a review of feline viral rhinotracheitis (feline herpesvirus i infection)

Comp. lmmun. Microbiol. infect. Dis., Vol. 2, pp. 373 387. 0147-9571/79/09014)373 $02.00/0 ,.~5 Pergamon Press Ltd., 1979. Printed in Great Britain

A REVIEW OF FELINE VIRAL RHINOTRACHEITIS (FELINE HERPESVIRUS I INFECTION)

R. CHARLES POVEY

Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada

A~traet--Feline viral rhinotracheitis (FVR) is a common and widely occurring disease of cats caused by a herpesvirus designated feline herpesvirus I. In this review (111 references) the virus and the disease are both considered. The virus is morphologically and physico-chemically typical of the herpesviruses, it has a limited host-cell range and appears to be of single antigenic type, unrelated to other herpesviruses. The disease, which affects only members of the cat family, is primarily respiratory but may generalise particularly in the neonate. Osseous pathology including bone necrosis and resorption has been shown to be a particular feature in the pathogenesis of FVR. Genital tract lesions occur experimentally but are not detected in natural infections. A carrier state with periods of latency exists in a majority of cats from FVR infection. Vaccines providing for reasonable protection against FVR have recently been developed.

Key words: Feline viral rhinotracheitis, feline herpesvirus I, respiratory disease, infection of neonate, review

R E V U E S U R L A R H I N O T R A C H E I T E I N F E C T I E U S E F E L I N E

( I N F E C T I O N P A R L ' H E R P E S V I R U S F E L I N I)

Resum~-La rhinotracheite infectieuse feline (FVR) est une maladie bien connue et fortement rrpandue, causee par un virus herpes: l'herpesvirus frlin I. Le virus, ainsi que la maladie font tous deux le sujet de cet article de synthrse (111 refrrences).

Le virus possrde les qualitrs morphologiques et physico-chimiques des virus herpes. Son envergure de rrceptivit6 cellulaire est limitee et il semble 6tre de nature antigenique distincte des autres virus herpes.

La maladie qui n'affecte que les frlides touche d'abord le systrme respiratoire mais peut egalement se generaliser, particuli+rement chez le nouveau-ne. Des atteintes squelettiques du genre nrcrose et resorption osseuse se sont avrrees pattie integrante de la pathogenie de cette maladie. On a aussi remarqu6 des lesions au tractus grnital, mais celles-ci n'apparaissent qu'au niveau experimental sans faire partie du syndrome naturel.

La plupart des animaux ayant souffert de rhinotrachrite infectieuse deviennent porteurs, et dans ce cas, il existe des periodes de latence regissant l'epid~miologie de la maladie. On a recemment mis au point un vaccin offrant un niveau de protection acceptable contre la rhinotracheite infectieuse feline.

Mots-clefs: Rhinotracheite infectieuse frline, herpesvirus felin I, maladie du systrme respiratoire, infection neonatale, revue

I N T R O D U C T I O N A N D H I S T O R Y

In fec t i ous d isease a f fec t ing the r e sp i r a to ry t rac t o f the d o m e s t i c ca t (Felis catus) has been

r ecogn i sed as an u b i q u i t o u s c l inical p r o b l e m for at least 100 years . Bake r [1] i so la ted a

s t ra in o f Chlamydia psittaci f r o m a d isease wh ich he de s igna t ed " f e l i ne p n e u m o n i t i s " , bu t

at the p re sen t t ime it is r ecogn i sed tha t C h l a m y d i a p lays on ly a m i n o r role in r e sp i r a to ry

in fec t ions in the ca t [2]. In 1957 C r a n d e l l a n d M a u r e r [3] i so la t ed an agen t c y t o p a t h o g e n i c

for fe l ine k i d n e y cell cu l tures , w i th p o l y k a r y o c y t o s i s and the a p p e a r a n c e in fixed s ta ined

373

374 R. CHARLES POVEY

preparations of intranuclear inclusion bodies, from kittens with acute upper respiratory tract disease in the United States. The designation "feline viral rhinotracheitis" (FVR) was proposed for the disease [4] and this has gained wide acceptance. Subsequent work [5, 6] supported Crandell's view that the virus should be classified in the Herpesviridae and the International Committee for the Nomenclature of Viruses proposed the identification feline herpesvirus I [7]. The abbreviation FHV is retained for simplicity throughout this review.

FHV is not the only herpesvirus to infect cats. Pseudorabies virus [8] produces an afebrile pruritis which rapidly progresses to paralysis and death [9]. Fabricant et al. [10] isolated a highly cell-associated herpes-like virus in autogenous cell cultures from cats with urolithiasis and urethral obstruction. This virus is serologically distinct from FHV and other mammalian herpesviruses [11].

Apart from FHV the only virus isolates of widespread importance in respiratory disease of cats are the feline caliciviruses (formerly known as feline picornaviruses) and these have been recently reviewed [12]. Since the original isolation, FHV has been shown to be of wide geographic distribution and to be the clinically most significant of the respiratory infections of cats [13].

This review is intended to update that of Crandell [14] and will consider firstly the virus and secondly the interaction of the virus with the cat. The abbreviation FHV will be used throughout for the virus feline herpesvirus I, and FVR for the disease feline viral rhinotracheitis, with which it is associated.

THE VIRUS Morphology

FHV conforms to the morphology of herpesviruses in general [15]. Using negative- staining electron microscopy Ditchfield and Grinyer [6], McEwan and Miles [16] and Mochizuki et al. [17] have described the two typical types of particles distinguished by the presence or absence of the outer coat or envelope (Fig. 1). The non-enveloped, "naked" particles have an average diameter of 108 nm; the capsids show varying degrees of angularity and in some cases are clearly hexagonal (Fig. 2). The capsid is composed of an undetermined number (presumably 162 [18]) of elongated capsomeres, 10 nm in length, with a prominent axial hole, 2.5 nm in diameter. The envelope surrounding some particles is very variable in shape and size but has an average diameter of 178 nm.

Ultrathin sectioning of FHV-infected cells [14, 17] shows intranuclear particles, 80.-108 nm in diameter, consisting of a central electron-dense or ring-like nucleoid and a single outer membrane. These particles correspond to the naked virion. Intracytoplasmic particles, 128-167 nm, have a double membrane and correspond to the enveloped virion. In extracellular spaces morphologically similar but somewhat larger (140 173 nm) particles are seen. Intranuclear aggregates of densely granular material and filamentous structures have also been seen in infected cells but their significance is unknown [19].

Physico-chemical properties

Chemical composition. Very little work has been published on the chemical composition of the virion of FHV, neither on the nucleic acid nor on capsid and envelope proteins. Crandell and Hersey [20] indicated indirectly the probability of FHV being a DNA virus by

A review of feline viral rhinotracheitis 375

Fig. 1. Negatively stained enveloped particle of feline herpesvirus I. x 250,000.

