ACUTE INFECTIOUS UPPER RESPIRATORY TRACT (URT) DISEASE

Séverine Tasker, BSc (hons) BVSc (hons) DSAM PhD DipECVIM-CA FHEA FRCVS
Chief Medical Officer, Linnaeus Veterinary Limited & Honorary Professor of Feline Medicine,
Bristol Veterinary School, University of Bristol, Langford, Bristol BS40 5DU, United Kingdom
s.tasker@bristol.ac.uk

Key Points:
• Diagnosis of the cause of acute infectious URT disease may not be required in many cases,
especially in individual cats, as the diagnosis may not affect the treatment given
• Supportive care for the treatment of acute infectious URT disease is extremely important;
nutrition, hydration, nebulisation
• Antibiotics are not needed in many cases of infectious URT DISEASE, unless secondary
bacterial infections are present and worsening clinical signs (i.e. withholding
antibiotics in the immediate period that clinical signs have developed, to see if self-
resolution occur, is preferable) or if a primary bacterial infection (Chlamydia felis,
Bordetella bronchiseptica and maybe Mycoplasma felis) is present. Use of 7-10 days
of oral doxycycline as 1st line antibiotic treatment is recommended when antibiotics
are needed: follow with food and water
• Famciclovir is likely to be useful for feline herpesvirus associated disease – use 90 mg/kg
PO q8h if possible but this dosage q12h is a very acceptable alternative (compliance,
cost)
• Be aware of feline calicivirus-virulent systemic disease so that you can act promptly:
facial/paw subcutaneous oedema, ulceration of face, pinnae and limbs, icterus,
nasal/GIT haemorrhage, pancreatitis, pneumonia with or without URT disease signs

Agents Responsible for Feline infectious URT disease

Several agents contribute to infectious upper respiratory tract (URT) disease (also known as
cat flu); feline herpesvirus (FHV-1) and feline calicivirus (FCV) (Table 1) are most commonly
involved, but Mycoplasma spp., Bordetella bronchiseptica, Streptococcus canis1 and
Streptococcus equi subsp zooepidemicus2 can also act as primary pathogens. Importantly, all
of these agents can be found in healthy cats, not associated with disease, causing dilemmas
in diagnosis. Chlamydia felis can also act as a primary pathogen but ocular signs dominate.
Secondary bacterial infections are also common e.g. Staphylococcus spp., Streptococcus spp.,
Pasteurella multocida, Escherichia coli and various anaerobes. These can all also be cultured
from the URT of healthy cats. Mycoplasma spp. and B. bronchiseptica are occasionally
associated with URT disease and Mycoplasma spp. are more likely to be associated with
lower respiratory tract signs.

In URT disease, primary bacterial disease is thought to be less common than bacterial
infections secondary to viral infections such as FHV-1 and FCV.
Acute and chronic URT disease is seen in cats; acute is defined as clinical signs being of ≤10
days in duration whereas chronic URT disease is >10 days in duration3.

These notes will focus on acute infectious URT disease.

Table 1: Summary of the features of feline herpesvirus (FHV-1) and feline calicivirus (FCV) is
shown; good reviews are available to consult from the European Advisory Board of Cat
Diseases (ABCD):4-6
FHV-1 FCV
Type of virus Enveloped DNA virus Unenveloped RNA virus
All strains belong to one serotype (very Considerable variation between strains but
Serotype small differences between different sufficient cross-reactivity between strains to be
isolates) – all FHV-1 classed as one serotype
Labile (fragile) - survives a maximum of 18 Fairly labile but generally can survive 7-10 days.
Survival hours (damp conditions only). Relatively In dry conditions can survive up to a month.
unstable as an aerosol Survival may vary with strain7
Incubation
~2-6 (up to 10) days for both FHV-1 & FCV
period
Assumed to be lifelong, with FHV-1 residing FCV persists in oropharyngeal and tonsillar
in neuronal tissue (trigeminal ganglia – tissue; many cats are long term carriers with
Carrier state
latent infection remains here) of all infected around 10% persistently infected whilst others
cats undergo repeated cycles of re-infection
Shedding 1-3 weeks of shedding post-infection with Usually at least 30 days but may be lifelong.
period intermittent reactivation of shedding from Shedding is continuous, c.f. latency seen with
latency due to stress such as cattery or vet FHV-1
visit/illness/pregnancy/immunosuppression
or can be spontaneous. Reactivation may or
may not be associated with clinical signs. If
clinical signs occur, they are often less
severe than with primary infection and
usually unilateral and ocular in nature
Inactivated by 1:32 dilution of 5.25% sodium hypochlorite (bleach) in water - need to ensure
use detergent first to clean away organic matter and then sodium hypochlorite for 10-minute
Disinfection
minimum contact time. NB. FCV more resistant than FHV; check that disinfectant is effective7,8
– see comments later regarding management of FCV-Virulent Systemic Disease

Prevalence
FHV-1 and FCV are widespread in the general cat population with increased prevalence in
multicat households, shelters and in younger cats. Clinical disease is most severe in kittens
and immunocompromised cats, and in cases of FCV-virulent systemic disease (FCV-VSD; see
later). Around 10% of household pets and 25-75% of shelter or colony cats are positive for
FCV; large number of strains can be found in rescue shelters9 and boarding catteries, where
lots of cats are potentially mixing from different backgrounds. In contrast in a more stable
breeding cattery or multicat household, with endemic FCV infection, less diversity (generally
1-2) of FCV strains occur and the higher prevalence of FCV seen in these settings is attributed
to recirculation and cycles of infection between multiple cats in close contact9. In a smaller
household setting with fewer cats, the lower prevalence of FCV is due to decreased
opportunity for reinfection. Recent studies10,11 found that cats living in groups/multicat
households were more likely to be shedding or infected with FCV. No association was found
in an Australian study between socioeconomic status and the prevalence of FCV or FHV-1
infection, which contrasted with findings for FIV infection in the same study12. Young cats
are more likely to be affected with infectious URT disease13. The prevalence of C. felis,
Mycoplasma spp. and Bordetella bronchiseptica tend to be lower than for FHV-1 and FCV,
but variations exist13.

