History
A 7-month-old 370-g (0.81-lb) sexually intact female common marmoset (Callithrix jacchus) that was kept as a pet was taken to a referring veterinarian after a sudden onset of lethargy and inappetence. A diagnosis of pulmonary consolidation and colic was made, and the owners were instructed to administer supportive treatments to the marmoset at home. The next day, the animal's condition slowly worsened with development of neurologic signs including disorientation, trembling, and ataxia. The marmoset was brought to the Zoological Medicine Service at Texas A&M University on an emergency basis but died during hospitalization the next day, approximately 72 hours following the initial onset of clinical signs. The marmoset was submitted for necropsy. The marmoset lived with an 11-month-old male marmoset and had access to an outdoor porch allowing for indirect contact with a feral cat. Human contact with the marmoset was limited to the 2 owners and the referring veterinarian and veterinary staff. According to the owner, not long after the death of the female marmoset, the male marmoset from the household developed similar clinical signs and died shortly thereafter. A necropsy was not performed on that animal.
Clinical and Gross Findings
On physical examination, the marmoset was unable to stand and continued to fall over as it attempted to walk. Multiple erythematous, slightly raised areas were present on the face, primarily surrounding the mouth and on the lips (Figure 1). The largest of these areas was lateral to the right eye and had slight superficial crusting. Necropsy was performed following the animal's death, and a few 1- to 2-mm-wide, round vesicles were identified on the caudodorsal portion of the tongue. The only other gross finding at necropsy was pulmonary edema.
Photographs of the face (A and B) of a common marmoset (Callithrix jacchus) that died after sudden onset of neurologic signs. Multifocal erythematous areas (arrows) with occasional ulceration are present on the periocular facial skin adjacent to the right eye, on the lower lip, and on the chin.
Citation: Journal of the American Veterinary Medical Association 253, 4; 10.2460/javma.253.4.423
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→
Histopathologic Findings
Collected tissue samples were fixed in neutral-buffered 10% formalin, routinely processed, and stained with H&E stain for histologic examination. The observed facial nodules grossly corresponded to multifocal areas of epidermal ulceration with superficial dermal necrosis. Lesions on the tongue were multifocal areas of epidermal necrosis with ballooning degeneration of keratinocytes (Figure 2). Keratinocytes along the margins of the necrotic areas frequently contained amphophilic intranuclear inclusion bodies that caused margination of nuclear chromatin. There were rare syncytia that contained as many as 12 nuclei.
Photomicrograph of a section of affected tongue from the marmoset in Figure 1. There is a focal area of epithelial necrosis with ballooning degeneration of epithelial cells. H&E stain; bar = 300 μm. Inset—Higher-magnification view of the outlined area. Multiple amphophilic intranuclear inclusion bodies (arrow) are evident within basal keratinocytes bordering the necrotic areas. H&E stain; bar = 15 μm.
Citation: Journal of the American Veterinary Medical Association 253, 4; 10.2460/javma.253.4.423
The cerebrum and cerebellum contained clusters of lymphocytes and plasma cells that multifocally expanded the meninges and surrounded parenchymal vessels (perivascular cuffing; Figure 3) with the cerebellum being more severely affected. Rare amphophilic to eosinophilic intranuclear inclusion bodies that caused margination of chromatin were found within glial cells, neurons, and a Purkinje cell.
Photomicrograph of a section of the cerebrum from the marmoset in Figure 1. Cerebral vessels are surrounded by lymphocytic perivascular cuffing. Nearby neurons contain pale amphophilic intranuclear inclusion bodies (arrows). H&E stain; bar = 20 μm.
Citation: Journal of the American Veterinary Medical Association 253, 4; 10.2460/javma.253.4.423
Ancillary Testing
Fresh frozen tissue samples from ulcerated facial lesions were submitted to a molecular diagnostic testing laboratorya for PCR assay for herpes simplex virus type 1 (Human herpesvirus 1 [HHV-1]); the result of this testing was positive. In addition, sections of the cerebrum, cerebellum, tongue, spleen, and liver were submitted to the CDC for immunohistochemical analysis for HHV-1. Viral antigen was detected in neurons of the CNS and keratinocytes in the areas of the tongue with ulceration and syncytia (Figure 4); there was no HHV-1–specific immunostaining of the spleen or liver tissue sections.
Photomicrograph of a section of affected tongue from the marmoset in Figure 1. Epithelial cells have cytoplasmic immunostaining for Human herpesvirus 1 (HHV-1). Human herpesvirus 1–specific stain and fast red chromogen with modified Mayer hematoxylin counterstain; bar = 50 μm. Inset—A cerebral neuron with cytoplasmic HHV-1 immunostaining. Human herpesvirus 1–specific stain and fast red chromogen with modified Mayer hematoxylin counterstain; bar = 20 μm.
Citation: Journal of the American Veterinary Medical Association 253, 4; 10.2460/javma.253.4.423
Morphologic Diagnosis and Case Summary
Morphologic diagnosis: moderate, acute, multifocal, vesiculoulcerative, necrotizing glossitis with intranuclear inclusion bodies and rare syncytia; and moderate, subacute, multifocal, lymphoplasmacytic meningoencephalitis with rare intranuclear inclusion bodies.
Case summary: fatal HHV-1 infection in a common marmoset.