Fig. 2. Enveloped particle of FHV I with PTA stain penetration of particle suggesting hexagonal outline ofcapsid and hollow capsomeres, x 250,000.

demonstra t ing Feulgen and acridine-orange positive staining which was intense in the early stages o f infection in the cell nucleus, and later was detectable, but less intense, in the cytoplasm. More direct evidence that F H V contained D N A came from the use o f 5-iodo-2- deoxyuridine ( IUdR) or its bromine analogue, B U d R [5, 6, 21, 22] which at 100 pcg/ml inhibited viral replication, but this inhibition could be overcome by the addit ion o f thymidine to the medium.

Physical properties. Neither the mass nor density o f F H V or its subunits has been reported upon.


Resistance to inactivation. A. Stability to chemicals. Herpesviruses are very sensitive to lipid solvents, which destroy the lipid-containing envelope [23]. The infectivity of FHV is greatly reduced or eliminated by the action of ether [5, 21, 24], chloroform [5, 6, 21, 25], and sodium deoxycholate [26]. FHV is also sensitive to the action of trypsin [21, 27] which also probably acts on the envelope. FHV is inactivated within 1 hr by 0.1~o beta-propiolactone [14, 28], within 24 hr by 0.5~o phenol and 0.1~ formalin [21], and within 13 days by 0.018~o formalin [24].

B. Stability to heat. FHV stored in cell culture fluid loses 90~o of its viability within 6 hr at 37°C, 6 days at 25°C, 1 month at 4°C, 4 months at - 5°C, and 5 months at - 50°C. There is complete loss of viability within 4-5 rain at 56°C, 36 hr at 37°C, 33 days at 25°C and 3 months at 4°C [21, 24, 29]. Lyophilisation results in an initial loss of some 70~o of total viability, but the lyophilised virus thereafter remains stable for more than 1 year at - 5°C [29].

Low temperature (25°C) passage has been used to select low-virulence strains of FHV for vaccine development [30]. A related approach was used by Davis and Beckenhauer [31], who used chemical mutagens and ultraviolet irradiation in succession to develop a mutant of FHV which appears to be temperature-sensitive.

C. Stability to pH. The pH stability of FHV is greatest at pH 6 [24] at which at 4°C, 90~o of viability is lost by 49 days, compared with 9 days at pH 5, 39 days at pH 7, and 15 days at pH 8. At pH 3, 99.99~o and at pH 9, 75~o of virus viability has gone within 3 hr at room temperature [21].

D. Stability in the environment. FHV can be recovered for up to 18 hr in a moist environment at 15°C, but for less than 12 hr in a similar but dry room [32]. As an aerosol, at an ambient temperature of 18-23°C, FHV is moderately stable at a relative humidity (RH) of 20-30~o but thereafter as RH rises viability loss in 5 rain is 99~o or greater [33].

Hemagglutination and hemadsorption. Bartholomew and Gillespie [26] failed to show hemagglutination by FHV using guinea-pig red blood cells at 4°C, or hemadsorption using the same cells at 4°C or 36°C. Gillespie et al. [34] confirmed these results but found that FHV grown in primary feline cells or a diploid feline tongue cell line, did show hemagglutination of feline red cells at 4, 20 or 37°C. However virus propagated in Crandell's feline kidney cell line did not hemagglutinate. Hemagglutinating (HA) titers were low, of the order of 1 : 2 to 1 : 8. Chicken or dog red cells were not agglutinated. Feline red cells were also hemadsorbed by FHV-infected cultures at 4°C. Mochizuki et al. I17] were able to enhance HA titers of FHV grown in either secondary feline kidney cells or a feline lung cell line, by treatment with 20~ peroxide-free ethyl ether at 4°C for 18 hr. They used feline red cells at 0.5~o suspension, and found HA titers were highest and most reproducible at 37°C. In a subsequent paper [35] these same authors reported a further four-fold enhancement of HA titers (32-64 HA units/ml) by supplementing virus material with 0.25~ poly-oxyethylene sorbitan mono-oleate (Tween 80; Sigma Chemical Company), immediately prior to the ethyl-ether treatment which was carried out for 2 hr. In general, HA activity paralleled infectivity titers of the virus, and the activity was shown to be associated with the viral envelope. The viral hemagglutinin was highly sensitive to trypsin (proteolytic enzyme), potassium periodate (oxidising agent), dithiothreitol (a disulphide-bond reducing agent), sodium deoxycholate (anionic detergent) and the


carbohydrase, alpha-amylase. The HA activity was eliminated by heat at 56°C for 30 min. The receptor(s) on the feline erythrocytes were destroyed by trypsin.

Replication

Host cell range. FHV replicates readily in all of the many types of cells of feline origin that have been investigated. These include primary, secondary and established lines of cells of kidney, thymus, tongue, neurofibrosarcoma, and lung (type II pneumocytes and alveolar macrophages) origin [3, 36, 37]. Cytopathic effect was also shown in a secondary lion kidney cell culture [36]. Many non-feline cell systems have been found not to support FHV (kidney cells of calf, sheep, pig, rabbit, chicken, dog, human embryo, African green monkey, dolphin and whale; testicle cultures of sheep and calf; lung of bat and mink; racoon uterus; human amnion; HeLa cells; bovine bone marrow; and rabbit cornea). Ditchfield and Grinyer [6] reported successful adaptation of FHV to a continuous cell line of rabbit kidney origin (RK13) but this has not been repeated. Tegtmeyer and Enders [27] demonstrated attachment of FHV to human embryo lung cells but failure of penetration. However if the cells were pre-treated with inactivated Sendai virus such that cell fusion occurred then FHV produced a cytopathogenic infection but it was abortive in that no infective virus could be recovered from affected cells.

In vivo the host range seems confined to members of the Felidae. FHV does not propagate in newborn or weanling rats, mice, rabbits, guinea-pigs and Syrian hamsters inoculated intracerebrally [3, 28]. Rabbits, guinea-pigs, mice and dogs are not susceptible to intranasal, intramuscular, intraperitoneal injection or, in the case of rabbits, to corneal scarification [25]. The virus does not grow on the chorio-allantoic membrane of chick embryos [3].

The restricted host range of FHV in vitro and in vivo is quite different to the wide variety of animals and cells that can be infected experimentally with some herpesviruses, such as herpes simplex or pseudorabies, but is comparable to the limited infectivity of other herpesviruses such as Varicella-zoster or cytomegaloviruses.

Growth curve. Typical virus growth curves have been demonstrated [29, 38]. Tegtmeyer and Enders [27] published a single-step growth curve for FHV in secondary feline kidney cell cultures (input multiplicity of 3) at 36°C and Wardley et al. [39] in a similar study used an input multiplicity of 1 and incubation at 37°C. Infective intracellular virus was first detected between 6 and 8 hr but not released into the extracellular environment until 9 to 10 hr post-infection. However direct cell-to-cell spread of FHV via an intracellular route was demonstrable from 6 to 7 hr onwards [39]. This growth cycle is very similar to that of several other herpesviruses including herpes simplex, pseudorabies and equine abortion [40]. An average maximum yield of 200 infectious particles per cell was achieved by 30 hr [27]. Growth curves at varying temperatures both of wild-type virus and the temperature sensitive strains of FHV being developed for vaccines [30, 31] would be of considerable interest but have not been published.

