PATHOGENS COMMONLY ASSOCIATED WITH BRONCHOPNEUMONIA:

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1 BOVINE RESPIRATORY DISEASE AN OVERVIEW OF A CONTINUING CHALLENGE Jeff Lakritz DVM, PhD, Dip ACVIM The Ohio State University Veterinary Medical Center Hospital for Farm Animals Bovine respiratory disease complex, remains an important economic disease affecting food animals in North America and worldwide, despite improvements in production management, approval of new medications and continuing research in this area. Production losses due to pneumonia remain nearly constant, adding millions of dollars in industry costs annually. Bovine respiratory disease complex results from the temporal coincidence of variety of events including: stress, viral and bacterial infection and management decisions that have varying impact upon animals raised under widely different conditions. The host s response to these events varies and dictates the clinical and pathologic responses of these animals. With 9-10 million head of cattle on feed at any one time, managing animals under intensive conditions requires skill and effort. The 1999 NAHMS feedlot survey (National Animal Health Monitoring System), BRDC comprised 17.5% of all production diseases in feedlots. If this percentage is relevant today (and it is likely close to this), this means ~ 1.7 million head required treatment. If the average cost of one treatment per head was $8 ($ ; NAHMS, 1999), this means that one treatment added million dollars to production costs. This amount does not include vitamin injections, vaccines, anthelmintics, labor, etc. Furthermore, in those instances where animals require multiple treatments, or are metaphylactically treated, the total cost increases significantly (for 6 or more treatments, cost was $16 in 1999). Respiratory disease remains second to diarrhea as the cause of morbidity and mortality in dairy calves in the USA. It is also a significant cause of morbidity and mortality in dairy animals. PATHOGENS COMMONLY ASSOCIATED WITH BRONCHOPNEUMONIA: VIRAL AGENTS Viral infections: Although viral infection is common in North America, replication of virulent field strains can occur when animal immune defenses are reduced. The most important viruses associated with BRDC in North America remain those listed in Table 1. Exposure of naïve animals and viremia when stressed leads to inappropriate immune responses. These conditions, promote viral multiplication and dissemination with heightened exposure in groups of animals. Table 1 Viral agent Pathogenicity IBR Primary respiratory PI3 pathogens BRSV BVDV Immunosuppression BCV??? Modified from Panciera and Confer, VCNA 2010; 26(2):

2 BACTERIAL AGENTS Bacterial infections: Mannhemia (Pasteurella) hemolytica A1, P. multocida, Haemophilus somnus, Archanobacter pyogenes, Bibersteinia trehalosi. Commensal inhabitants of the upper respiratory tract in all species of cattle. These organisms have a variety of strain and type differences, with documented variation in virulence. While commensals of the upper respiratory tract, they generally do not cause significant problems; however, should virulent strains gain access to the lower respiratory system, they may cause severe disease or death when proliferating within the airways and lungs through production of virulence factors (Table 2). Bacteria Endotoxin Exotoxin M. hemolytica LPS LKTa P. multocida LPS PMT H.somnus LOS None M. bovis No PolyT A. pyogenes No Pyolysin B. trehalosi LPS LKT Modified from Panciera and Confer, VCNA 2010; 26(2): The first three organisms above are gram negative non-enteric bacteria (endotoxins), and M. hemolytica produces a virulence factor known as leukotoxin (LKTa) which injures or kills white blood cells amplifying the inflammatory response to pneumonia. Mannhemia (Pasteurella) hemolytica serotype A1. Normal inhabitant of the upper respiratory tract. This bacterial agent is in part responsible for millions of dollars in extra costs and lost productivity to the cattle industry in the USA. Like P. multocida and H. somnus, M. hemolytica is a normal inhabitant of the upper respiratory tract. When stressed, decreased clearance of the bacterial agents of the upper respiratory tract results in colonization of the lower airways. Pathologic Classification - Fibrinous bronchopneumonia More acute onset and associated with M. hemolytica A1 and sometimes H. somnii. Most common form of pneumonia in feedlot calves and has been referred to as shipping fever in stressed beef cattle. This is a fulminant process where the airway centered inflammation extends outward from one lobule to another across interlobular septa. The combination of LPS causing vascular compromise and leakage as well as LKTa damage to leukocytes results in tissue damage, including inter-lobular spread, bilateral lesions of the cranioventral ventral lung lobes. Pleuritis and effusion may be common in associated with thrombosis of vessels, dilation of pulmonary lymphatics. Interlobular edema, with yellow color associated with hemorrhage and edema fluid (color comes from hemoglobin breakdown) and substantial fibrin formation and deposition within the parenchyma and interlobular tissues. Pasteurella multocida Enzootic pneumonia- Is a normal inhabitant of the upper respiratory tract. This pathogen is commonly associated with bronchopneumonia of younger calves in housed dairy calves. Although fully capable of inducing disease, there is some thought that long 2

