Viral Diseases

UPDATE ON LLAMA MEDICINE

0749-0720/94 $0.00 + .20

VIRAL DISEASES Donald E. Mattson, DVM, PhD

There are relatively few reports in the literature concerning viral diseases of new-world camelids (NWC) because of limited financial resources dedicated for the purpose and correspondingly few investigators engaged in such research. As a result, much of the information in this review is based on data from serologic surveys, personal communications, and reports obtained from diagnostic laboratories. Our knowledge, to this point, must be considered preliminary in that it only affirms that the animals in question were exposed to a specific virus. It fails to provide more complete information such as the relative susceptibility of the species to the virus and details of the pathogenesis of infection. It is assumed that alpacas and llamas are equally susceptible to the viruses reviewed in this report. Both species possess multiple physiologic and anatomical similarities and there is no reason to believe they differ in their susceptibility to viruses. One exception to this generality can be attributed to the disease of llamas known as immunodeficiency syndrome. Llamas with this disease possess exceptionally low levels of immunoglobulin gamma (IgG) with an associated B-Iymphocyte and possible T-Iymphocyte deficiencyP These animals are much more susceptible to all infectious diseases. As we continue our efforts for more efficient diagnosis of viral diseases of llamas, it is especially important that decreased resistance to disease as a result of this syndrome be addressed. ADENOVIRUS

Adenoviruses have been isolated from five llamas and one alpaca with diarrhea in Oregon (Mattson D, unpublished data, 1993). The subjects varied from 5 weeks to 3 years of age; four isolations were made from llamas fewer than 12 months of age. Diarrhea was of brief duration (5 to 7 days) except in two cases. An adult alpaca had diarrhea for approximately 14 days and subsequently made an uneventful recovery. In the other case, an 18-month-old llama developed acute progressive diarrhea of 8 days' duration, at which time it was euthan-

From the Department of Veterinary Virology, Oregon State University, College of Veterinary Medicine, Corvallis, Oregon

VETERINARY CLINICS OF NORTH AMERICA: FOOD ANIMAL PRACTICE VOLUME 10· NUMBER 2· JULY 1994

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ized. Histologic examination showed the subject had severe necrotizing enteritis and colitis. There were numerous intranuclear inclusion bodies in epithelial cells of the intestinal tract. The llama had an IgG level of 375 mg/ dL and was diagnosed with immunodeficiency syndrome and secondary adenovirus infection. Galbreadth and coworkers8 in Michigan isolated an adenovirus from the lungs of a 5-month-old llama with pneumonia and hepatitis. There were areas of consolidation in the lungs and an associated pleuritis. The liver contained raised multifocal granulomatous areas. Intranuclear inclusion bodies characteristic of adenovirus infection were detected in both organs. This case was similar histopathologically to three other cases described in this study. The seven isolates of adenoviruses from Oregon and Michigan were shown to be of two antigenic species. Both species differed antigenically from bovine, ovine, or equine adenoviruses (Mattson D, unpublished data, 1993). In a serologic survey involving 270 llamas from 21 ranches in Oregon, prevalence of antibodies to one of the adenovirus species (isolate 7649) was 93%? Similar to adenoviruses of other species of animals, incidence of exposure in llamas appears to be high.16, 17 Most infections are subclinical in nature but, on occasion, infection can initiate disease of the respiratory or enteric tract. BLUETONGUE VIRUS

In a seroprevalence study conducted in Peru by Riviera and coworkers, 21 % of 114 alpacas were shown to possess antibodies to bluetongue (BT) viruses. 26 In a seroprevalence study completed in Oregon, 1.5% of 270 llamas had antibodies to these viruses? Many of the llamas in the Oregon survey were from areas where BT viruses were not enzootic in livestock. Accordingly, the actual incidence of exposure in NWC may be much higher in other areas of the United States. Although NWC may possess antibodies, there has been no confirmed report of BT viruses inducing clinical disease in adult alpacas or llamas. Their role in initiating fetal infection (abortion and teratogenic defects) in NWC has not been explored adequately. To date, the significance of a BT-titer and correlation with carrier status remains unknown in camelids. BOVINE VIRAL DIARRHEA VIRUS

