The inner workings of BRSV

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Bovine respiratory syncytial virus (BRSV) infects many types of epithelial cells in both the upper and lower respiratory tracts, including tonsilar epithelium. In humans, HRSV is considered one of the “common cold” viruses in older children, adolescents and adults, especially in those that have some level of immunity as a result of previous RSV infections. It is likely that the same thing occurs in cattle with BRSV infections explains John Ellis, DVM, PhD, Dipl. ACVP, Dipl. ACVM, Western College of Veterinary Medicine, University of Saskatchewan.

“In other words, in older calves and cattle with partial or waning immunity to BRSV, the primary clinical signs may be those of upper respiratory tract disease, i.e. ‘cold-like’ symptoms that could easily be confused with respiratory infections due to bovine coronavirus or PI3,” Ellis says. “Lower respiratory tract disease, especially severe lower respiratory tract disease that is often considered characteristic of BRSV infection, probably occurs most often in calves with waning passive immunity, or in older naïve cattle. HRSV, as well as other viruses that infect the upper respiratory tract, are well documented etiologic agents in otitis media. There are no reports of a similar clinical phenomenon with BRSV in cattle, but then, maybe no one has looked.”

You can see some upper respiratory tract signs with BRSV such nasal and ocular discharge, but these are not severe and prominent as they can be with BHV-1. “You don’t see much, if any, evidence of laryngeal or tracheal inflammation (e.g., inspiratory noise [stridor]) clinically or grossly at necropsy,” adds Amelia Woolums, DVM, PhD, Dipl. ACVIM, Dipl. ACVM, University of Georgia. “However, the virus can be found in the nasal and tracheal mucosa in infected calves, so it does replicate and cause some inflammation in these tissues. But the most important problems due to BRSV occur in the bronchi, bronchioles and alveoli.”

The lower respiratory system traditionally is considered to begin at the end of the trachea, where it branches into the two mainstem bronchi. The mainstem bronchi branch repeatedly to form additional bronchi, and then bronchioles. Terminal bronchioles end in the alveoli, where gas exchange occurs and oxygen is taken up and carbon dioxide is released.

BRSV is a major lower respiratory tract pathogen, but it’s not the only one that can cause damage. Another recognized viral pathogen that primarily affects the lower respiratory tract is parainfluenza 3 (PI3), says Ellis. “Important bacterial pathogens that can cause disease in the lower respiratory tract include, Mannheimia hemolytica, Pasteurella multocida and Mycoplasma spp.

Woolums adds that, bovine viral diarrhea virus (BVDV) sometimes affects cells of the lower respiratory tract. Although BHV-1 primarily causes disease in the upper respiratory tract, it can spread to the lower respiratory tract and, especially in newborn or debilitated calves, can occasionally cause severe viral pneumonia.

Calves are the main target

Although BRSV can certainly be an important viral co-factor in bovine respiratory disease (BRD) in feedlot cattle, Ellis says in terms of prevalence and severity of disease, that dairy calves are the most important “targets” of BRSV infection. Several factors account for this, including the housing and management of calves in close confinement that enhances transmission of the virus, and perhaps more variability in passive immunity, especially in the case of male dairy calves.

“Summer pneumonia” is a classical example of a virus taking advantage of the “window of susceptibility”, in other words, that time when maternal anti-bodies have decayed to nonprotective levels and the calf has not developed active immunity through vaccination or exposure. “That syndrome is probably most important in beef calves, that, some-what ironically, if they are born and reared on pasture, probably have less opportunity to be exposed to the virus,” Ellis says. “That reduced exposure not only reduces their chances of developing clinical infections early in life, but also reduces the ‘free vaccination’ or the immune priming that they would get by natural exposure in the face of disease-sparing maternal antibodies.”

BRSV can cause clinical disease in older heifers and adult cows, but generally, as in the case of HRSV, older individuals will often have less severe or subclinical BRSV infections by virtue of naturally acquired immunity due to the endemicity of the RSV infections in populations. Nevertheless, there is some evidence that even subclinical BRSV infections can have an economic impact in dairy operations by reducing milk yields, “Which makes sense maybe even from the perspective of reduced feed intact in an individual that just doesn’t ‘feel right’ due to cold-like symptoms,” Ellis notes.

Woolums adds that feedlot cattle have definitely been found to seroconvert to BRSV around the time of shipment to the feedlot, and in some studies, this seroconversion was associated with treatment for BRD. “So, BRSV does contribute to BRD in feedlots,” she says.

Profiling BRSV

Experimental BRSV infection demonstrates that the virus is shed from approximately day 4 to day 8 post infection. Ellis says shedding usually stops by about 8–9 days. “This is likely the case following natural infection as well, so this is truly an acute infection in most animals.”

Compared to BHV-1, and similar to influenzavirus, BRSV is rather labile in the environment, which can make the diagnosis of active infection by virus isolation difficult, since the virus will often not survive transport to the laboratory, Ellis says. “Having said that, I am always amazed how BRSV can show up in a group of calves when you don’t expect it.”