Transmission
Transmission occurs (Table 1) via direct contact with ocular or oronasal secretions, usually
via contact with a clinically affected or asymptomatic carrier cat, or via indirect transmission
on fomites or in the environment (FCV is more likely to be transmitted this way c.f. FHV-1).
Infection occurs via the nasal, oral, and conjunctival surfaces with viral replication taking
place in the mucosa of the oral cavity and respiratory tract. Similar routes of transmission
exist for C. felis and B. bronchiseptica, although C. felis is very labile. Interestingly, one
experimental study14 has also reported the successful transmission of FCV to kittens via
contact with fleas or flea faeces.

Clinical Signs
Typical signs of acute URT disease/cat ‘flu are pyrexia, sneezing, conjunctivitis (hyperaemia,
chemosis), oculonasal discharge (initially serous then mucopurulent as secondary bacterial
infections occur → crusting of external nares and eyelids), depression, inappetence,
dehydration, salivation with drooling (FHV-1>FCV), oral ulcers (FCV>FHV-1) and ulcerative
keratitis (FHV-1). Occasionally we see ulcerated/erosive facial skin lesions with FHV-1. FHV-1
can cause more severe URT disease, especially in young kittens15, whilst FCV-associated
disease tends to be milder, except for FCV-VSD. Disease manifestation varies in severity and
manifestation depending on the FCV strain involved4. Generally, no association has been
demonstrated between FCV outer capsid gene sequences (which code for the
likely immunodominant capsid proteins) and/or antigenic characteristics and different FCV
disease manifestations9,16. Similarly no specific mutations association with FCV-VSD have
been discovered17,18; one study on FCV-VSD strains showed some potential differentiating
properties of part of the capsid protein19, but no such differentiation was found in a
subsequent study18.

Clinical Signs of FHV-1

• Acute URT disease (rhinotracheitis) – as described above, oral and nasal discharge,
sneezing, pyrexia, lethargy, inappetance ± ocular involvement. Gagging and retching may
occur due to pharyngitis
• Ocular disease20 – ophthalmia neonatorum, conjunctivitis and keratitis (dendritic
[branching] ulcers, when seen, are pathognomonic for FHV-1, however these very
superficial epithelial ulcers are often missed as they are transient and occur early
following infection or reactivation of infection before rapidly coalescing to form
geographic ulcers; chronic stromal keratitis is also seen with FHV-1 as an immune-
mediated reaction), and if conjunctival ulceration occurs concurrently with ulcerative
keratitis, symblepharon formation is possible (when adhesions occur of the conjunctiva
against each other or with cornea; affects mobility of third eyelid and eye lids and may
also obliterate the lower tear puncta leading to epiphora). Corneal sequestrum,
keratoconjunctivitis sicca (KCS), eosinophilic conjunctivitis and keratitis, and uveitis
may all be associated with FHV-1. Ocular damage due to FHV-1 has varied
pathophysiological mechanisms21: immunopathological (i.e., immune-mediated, but not
necessarily autoimmune e.g. herpetic stromal keratitis or eosinophilic keratitis), cytolytic
(i.e. ulcerative) or metaherpetic (i.e. resulting from structural tissue damage subsequent
to cytolytic or immunopathologic disease e.g. KCS). A black colouration of discharge
around the eyes may be seen with FHV-1
• Ulcerative dermatitis - eosinophilic dermatitis of nasal planum and face, but also on
other sites of body; ulceration of the nose and eye is more often associated with FHV-1
in acute infectious URT disease. Non-facial involvement has been reported; unilateral
pinna 22 and flank23
• Rarely bronchopneumonia24 – more likely if a very young kitten or immunocompromised
cat is infected → coughing & dyspnoea. Kittens with FHV-1 associated pneumonia have
been shown to often have concurrent FCV infection too, with FCV involvement in the
pathogenesis of pneumonia25
• Oral ulceration is rare with FHV-1 (more common with FCV)
• Severe non-suppurative meningoencephalitis has been described in one kitten26
• Reproductive failure – considered to be the effect of systemic illness as opposed to direct
effect of FHV-1 causing abortion
• Chronic rhinosinusitis sequelae – FHV-1 has an osteolytic effect in nasal turbinates and
can cause permanent mucosal and bone changes, which may predispose to secondary
bacterial infections

Clinical Signs of FCV

• Wide range of FCV disease phenotype due to the variation in FCV strain virulence and
host factors including route of exposure, dose of FCV, age, vaccination status and
immune status – spectrum of disease18
• Acute URT disease – as described above; oral, ocular and nasal discharge – may also
have lethargy, pyrexia, inappetence etc.
• Oral ulceration – begins as vesicles, which rupture and heal over 2-3 weeks, usually
lingual but can also be elsewhere in the mouth, on the lips or nose
• Skin ulceration is rare but can see ulceration of the nasal philtrum
• Corneal ulceration has rarely been reported in FCV-infected cats27, but is far more
common with FHV-1
• Pneumonia rare too – more likely if a very young kitten or immunocompromised cat is
infected and can occur secondary to FHV-1 associated pneumonia25
• Recently FCV has been isolated from cats with enteritis28, but more work is required to
determine if FCV can truly act as an enteric pathogen

Lameness (FCV polyarthritis/transient limping syndrome)29 – pyrexia and acute transient

lameness seen ± URT disease signs; the lameness can be severe and may shift quickly from
one limb to another. Full recovery usually occurs within 24-48 hours without treatment, but
NSAIDs may be useful. Due to acute synovitis, with immune complexes believed to play a
role and FCV antigen has been demonstrated in synoviae in affected cats29. Some cases of
transient limping syndrome develop following vaccination with modified live vaccines, but
investigations usually find that the FCVs causing the lameness are strains acquired from the
field i.e. from other cats, and not the vaccine strains i.e. vaccination was incidental and not
the cause of the limping syndrome.

Feline chronic gingivostomatitis (FCGS): An excellent review on periodontal disease and

FCGS has been published30, and this cautions that severe gingivitis in a cat infected with FCV
does not automatically provide for a diagnosis of FCGS – the inflammation in FCGS, by
definition, extends beyond the mucogingival junction to encompass the alveolar mucosa and
other soft tissues – if the inflammation is confined to gingival tissues, by definition a
diagnosis of FCGS cannot be made. The prevalence of this condition has been estimated at
0.7% of consultations in first opinion practice in the UK.