Serologic studies indicate NWC are susceptible to infection with bovine viral diarrhea virus (BVDV).4,20 In a serologic survey conducted in Peru involving 117 alpacas that grazed with cattle and sheep during the winter months, prevalence of antibodies to BVDV was 11%.26 In a serologic survey conducted in Oregon involving 270 llamas from 21 herds, prevalence of antibodies was 4.4%? Seven of the 12 animals possessing antibodies in the Oregon study were located on one farm where cattle were in contact with the llamas. A limited number of isolations of BVDV from NWC have occurred. The virus has been recovered from two llamas with excessive nasal discharges and a llama with diarrhea. In all three cases, the subjects made uneventful recoveries (Mattson D, unpublished data, 1993). Evermann and coworkerss isolated BVDV from two llamas with diarrhea. In contrast to cattle, BVDV appears to replicate to a limited extent in buffy coat cells of NWC (Evermann J, personal communications, 1993; Mattson D, unpublished data, 1993). Studies have not been undertaken to determine whether NWC are immunosuppressed during infection with this virus, as is observed in cattle. 1,27

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Considering the prevalence of BVDV in cattle, and based on data from seroprevalence and virus detection studies in NWC, it appears that NWC are not frequently infected with BVDV. Alpacas and llamas are either relatively resistant to infection or virus is shed in such a low concentration that transmission of the agent to susceptible llamas does not occur in an efficient manner. Because of the comparatively low risk of infection, it is not recommended that NWC be vaccinated routinely for BVDV. If a decision is made to vaccinate because of an unusual risk of exposure to the virus, a regimen of three vaccinations using a killed-virus preparation has been shown to provide low levels of serum-virus neutralizing antibodies (Mattson D, unpublished data, 1993). CONTAGIOUS ECTHYMA

NWCs are susceptible to contagious ecthyma (CE) virus. 18,24,28 Affected animals develop typical proliferative lesions of the epidermis at the commissures of the mouth. Lesions also may extend to regions of the face and perineum. Nursing crias may spread infection to the teats of their dam. Disease may be more chronic than that observed in sheep and affected areas of skin may resemble sarcoptic mange or ringworm infestation.6 Transmission of virus usually is by direct con~ tact, but virus may remain viable on premises for months. It would be prudent to keep NWC separated from infected sheep and goats or places where such animals have been stabled. Because of public health considerations and the sometimes chronic nature of CE in NWC, animals suspected of being infected with CE virus should be kept isolated from the herd until they recover fully. For an expedient diagnosis of this disease, biopsies of fresh proliferative lesions should be submitted to a veterinary diagnostic laboratory and subjected to negative stain electron microscopic examination. FOOT-AND-MOUTH DISEASE

Foot-and-mouth disease (FMD) is considered to be a highly contagious disease, especially for cattle, sheep, goats, and swine. Clinical signs include pyrexia, lameness, and excessive salivation and nasal discharges. Lesions generally consist of areas of inflammation, with vesicles and ulcer formation on the oral and nasal mucosa and the coronary band. 2 A limited number of cases of FMD have been documented in NWC. Natural disease has been described in alpacas following a disease epizootic in cattle. 19 Signs of disease generally were mild, with affected alpacas showing vesicular lesions on their tongues.19 Llamas and alpacas have been infected experimentally with the virus isolated from naturally occurring disease. Clinical signs of disease, distribution of lesions, and pathologic changes were similar to those observed in other species of domestic animals.14, 15 It was concluded from these studies that NWC are more resistant to virus infection than cattle and sheep. Some llamas and alpacas did not show clinical signs of disease even though they shed virus in oral secretions. Likewise, infected subjects shed virus for a comparatively brief period of time (~ 14 days), compared with cattle, which routinely shed virus for weeks or months.2,14 In addition, susceptible cohorts did not become infected in a consistent manner when placed in close contact with infected alpacas and llamasy,15 More importantly, it was concluded from these studies that currently used disease-monitoring procedures and quarantine restrictions are adequate to prevent FMD from entering the United States (Callis J, personal communication, 1993).14