Cytopathology. The two types of cytopathogenic effect (CPE) most commonly seen in herpesvirus-infected cells are rounding and degeneration often preceded by macrocytosis or ballooning of the infected cell; and formation of syncytia or polykaryocytes which are multinucleated cells [40]. These changes are features of the CPE of FHV also [3, 4, 37, 41].


The earliest changes are the appearance of groups of refractile, rounded or elongated cells in the infected monolayer, 6-48 hr post-inoculation depending on the level of inoculum. Cytoplasmic vacuolation is seen in some ceils. As with herpesviruses generally, FHV can spread from an infected cell to an adjacent uninfected cell by the intracellular route [39]. Affected cells progressively detach from a culture surface leaving plaques which can reach a maximum size of 1 cm by day 12 of culture [42]. Polykaryocyte or syncytia formation is usually present but varies in degree. The influences for this variability are not known but for other herpesviruses, the host cell, the strain of virus and environmental factors such as serum concentration and type are all known to influence polykaryocytosis [43]. The key event in polykaryocyte formation has been shown to be a decrease in thickness of the cell membrane immediately preceding fusion, and such a thinning (by one-third) has been shown for FHV-infected feline lung cells [44].

Intranuclear inclusions, Cowdry type A [45], are the characteristic cellular lesion associated with herpesviruses, and have been described for FHV from its initial isolation [3]. They are only apparent in fixed, stained cultures. The earliest changes in stained preparations occur coincident with rounding and increased refractility of the cell and involve an enlargement of the nucleus and a stippling of basophilic nuclear chromatin. This stippled chromatin condenses into larger granules which marginate to the nuclear membrane leaving a homogeneous acidophilic central area which, as an apparent artifact of fixation, contracts to give an inclusion with a clear halo [4, 41]. Polykaryocytes often show inclusions at various stages of development in peripherally located nuclei (Fig. 3).

Although appearance of CPE usually coincides with detectability of extracellular infective virus [38], it is not necessary that infective virus be formed for CPE to occur. Thus FHV was capable of inducing typical CPE in human embryo lung cells when inactivated Sendai virus was added to the system [27], but infective virus could not be demonstrated.

Morphogenesis as observed by thin section electronmieroscopy. The morphogenesis of FHV has not been extensively studied compared with other herpesviruses [46], Langloss et al. [37] added a temporal dimension to the studies of Crandell and Tousimis [14] and Mochizuki et al. [17], which have already been referred to. Thin section electronmicroscopy of pneumocytes infected with FHV showed nucleocapsids (nucleoid and single outer membrane) in the nucleus by 12 hr post-infection. At this time also the clumping of chromatin was seen, together with focal reduplication of the nuclear membrane. Double- membraned (enveloped) particles were found in association with the duplicated nuclear membrane, between the inner and the outer nuclear membrane, and a few were present in the cytoplasm. By 24 hr, the enveloped, intracytoplasmic particles were prevalent. Mitochondrial degeneration and cytoplasmic vacuolation occurred late in the infectious cycle.

Biochemistry of replication. Apart from the limited studies referred to earlier indicating the synthesis of DNA associated with FHV replication no work has been reported on the details of how FHV interacts with and controls host cell metabolism and viral replication.

Antigenic properties

Many serological comparisons have been made between FHV isolates from many parts of the world and all have shown a homogeneity with the prototype strain designated "C-


Fig. 3. Polykaryocyte in secondary feline embryo lung cells infected with FHV I, showing various stages of intranuclear inclusions. H.E. x 1400.

27" [3, 6, 28, 42, 47-50]. These serological studies have been made most often using the serum neutralisation reaction and antisera raised in rabbits. A standardised constant-virus varying-serum neutralisation test has been reported [29, 32]. Complement-potentiated, serum-neutralising antibody as reported for herpes simplex [51] is not apparent in anti- FHV sera [32, 52]. Other serological tests used have been complement fixation and immunodiffusion [53] and hemagglutination inhibition [17, 35, 52]. These have also shown identity between FHV isolates. However, no refined serological comparisons have been made between FHV strains using techniques such as neutralisation kinetics and microquantal neutralisation that have been used for differentiating strains of herpes simplex virus [54, 55]. That strains of FHV of varying virulence occur is clear from several reports in which either less virulent or more virulent strains have been selected or developed [30, 31, 56-58].

Serological cross-reactions occur between several members of the herpesviruses but FHV does not show any cross-neutralisation with a second feline herpesvirus (FHV-2) which has been associated with urolithiasis [11], or with herpes simplex, pseudorabies [22], infectious bovine rhinotracheitis (IBR) or bovine herpes mammillitis [47]. Fluorescein-conjugated, specific anti-FHV serum does not show cross-immunofluorescence with FHV-2, IBR, or equine herpesviruses 1, 2, 3 and 4 [59].

THE DISEASE

Feline viral rhinotracheitis ( FVR)

Definition. FVR is a typically acute, febrile, contagious disease of felids characterised by sneezing with ocular and nasal discharges. The incubation period is 2-4 days, sometimes longer. Mortality is high in young or debilitated cats, but most recover in 7-10 days.

380 R, CHARLES POVEY

Distribution and occurrence. Reports of FVR coming from North America, Europe, Asia (Japan) and Australia, indicate the disease is common and widespread in these areas. There are as yet no definitive reports of FVR from tropical areas. Serological surveys show detectable serum neutralising antibody to FHV in 50-75G cats [49, 60]. The higher frequencies are found in cats from multi-cat colonies or households rather than individual pets. FHV and feline caliciviruses are by far the most frequently isolated viruses from cats with respiratory diseases, and also from healthy cats. From various combinations of nasal, conjunctival and oropharyngeal swabs of 132 cats with signs of upper respiratory infection, isolations of FHV (14) and FCV (20) were obtained in 25~ of cases [61]. Similar results were obtained by Povey and Johnson [60] with 24.6~o of 69 cases yielding FHV and 17.4~o, FCV. The frequency of virus isolation was much higher (52.3~) in the first week of illness than thereafter (24~o). In the same report respiratory disease accounted for death in 50.3~o of 148 kittens of up to 6 months of age. FHV was isolated from 28~o of this group, and FCV from 5.3~o. Jensen et al. [62] surveyed cats with respiratory disease in rural and urban environments in the U.S.A. and found FHV (30.5~o) slightly more frequently than FCV (25.4~o) in the former situation, but FCV (10.2~) nearly twice as frequently as FHV (5.5~o) in the urban environment. Dual recovery of FHV and FCV is not uncommon [17, 63].