The aetiology of FCGS remains uncertain and the disease has not been reproduced in
experimental studies. Several infectious agents can be associated with FCGS. In a prospective
study, FCV was more commonly detected by RT-PCR in 52 cats with FCGS (54%) than in 50
healthy age-matched control cats (24%)31. Similar results were found in a study investigating
42 oral biopsies of cats with FCGS (40% RT-PCR FCV positive versus none of the 19
controls)32. Additional studies confirmed these observations in a larger population of cats in
Spain (n = 260 cats with FCGS, 59% FCV-positive versus 98 controls, 15% FCV-positive33; and
in cats in Japan34. Likewise, using unbiased metagenomic and transcriptomic analyses of 23
cats with FCGS and 19 control cats, the only microbe strongly associated with FCGS was
FCV35. However, in FCV-infected cats with FCGS, FCV RNA loads were not associated with
disease severity36 and no FCV was found in the FCGS lesions of 26 cats examined by
immunohistochemistry37. Thus, FCGS is likely to be a multifactorial disease.

It has been suggested that FCGS is an immune-mediated reaction to FCV and potentially
other oral antigens. Experimental infection of FCV isolates from cats with different acute or
chronic respiratory disease or from cats with chronic oral lesions into kittens induced acute
 disease with fever, apathy, oral ulcers, gingivitis, rhinitis and/or conjunctivitis, indicating that
chronicity is probably more related to the host immune response than to any particular
biotype of FCV38. FCV does not appear to play a role in feline odontoclastic resorptive
lesions39.

FCV-virulent systemic disease (FCV-VSD) – this is an uncommon but important syndrome to

recognize. It is usually highly contagious within a group of cats, and nosocomial infections
are commonly described. Often associated with shelter cats moving into another population;
could be because high levels of replication of normal strains of FCV in large groups of cats in
shelters provide suitable conditions for hypervirulent FCVs to emerge (it is possible that such
populations with higher levels of immunity support emergence of hypervirulent strains, and
within that population there is a matched immune response to those FCVs, preventing
expression of FCV-VSD, but when such FCVs gain access to naïve cat populations that have
not been previously exposed to them, FCV-VSD can develop). Specific genetic mutations
associated with VSD FCVs have not been found in some analyses17,18 and it is possible that
several mutations are involved. However, some domains on the capsid protein are thought
to influence the faster in vitro growth of virulent FCV isolates40. Analysis of the amino acid
properties of part of the capsid protein (which could affect post-binding events of FCV) did
differentiate FCV-VSD and classical FCV strains in one study19 but not another18.

The diagnosis of FCV-VSD4 outbreaks relies on clinical signs, high contagiousness and high
mortality rate and the isolation of the same strain from the blood of several diseased cats,
assessed by sequencing hypervariable regions of the capsid gene. Samples for RT-PCR can be
collected from the oropharynx or from ulcerated lesions or the blood.

FCV-VSD has been reported in the USA, China41, Australia18 and Europe42, usually in groups43,
but reports in individual cats have also been published44,45 and cases do not always occur in
large outbreaks associated with high contagion17. FCV-VSD is associated with high mortality
(usually ~30-50%, although a mortality rate of 79% was reported in one outbreak43),
especially in adult cats and FCV-VSD can occur in vaccinated cats.

Clinical signs of FCV-VSD include:

• facial and paw subcutaneous oedema • anorexia
• ulceration of face, pinnae & feet/limbs • pneumonia
• bruising • pancreatitis
• pyrexia • signs of sepsis
• icterus (due to hepatic necrosis) • coagulopathy - haemorrhage
• typical URT disease signs
Clinical Signs of Chlamydia felis
C. felis is a common cause of conjunctivitis, especially in young (<1 year) cats46.
Conjunctivitis, ocular discharge (initially serous and unilateral, then mucopurulent and
rapidly bilateral), blepharospasm and chemosis occur but corneal ulceration is not a feature
(Table 2). Occasionally sneezing, nasal discharge and mild respiratory signs occur. Chronic
infection can occur.

Table 2: Ocular clinical signs that can help differentiate Chlamydia felis (C. felis) from feline
herpesvirus (FHV-1) (table adapted from21).

Clinical Signs FHV-1 C. felis

Unilateral involvement Can remain unilateral Usually becomes bilateral
quite quickly
Conjunctival hyperaemia +++ ++
Chemosis + +++
Conjunctival ulceration ± -
Keratitis ± -
Dendritic ulcers When present, pathognomonic for FHV-1 -
Respiratory signs/malaise ++ (primary infection), ± (reactivation of infection) ±

Clinical Signs of Mycoplasma spp.

Mycoplasma spp. are highly pleomorphic, facultative anaerobic, gram negative bacteria that
lack a cell wall. They can be found in the URT of normal cats and can also be associated with
disease, possibly as a result of opportunistic infection following damage by another
pathogen, although sometimes it is the only pathogen identified in clinical cases.
Mycoplasma spp., especially Mycoplasma felis, can cause URT disease and a unilateral or
bilateral conjunctivitis, and an association with URT disease has been reported47.

Clinical Signs of Bordetella bronchiseptica

B. bronchiseptica is gram negative, aerobic, coccobacillus that can be found in the URT of
normal cats and can also be associated with disease, possibly due to opportunistic infection
following damage by another pathogen but it can also act as a primary pathogen. However,
it is rarely identified as the cause of URT disease in cats. B. bronchiseptica can cause ocular
and nasal discharge, sneezing, pyrexia ± coughing48, and pneumonia can be a complicating
factor, especially in younger cats. Risk factors for B. bronchiseptica infection in cats include
living with dogs with respiratory disease and living in multicat households or shelters48.

Carrier Cats
As described in Table 1, all FHV-1 infected cats probably become lifelong carriers; FHV-1
exists in a latent form in nervous tissue (the trigeminal ganglia) and is shed intermittently
following activation e.g. stress due to boarding, travel or relocation49, immunosuppressive
treatment50; such reactivation may, or may not, be accompanied by clinical signs. If clinical
signs occur, they are often less severe than with primary infection and are usually unilateral
and ocular in nature.

