Overview of bovine respiratory disease (BRD) and status of research

The impact of BRD is extensive with economic losses occurring due to morbidity, mortality, treatment and prevention costs, loss of production and reduced carcass value (Griffin, Reference Griffin1997; Smith, Reference Smith2000; Irsik et al., Reference Irsik, Langemeier, Schroeder, Spire and Roder2006). Research on BRD has been a longstanding priority for the United States Department of Agriculture (USDA) and the veterinary profession. Various types of research are in place ranging from basic discovery to clinical studies in the field applying the knowledge gained from the basic studies. There has been a multistate research project, initially supported in the North Central (NC) region of the United States by agricultural experiment stations (AES), with projects involving veterinary medical colleges and veterinary science departments. That regional distinction (North Central US) does not reflect the national participation within the group, including California, Georgia and many states in between. This research group sponsored a BRD research symposium in 1983 in Amarillo, TX and the proceedings book was published in 1984 as Bovine Respiratory Disease: A Symposium (Reference Loan1984). That symposium was designed for researchers to interact with the industry and veterinarians involved with BRD, and to obtain guidance for future research.

This national research involvement reflects the fact that the cattle industry is represented by cowherds in most regions with the movement of cattle across many states from forage post-weaning to feedlots now predominating in the southwest and central regions where the feeds are grown for the feedlot rations. In addition to the multistate project, other funding sources are from the USDA, Hatch projects and commercial firms, as well as limited funds from producer groups and private foundations. To a small extent, some basic research with cattle as a model for human disease has been supported by the National Institutes of Health (NIH). Accountability for the BRD research positively impacting the industry will be critical for funding. Outcomes indicating the benefits of BRD research include but are not limited to: (1) reduction of disease incidence; (2) better understanding of the pathogenesis of BRD, especially viral–bacterial interactions; (3) detection of new infectious agents and new strains of the current agents; (4) understanding and application of knowledge of the acquired and innate immune systems; (5) development of new vaccines and therapeutic agents that complete the approval process, and are used in the industry and recommended by veterinarians; (6) industry and veterinarians successfully applying research findings to the prevention and control of BRD and (7) recognition by medical and basic science researchers of the scientific discoveries in veterinary medical research. On the latter point the US Library of Medicine website (PubMed) shows that from 1982 through 29 April 2009 there were 1952 publications on various aspects of ‘bovine respiratory diseases’ in that database.

Several publications have addressed the current state of BRD. Representative publications have surveyed the industry for BRD in feedlots. In a survey using a feedlot monitoring program through feedlot veterinary consultants overseeing 21.8 million cattle in 121 US feedlots, there was a trend for increased mortality ratio for respiratory tract disorders from 1994 to 1999 (10.3 deaths/1000 in 1994 to 14.2 deaths/1000 in 1999) (Loneragan et al., Reference Loneragan, Dargatz, Morley and Smith2001). Also, a 2005 survey (Woolums et al., Reference Woolums, Loneragan, Hawkins and Williams2005) of feedlots indicated that the BRD complex was the leading cause of morbidity and mortality: 12.8% of the cattle were treated for BRD and 0.8% died of BRD. Thus even with current prevention and control measures, the clinical impact of BRD continues. In addition to research publications and clinical reports, knowledge related to BRD has been summarized with reference to diseases and their control using modern terminology (Bovine Respiratory Disease Handbook, 2007).

