CANINE INFECTIOUS RESPIRATORY DISEASE (CIRD) Management of Outbreak Situations

ZOETIS

OCTOBER 2017 CANINE INFECTIOUS RESPIRATORY DISEASE (CIRD) Management of outbreak situations

Margaret Gober, VMD Manager, Product Support Veterinary Medical Information and Product Support Zoetis, Inc. Robert McCloskey, DVM

OVERVIEW

his technical bulletin is designed to assist the veterinary practitioner in the management of outbreak situations involving canine infectious respiratory T disease (CIRD). To this end, we have gathered opinions and articles from some of the leaders in the veterinary community. Our goal is to provide clinics with general guidelines regarding the handling, diagnosis, and treatment of their CIRD patients and support in the management of these potentially catastrophic events. We will explore the various pathogens implicated in CIRD, describe some of the currently recommended diagnostic tests, and review potential treatment options. We will discuss some of the current CIRD vaccines in broad terms to increase awareness around use, and lastly, we will outline some of the management factors which need to be undertaken in the face of an outbreak. Since CIRD is a complex syndrome involving a multifactorial etiology, diagnostic testing is always recommended to identify pathogens. Armed with this information, the practitioner may then determine the appropriate steps to help mitigate or reduce the effects associated with an outbreak situation. PATHOGENS Incubation Preclinical Duration of Subclinical Persistent VIRUS Period shedding shedding infection infection1 CRCoV < 1 week Yes 2 weeks Yes No CIV 2-4 days Yes 7-21+ days Yes No CHV < 1 week Yes 2 weeks Yes Yes CPiV < 1 week Yes 1 week Yes No CAV-2 < 1 week Yes 1 week Yes No CDV 1-3 weeks Yes < 1 month Yes No Incubation Preclinical Duration of Subclinical Persistent BACTERIA Period shedding shedding infection infection Mycoplasma 1-4 weeks Yes Several weeks Yes Up to 3 weeks in spp. lung tissue2 Bordetella 3-10 days Yes Several weeks Yes Recovered up to 14 bronchiseptica weeks after clinical signs resolved3 Streptococcus 1-3 weeks Yes 1-2 weeks4 Yes Possible (seen in zooepidemicus other species) Chlamydophila Unknown5 Yes Unknown5 Possible5 Possible (seen in other species)

hile these charts highlight many of the environment. None of the canine viruses commonly recognized CIRD establish persistent infection, but several of the Wpathogens, they are by no means bacteria can linger in tissues for weeks to comprehensive. In fact, emerging infectious months. All of the respiratory pathogens are agents such as reovirus and pneumovirus have transmitted by direct contact with respiratory been identified.6 These organisms may act secretions of infected dogs and by contact with alone to cause disease or they may intensify contaminated fomites. Veterinary clinic staff the effects of other known pathogens, resulting members are the most important vector for in more significant CIRD symptoms and fomite spread. In addition, canine viruses are compromising patient outcomes. One effectively distributed over distances >20 feet characteristic that the above etiologic agents in aerosols generated by sneezing and share in common is that they all contribute to coughing, significantly enhancing rapid preclinical shedding during the incubation transmission throughout a kennel.1 Unlike period, meaning infected animals are viruses, Mycoplasma spp. can survive for weeks contagious before they develop clinical signs.1 to months outside the host in the environment; Most of these bacteria and viruses are shed in therefore, the potential for reexposure from an respiratory secretions for 7 to 14 days, untreated environment exists.2 allowing ample opportunity for spread of Environmental factors and host immune disease. A subclinical carrier state may also response play equally important roles in the exist, further compound-ing the problem. development of CIRD. Several pathogens may Dogs with clinical signs shed greater amounts produce mild or subclinical disease in healthy of bacteria and/or virus which significantly animals in the absence of complicating factors increases the infectious dose in the