Since the oral cavity and the nasal passages meet at the pharynx, it’s likely that BRSV entering through the oral cavity is also an effective means of transmission. “Ditto for the eyes and lacrimal ducts,” Woolums says. “Since the lacrimal ducts drain into the nose, BRSV that gets into the eyes probably infects the animal effectively.”

“In contrast to BHV-1, there is no published evidence that BRSV is involved in ocular disease, however in the case of HRSV (human respiratory syncytial virus) it is thought that this virus can be spread in tears, therefore it is likely the same may be true for BRSV,” Ellis notes. BRSV is probably effectively transmitted by both inhalation and “ingestion,” since ingestion would allow contact with susceptible epithelial cells in either the oro or nasopharynx, including tonsilar epithelium.

Woolums adds that nose-to-nose or short distance aerosol are probably the two major means of transmission, but accumulation on fomites probably does contribute to transmission. “This hasn’t really been evaluated formally in cattle, as far as I know, but RSV infection in children is perpetuated in part by fomites like teddy bears, so buckets and bottles probably contribute for calves. Certainly BRSV can be transmitted by the hands orclothing of people handling affected animals and then handling unaffected animals.”

Ellis agrees that BRSV transmission via fomites occurs often. “This is certainly the case with the human respiratory syncytial virus (HRSV) where persistence of the virus on fomites is documented and nosocomial infection with HRSV in pediatric wards is well-recognized.” This has practical implications for biosecurity in a calf barn, especially if people handling calves are also handling cows that could be a source of the virus, he states.

As in the recent influenza pandemic in humans, Ellis suggests that perhaps some of the best advice with regard to iatrogenic transmission of BRSV is to simply wash your hands routinely when handling calves in an environment where BRSV may be present, and clean other equipment, especially rubber nipples and milk bottles if they are being used among a group of calves.

It’s been shown that HRSV and other viruses slow or stop the beating of cilia on ciliated epithelial cells, and this movement is important for moving mucus up out of the airways, preventing infection of the lower respiratory tract. BRSV infects ciliated epithelial cells, so this is likely operative in BRSV infection, too, Woolums suggests. “Of course, BRSV infection can ultimately lead to the death of respiratory epithelial cells, so if the ciliated cell is dead, it isn’t good at keeping bacteria or viruses out of the lower respiratory tract.”

Mechanical damage to the respiratory tract may also be a factor in BRSV infection. Ellis adds that although poorly documented, is almost certain that environmental factors such as dust, high ammonia concentrations, heat and relative dehydration that can cause physical damage non-specific defense mechanisms in the upper respiratory tract and increase the likelihood that inhaled BRSV particles will have an easier time ending up in the lower respiratory tract.

Respiratory tract defenses

The most important defense the lower respiratory tract has against BRSV are the alveolar macrophages, which can bind and engulf pathogens that make it to the alveoli. “Of course, by the level of the alveoli the BRSV is mostly inside of cells, so the macrophages probably don’t have much opportunity to bind and engulf the BRSV,” explains Woolums. Intraepithelial lymphocytes (mostly T cells) can be found within the epithelial cells of the bronchi and bronchioles, and these are mostly CD8 cells (cytotoxic T cells). “These probably kill virally infected epithelial cells in the bronchi and bronchioles, but we don’t know very much about how they work.”

Soluble factors in the lower respiratory tract, such as surfactant proteins, can also bind to bacteria and viruses and identify (opsonize) bacteria and viruses, helping the cells of the immune system bind and engulf or destroy them.

As in the upper respiratory tract, defenses in the lower respiratory tract comprise non-specific anatomical and physiological barriers such as cilia and mucus, innate immune mechanisms such as the phagocytic activity of neutrophils and macrophages and type I interferons, and specific immunity mediated by T cells, interferon gamma and BRSV specific IgA and IgG, Ellis adds. “In cattle, as opposed to some other species, IgG1 is the predominant immunoglobulin in respiratory secretions. So, if BRSV gets down into the lower respiratory tract, into the bronchioles and alveoli, it is potentially susceptible to all of these defense mechanisms.”

After disease-sparing passive immunity has waned, whether or not a bovid or a human develops severe disease subsequent to infection with their respective RSVs probably, in large part, depends on how fast their specific T and B cell immune mechanisms can respond and control virus replication, Ellis says. “In other words, it’s sort of a race between the virus and the immune response. Those individuals with immune memory by virtue of previous exposure or vaccination are more likely to control virus replication and have milder clinical disease. That’s been pretty clearly demonstrated in clinical trials of vaccine efficacy.”

Treating BRSV infections

Cattle with BRSV that do not become too severe often recover with no specific treatment at all. In a BRSV outbreak, it makes sense to avoid any stressful activities that might prolong disease. Woolums recommends putting off mixing in new cattle or any processing needed for a week or two after the last animal has been normal for a few days if at all possible.

It is rational to give antibiotic coverage for 3 to 7 days in a BRSV outbreak, to prevent secondary bacterial pneumonia. Woolums usually recommends furosemide for treatment of cases suspected to have acute interstitial pneumonia, along with antibiotics to prevent secondary bacterial pneumonia, but says none of these recommendations are evidence-based.