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HERPESVIRUSES

The role of bovine herpesvirus type 1 (BH-1) in diseases of NWC is not well established. A serologic survey conducted in Peru of alpacas that were in close contact with cattle, showed a seroprevalence to BH-1 of 5%.26 In a seroprevalence study in Oregon involving 270 llamas, only two had detectable antibodies to BH-1.22 BH-1 has been detected by fluorescent antibody (FA) examination or by virus isolation from three separate cases of bronchopneumonia in llamas (Mattson D, unpublished data, 1993).31 In all cases, clinical signs of disease, including progressive cough, were attributed to infection of the lower respiratory tract. Lesions were limited to the pleural cavity and were characterized by consolidation of lung tissue and pleuritis; the trachea and bronchi were partially occluded by fibrinonecrotic debris; and varying degrees of secondary bacterial pneumonia existed. BH-1 was detected by FA examination of brain tissue in a l.5-year-old llama with acute neurologic disease (Mattson D, unpublished data, 1993). There were marked accumulations of lymphocytes in perivascular brain tissue, consistent with the diagnosis of diffuse nonsuppurative encephalitis. From these preliminary data, it can be concluded that NWC can become infected with BH-1 but incidence of infection does not appear to be high. Additional studies are needed to more clearly define this issue. Due to the comparatively low incidence of infection, vaccination for this virus is not recommended at this time. Equine herpesvirus type 1 (EH-1) infection has been described in a group of over 100 alpacas and llamas on an exotic animal farmp,23,25 Approximately 20% of affected subjects developed blindness, with neurologic dysfunction evident in four of the blind animals. Two of the subjects, that developed neurologic signs succumbed to the disease. Ocular lesions varied from no detectable abnormalities to severe hemorrhagic chorioretinitis with detached retina and vitritis. Blindness was believed to be caused by chorioretinitis or retrobulbar optic neuritis. Six alpacas, were monitored over a 6-month period without noticeable clinical improvement in blindness. A herpesvirus indistinguishable seriologically from EH-1 was isolated from three alpacas and one llama. Paired serum samples from affected individuals showed rising antibody titers to the virus. Most of the alpacas and llamas in the herd did not show clinical signs of disease, but developed rising antibody titers to EH-l. Attempts to induce recrudescence of virus shedding with dexamethasone was not successful,25 Because the virus was isolated from just four subjects, during the acute stages of disease, it was speculated that NWC may be dead-end hosts for EH-1 infection. The original source of virus was presumed to be a zebra that arrived at the facility approximately 45 days previously and was believed to be shedding the virus. In a subsequent study, three llamas were experimentally inoculated with EH-1,u The researchers confirmed the neurotropic nature of the virus, but were unable to duplicate all clinical signs of disease originally described in the field outbreak. More importantly, these studies demonstrated the basic difference between EH-1 infection in NWC and equines. In NWC, virus is believed to replicate in the cells of the mucous membrane of the nasal cavity, where it gains access to the olfactory nerve. Infection progresses to the optic nerve and central nervous system. In equines, initial virus replication is followed by viremia or distribution of virus throughout the body by infected macrophages. Neurologic disease may develop in some infected equines due to vasculitis of the spinal cord. Clinical signs usually include paresis, paraplegia, and fecal or urinary incontinence.

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There have been no reports concerning the etiologic significance of EH-1 in inducing fetal disease and abortion in NWC. Certainly, this virus is involved in the abortion disease complex in equines. Routine efforts should be used for detecting this virus incases of abortion in NWC. Even though infection with EH-1 may result in severe clinical signs of disease, vaccination is not recommended on a routine basis. In a serologic survey conducted in Oregon to detect the presence of antibodies to various viral pathogens of cattle, sheep, and horses, only 1 of 270 llamas had detectable antibodies to EH-l.22 Vaccination should be considered when NWC are in close contact with equines or when EH-1 has been diagnosed in a herd of NWC. Vaccination with a killed-virus vaccine to EH-1 (Pneumobort-K, Fort Dodge Labs, Fort Dodge, IA) has been shown to induce antibodies in llamas when used according to the recommendations for equines (Dubovi E, personal communications, 1992), but this vaccination procedure has not been tested experimentally to determine efficacy in preventing disease. Modified-live virus vaccination with EH-1 is not recommended in NWC. PARAMYXOVIRUSES

Results from seroprevalence studies indicate NWC can become infected with parainfluenza-3 and respiratory syncytial viruses,22,26 but there have been no reports of these viruses causing clinical respiratory tract disease in NWC. NEONATAL DIARRHEA

Neonatal diarrhea does occur in NWC, but with a lower incidence than in cattle and sheep. This may be because of the lower concentration of susceptible newborns at any specific time during the neonatal period. There is one report of the dete~tion of antibodies to rotaviruses in alpacas in Peru. 26 There have been no reports concerning the detection of rotaviruses from NWC in the United States. Coronaviruses have been detected by electron microscopic examination of the feces in two llamas with diarrhea (Mattson 0, unpublished data, 1993)-a 12day-old llama and a 9-month-old llama. Attempts to isolate the virus in cell cultures were not successful. RETROVIRUSES