2 like stress, immunocompromised host, or high Bordetella through direct or indirect contact contact rates. All of the etiologic agents listed with other animals. Contaminated bedding or above can cause a similar clinical presentation water may serve as indirect vehicles of of coughing and/or nasal discharge.7 While transmission. Bordetella is unique in that it can canine parainfluenza virus and Bordetella induce temporary ciliary impairment. This bronchiseptica are classically thought of as allows the bacteria to be a primary, rather than causing only relatively mild disease, more an opportunistic, respiratory pathogen. Most severe illness may occur when secondary, adult dogs develop mild to moderate opportunistic pathogens become involved. tracheobronchitis after exposure, resulting in a Ultimately, in an outbreak situation, the harsh cough. Less frequently, sneezing and/or specific cause of CIRD cannot be definitively oculo-n asal discharge may also be observed. determined based on diagnostics from a single Damage to the respiratory cilia makes dog. Instead, pinpointing the source(s) of conditions ripe for a secondary, opportunistic, illness requires analyzing samples from a larger bacterial or viral infection which can make representative portion of the affected what would usually otherwise be a population of animals. As a result, we self-limiting condition more serious. Presence recommend at least five separate and discrete of contaminated fomites in the environment sample submissions to help determine the is short-lived and is directly related to the pathogenic players. Interpretation of the concentration of infected animals present. diagnostic test results must be made in Bordetella bacteria are readily killed by light of several factors. For instance, many decreased oxidation/reduction potentials, of the CIRD pathogens can be isolated UV irradiation, pH and temperature from clinically normal dogs. Additionally, extremes, and many common chemical if the same pathogen is found in several disinfectants.5 dogs, this raises the index of suspicion that Mycoplasmas a causative relationship exists, but still does Mycoplasmas, the smallest prokaryotic cells not rule out other contributing agents.7 In capable of self-replication, are pleomorphic the face of suspected severe infectious organisms. Since they are seldom identified to respiratory disease resulting in death or a species level during routine testing, they are euthanasia, necropsy should be utilized to often mistakenly thought of as a single entity. investigate the source of illness. If you are However, there are more than 15 different uncertain whether a single death might species of Mycoplasma which have been represent the beginning of an outbreak, isolated from pet animals.2 Most of these are collection of lung specimens and commensal organisms, with only a few serving oropharyngeal swabs for future analysis would as pathogens.2 There is evidence that be recommended. Formalin fixed, frozen, and Mycoplasma cynos can induce upper refrigerated specimens should be obtained for respiratory disease in dogs, and isolation of M. histopathology, viral isolation, and bacterial cynos has been correlated with an increased 7 culture respectively. severity of CIRD.2 One study isolated M. cynos from the air within a kennel, suggesting BACTERIAL PATHOGENS that environmental contamination may be a Bordetella bronchiseptica significant problem with this pathogen. Bordetella bronchiseptica is a Gram Clinical signs may include cough, accumu- negative bacteria that replicates in the lation of mucus and exudate. This pathogen respiratory tract. Dogs encounter does have the potential to develop into pneumonia. Mycoplasma can

3 often evade the immune response, resulting in both tracheal and lung samples in dogs with PATHOGENS a chronic, low grade infection and perhaps CIRD. As is true of many of the other predisposing patients to other, secondary pathogens mentioned above, Chlamydo-p hila bacterial infections.5 may contribute to subclinical infections in some animals, while causing severe signs of Streptococcus equi subspecies CIRD in others.8 At this time, most diagnostic zooepidemicus labs do not have PCR testing available for this Although this organism may occasionally be pathogen. found in the respiratory tract of healthy dogs, in some settings, it can be responsible for a VIRAL PATHOGENS severe, acute to peracute, respiratory infection Canine Adenovirus Type 2 (CAV-2) which may be either primarily airway-related or may cause a fatal hemorrhagic pneumonia. This virus was first identified in 1961 in Co-infection with various respiratory viruses Canada.9 Strain isolation identified the virus as may increase the likelihood of infection or CAV-2, differentiating it from CAV-1, which worsen severity of infection after exposure to S. causes infectious canine hepatitis. Infection zooepidemicus. Several outbreaks in shelter/ occurs via the oronasal route. Respiratory kennel settings have demonstrated that this can signs, which generally result from damage to be a highly contagious, frequently fatal disease. bronchial epithelial cells, include fever, a deep In its peracute form, infected dogs may simply sounding dry cough, watery nasal discharge, be found dead in the morning without having pharyngitis, and tonsillitis.5,9 While widespread acted sick the day prior. Pulmonary vaccination has lessened the prevalence of this hemorrhage, pleural effusion, and suppurative, viral pathogen, co-infections may still be seen. necrotizing pneumonia are characteristic When acting as a solo etiologic agent, CAV-2 findings on necropsy. Although this is a infections tend to be mild and self-limiting; bacterial infection, rapid destruction of lung however, when secondary pathogens become tissue means that antibiotic therapy may not be involved, more serious illness can ensue.5 sufficient to produce a cure, and death can Canine Parainfluenza Virus (CPiV) occur despite appropriate anti-infective administration.5 Human infection with S. Routine vaccination has diminished the impact zooepidemicus has been reported, but is most of this viral pathogen. CPiV is primarily spread often related to exposure to horses (in which through aerosolized respiratory secretions. the bacterium often serves as a commensal Symptoms generally begin 2-8 days after organism) or contaminated animal food. infection and are transient, resolving within an Caution would be recommended for pet average of 6 days.10 In uncomplicated owners and personnel exposed to outbreaks infections, clinical signs may include low-grade involving this pathogen, with immuno fever, deep sounding dry cough, watery nasal compromised individuals being at greatest risk. discharge, pharyngitis, and tonsillitis. In immunocompromised animals or young, Chlamydophila unvaccinated puppies, more severe illness may Little has been written about this potential occur, resulting in lethargy, fever, inappetence emerging pathogen at this time. A survey and pneumonia. Because this virus damages documented an increased prevalence of local respiratory defense mechanisms, Chlamydophila in cases involving respiratory secondary or concomitant bacterial infections disease.8 This organism has been identified in are commonly observed.5