Interestingly, when one examines the vaccines and therapeutic agents available in 1983 compared to 2009, it becomes clear that there have been considerable advances. This represents an impressive measure of the research over the past 26 years. The list of vaccines and therapeutic agents in the Veterinary Pharmaceuticals and Biologicals 1982/1983 revealed several modified live viral (MLV) vaccines containing bovine herpesvirus-1 (BHV-1), also known as infectious bovine rhinotracheitis virus; bovine viral diarrhea virus (BVDV) with no genotype noted, and parainfluenza-3 (PI-3V) for parenteral use. There were a limited number of MLV BHV-1 vaccines for intranasal use. One killed virus (KV) vaccine with BHV-1, PI-3V and BVDV, and a second KV vaccine with BHV-1 and PI-3V were noted. There were no licensed bovine respiratory syncytial virus (BRSV) vaccines available. Mannheimia haemolytica (formerly Pasteurella haemolytica) and Pasteurella multocida bacterins were available, but it is likely they have been replaced by the current products. Also many viral products were marketed with a leptospiral bacterin component. The antibiotics listed in 1982–1983 will be unknown to recent graduates. Those for BRD treatment included erythromycin, penicillin–dihydrostreptomycin, tylosin injectable and oral oxytetracycline, and injectable sulfamethazine. Also many of the animal health companies in 1983 have been merged, sold, or renamed. Twenty six years later in 2009 there is an extensive list of vaccines and therapeutics in the Compendium of Veterinary Products, 11th edition (2008). A new list of companies is noted in the reference above and the list will be entirely renamed as potential mergers are completed.

The available vaccines in 2009 reflect the research in the identification of selected viruses, and the addition of selected strains of viruses. There are MLV vaccines for injection or intranasal use for BHV-1, BVDV1a and BVDV2a, PI-3V, and BRSV as well as KV vaccines for these same viruses for injection. In some cases the vaccine strains of 1983 are now described more fully, such as the BVDV1a and BVDV2a identified in many current vaccines, which was simply listed as BVDV in 1983. Although updates have occurred, many of the vaccinal strains of BHV-1, BVDV, PI-3V are isolates from 35 to over 50 years ago. A case in point is the BHV-1 Colorado strain reported as an MLV vaccine in 1957. An almost-complete new list of therapeutic agents in 2009 is listed in the Compendium of Veterinary Products, 11th edition (2008).

Many of the antimicrobials available in 1983 are no longer available, often due to residue and safety issues. Antibiotics in use today include the principal marketed injectables: ceftiofur, oxytetracycline, enrofloxicin, florfenicol, danofloxacin, tilmicosin and tulathromycin. Also listed in the 2008 publication are injectable tylosin, erythromycin and penicillin. A new therapeutic agent available in 2009 is the non-steroidal anti-inflammatory product flunixin meglumine. There are also numerous oral medications such as sulfas, tetracyclines and tylosin.

Infectious agents

Research progress on infectious BRDs ranges from additional information on their epidemiology, role in clinical disease, characterization based on genomes and proteins of the agents, and demonstration of pathogenicity in challenge studies. The types of studies include reports of a single case; summaries of diagnostic lab reports (usually the end stage pneumonia and nasal swab isolates from sick calves); and studies over time, such as feedlot seroepidemiologic studies, with or without periodic virus isolation. Examples of these types of studies with the identification of agents including viruses and bacteria are reported (Martin and Bohac, Reference Martin and Bohac1986; Fulton et al., Reference Fulton, Purdy, Confer, Saliki, Loan, Briggs and Burge2000, Reference Fulton, Ridpath, Saliki, Briggs, Confer, Burge, Purdy, Loan, Duff and Payton2002b). Also reported are a wide variety of experimental challenge studies of susceptible calves with one or more of most of the agents involved in BRD. In addition studies have been performed where calves dying in a feedlot over time are necropsied, the pathologic lesions characterized, and the agents isolated or detected. Although such studies may emphasize end stage pneumonia, and initiating viruses and/or bacteria may not be detected, they do provide information regarding agents involved and lesions associated with fatal pneumonic cases.