FHV and FCV can be recovered from swabs, particularly those taken from nasal, oropharyngeal or conjunctival sites, of clinically healthy cats. FCV are more frequently isolated being present in 8~o of household pets, 24.02~o of cats attending cat shows, and 41.5% of cats in two colonies of over 100 cats each [15]. FHV, in the same survey, was only recovered from 1~o of household pets, 1.75~o of show cats and 0.4~ of cats from the two large colonies. Most of these isolations represented either asymptomatic reinfections or persistent infections in carrier animals. The carrier state is dealt with later.

Host range. Only members of the Felidae appear susceptible and of the non-domestic cats only the clouded leopard (Felis nebulosa) has had infection confirmed by virus isolation [64]. A herpesvirus which may have been FHV was isolated from cheetahs (Acinonyx jubatus) with conjunctivitis and rhinitis [65], and a similar outbreak without virus isolation being attempted was reported in cheetahs in Germany [66].

Pathogenesis. Natural infection seems most likely to occur by the intranasal, intraocular and oral routes and the former has been most frequently used in experimental studies. Other routes investigated have been intravenous, intramuscular, intracerebral, corneal and tongue scarification, and intravaginal.

Following intranasal inoculation with virus dosages of 100 median cell culture infective doses (CCIDs0) or greater [67], virus can be detected in nasal mucosa by post-infection day (PID) 1. Occasionally viremia has been detected coincident with a rise in body temperature on PID 2 [5, 68]. At this time intranuclear inclusions are numerous in the mucosa of nasal septum, turbinates, nasopharynx and tonsils [69], and these sites are those in which maximum viral concentrations of ~> 1045CCID5o/2 mm 3 of wet tissue are found [70]. Fewer inclusions and lesser amounts of virus are detectable in conjunctivae, mandibular lymph nodes and the upper trachea, and only irregularly is it found in salivary glands, lower trachea and the lungs. Almost concurrent with the appearance of intranuclear inclusions, and coincident with fever, sneezing, salivation and leukocytosis on PID 2, there is cytoplasmic hydropic degeneration of epithelial cells leading to multifocal epithelial necrosis with neutrophilic infiltration and exudation with fibrin [68]. Most extensive


damage is to the mucosal epithelium of the nasal, maxillary and ethmoid turbinates, nasal septum, frontal, maxillary and sphenoidal recesses, olfactory region and nasopharynx. These changes are relatively slow to repair but by PID 17 epithelial regeneration with some squamous cell metaplasia, sometimes proceeding to hypertrophy is seen [69]. The olfactory epithelium may be particularly slow to heal [68]. It has been suggested [71] that pathogenicity of FVR is increased by secondary bacteria and Povey [28] noted a milder disease in specific-pathogen-free cats as compared to conventionally-reared, but Hoover et al. [68] showed considerable pathogenicity in germ-free cats. However, Hoover and Griesemer [72] have noted that fever and neutrophilic exudation is more pronounced and persistent in the presence of respiratory bacterial flora.

Another feature of intranasal FVR is the necrosis and resorption of turbinate bone seen from PID 4 onwards [68, 69]. It has been shown [73] that intravenous inoculation of neonates and weanling (8-week-old) kittens (but not mature cats) with FHV, results in widespread necrosis in the growth regions of the skeleton including long bones and vertebrae as well as turbinates. Viral antigen is detectable in osteoblasts, osteoclasts and endothelial and perithelial cells of vessels within the osteogenic tissue. The factors responsible for the localisation of FHV in growing bone have not been determined but may be related to vascular morphology or dynamics [73].

The intravenous inoculation referred to above, besides the osteolytic effects, produced typical upper respiratory lesions, as did the intracerebral route [74], without producing neurological signs.

Intramuscular inoculation of virulent FHV does not produce disease nor is there apparently any spread of virus from the injection site [28].

Many herpesviruses in addition to their preference for respiratory epithelium have an affinity for genital tract tissues. Intranasal infection of pregnant cats results in abortion along with upper respiratory disease [72] but virus is not recoverable from the aborted material. However with intravenous inoculation abortion is associated with the presence of virus, inclusions, and pathological lesions in uterus, placenta and aborted fetus. Intravaginal instillation of FHV [75] results in vaginitis and congenitally infected kittens which develop generalised disease including hepatic necrosis with intranuclear inclusions in hepatocytes.

Apart from the neonatal period generalisation of FHV in diverse tissues is uncommon, possibly reflecting the infrequent viremia, but virus was recovered from such sites as liver, spleen, kidney and brain of a 3-month-old kitten 9 days after infection by tongue scarification [76].

Similarly from one of four 4-6-month-old kittens infected intranasally [70] virus was recovered at PID 6 from liver, spleen and trigeminal ganglion as well as from respiratory and adnexal sites.

Clinical signs. There have been many clinical descriptions of FVR. Most emphasise initial depression and sneezing which becomes increasingly frequent and paroxysmal. Fever (> 39.5°C) is usually present. Ocular and nasal discharges, at first clear, become mucopurulent. Appetite decreases and is often completely lost. Hypersalivation with tenacious secretion drooling from the mouth and contributing to dyspnoea by obstruction of the oropharynx is common. The salivation does not correlate with the presence of ulcers of the tongue or other areas of the buccal cavity. Such ulceration is not a very frequent


finding with FVR, compared to its frequent association with FCV infection [12]. A retching cough is characteristic when it occurs. The more severely-affected cat shows dehydration and weight loss occurs rapidly. In the absence of complicating bacterial infection or intercurrent debilitating diseases like the feline leukemia complex [77], clinical signs have usually resolved within 10-20 days. However some cases show chronic sequelae including persistent rhinitis. Abortion is usual in pregnant cats during the acute, and sometimes in the recovery phase of FVR [47, 78].

The ocular manifestations of FVR have been described in some detail [79, 80]. Three main categories of ophthalmic involvement have been listed. First, a neonatal ophthalmia in kittens 2-4 weeks of age. Purulent conjunctivitis may precede opening of the eyelids, or may glue the eyelids shut with consequent bulging. Second, acute conjunctivitis in kittens 4 weeks to 6 months. Third, keratitis, which principally affects older cats and often involves dendritic corneal ulceration and interstitial keratitis. Desmetocoele formation can occur.

The majority of fatal FVR infections occur in kittens and many show pneumonia which is often a bacterial bronchopneumonia but in young kittens it may be more purely viral [81] with non-suppurative bronchiolitis and interstitial pneumonia. As described for experimental infections neonatal kittens are prone to develop generalised disease which is rapidly fatal [78], with lesions demonstrable in liver and lungs. Generalised disease with focal necrotic hepatitis has been described in a 7-month-old cat which died following a 17- day illness with FVR [82].

Rare manifestations of FVR have been skin ulcers following ovariectomy and possibly associated with skin shaving in preparation for surgery [83]; and central nervous signs, particularly convulsive episodes, which have not been well documented [47, 76].

