Diagnosing and managing feline respiratory disease (Proceedings)

Acute upper respiratory tract disease (URTD) is a source of major morbidity and, less frequently, mortality in the domestic cat. It has been reported to be a major financial burden (Foley and Bannasch 2004) and a leading cause of euthanasia in shelters (Pedersen et al 2004). The syndrome is characterized by nasal discharge, conjunctivitis, ocular discharge, sinusitis, dyspnea, coughing, inappetence, lethargy, and in kittens or debilitated animals, death. Many pathogens are associated with the syndrome, including feline herpesvirus-1 (FHV-1), feline calicivirus (FCV), Chlamydophila felis, and Bordetella bronchiseptica. Additionally, several species of Mycoplasma have been isolated from cats with URTD (Campbell et al 1973, Haesebrouck et al 1991, Johnson et al 2004, Tan et al 1977), however, the role of this group of organisms as primary pathogens in respiratory disease remains contentious, as, similar to the above pathogens, some studies have isolated Mycoplasma species from the respiratory tract of healthy cats at a frequency similar to that found in cats with URTD (Foster et al 2004b, Haesebrouck et al 1991, Tan et al 1977, Tan and Miles 1974).

As expected, the relative frequency of organisms associated with URTD in cats varies from study to study. This fact can be attributed to differences in entry criteria (conjunctivitis compared to nasal discharge), geographic distribution, populations sampled (shelter vs. privately owned), detection methods (microbiological culture compared to nucleic acid amplification), and anatomic sampling site. Additionally, most studies to date have examined only a single class of pathogens (i.e. viral or bacterial), pathogens detected by a single detection method (virus isolation or nucleic acid detection), or a single sampling site (nasal, pharyngeal, or ocular), making identification of co-infections compared to primary infection and comparisons across studies difficult. Therefore, our laboratory examined the prevalence of all proven primary pathogens (FCV, FHV-1, Chlamydophila) as well as Mycoplasma species in shelter cats with URTD by both microbiologic culture techniques as well as nucleic acid amplification from two anatomic sampling sites (nasal and pharyngeal).

In most prevalence studies of URTD, including the aforementioned study, FHV-1 emerges as a major pathogen. Feline herpesvirus-1 was first identified as an organism associated with URTD in cats by Crandell et al in 1958 after in vitro culture of nasopharyngeal swabs from both diseased and healthy cats resulted in characteristic cytopathic effects in host feline cells. Primary sites of replication are epithelial cells, as is typical for the α-herpesviruses. These sites in the cat include corneal epithelial cells, conjunctiva, and nasal and pharyngeal epithelium (Gaskell and Povey 1979). The organism is a cause of neonatal death in cats and can be associated with the chronic sequelae of herpetic stromal keratitis (HSK), which is similar to the disease in man (Stiles 2003). Like herpes simplex virus-1 (HSV-1), the causative agent of HSK, FHV-1 is a classic alpha-herpesvirus and as such, readily establishes neuronal latency in the trigeminal ganglia with an incidence of up to 80% (Gaskell et al 1985, Nasisse et al 1992, Ohmura et al 1993) and can cause disease secondary to reactivation (Gaskell and Povey 1977). Latency is associated with transcription of short RNA transcripts termed latency associated transcripts (LAT) in infected neurons in experimentally infected animals (Daheshia et al 1998) and in naturally infected cats (Townsend et al 2004). This makes detection and isolation or removal of carriers difficult. Additionally, the virus is easily spread from cat to cat (Pedersen et al 2004) making spread of the virus from stressed, reactivated carriers to healthy animals in isolation or holding areas of shelters a significant problem. In one shelter study, the prevalence of FHV-1 shedding as detected by virus isolation increased from just 4% at admission to over 50% after just one week of housing at the shelter (Pedersen et al 2004).