A very significant study was reported in the late 1970s, which identified the pneumonic lesions and infectious agents found in a long-term survey of fatal pneumonia cases in a Colorado feedlot. This study was widely referenced and formed the basis for description of fatal feedlot pneumonias (Jensen et al., Reference Jensen, Pierson, Braddy, Saari, Lauerman, England, Keyvanfar, Collier, Horton, McChesney, Benitez and Christie1976a, Reference Jensen, Pierson, Braddy, Saari, Lauerman, England, Keyvanfar, Collier, Horton, McChesney, Benitez and Christieb). In 2006 and later there were additional studies of fatal feedlot deaths with lesions described and infectious agent reported. Many similarities were found between the 1976 study and the more recent studies, although some technologies for agent identification used in more recent studies (such as IHC and PCR) were not available in the 1970s. These 2006–2009 reports included an Ontario, Canada study of 99 calves dying in 72 Ontario feedlots in the first 60 days of the feeding period (Gagea et al., Reference Gagea, Bateman, van Dreumel, McEwen, Carman, Archambault, Shanahan, Shanahan and Caswell2006b); and a study by Booker et al. (Reference Booker, Abutarbush, Morley, Jim, Pitman, Schunicht, Perret, Wildman, Fenton, Guichon and Janzen2008) of 99 calves dying in the first 60 days after entry into 17 feedlots. A 2009 study (Fulton et al., Reference Fulton, Blood, Panciera, Payton, Ridpath, Confer, Saliki, Burge, Welsh, Johnson and Reck2009) was from one feedlot with 237 samples from animals dying in the feed yard regardless of time after arrival, with a range of 1–241 days after arrival.

Research on the viral infectious agents in BRD since 1983 has largely focused on BHV-1, BVDV and BRSV. Few publications dealing with PI-3V singly were reported, with most reports including PI-3V as one of multiple viruses and bacteria described. The bovine coronavirus (BCV) also received attention with its isolation from calves with BRD after shipment and commingling (detailed below). Beginning in the late 1970s and the early 1980s a major emphasis was placed on M. haemolytica as the stand alone disease potential for M. haemolytica was substantiated by challenge studies. Also P. multocida has received increased research focus. Histophilus somni (formerly Haemophilus somnus) remains a significant pathogen as reported by diagnostic laboratories; however, considerably more reports from Canada have been published on the prevalence of disease and specific lesions associated with H. somni, as compared to the US Mycoplasma spp. in cattle have long been recognized as a cause of respiratory disease, but the involvement of Mycoplasma bovis in respiratory disease and its relative role in BRD has received considerable attention since 1983, both from the diagnostic laboratory and in regard to the potential role for vaccination. The research on BHV-1, BVDV, BRSV, M. haemolytica and P. multocida has led to advances in the various vaccines for these agents, and their use in the management of cattle. Any discussion of the agents will include involvement of the immune system. The coverage of the research findings on each agent is extensive and the reader is referred to excellent review articles for each infectious agent. Selected publications will be cited to illustrate the basis for certain research directions.

Immune response and pathogenesis

The review of the literature since the 1983 symposium on BRD indicates a major emphasis on the host response/immune response to the various infectious agents. These reports often reflect advances made in the understanding of the immune system components and in the technology available to evaluate them, as research advances in lab animal models and human immunology have been applied to the bovine immune system. With advances in the characterization of the various components of bacteria and subunits of viruses, studies of the immune response now focus on the specific immune response to the subcomponents rather than the whole organism or virus. Often these specific immune responses can guide the selection of the most likely epitope for selection as immunogens. A review article by Ellis (Reference Ellis2001) summarized the immune responses to various viral and bacterial agents of BRD.

The immune system is complex with various components often working in concert. Advances in the understanding of acquired immunity have focused on the T-cell (cell-mediated immunity, CMI) and the B-cell (humoral) components of the response (Woodland, 2003). The T-cell system is further divided into classifications such as CD4+ T cells and CD8+ T cells (Esser et al., Reference Esser, Marchese, Kierstead, Tussey, Wang, Chirmule and Washabaugh2003). The CD8+ T cells are also referred to as cytolytic T cells. The CD4+ T cells can be differentiated into either T helper 1 (Th1) or T helper 2 (Th2) cells that secrete specific sets of cytokines. These cytokines can drive the immune response toward either a strong CMI response, or a strong humoral (antibody) response, and the direction the immune response takes is largely associated with specific cytokines produced by either Th1 or Th2 cells. In general, the Th1 response is associated with a CMI or pro-inflammatory response, while the Th2 response is associated with antibody mediated responses. Cytokine gene expression for CD4+ and CD8+ T cell subsets has now been described for cattle (Tanaka et al., Reference Tanaka, Aso, Miyazawa, Nagai, Watanabe, Ohwada, Kobayashi and Yamaguchi2007). In addition to the CMI and antibody response related to T cells, the T cell system in cattle includes other components such T regulatory cells (de Almeida et al., Reference de Almeida, Colvine and Coussens2008). T regulatory cells when activated may limit the Th1 response. In a review article, several studies indicated that numerous viruses, bacteria and parasites induce immunosuppressive T regulatory cells as a normal part of the immune response (Robertson and Hasenkrug, Reference Robertson and Hasenkrug2006). Also, T cells have a significant role in antigenic memory, especially for protective immunity in animals recovering from initial infection or in the response to vaccines (Esser et al., Reference Esser, Marchese, Kierstead, Tussey, Wang, Chirmule and Washabaugh2003). Assays of T cell responses to infectious agents in challenged and vaccinated animals have been used in numerous studies. This is illustrated in a study detecting the T-cell and antibody response to BHV-1, BVDV1 and 2, and BRSV in calves following vaccination with an MLV vaccine containing these antigens (Platt et al., Reference Platt, Burdett and Roth2006). There are several similar studies using T cell function assays as well as tests to measure the mRNA for various cytokines.