Epizootiology. Virus is present in the ocular, nasal or oropharyngeal secretions, or a combination of these, for 1-3 weeks, but seldom longer, during initial infections [68, 70]; for several days during reinfections [61]; and irregularly from persistently infected carriers (see later).

Transmission is most likely by direct contact between cats or sneezed macro-droplets which travel only a distance of approximately 1-2 m [84]. It would appear that infected cat does not generate an infectious aerosol during normal respiration [85]. Indirect or fomite transmission is only important within catteries because of the fragility of FHV mentioned earlier. Factors such as temperature, relative humidity and ventilation will affect the efficiency of transmission. A dose of 10 CCIDso of virus is not infective but thereafter there is a significant direct correlation between virus dosage and shortness of incubation period, and some correlation with severity of illness [67].

Carrier state. During early studies of FVR it was apparent that many recovered animals were probably persistently or latently infected with FHV and from time to time were capable of infecting or re-infecting in-contact cats [47, 69, 86]. Plummer et al. [87] were able to recover FHV from one of six cats, three months after FVR infection. Gaskell and Povey [88] achieved much more regular stimulation of FHV re-excretion from recovered cats using corticosteroids. At least 82~o of FVR-recovered cats could be demonstrated as being carriers by this method. A mean lag period of 7.2 days following the first of three corticosteroid infections was succeeded by a mean of 6.5 days of virus shedding as detectable by oropharyngeal or conjunctival swabs. It appears that there is a refractory period following the re-excretion during which further administration of corticosteroid is


less effective. In a number of cases mild clinical signs accompanied viral re-excretion. Naturally stressful situations such as kittening and lactation, and simulated stress (rehousing) were less successful as inducers of re-excretion, but four of six FVR-recovered queens shed virus within 2-10 weeks of parturition. Apparently spontaneous shedding of virus occurred on 10 occasions during a mean 8.8 months observations of 31 cats. Thus FHV in common with a number of other persistent herpesvirus infections has a carrier state characterised by a latent phase with only periodic episodes of virus shedding.

Despite extensive study [85] the tissue or cell location of virus during its apparent latent phase remains uncertain. Examination by a variety of techniques of a range of 22 tissues from 19 known-carrier cats failed to detect virus, but from one cat spontaneously shedding at the time of death, FHV was recovered from a trigeminal ganglion, which is of interest in view of the association between herpes simplex persistence and sensory ganglia [89]. In another cat FHV was detectable in the olfactory lobe of the brain, and the olfactory region of the nose was the most regular site of viral recovery from re-excreting cats [70]. The latent and persistent infection aspects of FHV in the cat offer a useful model for comparative studies in this area.

Immunity. Studies on the immune response to FHV have concentrated on the detection of virus neutralising serum antibody (SNab). Following primary infection SNab is first detected on about PID 16 and by PID 20, 40~ of exposed cats have assayable but low titers. This proportion rises to 73~o by PID 40 [67]. Thereafter SNab titers decline in the majority of cats but in some cases persist for some months [86]. Resistance to challenge re- exposure was demonstrated by Walton and Gillespie [61] at PID 21, and there was partial resistance at five months after initial exposure. Bartholomew and Gillespie [26] pointed out that there was not absolute correlation between detectable SNab and protection because some kittens with no SNab were immune and vice versa. Several authors have speculated that cell-mediated immune mechanisms would be important in immunity to FHV. Wardley, Rouse and Babiuk [39] demonstrated that FHV-infected cells could be destroyed by both antibody and complement mediated lysis and by antibody-dependent, cell- mediated cytotoxicity as mediated by both lymphocytes and macrophages. Direct lymphocytotoxicity of virus infected cells was also shown, but this effect was variable, These cytolytic mechanisms were effective between 6 to 8 hr post-infection of the cell, which is in advance of normal release of extracellular virus spread (9-10 hr) and concurrent with intracellular spread [39]. They are thus of probable great significance in checking the dissemination of FHV. It will be interesting to have further information on the functioning of these immune mechanisms with regard to the carrier state.

Maternal antibody transfer in the cat is essentially colostral rather than placental [90]. Serum antibody levels in kittens from immune dams rise rapidly in the first 72 hr but are not directly proportional to the queen's level [28, 85]. There is an exponential decay rate with a linear regression equation o f y = 4 .35-0.38x, where y is the antibody titer (log2) at x weeks of age [85]. Thus approximately 50~o of kittens born to immune dams have minimal or non-detectable SNab levels by 5-6 weeks of age, and virtually all kittens have lost maternal antibody by 9 weeks [28, 85, 91]. Gaskell [85] has shown that kittens with maternal antibody may still become infected and shed virus asymptomatically.

Treatment and prophylaxis. Specific antiviral therapy trials using isoprinosine, 6- azauridine, and 5-iododeoxyuridine [78, 92] have not proven useful. Ribavirin showed

384 R. CHARLES PovEv

p r o m i s i n g ac t iv i ty aga ins t F H V in vitro, bu t was no t inves t iga ted in vivo [93]. I o d o d e o x y u r i d i n e has been used topica l ly with some success to t reat dendr i t i c kerat i t i s assoc ia ted with F H V [79, 94].

Ear ly vacc ine expe r imen t s wi th F H V for p rophy lax i s o f F V R gave some e n c o u r a g i n g

ind ica t ions for i nac t iva t ed p r o d u c t s [28, 95], bu t it was modi f ied live virus vaccines which were first to be c o m m e r c i a l l y i n t r o d u c e d a n d a re ava i lab le , usua l ly in c o m b i n a t i o n wi th

o the r an t i gens such as feline p a r v o v i r u s ( p a n l e u k o p e n i a ) a n d cal ic ivirus a n d can be a d m i n i s t e r e d in some cases i n t r a n a s a l l y b u t usua l ly i n t r a m u s c u l a r l y or s u b c u t a n e o u s l y [30, 31, 56-58 , 63, 91, 96-98] . S o m e p r o b l e m s wi th these a t t e n u a t e d virus vaccines have been discussed [99] a n d a n inac t iva ted vacc ine o f c o m p a r a b l e efficacy a n d with safety a d v a n t a g e s has been deve loped [100]. N o n e o f the vaccines so far deve loped have been ab le to p rov ide comple t e p r o t e c t i o n in te rms o f p r e v e n t i n g viral r ep l i ca t ion o n re-exposure , bu t c l inical p ro t ec t i on is a d e q u a t e to very good. W h e t h e r or no t v a c c i n a t i o n p r io r to ini t ia l exposu re can p reven t the e s t a b l i s h m e n t o f a car r ie r s tate is no t clear. There is p r e l i m i n a r y evidence tha t it c a n n o t [70].

REFERENCES

1. Baker, J. A., A virus obtained from a pneumonia of cats and its possible relation to the cause of atypical pneumonia in man, Science 96, 475-476 (1942).