Most cats shed FCV following infection (continuously; no latency), but the number shedding
virus progressively decreases over time such that lifelong carrier status and shedding occurs
in only around 10% of cats.

Asymptomatic carriers also exist for B. bronchiseptica and C. felis.

Diagnosis
In an individual cat, identification of the aetiological agent(s) responsible for acute URT
disease is unlikely to be required unless it is particularly severe or recurrent disease.
Aetiological agent determination may be required more often for chronic URT disease cases
that may need more focused management, or when groups or cats are affected and/or again
when clinical signs are particularly severe or recurrent. However, it is likely that FHV-1 is
most likely to be identified in acute URT disease cases, rather than in chronic recurrent
cases, and so failing to identify aetiological agents in early disease may mean cases are
harder to manage due to a lack of finding of FHV-1 in particular.

Assessment of the eyes, in particular looking for evidence of ulceration and dendritic ulcers,
is important to guide treatment but also because dendritic ulcers are pathognomonic for
FHV-1 infection. Evaluation is performed using fluorescein dye – this detects a break in the
epithelium and basement membrane staining the underlying hydrophilic stroma – it also
stains conjunctival erosions and abrasions. Rose Bengal staining is useful to do if fluorescein
staining is negative as it is a more sensitive method of detecting corneal ulceration, staining
tiny areas of non-vital cells. Brush swabs can also be used to take samples for cytology.

Cytology and culture of nasal discharges are of little help in the diagnosis of infectious URT
disease in cats3, neither for confirming bacterial infection nor in helping the choice of
antibiotics, due to the presence of commensals and the difficulty in culturing some of the
bacteria associated with infectious URT disease such as Mycoplasma spp.

Commercial veterinary laboratories offer polymerase chain reaction (PCR) testing for feline
URT disease pathogen DNA and RNA, including FHV-1, FCV (see Table 3) and C. felis. A sterile
cotton-tipped swab with a plastic (not wooden) stem is used to collect samples from the
conjunctival sac and tongue/oropharynx – sampling from more than one site (sequentially,
starting with the conjunctiva) increases sensitivity but an oropharyngeal swab is
recommended if only one site can be sampled51. Most labs advise submission of swabs in
plain sterile tubes without transport medium, although one study on FCV RT-PCR suggested
that transport medium improved sensitivity detection52. Ideally, conjunctival swabs for PCR
should be taken before the use of antibiotics in case of an effect on PCR sensitivity;
 preliminary studies showed little effect of fluorescein and topical anaesthetics on PCR
sensitivity though20,53. A quantitative PCR, determining how much DNA or RNA of a
pathogenic agent is present, can further guide the clinician in the interpretation of a positive
PCR result but must always be interpreted in conjunction with the presenting clinical signs. A
negative result does not rule out infection as sometimes the amount of DNA and RNA
present is below the level of detection of the PCR. Virus isolation (VI) for the detection of
FHV-1 and FCV is available in some laboratories; although it is cheaper than PCR and confirm
the presence of infectious virus, it does take longer than PCR and many laboratories have
stopped offering this methodology. Because of the high number of vaccinated cats (for FHV-
1 and FCV) and the frequency of chronic carrier cats (85% of cats in stray colonies were
antibody positive in a recent Italian study54), serology is not useful in the diagnosis of active
infection. The diagnosis of cases of FCV-VSD usually includes both positive FCV PCR but also
confirmation of the presence of FCV antigen by immunostaining (in specialised veterinary
diagnostic laboratories) in what are otherwise considered unusual tissue sites, such as the
liver17. Immunostaining for FHV-1 and FCV antigen detection is also available25, and can be
useful to confirm aetiology e.g. in skin biopsies23, conjunctival/corneal smears (FHV-1)

Table 3: Summary of diagnostic test methods available for FHV-1 and FCV

Diagnostic Sample Target of the False positive False negative Comments

test test
Virus Swab(s): Whole FHV-1 & Unlikely if good Low level of virus Less commonly used
isolation (VI) oropharyngeal FCV quality controls in samples, co- following development of
(OP) / used in the infection of FCV & PCRs as can take 2-7 days
conjunctival / laboratory FHV-1 (FCV grows for VI results. Swabs
nasal55, or quicker and may submitted in viral
bronchoalveolar mask FHV-1 in cell transport media. Multiple
lavage (BAL) culture due to site swabs may ↑
samples if lower cytolytic effect), likelihood of success of VI
respiratory presence of but positive results
disease antibody in the confirm presence of
sample can replicating virus. Less
neutralize virus in influenced by strain
vitro, poor sample variation c.f. RT-PCR for
quality FCV (see below)

Polymerase As above: FHV-1 (DNA Possibly following Low level of virus Preferred method for
chain swab(s): OP / virus) - some modified live in sample, no detection. Quantitative
reaction conjunctival / PCR assays can virus (MLV) shedding of FHV- PCR may assist
(PCR) nasal, or BAL quantify viral vaccination56,57, 1 if cat in latent interpretation of positive
samples if lower copies present especially with state result as low levels of FHV-
respiratory intranasal 1 may be more suggestive
disease vaccines58, of latent infection. FHV-1
contamination, PCR most likely to be
laboratory error positive during acute URT
disease
Diagnostic Sample Target of the False positive False negative Comments
test test
Reverse- As above: FCV (RNA virus) Possibly following Low level of virus RT-PCR followed by
transcriptase swab(s): OP / - some PCR MLV in sample, large sequencing has been used
(RT)-PCR conjunctival / assays can vaccination56,57, amount of FCV to identify unique virus
nasal (but study quantify viral contamination, strain RNA strains in FCV-VSD and
suggested OP copies present laboratory error sequence vaccine strains implicated
best), or BAL variation means in disease
samples if lower unlikely that all
respiratory strains
disease amplifiable by RT-
PCR52

Serology Serum or Antibodies to Antibodies VN technique - Interpretation following