Research on the pathogenesis of BRD undertakes examination of the interaction of the agent and the host immune response, including the synergistic effect of viral–bacterial co-infection, which may lead to enhanced disease. For example, increased fatal bacterial respiratory disease following primary viral infection has been observed for several species (Hodgson et al., Reference Hodgson, Aich, Manuja, Hokamp, Roche, Brinkman, Potter, Babiuk and Griebel2005). An experimental model of this viral–bacterial synergy has been described that utilizes primary BHV-1 respiratory challenge followed by aerosol challenge with M. haemolytica (Ohmann and Babiuk, Reference Ohmann and Babiuk1985; Ohmann et al., Reference Ohmann, Babiuk and Harland1991; Babiuk et al., Reference Babiuk, van Drunen Little-van den Hurk and Tikoo1996). This model has been used to elucidate mechanisms of viral–bacterial synergy; for example, as found with functional genomic analysis indicating that BHV-1 altered Toll-like receptor (TLR) expression and pro-inflammatory responses, which contributed to the severity of M. haemolytica infection (Hodgson et al., Reference Hodgson, Aich, Manuja, Hokamp, Roche, Brinkman, Potter, Babiuk and Griebel2005). This study was based on advances in immunology that show the importance of pro-inflammatory responses stimulated by interaction of bacterial components with TLR; it is further evidence of the use of molecular techniques to better understand the host response related to viral–bacterial synergy in BRD.

The ability of infectious agents to evade the immune system complicates the pathogenesis of BRD and may render the host unable to develop a protective immune response (Srikumaran et al., Reference Srikumaran, Kelling and Ambagala2007). This review summarizes how infections alter the acquired and innate immune systems, and how infectious agents modify themselves to evade the host responses. These points offer explanations for the failure of vaccines to provide complete protection against BRD.

Prevention and control

There are far more effective vaccines and therapeutic agents available today as compared to 1983. The viral and bacterial vaccines have modifications including adjuvants and addition of new strains and serotypes. Vaccine production involves monitoring for contamination by adventitious agents. The M. haemolytica vaccines are excellent examples of the upgrading of BRD vaccines, which includes completion of efficacy studies. There have been remarkable changes in available antibiotics since 1983. Despite these new products there continues to be respiratory disease issues among various components of the cattle industry. The BRD losses in the feedlot are noteworthy, as shown by the survey of feedlots by Woolums et al. (Reference Woolums, Loneragan, Hawkins and Williams2005) indicating the continued presence of BRD.

