherosclerotic cardiac disease. Initial IHC stains for various flaviviruses, adenoviruses, and herpesviruses were negative. Special stains showed no bacteria or fungi. Cell culture isolates from CSF of two patients were subsequently identified as an arenavirus by EM and IFA, and further characterized as identical strains of a unique genotype of LCMV by RT-PCR and sequencing. IHC staining demonstrated LCMV antigens in various cell types of various tissues, including liver, adrenals, lung, spleen, kidney, or skin of three recipients. No viral antigens were identified in any CNS tissues or in remaining donor tissues. The ascertaiment of a cause of death for these patients was accomplished rapidly because of: (1) clinical acuity that recognized the potential for a common source of infection of the recipients, and (2) a multidisciplinary laboratory approach that used traditional and contemporary methods to establish an etiological diagnosis.

Lymphocytic choriomeningitis virus is a rodent-borne, Old-World arenavirus that causes a spectrum of manifestations in human hosts that range from subclinical infection to severe meningoencephalitis; however, the case-fatality rate of this infection is generally <1%. The natural reservoir of LCMV is the house mouse (Mus musculus); however, the virus also can be maintained in hamsters and many cases of LCM in humans have resulted from exposures to pet or laboratory rodents [5]. Human infections are not infrequent: a contemporary study from a large urban center in the United States reported human seroprevalence to LCMV of approximately 5% [6], and LCMV was determined to be the etiologic agent in 69 (8.3%) of 828 patients hospitalized for aseptic meningitis during 1941-1951 [7]. Recent attention has focused the role of congential LCMV infection as a cause of hydrocephalus, microcephaly, chorioretinitis, and fetal demise [8, 9]

There are relatively few histopathologic studies of microbiologically confirmed LCMV disease in humans. Lesions of acute LCM are typically most prominent in sections of brainstem and spinal cord and include predominantly mononuclear, perivascular inflammatory cell infiltrates with endothelial swelling, perivascular glial nodules, parenchymal hemorrhage and necrosis, and lymphocytic infiltrates of the leptomeninges. Viral inclusions are not evident by routine stains in infected tissues [10, 11] . Only limited data are available that document the cellular targets and distribution of LCMV in human tissues [9].

A rare hemorrhagic fever-like syndrome has been described involving a patient infected with LCMV during autopsy [12]. Interestingly, several histopathologic and immunohistochemical features of transplant-associated LCMV infection are reminiscent of the pathology of Lassa fever, a hemorrhagic fever caused by a closely related, rodent-borne, Old World arenavirus [13]. In the liver, these findings include multifocal hepatocellular necrosis and hemorrhage with relatively little inflammatory response. Parallels also exist beteween the LCMV-associated hepatic pathology observed in several of the transplant recipients and the pathology of callitrichid hepatitis, a fatal disease of captive marmosets and tamarins, caused by LCMV [14]. The contributory role of immunosuppression in the pathology and pathogenesis of LCMV in transplant recipients deserves further study.

References

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