(Virus plasma FHV-1 or FCV induced by both use of a vaccination & exposure is
neutralization natural infection laboratory FCV complicated; titre does
[VN] or ELISA) & vaccination; strain that is not not necessarily infer level
serological tests neutralised by of immunity in the
can not cat’s antibodies; individual cat if low e.g.
differentiate the VN antibodies can cats can be protected
two take 20-30 days from FCV in absence of
to become detectable VN antibodies4,
detectable after mucosal IgA immunity
primary FHV-1 may be important for FCV
infection & cell-mediated immunity
for FHV-159

As M. felis and B. bronchiseptica can be detected by PCR and/or culture from respiratory
secretions in the oropharynx, nasal cavity or conjunctiva of both healthy kittens and cats and
those with URT disease, positive results do not equate to causation of clinical signs in these
cases, and interpretation needs to be based on the results of other diagnostic tests and the
pattern of disease e.g. are lower respiratory signs present?. If lower respiratory signs are
present, testing of bronchoalveolar lavage (BAL) samples by PCR and/or culture may be
more appropriate. Mycoplasma spp. can be very fastidious and difficult to grow in culture,
and thus PCR is often recommended for the detection of M. felis. Streptococcus spp.
infections are diagnosed by PCR and/or culture. B. bronchiseptica requires culture (usually
from OP swabs) transported in Amies charcoal medium or similar.

Treatment
Rationale and recommendations for antibiotic treatment
Although the majority of acute URT disease cases will be due to viral infections, if primary
(Mycoplasma spp., B. bronchiseptica) or secondary bacterial infections are present and
believed to be associated with disease, antibiotic therapy may be indicated. An empirical
choice is usually made initially as diagnostic tests are unlikely to be indicated or performed
in acute infections. Published ISCAID (http://www.iscaid.org/) guidelines on antibiotic use in
dogs and cats with respiratory tract disease3 exist. Although a mucopurulent nasal discharge
can indicate bacterial infection, the ISCAID guidelines3 suggest withholding antibiotics in the
immediate period that clinical signs have developed, to see if self-resolution occurs. In
human medicine, antibiotics are only prescribed following 10 days of URT clinical signs or
worsening of signs after 5-7 days. The length of such a period of wait in cats will depend on
the nature, duration and severity of signs (e.g. if pyrexia, lethargy &/or anorexia are
present).

If a decision to give antibiotics has been reached, doxycycline (10 mg/kg PO q24h or 5 mg/kg
PO q12h) for 7-10 days 1 is recommended as 1st line treatment in the ISCAID guidelines3; this
was chosen as it is effective against many of the common agents that cause secondary
bacterial infections and also has efficacy against Mycoplasma spp., B. bronchiseptica and C.
felis60,61 and it may have anti-inflammatory effects too. Doxycycline was found to be
effective when given to shelter cats with clinical signs of URT disease62. Care must be taken
to ensure complete swallowing of doxycycline tablets, due to the risk of oesophagitis.
Amoxicillin was the alternative 1st line agent recommended in the ISCAID guidelines, to be
used especially when Mycoplasma spp. and C. felis infections are not highly suspected as
amoxicillin is not active against these agents. The recommendation for amoxicillin use was
based on studies that showed that amoxicillin treatment can be useful in URT disease
cases63,64. Amoxicillin-clavulanate is an alternative to use in geographical areas where beta-
lactamase producing organisms are thought to be common; indeed amoxicillin-clavulanate
can be effective against C. felis65, but is not as good as doxycycline. If C. felis is being treated,
some have suggested that treatment should continue for 2 weeks beyond clinical cure66, but
this may not be necessary. Ideally, in-contact cats should also be treated since “silent
shedding” of C. felis by untreated animals can lead to reinfection of treated animals.
Systemic azithromycin or pradofloxacin reduce clinical signs but do not clear C. felis
infection61,67. B. bronchiseptica isolates are also susceptible to amoxicillin-clavulanate68.

The ISCAID guidelines recommend that if these antibiotic treatments do not work, and
bacterial infection is still suspected after 7-10 days, diagnostic investigations should be
recommended to the owner before starting another antibiotic, and URT disease is regarded
as being chronic if it has lasted for >10 days. In reality, invasive diagnostic investigations are
unlikely to be favoured after just 10 days, but they should be considered. It is at this stage
that diagnostic swabs for PCR for example might be collected.

Supportive Care
The importance of aggressive supportive care cannot be overstated for the effective
management of acute infectious URT disease.

Diligent supportive nursing is important; cleaning away discharges, grooming, regular

application of barrier creams to the face if needed, consideration of the best method to

1
It may be that shorter courses of 3-5 days are adequate as we maximise our efforts to reduce antibiotic use
with good stewardship, but research is required to confirm this
administer medicines (e.g. injectable if sore mouth or pharyngitis, liquid oral preparations,
administration via feeding tube if placed), providing nebulisation (see below), placing
feeding bowls at a higher than ground level to avoid the cat having to have its head down to
eat as this may worsen the feeling of congestion. It is also important to consider restraint
techniques too; if a jugular blood sample is being taken, one should gently restrain the cat
without having one’s hand under the lower jaw/chin (instead having hands at the sides of
the upper jaw instead) so that the cat can still mouth breath by lowering its jaw (i.e. opening
its mouth) if needed.

Fluid therapy to correct dehydration is important (as this is debilitating and worsens
congestion) – check electrolytes too (especially potassium) and correct accordingly.

Steam therapy can be provided in non-hospitalised patients by owners in their home sitting
with the cat in a bathroom with hot running water (e.g. shower) q4-6h, if possible, for 15
mins at a time, or by placing the cat in a cat carrier/basket with a bowl of steaming water
close by and covering both. Alternatively, cheap small nebulisers can be purchased for use in
the veterinary clinic (and/or loaned to owners for use at home) for regular nebulisation
therapy with saline – in the hospital setting this can be applied close to the cat’s face by
placing the cat in an igloo and covering the igloo for example. These techniques rehydrate
the URT, loosen secretions, reduce congestion and increase comfort. An alternative is to
directly apply saline drops to the nose to loosen secretions – tolerance of this can be difficult
by the cat. Although the latter is called ‘nasal flushing’ by some, it is different to the
therapeutic nasal flushing performed under general anaesthesia for chronic nasal cases, as
described elsewhere69.