2. Shewen, P. E., Povey, R. C. and Wilson, M. R., Feline chlamydial infection, Can. vet. J. 19, 289 292 (1978). 3. Crandell, R. A. and Maurer, F. D., Isolation of a feline virus associated with intranuclear inclusion bodies,

Proc. Soc. exp. Biol. Med. 97, 487-490 (19583. 4. Crandell, R. A. and Despeaux, E. W., Cytopathology of feline viral rhinotracheitis virus in tissue cultures of

feline renal cells, Proc. Soc. exp. Biol. Med. 101,494~497 (1959). 5. Burki, F., Lindt, S. and Freudiger, U., Enzootischer, virusbedingter Katzenschnupfen in einum Tierheim 2.

Virologischer und experimenteller Tell, Zentbl. VetMed. II, 110 118 (1964). 6. Ditchfield, J. and Grinyer, 1., Feline rhinotracheitis virus: a feline herpesvirus, Virology 26, 504~506 (1965). 7. Roizman, B., et al., Provisional labels for herpesviruses. A report of the International Committee for the

Nomenclature of Viruses, Herpesvirus Study Group, J. gen. Virol. 20, 417 (1973). 8. Aujeszky, A., Ueber eine neue Infektionskrankheit bei Haustieren, Zentbl. Bakt. Abt. I. Orig. 32, 353 357

(1902). 9. Horvath, Z. and Papp, L., Clinical manifestations of Aujeszky's disease in the cat, dcta vet. hung. 17, 49 54

(1967). 10. Fabricant, C. G., Gillespie, J. H. and Krook, L., Intracellular mineral crystal formation induced by viral

infection of cell cultures, lnJect. Immun. 3, 416 (1971). 11. Fabricant, C. G. and Gillespie, J. H., Identification and characterization of a second feline herpesvirus,

Inject. lmmun. 9, 460-466 (1974). 12. Studdert, M. J., Calicivirus: brief review, Arch. Virol. 58, 157-191 (19783. 13. Povey, R. C., Feline respiratory infections--a clinical review, Can. re1. J. 17, 93 100 (1976). 14. Crandell, R. A., Feline viral rhinotracheitis, Adv. vet. Sci. comp. Med. 17, 201-224 (1973). 15. Wardley, R. C., Gaskell, R. M. and Povey, R. C., Feline respiratory viruses--their prevalence in clinically

healthy cats, J. Small Anita. Pratt. 15, 579-586 (1974). 16. McEwan, P. J. and Miles, J. A. R., An electron microscope study of viruses associated with upper

respiratory tract infections in cats, Proc. Univ. Otago med Sch. 45, 21-23 (1967). 17. Mochizuki, M., Konishi, S. and Ogata, M., Studies on cytopathogenic viruses from cats with respiratory

infections III. Isolation and certain properties of feline herpesviruses, Jap. J. vet. Sci. 39, 27 37 (1977). 18. Horne, R. and Wildy, P., Symmetry in virus architecture, Virology 15, 348 373 (1961). 19. Abraham, A. and Tegtmeyer, P., Morphological changes in productive and abortive infection by feline

herpesvirus, J. Virol. 5, 617 623 (1970). 20. Crandell, R. A. and Hersey, D. F., Cytochemical observations on intranuclear inclusion of feline viral

rhinotracheitis virus, Proc. Soc. exp. Biol. Med. 114, 187 189 (1963). 21. Johnson, R. H., Feline panleucopaenia virus Ill. Some properties compared to a feline herpesvirus, Res. vet.

Sci. 7, 112 115 (19663.


22. Crandell, R. A. and Weddington, G. R., Effects of nucleic acid analogues on the multiplication and cytopathogenicity of feline viral rhinotracheitis virus in vitro, Cornell Vet. 57, 38-42 (1967).

23. Darlington, R. W. and Moss, L. H. III, The envelope of herpesvirus, Prog. Med. Virol. 11, 16-45 (1969). 24. Miller, G. W. and Crandell, R. A., Stability of the virus of feline viral rhinotracheitis, Am. J. vet. Res. 23,

351-353 (1962). 25. Horvath, Z., Bartha, A., Papp, L. and Juhasz, M., On feline rhinotracheitis, Acta vet. hung. 15, 415-420

(1965). 26. Bartholomew, P. T. and Gillespie, J. H., Feline viruses. 1. Characterization of four isolates and their effect

on young kittens, Cornell Vet. 58, 248 265 (1968). 27. Tegtmeyer, P. and Enders, J. F., Feline herpesvirus infection in fused cultures of naturally resistant human

cells, J. Virol. 3, 469-476 (1969). 28. Povey, R. C., Viral-induced respiratory disease of cats, Ph.D. Thesis, University of Bristol 1970. 29. Povey, R. C. and Johnson, R. H., A standardized serum neutralization test for feline viral rhinotracheitis. 1.

Virus assay, J. comp. Path. 79, 379-385 (1969). 30. Slater, E. and York, C., Comparative studies on parenteral and intranasal inoculation of an attenuated

feline herpesvirus, Devl biol. Stamlard. 33, 410-416 (1976). 31. Davis, E. V. and Beckenhauer, W. H., Studies on the safety and efficacy of an intranasal feline

rhinotracheitis-calici virus vaccine, Vet. Med. small Anon. Clin. 71, 1405-1410 (1976). 32. Povey, R. C. and Johnson, R. H., A standardized serum neutralization test for feline viral rhinotracheitis, II.

The virus-serum system, J. comp. Path. 79, 387-392 (1969). 33. Donaldson, A. I. and Ferris, N. P., The survival of some air-borne animal viruses in relation to relative

humidity, Vet. Microbiol. 1, 413-420 (1976). 34. Gillespie, J. H., Judkins, A. B. and Scott, F. W., Feline viruses XII. Hemagglutination and hemadsorption

tests for feline herpesvirus, Cornell vet. 61, 159-171 (1971). 35. Mochizuki, M., Konishi, S. and Ogata, M., Studies on cytopathogenic viruses from cats with respiratory

infections IV. Properties of hemagglutinin in feline herpesvirus suspensions and receptors on feline erythrocytes, Jap. J. vet. Sci. 39, 389-395 (1977).

36. Lee, K. M., Kniazeff, A. J., Fabricant, C. G. and Gillespie, J. H., Utilization of various cell culture systems for propagation of certain feline viruses and canine herpesvirus, Cornell Vet. 59, 539-547 (1969).

37. Langloss, J. M., Hoover, E. A., Kahn, D. E. and Kniazeff, A. J., In vitro interaction of alveolar macrophages and pneumocytes with feline respiratory viruses, Infect. lmmun. 20, 836-841 (1978).

38. Ebner, F. F. and Crandell, R. A., Growth of feline viral rhinotracheitis virus in cultures of feline renal cells, Proc. Soe. exp. Biol. Med. 105, 153-156 (1960).

39. Wardley, R. C., Rouse, B. T. and Babiuk, L. A., Observations on recovery mechanisms from feline viral rhinotracheitis, Can. J. comp. Med. 40, 257 264 (1976).