4 Practitioners need to recognize the challenge that in cases of stress caused by other bacterial in understanding the significance of CPiV and viral pathogens, CHV may become since studies have shown no clear reactivated and thus appears present in correlation between the presence of this animals with severe clinical signs. A study of a virus and severity of respiratory symptoms.9 CHV outbreak in a referral veterinary hospital in Japan showed that following treatment with Canine Respiratory Coronavirus agents that induce stress, the recrudescence of (CRCoV) latent CHV occurs within a week.12 This pathogen is a group 2 coronavirus, which Additional studies have shown the virus can is antigenically distinct from group 1 enteric be activated 10 days after exposure to systemic coronavirus. It was initially discovered as a prednisolone (3 mg/kg of body weight for 7 cause of CIRD in Europe in 2003, but has consecutive days).15 since been identified globally.5 Serologic Canine Distemper Virus (CDV) studies conducted in the U.S. and Canada have demonstrated that as many as 50% of Canine distemper virus is an enveloped, dogs have been exposed to this virus.5 Clinical pleomorphic, single-stranded RNA virus which signs are most frequently seen 1-2 weeks after is susceptible to environmental factors such as exposure. In some animals, the virus causes a extremes of temperature, pH and to severe self-limiting tracheobronchitis. However, disinfectants. The virus can survive in tissues because the virus can damage respiratory for 48 hours at 77°F and for 14 days at 41°F epithelium, secondary bacterial infections may and persists longer in cool, shady cause significant respiratory illness. Since environments or in tissue debris. Canine CRCoV, like bovine coronavirus (BCV) may distemper virus is readily inactivated by several show dual tropism, possessing the ability to dis-infectants, including quaternary replicate in both the epithelium of the ammonium compounds and 0.75% phenol gastrointestinal tract and the respiratory tract, solution. Canine distemper virus infects a wide fecal-oral transmission may be possible.11 range of animals, but dogs are the principal reservoir. Infection usually is transmitted by Canine Herpesvirus (CHV) aerosol or by direct contact, leading to respiratory infection of susceptible animals.5 Canine herpesvirus was first described in 1965 While the respiratory tract often displays the as a pathogen responsible for fatal, initial clinical signs of this disease, it is not the hemorrhagic disease of newborn puppies. In primary system to be affected. Unvaccinated older puppies, a less virulent respira-t ory animals affected by CDV will go on to manifest illness has been attributed to CHV. The virus is systemic signs of the disease including spread primarily through oronasal and neurologic, ocular and skin lesions.16 venereal transmission. Following initial infection, CHV, like other herpesviruses, Canine Influenza Virus (CIV) becomes established within several tissues and Canine influenza was first described in a kennel may persist for life.12 Experimental infections of racing greyhounds in 2004.5 The H3N8 virus have been shown to cause mild clinical appears to have adapted well to dogs, although symptoms including rhinitis and pharyngitis.13 the initial virus started within the horse. Today Infection with this virus was detected 3-4 the course of infection is less severe and is more weeks after exposure, much later than many of likely to result in tracheobronchitis. H3N8 CIV the other viruses.14 It is this persistent is now endemic in some shelters in the infection which has led researchers to theorize Northeast.1

5 Since the discovery of H3N2, CIV more likely act in synergism with other PATHOGENS has rapidly spread to 30 states, infecting respiratory pathogens, aggravating the course thousands of dogs, including those in shelters. of concomitant infections. Diagnosis As of July 2016, H3N2 CIV was actively of reovirus infection is usually based on virus circulating in some Midwestern states, notably isolation on cell cultures, electron Illinois. "Studies performed after the 2015 microscopy and polyacrilamide gel Chicago H3N2 outbreak suggest that the electrophoresis (PAGE). These methods are duration of virus shedding from dogs naturally proving to be poorly sensitive and likely infected with H3N2 virus is longer, with underestimate the presence of MRV in intermittent negative and positive test results, animals and humans.8 compared with dogs infected with H3N8 virus or dogs with experimentally induced H3N2 Canine Pneumovirus virus infections. The duration of virus shedding was 2 to 3 times as long as the 1 to 7 days that In a shelter study performed between has been reported for H3N8 and shelters are 2008-2009, authors from the Animal Health now recommending a 21 day isolation Diagnostic Center at Cornell University period".17 Prolonged virus shedding is a critical discovered an unknown virus from dogs driver of transmission and has been associated housed in shelters.6 Mono-clon al antibody with increased severity and weakened host testing indicated that it was probably a defenses in humans.17 pneumovirus. PCR and sequence analysis While extended shedding periods help to indicated that it was closely related to murine explain why so many dogs have been impacted pneumovirus (MPV). The isolation of a by H3N2, the ability of the virus to propagate previously unknown virus from dogs does not on other species also helps to highlight some of imply disease causation. However, comparison the significant differences found between H3N8 with MPV leads to speculation that the virus and H3N2. isolated in this study may have pathogenic Compared to common kennel cough potential. MPV is commonly known to infect associated with Bordetella bronchiseptica , dogs laboratory rodent colonies, however, little is with canine influenza are often described as ill, known about MPV epidemiology, such as and more likely to act lethargic, have a soft, whether MPV has multiple natural hosts or moist cough, have purulent nasal discharge, whether closely related viruses are circulating and are more likely to be febrile.5 in other species. Questions remain as to whether this newly isolated virus commonly OTHER EMERGING infects dogs and, if so, why it has not been PATHOGENS previously isolated. Perhaps the strain that was Canine Reovirus circulating in these particular animal shelters is Murine reoviruses (MRV) have a wide more easily isolated in culture. Or, because the geographic distribution and can virtually initial cytopathic changes observed with these infect all mammals, including humans. Three isolates were subtle, they could easily have been serotypes have been isolated from dogs and missed. Outbreaks of acute respiratory disease cats; MRV-1, MRV-2 and MRV-3, but only in dogs often involve multiple pathogens, and MRV-2 has been isolated from dogs with other viruses were often isolated from the same disease of the upper respira-tory tract. animals that carried the pneumovirus. Work is Experimental infections with MRV in germ- ongoing to further determine pneumovirus and disease-free dogs failed to give conclusive prevalence among dogs and its involvement in results. Accordingly, it appears that MRV does acute respiratory disease of dogs.6 not exert direct pathogenic activity and