Nutritional support is important as inappetance is common in the more severe cases of

feline acute infectious URT disease; tempting the cat to eat by hand feeding of warm smelly
blended foods may be sufficient in mild cases but appetite stimulants (e.g. mirtazapine; 2
mg/cat PO q24h – available as a transdermal preparation – can give q48h if renal or hepatic
dysfunction is present) and/or enteral tube feeding may be required. A commonly used
option for tube feeding is naso-oesophageal tube (NOT) feeding; this is advantageous as no
sedation is required for placement. Although URT disease cats may resent the NOT around
their nose, intermittent placing of the NOT for each individual feed may work better for the
cat than leaving the NOT in place. Softer silicone tubes are available that can be used for cat
‘flu cases, which may be better tolerated than the harder polyvinyl chloride (PVC) tubes (e.g.
Vygon Vet have silicone tubes in their Nutrisafe range, however this range requires special
syringes and adaptors for feeding). Sometimes, in severe cases, oesophagostomy (O-) tube
feeding is used but these tubes do need short general anaesthesia for placement. However,
O-tubes, being wider than NOTs, do allow for easier medicating and feeding, and the
positioning of an O-tube away from the cat’s face can facilitate acceptance of the tube.
NSAID therapy e.g. meloxicam, may be helpful as an anti-inflammatory, antipyretic and
analgesic agent, although it is important to ensure the cat is hydrated and is eating before
NSAID use. The use of topical ocular NSAID therapy (e.g. flurbiprofen 0.03%) is controversial
as, although anti-inflammatory therapy could be helpful in cases of FHV-1 chronic stromal
keratitis, some have suggested this can lead to exacerbation of FHV-1 associated disease20.
However, topical ocular NSAIDs are definitely worth considering in very painful eyes; even
just 1 or 2 drops a day for the 1st few days of treatment, until things settle down

Ocular lubricants (q6-8h) are often very helpful to ease ocular discomfort and can be used
alongside systemic famciclovir for FHV-1 associated ocular disease (see below). It is worth
considering the use of those containing sodium hyaluronate, which may help regenerate
conjunctival goblet cells in FHV-1 infection (e.g. Remend, Celluvisc, an-HyPro) Ideally one
should do a Schirmer Tear Test (STT) in any cat with URT disease and ocular signs; STT should
be > 15 mm/min affected cats and as FHV-1 affects tearfilm quality and quantity (via
metaherpetic disease), this is particularly important in FHV-1 infected cats, or cats suspected
to have FHV-1.

Nasal decongestants e.g. phenylephrine and/or mucolytics e.g. bromhexine are used by
some, but evidence for efficacy of these agents is lacking.

Maropitant is licenced for nausea and vomiting. It acts to inhibit tissue binding of substance
P at NK-1 receptors. As substance P is one of the primary neurotransmitters of inflammation,
blocking NK-1 receptors can potentially reduce inflammation, pain, exudation and oedema.
Online forums discuss the successful use of maropitant in chronic rhinitis cases (an intranasal
solution is made by mixing the injectable agent 1:10 in saline and giving 1 drop once a day
for a week, before reducing frequency) but no studies have been published on its efficacy to
the author’s knowledge, and the author has no personal experience of its use in rhinitis
cases.

Antivirals & Immunomodulatory Agents

In the past, the use of antivirals has been limited due to cost, side effects and the
practicalities of application but more feasible options are now available. Most antivirals used
in veterinary medicine only inhibit replication of DNA viruses such as FHV-1 and antivirals for
the specific treatment of FCV infections alone are not available. Antivirals are virostatic
rather than being virocidal and this explains why they often need to be given quite
frequently to combat active viral replication; they are ineffective against latent virus.
Antivirals should not be tapered as this may induce drug resistant viral strains.

1. FHV-1 Antivirals
Topical ocular antiviral treatment is not usually indicated in acute infectious URT disease
unless corneal ulceration is present or the ocular disease is particularly severe in association
with FHV-1 (or if chronic FHV-1 associated ocular problems are present). The antiviral agents
for FHV-1 ending in ‘-vir’ are active against FHV-1 due to the viral thymidine kinase (TK)
present in cells infected with FHV-1. The TK phosphorylates the ‘-vir’ compounds which then
inhibit the FHV-1 viral replication by chain termination.

Cidofovir (0.5% ophthalmic drops) is a topical nucleoside analogue antiviral for FHV-1 that is
practical to use as it only requires twice daily administration (1-2 drops into eyes q12h for 2-
3 weeks)70 because of its accumulation in cells, and is associated with improved clinical
scores and reduced ocular FHV-1 shedding. However, it is not readily available in all
countries and the human product is for infusion and not for topical use – in US 0.5%
ophthalmic drops are available from compounding pharmacies.

Ganciclovir (0.15% ophthalmic gel) is a topical nucleoside analogue antiviral for FHV-1 that
also shows promise in preliminary studies (used q8h for 1 week)71 although it may need
more frequent application at q4-6h; available as human licensed drug (Virgan) – give for at
least 3 weeks to clinical cases ideally.

Famciclovir is a systemic oral nucleoside analogue antiviral agent that is now commonly used
for FHV-1 associated disease (especially ocular disease but for other URT disease signs too
now and also FHV-1 ulcerative skin disease72), with a review of evidence available on its
efficacy available73. It is well tolerated and readily available. However it is very expensive (in
the UK around £500 for a course). It should not be tapered.