Antibodies to ovine progressive pneumonia (OPP) were not detected in a serologic study conducted in Peru where alpacas were grazed with sheep,26 although sheep in the region were believed to be infected with the virus. In a seroprevalence study in Oregon involving 270 llamas, none of the llamas had antibodies to the OPP virus,22 although sheep in the region were infected with OPP. Even though these studies suggest NWC do not become infected with the virus, it should be stressed that OPP virus is transmitted by very close contact between animals.3,9 It could be that sheep and llamas normally are not in close enough contact to allow for efficient virus transmission. These studies also imply that llamas may not become infected with caprine arthritis encephalitis virus (CAE), because antibodies to both OPP and CAE can be detected by the same test. Because of the fact that colostrum-deficient crias often are fed unpasteurized

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goat colostrum, one would expect the newborn llamas would become infected if they were susceptible. A serologic study conducted in Peru also showed no evidence of antibodies to bovine leukemia virus,26 but there have been several reports that llamas develop multicentric lymphosarcoma characteristic to that induced by bovine leukemia virus (Snyder S, personal communication, 1993).7,21 Until a leukemia virus is cultured and characterized from such cases, the susceptibility of NWC to leukemia virus remains uncertain. There has been one report of a retrovirus associated with immunodeficiency disease syndrome in llamas. 29 Evidence for the detection of the punitive virus has been subjected to question.3D Until the alleged virus can be cultured and shown to reproduce the disease, this question will go unresolved. VESICULAR STOMATITIS

A limited number of studies involving the susceptibility of NWC to vesicular stomatitis (VS) virus have been conducted. Naturally occurring disease has not been observed in these animals. In one report, two llamas were in contact with cattle experiencing natural disease with VS.28 Even though the llamas shared the same watering and feeding facilities with infected cattle, they failed to show signs of disease or to seroconvert to the virus. Alpacas have been shown to be susceptible to infection with VS by experimental inoculation. tO Clinical signs of disease consisted of transitory pyrexia and anorexia, with vesicles appearing at the site of inoculation (dorsum of tongue). In a seroprevalence study conducted in Oregon, none of the 270 llamas tested had antibodies to VS strain New Jersey or Indiana.22 It should be mentioned that VS has not been detected in cattle or horses in the region surveyed for at least the past 15 years. References 1. Bolin SR, McClurkin AW, Coria MF: Effects of bovine viral diarrhea virus on the percentage and absolute numbers of circulating B- and T-lymphocytes in cattle. Am J Vet Res 46:884-886,1985 2. Callis JJ, Craig DA: Foot-and-mouth disease. In Castro AE, Heuschele WP (eds): Veterinary Diagnostic Virology, A Practitioner's Guide. St Louis, Mosby Year Book, 1992, pp 100-103 3. Cross RF, Smith CK, Moorehead PD: Vertical transmission of progressive pneumonia of sheep. Am J Vet Res 36:465-469,1975 4. Doyle LG, Heuschele WP: Bovine virus diarrhea infection in captive exotic ruminants. J Am Vet Med Assoc 183:1257-1259, 1983 5. Evermann JF, Berry ES, Baszler TV, et al: Diagnostic approaches for the detection of bovine viral diarrhea (BVD) virus and related pestiviruses. J Vet Diagn Invest 5:265269, 1993 6. Fowler ME: Medicine and Surgery of South American Camelids. Ames, Iowa State University Press, 1989, pp 105-107 7. Fowler ME, Gillespie D, Harkema J: Lymphosarcoma in a llama. J Am Vet Med Assoc 187:1245-1246,1985 8. Galbreadth EJ, Holland RE, Trapp AL, et al: Adenovirus-associated pneumonia and hepatitis in four llamas. J Am Vet Med Assoc, accepted for publication 9. Gates NL, Winward LD, Gorham JR, et al: Serologic survey of prevalence of ovine progressive pneumonia in Idaho range sheep. J Am Vet Med Assoc 73:1575-1577, 1978 10. Gomez D: Ensayos sobre susceptibilidad de los Auguenidoes a la ectomatitis vesicular. Anales II Cong Nac Med Vet y Zoot, Lima, Peru, 1964, pp 403-406