Some cattle infected with BRSV develop very severe disease characterized by open-mouthed breathing and subcutaneous emphysema. There are no evidence-based recommendations that can be made about successfully treating such cattle, but since such cattle may have severe alveolitis or even acute interstitial pneumonia, steroids might be helpful for such cases. However, says Woolums, a recent study of the efficacy of steroids in infants with severe human RSV infection showed no benefit, and viral shedding was prolonged in affected infants.

Ellis adds that until recently, in human medicine, ribavirin a specific antiviral agent that interferes with RNA metabolism that is used in treatment of pediatric HRSV cases has been used; however, studies questioning its efficacy have greatly reduced its use. “A humanized monoclonal antibody against the HRSV fusion or F protein that is injected intramuscularly, is pretty routinely used in the treatment and prophylaxis of pediatric HRSV, especially in high risk individuals,” he says. “Given the high degree of sequence homology in the F protein between HRSV and BRSV, this monoclonal antibody would pro-bably have a disease-sparing effect in BRSV-infected calves as well, but it is over $1,000 per milliliter.”

That together with the amount antibody that would be required to treat a >100 lb baby bovid obviously precludes it use. “Increasingly, we are recognizing the role that the host inflammatory response plays in RSV-associated disease, and in infectious diseases in general,” Ellis says. “There are relatively few and inconclusive studies that have examined the use of anti-inflammatory drugs in BRSV infected cattle, but I think this is fertile ground for research which could lead to improved adjunct therapy in cattle with BRSV-associated respiratory disease.”

The “carrier” state

It’s not fully understood how BRSV maintains itself in cattle populations. Ellis believes that epidemiologic evidence indicates the importance of “carrier” animals. Just how and where these individuals carry BRSV remains unresolved. “Certainly, it is different than in the case of BHV-1 where there is well documented latency in both neural and lymphoid tissue,” he says. “Since true latency is not a feature of BRSV infection, it is not as apparent how stressful situations impact on BRSV replication and transmission, but they undoubtedly do, maybe by simply suppressing the immune response to BRSV. As well, the apparent short duration of clinical immunity also probably plays a role in persistence of BRSV in cattle populations, since individual animals can be reinfected and have some level of disease within a few months of a previous infection.”

Whatever the mechanism, Ellis says this could explain outbreaks in the absence of acute infection or introduction of new animals, for example, “summer pneumonia” in a group of suckling beef calves on pasture.

Early prevention of BRSV

In contrast to BHV-1 and BVDV, it is highly unlikely, if not impossible for calves to acquire BRSV infections in utero, primarily due to differences in target cell tropism. BHV-1 and BVDV infect a variety of cell types, including white blood cells. Depending on the immune status of the cow, viremia can occur, thereby providing the opportunity to cross the placenta. “In comparison, BRSV only infects epithelial cells of the respiratory tract to any significant extent, so even if a pregnant cow has an active BRSV infection, the virus is very unlikely to breach the placental barrier,” explains Ellis.

Calves are most likely infected by contact with other calves, or possibly with their mother if she would happen to be infected. Colostral antibody decreases the severity of disease due to BRSV, so good colostrum management is very important for controlling BRSV. However, colostral antibody transfer cannot completely prevent BRSV infection. Ellis says how other colostral constituents may affect BRSV infection, especially in early stages in the nasopharynx, is unknown.

Woolums suggests limiting the disease in calves by separation of age groups—for example, avoid housing situations where calves from birth to 8 months of age are all in contact.

BRSV vaccination

Prior to vaccination, good colostral transfer is a must for calves. After this, a BRSV vaccination should be administered at least a couple of weeks before outbreaks are predicted (e.g., in a situation where past outbreaks have been a problem in calves of a certain age group). Vaccination in the face of maternal antibody may be helpful, though there are examples where calves vaccinated in the face of maternal antibody were not protected from later challenge, Woolums notes. “If calves are suspected to have some maternal antibody, two doses of vaccine at a 2- to- 4-week interval may be more helpful than just a single dose. From work with other viruses and a small amount of BRSV research, it looks like MLV vaccines are better for inducing immunity in the face of maternal antibody, so I recommend MLV vaccines for such situations.”

Although several studies have now documented the significant disease-sparing effect of many commercially available BRSV vaccines, control of BRSV-associated disease in the preweaning calf, is still a challenge, Ellis says, because we don’t completely understand the interaction between passive immunity and the develop-ment of acquired immunity, especially as it relates to the timing of vaccination, the route of vaccine delivery and vaccine formulation. These same challenges are faced in human medicine with HRSV, even though there are still no HRSV vaccines, Ellis says.

Vaccination at weaning/branding (>3 months of age) will generally be effective at stimulating protective BRSV-specific immune responses, because by that time maternal antibodies will have decayed to non-inhibitory concentrations in virtually all calves, but by that age, depending on the management system, many calves will have already been primed through natural exposure, and are thereby less susceptible to developing severe clinical infections anyway.

The same is true in the case of HRSV. “It’s really a timing issue that is almost unique to RSVs and different from BHV-1 and BVDV,” Ellis says. “I think we still don’t know what the ‘best strategies’ are related to BRSV vaccination of young calves.”  

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