As with all of the primary pathogens, prevalence rates of FHV-1 vary depending on sampling site and method of detection. Studies have reported detection rates of FHV-1 in healthy cats ranging between 0 and 31% and the organism has been detected in up to 69% of cats with nasal discharge as a component of their URTD (Bannasch and Foley 2005, Holst et al 2005, Pedersen et al 2004, Rampazzo et al 2003a, Sykes et al 1999). Despite these high rates of detection in affected animals, a recent study has demonstrated that the mere detection of FHV-1 DNA by polymerase chain reaction (PCR) is not significantly correlated with disease (Rampazzo et al 2003b) given the high rate of detection in healthy animals. Correspondingly, there was no significant difference in detection of infection with FHV-1 by virus isolation (VI), the immunofluorescent antibody assay (IFA), or seroprevalence in normal cats, cats with acute URTD or conjunctivitis, or chronically infected cats (Maggs et al 1999). Confusing interpretation of test results even further, several studies have demonstrated that many commonly used PCR protocols for FHV-1 are capable of detecting FHV-1 in widely available and utilized commercial vaccines (Lappin et al 2006, Maggs and Clarke 2005, Weigler et al 1997) both in vivo and in vitro. In a review of FHV-1 diagnosis and pathogenesis, possible reasons for a positive result for FHV-1 by PCR were characterized as: 1) coincidental, 2) consequential (recrudescence secondary to a primary disease), and 3) causal (recrudescence is the primary disease) (Maggs 2005). For these reasons, a positive result by any method of detection cannot be used as the sole means of diagnosis.

The exact protective immune responses in α-herpesvirus infections are unknown, either in man or cat. However, previous studies initially focused on maximizing antibody responses in the development of vaccines for HSV, perhaps because glycoprotein specific neutralizing antibodies reduced mortality and even protected from infection in some animal models in passive immunity studies (Rajcani and Durmanova 2006) and antibodies specific for glycoprotein D are able to neutralize the virus in vitro. However, one author suggested a compelling argument against the importance of humoral immunity by pointing out that there is a significantly increased presence of disease in patients lacking cell-mediated immunity (AIDS, immunosuppression secondary to organ transplantation) but not in patients that are agammaglobulinemic (Krause and Straus 1999).

Because of the possibility of lifelong infection with periodic recrudescences, shedding, and spread to other cats as well as the confounding nature of diagnostics associated with FHV-1, prevention from infection would be ideal. Vaccination for FHV-1 has been widely administered for decades and has been shown to decrease severity of clinical signs in experimentally infected cats when challenged (Scott and Geissinger 1999). However, vaccination with currently available products does not prevent establishment of latency (Weigler et al 1997) and vaccine efficacies do not approach 100% as they do for panleukopenia, another component of multivalent "kittenhood" vaccines. The ideal vaccine would completely prevent infection and subsequent latency and this has been attempted by using both killed (Scott and Geissinger 1999, Tham and Studdert 1987) and gene deleted or subunit vaccines (Yokoyama et al 1996). However, as with all vaccines of these types studied to date, severity of clinical signs on challenge can be reduced but signs were still present but whether the latent state was prevented is unknown.

In some cats with URTD, clinical signs continue for prolonged periods of time and may develop into the chronic rhinitis-sinusitis syndrome (CRS). Clinical signs are similar to those in URTD and include nasal discharge, sneezing, anorexia, ocular discharge, and unlike most URTD, can progress to severe turbinate destruction. Treatment of these animals is frequently unrewarding and frustrating for owners and clinicians. Transient responses to antimicrobials are common, but relapses are frequent. Similar to URTD, the syndrome probably has many etiologies and as such, the role of individual organisms has been hard to define. In the only prospective study of the prevalence of bacteria, viral, and fungal organisms in the literature there was no statistically significant difference in the rate of detection of FHV-1 between the disease and control groups (Johnson et al 2005). However, the study was limited in the numbers of animals available to be enrolled in the study and quantitative data regarding viral DNA was not available. Additionally, given the role of FHV-1 in acute disease, the sequelae of turbinate destruction in experimentally induced FHV-1 infection, and the ability of the virus to produce lifelong infection with either chronic clinical signs or intermittent relapses, FHV-1 would seem to be a logical organism to investigate as an etiologic agent in CRS.

As previously noted, FHV-1 is not the only organism commonly detected in cats with URTD. Viral infections and mycoplasmal infections are often implicated as well. Diagnosis of these infections in the single animal is different than from a "herd health" perspective as is encountered in the shelter situation. Some agents have a clear cause and effect relationship established, such as feline calicivirus or Bordetella bronchiseptica.