Bovine respiratory disease is a major cause of morbidity and mortality in cattle in the United States. This complex disease is caused by the combination of multiple factors, including various viral and bacterial pathogens and environmental and management-related stressors. The illness affects all segments of the cattle industry and all classes of cattle. A previous report indicated that BRD affects 16.2% of all cattle at feedlots, and 96.9% of feedlots reported cases of BRD (USDA, 2013). Even though there is a lack of information about the incidence of BRD in the stocker sector, it is possible that BRD occurrence at this segment is higher than that reported for feedlots, due to stress associated with management practices and the young/lightweight state of cattle in these operations. In cow-calf operations, BRD is responsible for 31.4% of total pre-weaning calf mortality (USDA, 2010). In the dairy industry, BRD was reported by 60.5% of dairy operations (USDA, 2018) and accounts for 24.0% and 58.9% of mortality in pre-weaned and weaned dairy heifers, respectively (USDA, 2018). According to the USDA, BRD accounted for 23.9% of deaths in cattle. This mortality results in economic losses of $907.8 million (USDA, 2017). This calculation does not include costs of treatment, labor, and production losses associated with BRD; those costs, which have not been well estimated, likely increase all BRD-related losses to over $1 billion per year (Ishmael, 2001).

     Bovine respiratory disease is a multifactorial and polymicrobial illness caused by viral and bacterial co-infections. Viral agents such as Bovine viral diarrhea virus (BVDV), Bovine respiratory syncytial virus (BRSV) Bovine herpes virus 1 (BHV1), Bovine parainfluenza 3 virus (BPI3V) are commonly involved as causative agents. Commensal bacteria of the upper respiratory tract including Mannheimia haemolytica and Pasteurella multocida, can often cause secondary infections that complicate the pathogenesis of BRD and may result in severe illness. In addition, Histophilus somni and Mycoplasma bovis often contribute as causal microorganisms of BRD. These pathogens elaborate virulence factors that allow them to evade clearance by the immune system but can induce significant inflammation (Shirbroun, 2020). In addition, Bovine coronavirus (BCoV) and Influenza D virus (IDV) have been identified in the bovine respiratory tract and have recently gained considerable attention in the etiology of BRD.

     Multiple factors influence the occurrence of BRD, including management-environmental conditions, host immune status, and virulence of pathogens. Therefore, BRD control should focus on mitigation of all involved factors. Management practices such as weaning without pre-conditioning, long distance transportation, multi-source comingling and on-arrival castration are major risk factors for BRD. However, the economic pressure of cattle industry and the lack of inducements at the cow-calf operation level limit incentive for significant management improvements that reduce the risk of BRD and the associated economic losses at the subsequent cattle production segments (e.g. feedlot operations). A holistic approach to BRD control should focus on producing less susceptible calves (with stronger immunity) to enter the stocker/back-grounding and feedlots operations, which would result in reduced BRD morbidity and less treatment costs (Peel, 2020). These risk factors that make a calf more susceptible to suffer clinical respiratory disease may affect the host immune interactions at different degrees depending on their genomic background. Research performed by members of the NC1192 identified several differentially expressed genes in whole blood at arrival that revealed clear differences between calves that succumbed with BRD and those that resisted BRD, suggesting the existence of host immune factors that confer protection against BRD (Scott et al., 2020). Further studies have demonstrated that there is a considerable variation in the calves’ response to bacterial lung infection that may represent “tolerance” to pulmonary infection (Bassel et al., 2020). The aforementioned risk factors may affect the host immune interactions resulting in loss of such tolerance that leads to a severe lung inflammatory response after infection. In addition, significant efforts have been directed toward the study of genetic variation of pathogens involved in BRD and virulence factors associated with evasion of the immune response and antimicrobial resistance. A better understanding of this host-environment-pathogen triad and its complex interactions determines the success of BRD control and is one of the main areas of focus of the current NC1192 research project.