6 Influenza Viruses: In China, a study in 2011 found 7% of the 462 serum In the US, Canine InfluenzaViruses H3N2 and samples tested were seropositive for H3N2 CIV by H3N8 are major pathogens. Bivalent vaccines ELISA.18 These findings demonstrate that avian are now available and dogs with at risk origin canine influenza virus infection was able to lifestyles should consider this preventative move into the US as an epidemic within 4 years and measure. new global influenza viruses should be anticipated.

All of the canine respiratory pathogens can the beginning of an outbreak, it is prudent to cause similar clinical syndromes, at least obtain lung specimens and oropharyngeal DIAGNOSIS during the first week of illness. Therefore, the swabs and hold for future analysis if indicated. cause of infection cannot be diagnosed based Formalin fixed, frozen and refrigerated solely on clinical signs. Most clinics still specimens should be obtained for assume that “kennel cough” in dogs is due to histopathology, virus isolation, and bacterial Bordetella bronchiseptica bacterial infection. culture respectively.7 Accumulating evidence from diagnostic testing Several companies now offer PCR panels for indicates that many respiratory infections in canine infectious respiratory disease. Most are dogs are viral.1 In outbreak situations, specific performed on nasal and/or deep pharyngeal determina-tion of the most frequently isolated swabs. The pathogens incorporated in these pathogens may be useful in disrupting the panels vary, but most include Bordetella cycle of exposure and infection. When a bronchiseptica, H3N8 canine influenza virus, kennel or outbreak situation is suspected, H1N1 influenza virus, canine distemper virus, multiple dogs should be tested (minimum of canine adenovirus type 2, canine para- 3-5, or 10-30% of the affected population).5 influenza virus type 3, canine herpesvirus and Conjunctival, nasal, and pharyngeal swabs canine respiratory coronavirus. Some include should be collected from dogs with clinical Streptococcus zooepidemicus and other signs for <4 days in order to catch the influenza viruses.7 pathogens in their peak shedding period.1 In It is vital to remember that the mere presence situations where diagnostic testing has failed to of nucleic acids from a pathogen, a positive identify a pathogen among symptomatic PCR result, does NOT mean that the pathogen patients, a clinic may choose to sample animals caused disease in any particular animal. which have been exposed but aren't sick. While Instead, the clinician should look for patterns not covered by the Companion Animal of frequently isolated pathogens in a group of Immunization Support Guarantee, these infected dogs.5 Most of the pathogens results may be more useful when animals are associated with CIRD can be isolated with sampled very early in the course of disease some frequency even from clinically normal rather than later, when secondary infections dogs. If the same pathogen is found in several Reasons for are more likely to cloud the diagnostic results. dogs, this raises the index of suspicion that a False Negative Any animals which die or are euthanized causative relationship exists, but still does not Results: during an outbreak should be necropsied with rule out other contributing, or even primary • Sample collection samples submitted for bacterial culture as well agents.7 In general, most uncomplicated cases issues as PCR for respiratory pathogens; other tests of CIRD have unremarkable bloodwork and • Sample handling may be indicated depending on the specific radiographic results. However, animals with 5 • Timing of sample situation. If you are uncertain whether a evidence of pneumonia may need a more in- collection single death represents an isolated incident or depth evaluation including these diagnostic