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11. House JA, Gregg DA, Lubroth J, et al: Experimental equine herpesvirus -1 infection in llamas (Lama glama). J Vet Diagn Invest 3:137-143, 1991 12. Hutchison JM, Garry FB, Johnson LW, et al: Immunodeficiency syndrome associated with wasting and opportunistic infection in juvenile llamas: 12 cases (1988-1990). J Am Vet Med Assoc 201:1070-1076, 1992 13. Jenkins D: Alpacas and llamas are susceptible to an equine disease. Llama Magazine, Nov IDee 1985, pp 15-16 14. Lubroth J, Yedloutsching RJ: Foot-and-mouth disease studies in the llama. In USAHA Proc 91st Annual Meeting, Richmond, VA, October, 1987, pp 313-315 15. Mancini H: Ensayos sobre La Receptividad de los Anguenidas a La Febre Aftosa. Bol Inst Nac Antiaftoso, Lima, Peru 1:127-145, 1952 16. Mattson D: Bovine adenoviruses. In Howard JL (ed): Current Veterinary Therapy 3, Food Animal Practice. Philadelphia, WB Saunders, 1993, pp 429-430 17. Mattson D: Ovine and caprine adenoviruses. In Howard JL (ed): Current Veterinary Therapy 3, Food Animal Practice. Philadelphia, WB Saunders, 1993, pp 461-462 18. Moro M: Ectima. En: La Alpaca. Enfermedades Infecciosas y Parasitarias. Bol Divulgacion Instituto Veteranario de Investigaciones Tropicales y de Altura. Unva Nac San Marcos. Lima, Peru, 1971, p 30 19. Moro M: Fiebre Aftosa en Alpaca. En La Alpaca. Enfermedades Infecciosas y Parasitarios Instituto Veteranario de Investigaciones Tropicales y de Altura. Nac San Marcos. Lima, Peru 8:34, 1971 20. Motha J, Tham K: Pestivirus infection in a llama (Lama glama). N Z Vet J 40:126, 1992 21. Moulton JE, Dungworth DL: Tumors of the lymphoid and hematopoietic tissue. In Moulton JE (ed): Tumors in Domestic Animals, ed 2. Berkeley, University of California Press, 1978, pp 165-170 22. Picton R: Serologic survey of llamas in Oregon for antibodies to viral diseases of livestock [MS thesis]. Corvallis, Oregon State University, 1993 23. Pursell AR, Sangster LT, Byars TD, et al: Neurological disease induced by equine herpesvirus 1. J Am Vet Med Assoc 175:473-474, 1979 24. Ramirez A: Ectima Contagioso en alpaca. En Aspectos Santarios en la Alpaca. Curso Sistema de Production Pecuaria en Los Altos Andes. Assoc Peruana Prod Anim. Lima, Peru, 1980, p 94 25. Rebhun WC, Jenkins DH, Riis RC, et al: An epizootic of blindness and encephalitis associated with a herpesvirus indistinguishable from equine herpesvirus 1 in a herd of alpacas and llamas. J Am Vet Med Assoc 192:953-956, 1988 26. Rivera H, Madewell BR, Ameghino E: Serologic survey of viral antibodies in the Peruvian alpaca (Lama pacos). Am J Vet Res 48:189-191, 1987 27. Roth JA, Bolin SR, Frank DE: Lymphocyte blastogenesis and neutrophil function in cattle persistently infected with bovine viral diarrhea virus. Am J Vet Res 47:1139-1141, 1986 28. Thedford T, Johnson L: Infectious diseases of new-world camelids (NWC). In Johnson L (ed): Veterinary Clinics of North America: Food Animal Practice. Philadelphia, WB Saunders, 1989, p 154 29. Underwood WJ, Morin DE, Mersky ML, et al: Apparent retrovirus-induced immunosuppression in a yearling llama. J Am Vet Med Assoc 200:358-362, 1992 30. Vogel P: Retroviral basis for immunosuppression remains to be proven. J Am Vet Med Assoc 201:1318, 1992 31. Williams JR, Evermann, JF, Beede RF, et al: Association of bovine herpesvirus type 1 in a llama with bronchopneumonia. J Vet Diagn Invest 3:258-260, 1991

Address reprint requests to Donald E. Mattson, DVM, PhD Department of Veterinary Virology Oregon State University College of Veterinary Medicine Corvallis, OR 97331