     Bovine respiratory disease is routinely diagnosed based on clinical signs. Improvement of case definition is crucial to develop reliable tests. Significant efforts of NC1192 have been directed at improving clinical BRD diagnosis. The California Experiment Station developed a clinical scoring system for BRD that allows quick and easy assessment of calves housed in group pens for BRD (Maier et al., 2019). In addition to clinical diagnosis, improvements in diagnosis of infectious agents have been performed and these may help to develop improved control measures. Unfortunately, the clinical significance of some detected pathogens in addition to difficulties in the interpretation of diagnostic tests make BRD diagnosis complex, and reveal huge gaps in the current knowledge. Development of field tests for rapid pathogen detection (e.g. colorimetric spot tests for BRD pathogens) would permit immediate isolation of positive animals limiting disease transmission. Such tests may also have a significant impact on disease control. Practical diagnostic tests for BRD should be meticulously validated based on accuracy, repeatability and agreement before they are used by veterinary practitioners and producers. Diagnostic laboratories have evolved to the use of genomics, developing and validating PCR protocols for virus detection. This has allowed to identify new pathogens from BRD cases (e.g. BCoV and IDV, (Fulton, 2020). However, current investigation should be focused on determining the contribution of such newly identified pathogens in the pathogenesis of BRD.

     A review of the scientific literature published during the last 37 years revealed solid evidence of the benefits of vaccinating beef calves around the time of weaning with multivalent modified-live viral (MLV) vaccines reducing BRD morbidity and mortality after weaning. However, it is uncertain if vaccination of young beef calves reduces BRD illness and death before weaning. Regarding vaccination of young dairy calves, there is still conflicting evidence of the efficacy of MLV vaccines on the reduction of BRD morbidity and mortality (Chamorro and Palomares, 2020). It is clear that the level of maternally derived antibodies, the infectious pressure of each farm, and the degree of homology of field versus vaccine virus strains affect the efficacy of BRD vaccination of cattle. Knowledge gaps about diagnosis and efficacy/safety of vaccination will be addressed by research in the proposed NC-1192 project.

     The work described in this project is the result of multidisciplinary and collaborative efforts of NC1192 state members and their interaction with other researchers, state diagnostic laboratories, veterinary practitioners, pharmaceutical industry and cattle producers with the long-term goal of preventing and controlling BRD in North America. Multiple research studies will be performed in the areas of epidemiology, molecular biology and genetics, immunopathogenesis of BRD pathogens, bacteriology, virology, diagnostics and vaccinology, nutrition, animal behavior and husbandry to provide science-based recommendations that enhance diagnosis, prevention and treatment for BRD. In addition, members of NC-1192 consistently work to maintain excellent relationships with national organizations such as the American Association of Bovine Practitioners (AABP) and Academy of Veterinary Consultants (AVC) to understand the challenges cattle industry faces and keep a clear focus on the priorities to be investigated regarding BRD. A significant portion of the research performed by NC1192 stations translates into practical applications to cattle production systems. The project’s research efforts help to provide improved information regarding the causes and risk factors associated with the occurrence of BRD, enhances understanding the interactions between pathogens and the host immune response during co-infections, and assesses the accuracy of new diagnostic tools and the efficacy of novel control strategies. Furthermore, recognizing the substantial economic losses caused by BRD, the current NC1192 project is including an additional objective to quantify the economic impact of the disease among the different sectors of cattle industry and how the implementation of control may reduce the incurred losses.

     Through integrated efforts, NC1192 will facilitate the dissemination of this information to the cattle industry where it can be applied. An effective way that the NC1192 multistate project has found to share this information with veterinary practitioners and producers is through regional and national events such as the “BRD Symposium” organized by its members every 5 years (www.brdsymposium.org). Impacts of the proposed research will include: 1. Veterinarians and cattle producers will have access to science-based recommendations for the control and prevention of BRD in cattle managed in modern U.S. production systems; 2. Researchers in academic, government, and industry laboratories will be provided with basic foundational and applied information regarding BRD that will be necessary for their ongoing work to advance scientific discovery in the fields of vaccinology, immunology, microbiology, pharmacology, and animal husbandry; 3. Scientists, veterinarians, and policy makers working to minimize unnecessary use of antimicrobials will be provided with basic and applied information regarding methods to enhance resistance to BRD by maximizing the use of vaccines and management strategies that will minimize the need for antimicrobials; 4. Scientists, educators, and policy makers will be provided with cutting-edge information regarding the mechanisms by which cattle develop BRD, and regarding science-based methods to minimize or prevent the impacts of BRD; 5. Veterinarians and cattle producers will be regularly educated regarding both new developments in the science of BRD, and in rational and practical methods to limit the impact of BRD in U.S. cattle, and 6. Cattle producers, veterinarians, and scientists will have updated information regarding the economic impact of BRD, enabling the development of cost-effective control strategies.