7 tools. If the presence of broncho-p neumonia vaccines have been documented to DIAGNOSIS is observed, bacterial culture and sensitivity contribute to positive PCR results as long testing may be needed to assist in the as three weeks following their selection of a prolonged course of antibiotics. administration.5,7 Keep in mind that false negatives may be Paired serology is the most sensitive means of caused by problems with sample collection, confirming canine influenza infection, but serology cannot differentiate between Reasons for handling, or timing. For instance, canine influenza is shed only very early in the course vaccination and infection. More timely results False Positive are possible with antigen detection methods Results: of disease and may be missed by the time clinical signs are recognized. RNA samples and PCR. Specimens that can be submitted for • Recent vaccination are more labile than DNA samples and can virus isolation or PCR are pharyngeal swabs, • Sample contamination easily be degraded during sample storage and tracheal wash fluid, or lung tissue. Results from • Lab technique transport. any test for viral detection can be falsely • Sample handling False positive results may also be observed negative because of the relatively short period with PCR testing, resulting from factors such of shedding after the development of clinical as sample contamination, laboratory signs in most patients. For best results, samples technique, and recent vaccination. As an are collected from febrile dogs very early in the example, modified-live canine distemper virus course of disease.5

There is no single “drug of choice” for generation cephalosporins and ampicillin. TREATMENT treatment of CIRD. For many dogs, treatment Although amoxicillin/ clavulanate is not of these disorders is supportive and most are thought to reach high concentrations in the self-limiting. Common sense measures like epithelial lining fluid of healthy dogs, it has a strict rest, avoidance of excitement, avoidance high margin of safety and is a reasonable of neck leashes and nominal exercise are consideration for dogs with non-life indicated to minimize cough-precipitating threatening infection. Fluoroquinolones reach situations and avoid perpetuating airway high concentrations in the epithelial lining irritation.19 fluid but should generally be reserved for more For dogs with evidence of bacterial disease or significant infections. It is important to those at risk for secondary bacterial infection consider the age of the patient when using this (immunosuppression, contaminated category of antibiotic, given the known risk for environment, etc.) antibiotic treatment is often the potential of cartilaginous defects in indicated. Antibiotics do not necessarily skeletally immature animals. Chloramphenicol reduce duration or severity of infection with reaches reasonable airway concentrations and Bordetella bronchiseptica if it is limited to a is a rational choice for puppies where tracheobronchitis due to the inflammatory fluoroquinolones and tetracyclines may be nature of the disease.5 Sensitivity of Bordetella relatively contraindicated. Doxycycline reaches bronchiseptica to antibiotics is not predictable, reasonable airway concentrations in people, and published reports have shown an but is more highly protein bound in dogs and evolution in sensitivity over time. Over the may not penetrate into the epithelial lining past ten years, most isolates were sensitive to fluid as readily. It also has the potential doxycycline, chloramphenicol, enrofloxacin, disadvantage of dental staining in puppies. and amoxicillin/clavulanate. Fewer isolates Azithromycin can achieve high airway were sensitive to trimethoprim-sulfa, and concentrations, is convenient for owners, and much resistance was found to first is used to treat Bordetella pertussis in people,

8 but sensitivity to B. bronchiseptica has not Some authors recommend a course of orally Common been reported and the spectrum of activity is administered prednisone to reduce the severity Treatments for quite narrow. Another strategy to reach high of symptoms, but it has not been found to Uncomplicated airway concentrations is by nebulization of shorten the course of illness.7 Other experts CIRD: antibiotics. Some veterinarians report success indicate there is no evidence to support the use in controlling signs and kennel outbreaks with of steroids in these animals.5 If considering • Avoidance of nebulized gentamicin, but no controlled the use of steroids, it is important to remember neck leashes studies have been published. As with oral many of the antibiotics effective against B. • Nominal exercise antibiotic therapy, it has been shown that bronchiseptica are bacteriostatic, the • Avoidance of nebulized antibiotic therapy does not eliminate concurrent use of corticosteroids and these excitement Bordetella bronchiseptica afrom the irways of antibiotics should be avoided.19 • infected dogs. Be cautioned that nebulized Some clinicians feel there is no evidence that Rest antibiotics should never be used as a substitute antitussive or expectorants are beneficial to for systemic antibiotics in a dog with reduce symptoms of CIRD in dogs, however, pneumonia since it is a lung tissue infection others feel that as long as lower respiratory and not simply an airway infection. Also be signs are absent, antitussive therapy can be cautioned that despite results on an in vitro used.5,7 Narcotic antitussives are specifically susceptibility profile, Bordetella sometimes are not recommended because they can decrease not eliminated in vivo by an antibiotic which respiratory function.7 5 “should” work. Greene’s notes “Neither B. Bronchodilators may be considered when bronchiseptica nor Mycoplasma are readily pharmacological intervention is required to cleared from the respiratory tract of infected control coughing, but others report no dogs; hence, shedding can persist for several observable improvement with use.19,20 weeks.20 Mycoplasma do not have cell walls Antivirals are not recommended to treat and are therefore not damaged or killed by canine influenza since there are no controlled antimicrobial agents that affect the cell wall or efficacy trials available for dogs, and to date, its synthesis, such as penicillin. They are dose and toxicity studies have not been susceptible to antimicrobials such as performed.5 doxycycline or azithromycin.5 Treatment, therefore, is based on Since Bordetella bronchiseptica is not the only diagnostic results, clinical signs and bacterial pathogen that may be involved with vaccination history. For many animals, CIRD, and secondary infections subsequent to supportive care is the most important canine influenza or other viral infections may treatment available to the veterinarian be seen, fluoroquinolones, amoxicillin/ and when used in combination with clavulanate or other broad spectrum management techniques described within this antibiotics are more likely to be effective than bulletin, may help to shorten the course of an doxycycline. Consideration around drug outbreak. selection should include the awareness that When we think beyond today and our drugs such as doxycycline, fluoroquinolones, standard protocols, what may the future hold? and azithromycin achieve good airway In an article published in Insights into concentrations, while beta lactam drugs Veterinary Medicine21, Dr. Steven Krakowka achieve lung tissue concentration but don’t offered the following thoughts about the penetrate airway secretions well.5 Culture and potential role of immune modulators as sensitivity is indicated in an outbreak or an adjunctive therapy for Canine Infectious individual dog that fails to respond to Tracheobronchitis (CITB): empirical therapy.7