Studies have documented improvements in systemic and ocular signs of experimental FHV-1
infection at a dose of 90 mg/kg PO q8h for 3 weeks74, and this dosage results in therapeutic
levels in tears. However lower dosages and shorter courses have also been beneficial (125
mgs PO q12h in adult cats, or 30-50 mg/kg PO q12h in kittens, for 2-3 weeks) in naturally
infected cats75. One study72 retrospectively evaluated 59 client owned cats that were given
either low (~40 mg/kg) or high (~90 mg/kg) doses of famciclovir PO q8h. The cats ranged in
age from 0.03 to 16 years old and presented with conjunctivitis, keratitis, blepharitis, nasal
discharge or sneezing and dermatitis. Clinical improvement was subjectively graded as
marked in 51% of cats, mild in 34%, or unapparent in 15%. Median time to improvement was
significantly shorter, and the degree of improvement was significantly greater, in cats
receiving 90 mg/kg PO q8h than in cats receiving 40 mg/kg PO q8h, suggesting that in this
cohort a higher dosage of famciclovir is more favourable, although larger studies are
needed. Adverse events, potentially attributable to famciclovir administration, were
reported in 17% cats but were reversible/mild and comprised diarrhoea, inappetence and
vomiting. Owner satisfaction was rated at 91%. Limitations of this study were that FHV-1
infection was not confirmed in all cases and no placebo control group was included, as it was
a retrospective study. In terms of duration of treatment, some have suggested using
famciclovir until 5 days after resolution of clinical signs.
More recent studies have looked at twice daily dosing of famciclovir. One evaluated the
prophylactic and therapeutic effect of 7 days of famciclovir at ~30 mg/kg or ~90 mg/kg PO
q12h in shelter cats, of which only 16.5% were shedding FHV-1 at the start of the study76.
Although this study did not demonstrate a significant effect of famciclovir treatment upon
clinical signs of infectious URT disease or adoption rates, 30 or 90 mg/kg q12h for 7 days
significantly reduced ocular FHV-1 shedding, suggesting a potential role in interrupting the
infectious cycle within a shelter population. The cost in time and resources, and potential
stress and pathogen transmission induced by oral administration, probably precludes
famciclovir use in this setting. Another study77 revealed no significant difference in response
to therapy (severity and duration of clinical signs) between cats with signs of URT disease
treated with doxycycline alone or with doxycycline and 90 mg/kg PO q12h famciclovir; cats
improved rapidly in both groups. However, FHV-1 PCR was only positive in 29% of the cats at
the start of the study, limiting evaluation of famciclovir efficacy in this study. The less
convincing results of these studies might favour that a dosage of 90 mg/kg PO q8h of
famciclovir should be the target, although 90 mg/kg PO q12h dosing is an alternative.
However, another study78 in shelter cats with URT disease clinical signs (11/21 [52.4%] were
FHV-1 infected) showed that 40-90 mg/kg PO q12h of famciclovir for up to 21 days was
associated with a significantly reduced risk of worsening clinical signs with each day of
treatment compared to placebo; thus lower dosages can be effective.

Famciclovir is available as a human drug in 125, 250 and 500 mg tablets, which can be given
to cats at the appropriate dose, and formulations are available e.g. oral flavoured famciclovir
paste for cats at a concentration of 100 mg/ml, but acceptance of the paste by cats is
variable. Formulations aid compliance, particularly in younger cats, but one must be aware
of the considerable variation in famciclovir content present in compounded preparations, as
reported in US studies79,80, where these products are not evaluated for efficacy, content or
stability. This is in contrast to the compounded formulations available in the UK, for
example, as their manufacture is subject to good manufacturing practice standards which
legally ensures the composition of the formulation is accurate as well as its stability etc.

One descriptive study of treatment of FCV-VSD with famciclovir exists81, raising the
suggestion that there may be an antiviral effect of famciclovir against FCV, but more studies
are needed before recommendations can be made, especially as famciclovir’s action should
be specific to FHV-1.

Oral lysine (250 mg for small cat, 500 mg for large cat, PO q12h without food) competes with
arginine, which is essential for FHV-1 replication, and is frequently recommended as
treatment for feline herpetic disease. However published evidence confirming lysine’s
benefit is lacking82-87 and a recent systematic review of papers evaluating the efficacy of
lysine88 categorically stated that ‘lysine supplementation is not effective for the prevention or
treatment of FHV-1 infection in cats’. However, world-leading ophthalmologists (David
Maggs & Ursula Dietrich, personal communications) believe that lysine may help some cats
infected with FHV-121, and other ophthalmologists regard lysine as being useful. When given,
lysine should be administered at 500 mg PO q12h directly, and not in the food, as dietary
supplementation appears to be ineffective.

Polyprenyl immunostimulant (PPI)

PPI, an immunomodulatory veterinary product, was given in a randomized blinded placebo-
controlled study funded by the manufacturer in FHV-1-experimentally infected cats, starting
on the day of infection, where it led to an improvement in ocular and nasal clinical scores
but did not affect duration of signs89. A separate field safety study, which included young
kittens, showed no evidence of side effects with the dosage of 0.5 mg/kg of PPI PO q12h for
at least 14 days89. PPI is licensed for FHV-1 disease in the USA but more studies are required
to confirm its benefit.

Raltegravir therapy
Raltegravir is an integrase inhibitor used for HIV infection in humans. It has been used in cats
with experimental FeLV infection90,91, although control of FeLV viraemia was not achieved.
One study92 showed raltegravir to be effective at reducing ocular and respiratory signs of
FHV-1, as well as FHV-1 shedding, at 80 mgs PO q12h for 2-weeks in experimentally infected
cats. Further work on naturally infected cats is required before recommending its use.

2. Antivirals investigated for FCV

Equine immunoglobulin anti-FCV specific F(ab')2 fragments
IgG was extracted from inactivated FCV-immunized horse sera and used to produce equine
F(ab')2 fragments, which showed efficient neutralizing activity in vitro against FCV and also
improved the clinical signs of FCV-infected cats and reduced the FCV loads in tissues when
given subcutaneously on days 1-3 after infection and prophylactically 1 day before
infection93. This shows promise for future use as a prophylactic and therapeutic agent for
FCV disease.

Mefloquine
Mefloquine, an anti-malarial agent in humans that may also be helpful in feline infectious
peritonitis, demonstrated a marked inhibitory effect on the replication of FCV F9 and seven
Australian FCV isolates in vitro and an additive effect was found in combination with
interferon-ω94. Further studies are needed to see if the mefloquine effect on FCV occurs in
vivo too.