40. Darlington, R. W. and Granoff, A., Replication--Biological aspects. In The Herpesviruses, Kaplan, A. S. (ed.), p. 103. Academic Press, New York (1973).

41. Scott, F. W., Csiza, D. K. and Gillespie, J. H., Feline viruses. IV. Isolation and characterization of feline panleukopenia virus in tissue culture and comparison of cytopathogenicity with feline picornavirus, herpesvirus, and reovirus, Cornell Vet. 60, 165-183 (1970).

42. Crandell, R. A., Ganaway, J. R., Niemann, W. H. and Maurer, F. D., Comparative study of three isolates with the original feline viral rhinotracheitis virus, Am. J. vet. Res. 21,504-506 (1960).

43. Poste, G., Virus-induced polykaryocytosis and the mechanism of cell fusion, Adv. Virus, Res. 16, 303-356 (1970).

44. Poste, G., Cell surface changes in virus-induced cell fusion, 2. Changes in cell coat thickness, Microbios 3, 55-61 (1971).

45. Cowdry, E. V., The problem of intranuclear inclusion in virus diseases, Archs Path. 18, 527-534 (1934). 46. Watson, D. H., Replication of the viruses--morphological aspects. In The Herpesviruses, Kaplan, A. S.

(ed.), p. 133. Academic Press, New York (1973). 47. Johnson, R. H. and Thomas, R. G., Feline viral rhinotracheitis in Britain, Vet. Rec. 79, 188-190 (1966). 48. Bittle, J. L., York, C. J., Newberne, J. W. and Martin, M., Serologic relationship of new feline

cytopathogenic viruses, Am. J. vet. Res. 21, 547-550 (1960). 49. Studdert, M. J. and Martin, M. C., Virus diseases of the respiratory tract of cats. 1. Isolation of feline

rhinotracheitis virus, Aust. vet. J. 46, 99-104. 50. Metianu, T. and Virat, J., Etude de huit souches virales isol~s de chats atteints de rhinotracheitis

infectieuse, Reel. Mkd. Vbt. 150, 113-119 (1974). 51. Yoshino, K. and Taniguchi, S., The appearance of complement requiring neutralizing antibodies by

immunization and infection with herpes simplex virus, Virology 22, 193-201 (1964). 52. Mochizuki, M., Konishi, S. and Ogata, M., Serodiagnostic aspects of feline herpesvirus infection, Jap. J. vet.

Sci. 39, 191-194 (1977).


53. Tan, R. J. S., Serological comparisons of feline respiratory viruses, Jap. J. med. Sci. Biol. 23, 419 424 (1970). 54. Plummer, G., Serological comparisons of the herpesviruses, Br. J. exp. Pathol. 45, 135 141 (1964). 55. Pauls, F. P. and Dowdle, W. R., A serologic study of Herpesvirus hominis strains by microneutralization

tests, J. Immunol. 98, 941 947 (1967). 56. Bittle, J. L. and Rubic, W. J., Studies of feline viral rhinotracheitis vaccine, Vet. Med. small Anita. Clin.,

1503-1505 (1974). 57. Bittle, J. L. and Rubic, W. J., A feline calicivirus vaccine combined with feline viral rhinotracheitis and feline

panleukopenia vaccine, Feline Practice, 13 15 (1975). 58. Edwards, B. G., Buell, D. J., Acree, W. M. and Payne, J. B., Evaluation of feline rhinotracheitis/feline

panleukopenia combination vaccines by consecutive virulent challenge, Feline practice 7, 45-50 (1977). 59. Carlson, J. H. and Scott, F. W., An immunofluorescent diagnostic test for feline viral rhinotracheitis, Am. J.

vet. Res. 39, 465-467 (1978). 60. Povey, R. C. and Johnson, R. H., A survey of feline viral rhinotracheitis and feline picornavirus infection in

Britain, J. small Anita. Pratt. 12, 233-247 (1971). 61. Walton, T. E. and Gillespie, J. H., Feline viruses. VI. Survey of the incidence of feline pathogenic agents in

normal and clinically-ill cats, Cornell Vet. 60, 215 232 (1970). 62. Jensen, M. M., Buell, D. J. and McKim, R. M., Isolation rates of feline respiratory viruses in local cat

populations, J. small Anita. Pract. 18, 659 661 (1977). 63. Folkers, C. and Hoogenboom, A. M. M., Intranasal vaccination against upper respiratory tract disease

(URD) in the cat--1. Virological and serological observations in cats suffering from URD, Comp. Immun. Microbiol. in/eet. Dis. 1, 37 41 (1978).

64. Boever, W. J., McDonald, S. and Solorzano, R. F., Feline viral rhinotracheitis in a colony of clouded leopards, Vet. Med. small Anim. Clin. 72, 1859-1866 (1977).

65. Tan, R. J. S. and Miles, J. A. R., Further studies on feline respiratory virus diseases. 2. lmmunodiffusion tests, N.Z. vet. J. 19, 15 18 (1971).

66. Gass, H., Virusschnupfen bei Geparden, Kleintier-Prax. 19, 97-98 (1974). 67. Gaskell, R. M. and Povey, R. C., The dose response of cats to experimental infection with feline viral

rhinotracheitis virus, J. comp. Path. in press. 68. Hoover, E. A., Rohovsky, M. W. and Griesemer, R. A., Experimental feline viral rhinotracheitis in the

germ-free cat, Am. J. Path. 58, 269 282 (1970). 69. Crandell, R. A., Rehkemper, J. A., Niemann, W. H., Ganaway, J. R. and Maurer, F. D., Experimental

feline viral rhinotracheitis, J. Am. vet. med. Ass. 138, 191 196 (1961). 70. Gaskell, R. M. and Povey, R. C., Sites of feline viral rhinotracheitis replication and persistence in acutely

and persistently infected cats, Res. vet. Sci. in press. 71. Lindt, S., Muhlethaler, E. and Burki, F., Enzootischer, virusbedingter Katzenschnupfen in cinem Tierheim.

1. Klinik, Patho-Histologie, Atiologie and Epizootologie, Schweizer Arch. Tierheilk 107, 91 101 (1965). 72. Hoover, E. A. and Griesemer, R. A., Experimental feline herpesvirus infection in the pregnant cat, Am. J.