The successful application of prevention and control programs based on reduced disease and economic benefit from these programs is often not realized. Those promoting the use of vaccines and therapeutic agents must look for the critical control points for the intervention, especially, regarding the pathogenesis of the disease. It is difficult to ask a vaccine to alter the pathogenesis of disease if given to an already infected animal with a compromised immune system. Many believe the health status begins in the breeding herd for cattle destined to remain healthy and return a profit. While not a fundamental or basic research assignment, the economics of the beef industry largely drive the marketing and sale of cattle and may impact the effectiveness of these better vaccines and antibiotics. Several studies have shown that the ‘preconditioned calf ‘ that was weaned 30–45 days with proper vaccines and anthelmintic treatment will be more valued and will bring a higher price. However, some believe that there is a potentially greater economic return for the management of disease than can be realized by paying a higher price for healthy calves, thus justifying the lower price for the high risk calves. A relatively new term is ‘metaphylaxis’ which is the use of antibiotics in calves considered ‘high risk’ before the clinical signs of bacterial disease are evident (Bovine Respiratory Disease Handbook, 2007). Measuring success of new technologies used to manage high risk calves is often difficult. A case in point is the use of vaccines in high risk calves at feedlot arrival and the resulting failure to see benefit for the vaccine at the feedlot. One such example is a study with M. haemolytica vaccine given to calves at entry to the feedlot, with performance compared to non-vaccinates. There was no difference in BRD mortality, morbidity, or average daily gain (MacGregor et al., Reference MacGregor, Smith, Perino and Hunsaker2003). However there are reports where cattle with high levels of immunity to selected agents prior to entry to the feedlot had less illness and reduced treatment costs and returned more value to the owner at the end of the feeding period (Fulton et al., Reference Fulton, Cook, Step, Confer, Saliki, Burge, Welsh, Blood and Payton2002a).

The potential for the industry to change offers opportunities for the promotion of health versus managing disease. There have been studies reporting on the economic benefit and disease reduction benefit to ‘preconditioned calves’. Calves vaccinated or conditioned and sold through special auctions received a premium compared to producers selling at conventional auctions, and vaccinated and conditioned calves were less likely to receive treatment for BRD in the first 28 days in the feedlot (Macartney et al., Reference Macartney, Bateman and Ribble2003a, Reference Macartney, Bateman and Ribbleb). A summary of certified health programs indicated that cattle from the certified health program when sold through livestock videotape auction service consistently yielded improved price and these increased over time (King et al., Reference King, Salman, Wittum, Odde, Seeger, Grotelueschen, Rogers and Quakenbush2006). Another study from a commercial feedlot where calves from different backgrounds were purchased and fed until processed showed that calves receiving the certified health protocol yielded more net income compared to those with unknown health history (Seeger et al., Reference Seeger, Grotelueschen, Stokka and Sides2008). In summary there is evidence that under certain conditions cattle with documented health programs may perform better and return more value to the owner than those of unknown history.

Research areas

BRD will continue to be a significant clinical issue for all phases of the cattle industry, affecting value of animals marketed, profitability to producers, and providing challenges to veterinarians and diagnosticians faced with a need to make accurate and timely diagnoses. Research findings validated to improve production will assist veterinarians in making prevention and control recommendations. Animal health companies will be challenged to develop therapeutic agents and vaccines that meet the industry's needs and capabilities, and regulatory agencies' requirements for approval. The industry will potentially have to deal with the disease as an animal welfare issue, and also to attempt to lessen the use of therapeutic agents that have use in human therapy. Public concern over animal welfare and antibiotic use in food animals will likely continue. With numerous technologies available to investigate the agents and the immune system, there is great potential for discoveries. Granting agencies will be expected to assist in the extramural funds required for these projects. Future research areas for investigation include: (1) monitoring for emerging or re-emerging infectious agents and antigenic variants; (2) evaluation of acquired immunity (T- and B-cell) involved in recovery and vaccine-induced protection; (3) evaluation of innate immunity; (4) development of innovative vaccines using new technologies, and perhaps addition of current strains, as some vaccine strains have been in use for over 50 years ago; (5) development of diagnostic tests for field use; (6) delivery of vaccines given by different routes or based on new technologies; (7) adjuvants that are effective and safe for use in food animals; (8) diagnostic tests that differentiate vaccine-induced immunity versus response to natural infections; (9) new therapeutic agents; (10) studies to determine the economic cost of disease and to confirm enhanced economic return for prevention and control programs; (11) bovine genome mapping with the use of markers for resistance to disease and enhanced immune response to vaccines (The Bovine Mad Consortium [2009]); (12) application of research results to the current marketing system for cattle and (13) animal welfare issues for the cattle industry and producers, including reduction in use of therapeutic agents.