Nitazoxanide
Nitazoxanide (NTZ), initially identified as an anti-parasitic drug, showed dose-dependent
antiviral activity in vitro against different strains of FCV and a synergistic effect was observed
with mizoribine (MZR), an imidazole nucleoside with anti-proliferative activity against some
immune cells95. Both substances had low cytotoxicity in vitro. Moreover, in experimentally
FCV-infected cats, oral NTZ treatment (5-20 mg/kg suspended in 500 µL phosphate buffered
saline) at day 3 post-infection significantly reduced FCV viral loads in the trachea and lungs,
FCV RNA shedding and clinical signs of FCV infection as well as mortality95. No diarrhoea or
vomiting occurred in treated cats despite these being reported previously as potential side
effects95. The authors concluded that NTZ and MZR could be used as therapeutic agents to
treat FCV infection and that further studies should address potential synergy between NTZ
and MZR in vivo, as well as the potential development of drug resistance.

3. Antivirals investigated for both FHV-1 & FCV

Polymers - polysodium 4-styrenesulfonates (PSSNa)
PSSNa polymers were found to have no toxicity in vitro and in vivo, after topical application
to the skin in a mouse model, and in vitro these polymers inhibited FCV replication and
blocked attachment of FHV-1 to target cells96. Thus, PSSNa polymers are promising drug
candidates for the future treatment and prevention of the viral URT disease.

Interferon therapy
Recombinant feline interferon-omega (rfeIFN-ω) therapy has been recommended for both
FHV-1 and FCV-associated disease; it can be given systemically or topically with the following
dosages reported: 1 MU/kg SC q24-48 hours or 50,000-100,000 U PO q24h, or ocular drops
(30-50 U/ml in artificial tears) applied 3-5 times/day. However topical ocular administration
of human IFN alpha 2b or rfeIFN-ω to cats with conjunctivitis and URT disease signs (many,
but not all, were confirmed as having FHV-1 and/or FCV infection) was not effective at
lessening clinical signs or viral shedding compared to saline solution alone97. Similarly, a
study evaluating the effect of placebo or rfeIFN-ω (2.5 MU/kg SQ, then 0.5 MU topically [via
eyes, nose and PO] q8h) in cats with URT disease found no significant difference in clinical
signs between the treatment groups, although FCV loads may have decreased more rapidly
in the rfeIFN-ω treated group, but this was a non-significant difference98. Pre-treatment with
topical and PO rfeIFN-ω had no beneficial effect on the course of FHV-1 infection in a group
of experimental cats compared to a control mock-treated group99. Thus, there is little
convincing evidence for the use of IFN in viral URT disease cases in the author’s opinion.

FCV-VSD Treatment
In outbreaks of FCV-VSD, severely affected cats have been treated with intensive care
supportive treatment (e.g. fluid therapy) plus steroids and IFN, and in two cases famciclovir,
and clinical improvement was reported anecdotally. However, controlled clinical studies
have not been published; so specific treatment for the disease is not currently known4,43,81.
Early investigations have evaluated some promising antiviral compounds in vitro versus FCV-
VSD isolates18. Controlling a true outbreak is very challenging; all exposed cats must be
considered at risk for transmitting severe disease to others; there is no clearly defined
“quarantine period” after which we know cats are safe, although a minimum period of 2-
weeks has been suggested18; and vaccination is not generally protective. Analyses on FCV-
VSD isolates in one study17 showed very variable cross-neutralisation results with antisera
raised against each of 4 main FCV vaccine strains, suggesting that no single vaccine strain
would have predictedly protected against the FCV-VDS cases in the study. It is important to
create an immediate and complete break between exposed cats and newly admitted cats to
the hospital – veterinary practices have been closed following outbreaks to achieve this. The
exposed cats should be isolated/quarantined. Hygiene and disinfection are very important;
all surfaces are thoroughly cleaned followed by the application of a disinfectant active
against unenveloped viruses (e.g. accelerated hydrogen peroxide (RescueTM), potassium
peroxymonosulfate (Trifectant®, Virkon-S®), and sodium hypochlorite [bleach] are all
effective). Pre-cleaning is especially critical with sodium hypochlorite, as sodium
hypochlorite is substantially inactivated by organic matter. Allow to dry thoroughly and
repeat. For outbreaks in shelters, great online resources are available100.

Feline Chronic Gingivostomatitis Complex (FCGS) Associated with FCV Treatment

This disease syndrome should not feature in notes focused on acute infectious feline URT
disease as it is not usually an acute presentation and an aetiological association with FCV has
not been confirmed. However, it is included for completeness as information on FCGS is
commonly asked for when FCV is discussed.

For successful treatment of FCGS, dental care is essential - full dental radiographs are
required to identify any odontoclastic lesions or retained roots. A dental scale (subgingival
scaling is important), polish and surgical extractions should be performed, as required.
Referral to a specialist veterinary dentist can be considered, depending on facilities and
expertise, as some cats require full dental extractions for successful management with
associated dental radiography, and most will improve with appropriate dental treatment.
Chlorhexidine should be applied daily (e.g. Petdent) as home care. Judicious antibiotic and
NSAID treatment (especially post-dental treatment) can also be used. Stress reduction in the
home environment, considering environmental enrichment and management of the multicat
households, may be of help too (regarding FCV component). Some recommend rfeIFN-ω PO
post-dental treatment; 0.1 MU SID was shown to lead to a statistical improvement in clinical
scores in FCGS FCV infected cases with chronic caudal stomatitis, and a decrease in pain over
90 days, but this improvement was not different from cats receiving steroid alone except for
the lower pain scores101. However, the authors concluded that rfeIFN-ω resulted in
significant improvement and was found to be at least as good as short-term prednisolone
therapy in the treatment of FCV infected cats presenting with FCGS with caudal stomatitis
refractory to dental extractions. In another shorter duration study, FCV-infected cats with
FCGS were treated with either rfeIFN-ω SQ on days 1, 2, 3, 7, 8, 14, and 21 (n=13) or 1 mg/kg
prednisolone q24 h SQ (n=4) at the same time points102. There was a significant
improvement in clinical and salivation scores of the cats treated with rfeIFN-ω, but not in
pain on opening the mouth nor in halitosis or mandibular lymphadenopathy102. Oral
administration of rfeIFN-ω led to clinical improvement of lesions in two cats with type II
diabetes mellitus and concurrent FCGS and the required insulin dose could be decreased103.
rfeIFN-ω is relatively commonly used by specialist veterinary dentists104.

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