9 “Is there a role for immune modulators as biologic response modifiers, is not species or TREATMENT adjuncts to vaccination(s) for the treatment of cell specific; human origin IFN-α exerts Canine Infectious Tracheobronchitis (CITB)? biologic activities in dogs and other domestic As is true for any traumatic or infectious event, species. In general terms, IFN-α appears to the best protection is prevention, which in down-regulate manifestations of the proinflam many cases means vaccination. But what are the -matory immune and inflammatory responses options if prevention is not a viable alternative? in humans, laboratory animal species, and Symptomatic therapy including judicious use of domestic animals. Low-dose, oronasally cough sup -pressants and mucolytic agents has administered IFN-α has been shown to be a role in the therapeutic approach to CITB. efficacious in reducing both objective and There are other options, however, notably the subjective measures of severity for equine use of low-dose oral interferon for the COPD and CITB associated with adenovirus-2. treatment of CITB. Interferon-α (IFN-α) has a In the future, perhaps IFN-α therapy will even - central role in the regulation of immune tually become a common therapeutic adjunct responses. This cytokine, unlike many other for CITB.”21

VACCINATION Vaccines are not available for some the first response to an invader. It is now well contributory or primary pathogens of CIRD. It documented that infectious agents have is important to consider some of the vaccines generic “danger signals” that the vertebrate we do have as tools in helping protect our host recognizes in addition to the specific patients. Some studies have shown that animals antigens that stimulate acquired immune vacci-nated with current canine respiratory responses. These danger signals are specific vaccines help reduce the severity of clinical and unique structural components of viruses signs in infections involving multiple and bacteria, such as unique DNA motifs, pathogens.4,22 It is always important to endotoxin, and single-stranded RNA, consider the immune status of animals as we which vertebrates recognize as foreign. These vaccinate, since studies have shown microbial components interact with specific immunosupressed and stressed animals may receptors (i.e., toll-like receptors) on the surface develop significant respiratory disease of a variety of cell types, including cells of the secondary to respira-tory ML vaccine immune system. This interaction results in exposure.12 In some cases disease can be intracellular signal transduction and the virtually entirely prevented (e.g. canine secretion of a variety of cytokines, notably distemper). As we consider the lifestyle and interferon-α. Interferon has direct exposure risk of each patient, a conscious effort antimicrobial effects and enhances innate should be made to tailor vaccination strategies immunity by stimulating neutrophil and to the individual. macrophage functions. Although it has not yet Since the advent of vaccination to control been examined in detail in dogs, it is likely that infectious diseases in the 1790s, much of the intranasal delivery of vaccines containing B. focus in immunology has been on acquired bronchiseptica or viruses can stimulate local immunity, including antigen-specific antibody innate immunity through interactions with and cell-mediated immune responses. Recent several toll-like receptors. This stimulation of years have seen a renaissance of interest in the innate immune response may account for innate immunity and nonspecific responses, the observation that intranasal vaccine the evolutionarily ancient processes that are administration immediately before boarding