Comments
In the case described in the present report, the gross and histopathologic lesions were characteristic of HHV-1 infection. Human herpesvirus 1 is also known as herpes simplex virus or Herpesvirus hominis. Several primate alphaherpesviruses are known to cross interspecies barriers, particularly between humans and nonhuman primates. These herpesviruses typically cause mild disease in the natural host but can result in fatal encephalitis in nonnatural hosts.1 Arguably, the most well-known of these viruses is Cercopithecine herpesvirus 1 (herpesvirus simiae or monkey B virus), a virus carried by macaques that poses a serious zoonotic threat to humans.2 Conversely, humans serve as the reservoir for HHV-1 and can transmit the infection to nonhuman primates; for nonhuman primates, infection in New World species is usually acutely lethal.1,3–15
In humans, HHV-1 infection typically results in mild vesiculoulcerative lesions around mucocutaneous membranes, most classically within the oral cavity and on facial skin. Disease in Old World primates typically mimics that in humans and is generally mild and limited to oral lesions; however, as in humans, immunocompromised individuals (including young animals) may be susceptible to severe and disseminated disease. Natural HHV-1 infection in various Old World primates, including gibbons, gorillas, and chimpanzees, has been described.3–5 On the other hand, New World primates are exceedingly susceptible to HHV-1 infection, which is associated with a high mortality rate. Among New World primates, marmosets frequently become infected with HHV-1, perhaps as a result of increased human contact given that these animals are commonly owned as pets and kept as part of zoological collections.6–11 Other New World primates affected by HHV-1 infection include owl monkeys, white-faced saki monkeys, tree shrews, and black howler monkeys.12 −-15
Marmosets infected with HHV-1 generally develop oral lesions and neurologic signs, although both are not always present. Other differential diagnoses that should be considered in marmosets with neurologic disorders but no oral HHV-1 lesions include trauma, toxoplasmosis, rabies virus infection, and neoplasia. In a 24-hour period after infection, clinical signs may be absent and the animal may die suddenly.6,8 Oral lesions typically associated with HHV-1 infection include vesicles and ulcers on the facial skin, lips, and oral mucous membranes. Lesions on the tongue can vary from multifocal vesicles and ulcers around the mouth, as in the marmoset of the present report, to diffuse fibrinonecrotizing glossitis and stomatitis. Gross lesions in the brain are not always evident, but when present may include cerebral congestion, edema, and, rarely, hemorrhage.6 Other gross lesions associated with HHV-1 infection in marmosets include conjunctivitis and lymphadenomegaly.7,8
Histologically, affected marmosets have a nonsuppurative meningoencephalitis with mononuclear cells that expand Virchow-Robin spaces and extend into the meninges. In severe cases, there may be a vasculitis as well.6 Intranuclear herpetic inclusion bodies can be found within neurons and glial cells throughout the cerebrum and cerebellum. Oral HHV-1–induced lesions typically include epidermal vesiculation and ulceration with coagulative necrosis and ballooning degeneration of superficial epithelial cells. Basal keratinocytes bordering necrotic areas generally contain intranuclear herpetic inclusions, and characteristic syncytia are common. In addition to neurons and epithelial cells, viral inclusions in adrenocortical cells and in neurons in the myenteric plexus have also been described.6 Although gross and histopathologic lesions can be strongly suggestive of HHV-1 infection, a definitive diagnosis cannot be made without additional diagnostic testing such as PCR assay, immunohistochemical analysis, viral isolation, or immunofluorescence of affected tissue samples.
For the marmoset of the present report, the definitive source of infection was not confirmed. Marmosets are infected with HHV-1 following close contact with humans, and pet marmosets are particularly at risk because of intimate owner habits such as kissing, sharing food, and feeding from the mouth. The owners had no history of herpetic oral lesions; however, humans can harbor asymptomatic infections and, based on the time frame of the marmoset's disease, the owners represented the most likely source of infection. Another potential opportunity for exposure in this case was during the visit to the referring veterinarian's office. The rapid disease progression that ensued following the visit suggested an earlier time of exposure, in keeping with the typical incubation interval for HHV-1. In addition, the original clinical signs of inappetence and lethargy that prompted the initial veterinary examination were likely early signs of HHV-1 infection. Neurologic signs developed < 24 hours following initial examination at the referring clinic with death at approximately 60 hours following the visit. Infection with HHV-1 causes acute disease with a clinical course of 1 to 10 days' duration (mean duration, 3 days).6,7
In 2008, there was a similar case of HHV-1 infection in a common marmoset at our institution. The marmoset had a 6-day course of clinical disease before admission to our facility and had been evaluated by a referring veterinarian for a swollen mouth, dyspnea, and mild tremors. Two days after admission, the animal had cardiac arrest and died. At necropsy, diffuse necrotizing stomatitis and glossitis with numerous ulcers were detected. Histologically, frequent intranuclear inclusions were present in sections of the tongue, brain, and adrenal glands. Infection with HHV-1 was confirmed on the basis of PCR assay and immunohistochemical test findings. The owners of that marmoset also did not have HHV-1–associated lesions; however, exposure was linked to staff at the referring veterinarian's office a few weeks prior during a visit for routine castration.
In addition to nonhuman primates, domestic rabbits are susceptible to natural HHV-1 infection.16–18 Disease in rabbits is often confined to the nervous system. Histologically, infected rabbits have lymphoplasmacytic viral encephalitis similar to that which develops in HHV-1–infected nonhuman primates. Most cases of HHV-1 in rabbits have also been linked to human exposure.
The case described in the present report has highlighted the importance of considering reverse zoonotic transmission (zooanthroponosis) in the handling of veterinary patients. Veterinarians treating marmosets, other nonhuman primates, and rabbits should be aware of the risk of HHV-1 transmission through human contact. Client education regarding animal handling and biosafety is pivotal to disease prevention among susceptible pet species. Owners should minimize unnecessary contact with these animals, particularly contact with people who have oral lesions suggestive of HHV-1 infection. Exposure to veterinary staff should also be limited, especially given the risk of asymptomatic carriers and disease latency, and proper adherence to biosafety protocols should be enforced.
Acknowledgments
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.
Footnotes
Zoologix Inc, Chatsworth, Calif.
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