Path. 65, 173 184 (1971). 73. Hoover, E. A. and Griesemer, R. A., Bone lesions produced by feline herpesvirus, Lab. Invest. 25, 457-464

(1971). 74. Walton, T. E., Feline herpesvirus: in vivo and in vitro studies including a microbiological survey of the

domestic cat (Felis domesticus), Ph.D. Thesis, Cornell University (1968). 75. Bittle, J. L. and Peckham, J. C., Genital infection induced by feline rhinotracheitis virus and effects on

newborn kittens, J. Am. vet. med. Ass. 158, 927-928 (1971). 76. Karpas, A. and Routledge, J. K., Feline herpesvirus: isolations and experimental studies, Zentbl. VetMed. B

15, 599 606 (1968). 77. Cotter, S. M., Hardy, W. D. and Essex, M., Association of feline leukemia virus with lymphosarcoma and

other disorders in the cat, J. Am. vet. med. Ass. 166, 449-454 (1975). 78. Spradbrow, P. B., Carlisle, C. and Watt, D. A., The association ofa herpesvirus with generalized disease in a

kitten, Vet. Rec. 89, 542 544 (1971). 79. Bistner, S. I., Carlson, J. H., Shively, J. N. and Scott, F. W., Ocular manifestations of feline herpesvirus

infection, J. Am. vet. med. Ass. 159, 1223-1237 (1971). 80. Bodle, J. E., Feline herpesvirus infection, Survey Ophth. 21, 209 215 (1976). 81. Love, D. N., Feline herpesvirus associated with interstitial pneumonia in a kitten, Vet. Rec. 89, 178-181

(1971). 82. Shields, R. P. and Gaskin, J. M., Fatal generalized feline viral rhinotracheitis in a young adult cat, J. Am.

vet. reed. Ass. 170, 439-441 (1977). 83. Johnson, R. P. and Sabine, M., The isolation of herpesviruses from skin ulcers in domestic cats, Vet. Rec. 89,

360-363 (1971).


84. Povey, R. C. and Johnson, R. H., Observations on the epidemiology and control of viral respiratory disease in cats, J. small Anita. Praet. 11,485 494 (1970).

85. Gaskell, R. M., Feline viral rhinotracheitis with particular reference to the carrier state, Ph.D. Thesis, University of Bristol (1975).

86. Povey, R. C. and Johnson, R. H., Further observations on feline viral rhinotracheitis, Vet. Ree. 81,686-689 (1967).

87. Plummer, G., Hollingsworth, D. C., Phuangsab, A. and Bowling, C. P., Chronic infections by herpes simplex viruses and by the horse and cat herpesviruses, lnlect. Immun. 1, 351 355 (1970).

88. Gaskell, R. M. and Povey, R. C., Experimental induction of feline viral rhinotracheitis virus re-excretion in FVR-recovered cats, Vet. Ree. 100, 128 133 (1977).

89. Stevens, J. G. and Cook, M. L., Latent herpes simplex virus in sensory ganglia. In Persistent virus in/ections." Perspectives in Virology, VIII. Pollard, M. (ed.). Academic Press, New York (1973).

90. Okoshi, S., Tomoda, I. and Makimuru, S., Analysis of normal cat serum by immunoelectrophoresis, Jap. J. vet. Sci. 29, 337 (1968).

91. Edwards, B. G., Buell, D. J. and Acree, W. M., Evaluation of a new feline rhinotracheitis virus vaccine, Vet. Med. small Anim. Clin. 72, 205 209 (1977).

92. Glasgow, L. A. and Galasso, G. J. (Eds), Isoprinosine: lack of antiviral activity in experimental model infections, J. in/L Dis. 126, 162-169 (1972).

93. Povey, R. C., In vitro antiviral efficacy of ribavirin against feline calicivirus, feline viral rhinotracheitis virus, and canine parainfluenza virus, Am. J. vet. Res. 39, 175 178 (1978).

94. Roberts, S. R., Dawson, C. R., Coleman, V. and Togni, B., Dendritic keratitis in a cat, J. Am. vet. med. Ass. 161,285 289 (1972).

95. Tan, R. J. S. and Miles, J. A. R., Further studies on feline respiratory virus diseases. 1. Vaccination experiments, N.Z. vet. J. 19, 12-15 (1971).

96. Scott, F. W., Evaluation of a feline viral rhinotracheitis vaccine, Feline Practice 5, 17-22 (1975). 97. Scott, F. W., Evaluation of a feline viral rhinotracheitis-feline calicivirus disease vaccine, Am. J. vet. Res. 38,

229-234 (1977). 98. Wilson, J. H. G., Intranasal vaccination against upper respiratory tract disease (URD) in the cat. II. Results

of field studies under enzootic conditions in the Netherlands with a combined vaccine containing live attenuated calici- and herpesvirus, Comp. lmmun. Microbiol. inject. Dis. 1, 43-48 (1978).

99. Povey, R. C., Feline respiratory disease which vaccine?, Feline practice 7, 12 16 (1977). 100. Povey, R. C. and Wilson, M. R., A comparison of inactivated feline viral rhinotracheitis and feline caliciviral

disease vaccines with live-modified viral vaccines, Feline practice 8, 35-42 (1978). 101. Orr, C. M., Gaskell, C. J. and Gaskell, R. M., Interaction of a combined feline viral rhinotracheitis-feline

calicivirus vaccine and the FVR carrier state, Vet. Rec. 103, 200-202 (1978). 102. Bittle, J. L. and Rubic, W. J., lmmunogenic and protective effects of the F-2 strain of feline viral

rhinotracheitis virus, Am. J. vet. Res. 36, 89 91 (1975). 103. Brehaut, L., Jones, R. H., McEwan, P. J. and Miles, J. A. R., Viruses associated with feline respiratory

disease in Dunedin, N.Z. vet. J. 17, 82 86 (1969). 104. Doi, K., Kojima, A., Inami, Y., Yasoshima, A. and Okawa, H., Feline viral rhinotracheitis in Japan--

Isolation of herpes type virus and pathologic picture, Jap. J. vet. Sci. 37, 281 292 (1975). 105. Engel, G. Y., Herpes corneae bei Katzen, Kleintier-Prax. 19, 255 258 (1974). 106. Fabricant, C. G., Herpesvirus-induced urolithiasis in specific-pathogen-free male cats, Am. J. vet. Res. 38,

1837 1842 (1977). 107. Lindt, S., Zur Morphologie und Atiologie der Erkrankungen des oberen Respirationstraktes bei Katzen,

Schweizer Arch. Tierheilk. 107, 196-203 (1965). 108. Milek, M., Wooley, R. E. and Blue, J. L., Replication of feline herpesvirus and feline calicivirus in cell and

organ culture, Am. J. vet. Res. 37, 723-724 (1976). 109. Steffenhagen, K. A., Easterday, B. C. and Galasso, G. J. (Eds), Evaluation of 6-Azauridine and 5-

Iododeoxyuridine in the treatment of experimental viral infections, J. inlect. Dis. 133, 603-612 (1976). 110. Thompson, N. L., Sabine, M. and Hyne, R. H. J., Herpesviruses isolated from cheetahs, Aust. vet. J. 47, 458

(1971). 111. Walton, T. E. and Gillespie, J. H., Feline viruses. VII. Immunity to the feline herpesvirus in kittens

inoculated experimentally by the aerosol method, Cornell Vet. 60, 232-239 (1970).

a review of feline viral rhinotracheitis (feline herpesvirus i infection)

Documents