10 can have an apparent sparing effect on the IgG is produced systemically and normally incidence and severity of CIRD.21 resides in the plasma, but it exudes onto Intranasal and parenteral vaccines for mucosal surfaces through leaky capillaries at least some of the pathogens involved in during inflammatory processes such as CIRD. CIRD, including CPIV, CAV-2, and Supporting the protective effect of IgG on B. bronchiseptica, have been available for mucosal surfaces in Bordetella infections is the several years. These vaccines have generally wealth of data from human medicine been shown to be effective in helping spare correlating parenteral vaccine-induced serum disease in relevant licensing and post-licensing IgG responses with protection in Bordetella challenge studies, which is consistent with the pertussis infections in children.21 Based upon experience of many practicing veterinarians. So this understanding, priming the immune why is there continued controversy regarding system with an intranasal B. bronchiseptica "preferred" route(s) of vaccine administration? vaccine and following up with a parental B. One factor is a lack of understanding about the bronchiseptica vaccine would maximize the protective mechanisms of acquired immunity immune system response to vaccination. in the respiratory tract and how extant Vaccinating animals in the face of an outbreak immune (antibody) responses may affect the is controversial. In the event that patients induction of primary versus secondary or have already been exposed to CIRD, anamnestic responses. Focusing on B. vaccinating with existing respiratory vaccines bronchiseptica, it has been shown that both IgA and expecting the immune system to catch up and IgG can play a role in protection with each after the fact may convey little to no benefit. of these antibody isotypes acting in very Additionally, stimulating the immune system different ways. IgA, which is produced locally may be contraindicated depending upon the at mucosal surfaces and systemically, is not animal and the risk versus benefit of the very effective at killing bacteria; it acts vaccination. It is recommended that animals primarily by a process called immune exclusion. receive vaccines as labeled. In addition, the Immune exclusion occurs when a microbe (or AVMA and AAHA guidelines released in 2017 a vaccine antigen) is specifically recognized have very specific recommendations which and agglutinated, which allows it to be more can be reviewed online at the AVMA’s effectively removed by the mucociliary website, www.avma.org. escalator. It is difficult to maintain memory responses at mucosal surfaces. IgG, on the other hand, is an effective killer of bacteria via Additional information regarding CIRD a process called immune elimination, mainly by vaccines is available in the Zoetis Technical virtue of its complement activating Bulletin, Canine Infectious Respiratory properties.21 Disease (CIRD): More than Kennel Cough.

11 OUTBREAK The preemptive creation of a CIRD Success requires breaking the cycle of MANAGEMENT outbreak management plan is ideal. To help transmission between exposed, infected and ensure your clinic's success in handling new incoming dogs. Depending upon the respiratory disease on a large scale, the pathogen’s period of shedding this may be following important factors should be more manageable for some pathogens than considered: others. Prepare an outbreak All dogs in the hospital at the time a management plan case is identified should be considered 1. Determine the role of the veterinary exposed/at risk. clinic to the community, patients and These dogs may pose an infectious risk for up their owners. to 7-10 days after exposure and should be 2. Chain of communication: prevented from contacting naïve (unexposed) • How will the clinic communicate with dogs for two full weeks after exposure. After their clients? this period, even if they are still clinically ill, • What information should be conveyed to they are less likely to pass their infection to your clients and the community? other dogs.1 Gathering a complete history of 3. Educate staff and volunteers about the newly infected dogs may help identify signs and risk factors for CIRD including additional hot spots of the outbreak training staff to be alert to signs of respiratory (boarding kennels, shelters, etc.) leading to infection. Written and oral instructions for all quicker containment. staff members and volunteers should be Several authors recommend closing down a provided to ensure a consistent response if hospital during an outbreak situation to ensure they notice a dog with clinical signs of proper containment.1,22 When shutting down a respiratory disease (e.g. don’t take that dog for hospital is not an option, the following steps a walk, let a medical staff member know, post a can help manage an outbreak: sign on the dog’s run). • Create a clean, separate intake area for un- 4. Quarantine high risk dogs for 1 week exposed dogs and isolate all dogs showing clinical signs of - At least a separate ward, ideally with respiratory infection. As with other respiratory separate ventilation pathogens, mildly affected dogs may transmit - May consolidate all exposed dogs to a severe disease to others. Clean contaminated single ward in order to create a clean clothing, hands, equipment and surfaces after ward for new intakes exposure to a dog with respiratory disease and • For example, if a hospital has two wards, a history of boarding or recent transfer from collect all exposed dogs into one ward and What high risk areas. take in other non-affected animals into the second ward information 5. Ensure animals are appropriately - For hospitals with a single ward for all should be vaccinated for CPiV, CAV-2, CDV, Canine dogs, options to avoid ongoing disease conveyed to your Influenza and Bordetella bronchiseptica on spread include either diverting other non- clients and intake. affected animals to another facility (or community? 6. For groups which have contact with delay hospitalization) or sending exposed large numbers of animals, such as obedience dogs off site for quarantine. classes or in clinics, make sure areas are cleaned and employees wash hands and • Shut down release of exposed dogs until two change clothing between caring for week quarantine is completed hospitalized animals and handling pet - Alternately, release only to homes with no animals.17 other household dogs, with

12 stipulation that dogs not be taken out infectious agents on shoes and clothing in public for two weeks between housing areas, dedicated rubber boots - Advise owners of risk to other dogs and disposable gowns or smocks are • Adequate isolation includes recommended for each area. Gloves, gowns, - Limited, designated staff only to enter and boots are necessary for cleaning quarantine/isolation areas quarantine or isolation areas. Ideally, hands - Separate jumpsuits (full clothing should be disinfected after handling each dog coverage), gloves, boots or shoe with sanitizers containing 60-90% ethanol covers alcohol.1 - Separate cleaning, feeding and Daily cleaning and disinfection should include treatment supplies food and water bowls, animal transport • Foot baths may be used in addition, but vehicle, and hallways to reduce the risk for should not be exclusively relied upon environmental transmission of any infectious disease. Food/water bowls should be made of • Ventilation as separate as possible stainless steel instead of plastic because - At least separate by full wall and door - scratched plastic is difficult to fully disinfect.1 Designated area within a common air

space may not be sufficient17 Environmental decontamination/ removal of infected animals Cleaning and disinfection Most CIRD pathogens survive in the Careful and effective cleaning by well-trained environment no more than a few hours to a employees is mandatory for control of few weeks (Bordetella bronchiseptica) and are infectious disease and reducing the dose of inactivated by virtually all routinely used infectious agents in the environment. Time and disinfectants. Although most canine money spent on training and supplies for an respiratory pathogens are inactivated by effective cleaning program will result in quaternary ammonium products, it is still decreased costs due to disease. Cleaning/ recommended that the routine daily cleaning disinfection protocols should include runs, and disinfection regimen include the use of cages, walkways, carriers, doorknobs, exam bleach (5%sodium hypochlorite) diluted at tables, food/water bowls, and animal transport 1:32 (1/2 cup per gallon) or Trifectant®1. For vehicles. The protocols should be applied to all optimum killing activity, environmental housing areas, intake areas, and any other surfaces contaminated with feces, urine, vomit, location in the facility where there is animal blood, and nasal discharge must first be contact. Cleaning/disinfection should proceed cleaned with a detergent and rinsed before from the most vulnerable animals to the least applying the bleach or Trifectant solution. The vulnerable animals and from the cleanest areas minimum required contact time for bleach or to the most contaminated areas.1 The Trifectant is 10 minutes. Air drying is recommended order is: preferred if possible, but if an animal needs to be moved into the run or cage, the area should • Puppies in general kennel be rinsed after the 10 minute contact time and • Adults in the general kennel then dried using a squeegee or towel.1 • Quarantined puppies • Quarantined adults Survival of primary and secondary • Animals in isolation pathogens may be greatly enhanced by Separate cleaning supplies should be persistent moisture in the environment; dedicated to each area and not swapped therefore surfaces should be in good repair between areas. To avoid tracking of to prevent pooling of water, and

13 OUTBREAK cleaning should be followed by thorough followed. This depends on availability of MANAGEMENT drying on a daily basis.7 For disinfectants, empty clean runs/cages at the end of each more is not better! The more concen-t rated the row. The dog next to the empty run/cage is solutions, the more irritating and damaging to placed in that run/cage, and the vacated run/ skin, eyes, and the respiratory tract of animals cage is cleaned, disinfected, and dried. The and staff. If a dog has a respiratory infection, next dog in line is moved to the cleaned run/ the fumes generated by disinfectants that are cage. The process is repeated until all dogs on too concentrated only worsen the disease due a row have been moved down one run/cage, to tissue irritation.7 leaving an empty run/cage at the end that is There is no effective method to clean and cleaned and disinfected for repeating the disinfect dog runs and cages if all are occupied. process the next day.7 Automatic waterers, In these situations, there are two concepts for water bowls, food pans, and toys should be cleaning dog runs and cages. For “T” kennels included in the daily cleaning/disinfection.7 or double-sided runs separated by a guillotine Additional information comparing the most door, the dogs can be confined to one side commonly used disinfectants and pathogen with the guillotine door while the other side is susceptibility is available from Iowa State cleaned, disinfected, and dried. The process is University Center for Food Security and then repeated for the other side of the run.7 Public Health’s publication “The For runs without guillotine doors or a cage Antimicrobial Spectrum of Disinfectants”.23 setup, the“move down one” concept can be

CONCLUSION As with any situation, there are very few hard pathogen. If you have specific questions and fast rules. An examination of our data regarding testing, planning or managing an within the Zoetis database revealed more than outbreak of CIRD, we welcome the one quarter of practitioners reporting cases of opportunity to work with you and your coughing dogs were not pursuing diagnostic practice. This technical bulletin is intended to testing. As we consider the potential value of assist the veterinary practitioner manage an identifying emerging diseases and the need outbreak situation, but is not anticipated to If you have from an epidemiological standpoint to monitor replace the assistance of Veterinary Medical specific these pathogens, we believe the benefits of Information and Product Support questions diagnostic testing cannot be over-e mphasized. (VMIPS). You are welcome to contact us regarding Almost one-quarter of the cases reported directly at 888-Zoetis1 M-F 9-8 EST and testing, between 2011-2012 had two or more pathogens speak with one of our veterinarians regarding planning or identified which continues to support the your individual situation. management of conclusions of current CIRD research.24 For more information regarding the CIRD outbreak Almost as important is the finding that close to Immunization Support Guarantee or other please contact 15%of our reported cases had no pathogen Zoetis programs, please visit our website VMIPS at 888- identified. In these cases, it is difficult to know www.zoetisUS.com/VMIPS. If you have an Zoetis1 if we are not testing for the right pathogen, iPhone, our VMIPS app, VKNOW, is now sampling issues occurred, or if our timing of available in the itunes store. With this app, the sample collection missed the peak shedding VMIPS is available at your fingertips. of the

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