3 term, low dose infections associated with housing and environmental conditions lead to chronic respiratory inflammation and pneumonia. Pathologic Classification - Suppurative bronchopneumonia Bacterial, viral-bacterial in onset; environmental challenges leading to viral-bacterial or bacterial. This condition generally occurs in young calves, particularly dairy calves. The most likely organism is P. multocida This pathology is often limited to cranioventral portion of the lungs and the lesion is centered on the small airways and bronchi. Neutrophil recruitment is associated with presence of exudates which accumulate within the airways which eventually becomes more firm (abscesses). After chronicity sets in, A. pyogenes is commonly cultured from the lung. These lesions of the cranioventral lungs are more firm than acute toxemic bronchpneumonia. Sharp areas of demarcation between lobules/lobes. Histophilus somnus. Normal inhabitant of the upper respiratory tract. Factors predisposing calves to H. somnus are similar to those observed for M. hemolytica. H. somnus has been isolated from an increasing number of calves with bronchopneumonia. H. somnus causes a number of diseases including thromboembolic meningoencephalitis, infertility, mastitis, abortion and bronchopneumonia. Usually starts out as a dry, harsh cough, and progresses to either neurologic signs or bronchopneumonia. Cattle that develop neurologic disease do not develop bronchopneumonia. Pathologic classification Fibrinous bronchopneumonia Unlike the lesions observed when M. hemolytica is involved, H. somnii induced fibrinous pneumonia also presents with myocarditis and fibrinous changes in the synovium. Pathologic classification Caseonecrotic bronchopneumonia - Mycoplasma pneumonia. This is more common in North American studies in recent years than previously. Perhaps more diagnosed now that reagents are available and techniques are more sophisticated. Once animals are infected, they carry Mycoplasma for a long time (perhaps forever), leading to bronchiolitis, peribronchial lymphoid hyperplasia, and lungs appear similar to suppurative bronchopneumonia. As lesions persist, caseous bronchopneumonia develops with nodules disseminating throughout the lung. Lesions such as osteoarthritis, synovitis, otitis media/interna are also commonly observed in calves. Archanobacter pyogenes. Gram positive, anaerobe. It is most commonly isolated from lungs of calves with chronic pneumonia and associated with abscessation; potentially in combination with other anaerobes and Mycoplasma. Often the organism is present in chronic pneumonia whether the initial insult with M. hemolytica, P. multocida and H. somnus occurred leading to irreparable tissue damage. Pathogens and lesions associated with BRDC. Differences in the expression of bacterial virulence factors (Table 2), in conjunction with the host s immunologic responses to pathogens and virulence factors result in pathology. Some investigators have demonstrated that lesions associated with combinations of microbial infections (viral + bacterial) lead to the production of lesions suggestive of specific agents.(panciera and Confer 2010) For example, M. hemolytica pneumonia is characterized by systemic toxemia, severe inflammation and vasculitis produced in response to LPS. Host responses to LPS serve to magnify inflammation and immunosuppression through a variety biochemical pathways. One of which (inducing 3

4 expression of leukocyte CD11/18) increases the expression of the receptor for M. hemolytica leukotoxin (LKTa). Once LKTa binds to CD18, resident cells or those recruited to the lungs, cellular injury, cell death and necrosis occurs in an LKTa dose dependent manner.(czuprynski et al 2004, Czuprynski and Welch 1995, Leite et al 2004) Other bacterial agents also produce virulence factors leading to lesion production based upon specific virulence factor expression. Pasteurella multocida produces endotoxin as well as other virulence factors capable of inducing damage and host responses that lead to pathology indicative of this BRD agent.(panciera and Confer 2010b) Calves with Pasteurella multocida pneumonia are most commonly chronically infected, however in this authors experience, young housed dairy calves may undergo acute, toxemic pneumonia episodes that are similar clinically to that of M. hemolytica. Histophilus somnii produces a lipooligosaccharaide and outer membrane proteins that allow this agent to produce vasculitis, evade host defenses and other factors that lead to lesions associated with this agent. Mycoplasma bovis has a variety of surface proteins which support adherence and colonization of the animal. Furthermore, these adhesins can undergo modification over time and passage through hosts leading to lack of recognition by the host immune system. Traditional bacterial culture, identification and susceptibility have been used for some time, however; recent efforts suggest combinations of traditional culture with modern molecular methods may improve diagnostic capabilities significantly. Identification of specific bacterial species in clinical or necropsy specimens can now be performed using culture, ID and susceptibility in conjunction with immunohistochemistry, In situ hybridization, and PCR for specific bacterial pathogens. Combining culture with one or more of these tests has both provided more complete pictures of events occurring during the development of lesions. Molecular methods may identify components of bacterial agents in specimens that are culture negative. Tegtmeier et al., (2000), demonstrated H. somnii by bacterial culture in 10/65 cases of pneumonia. However, when coupled with IHC and ISH and PCR for H. somnus, these techniques identified H. somnii in 17, 19 and 29 of the 65 animals respectively.(tegtmeier et al 2000) Using similar methods, Booker, et al., (2008) recently demonstrated strong correlations between bacterial species, time of disease onset and severity of lesion(s).(booker et al 2008) In their study, feedlot animals dying from peracute to subacute pneumonia, M. hemolytica, H. somnii and M. bovis were isolated in >80%, <20%, and 50-60% of lung lesions respectively. Further, when animals died or were euthanized for pneumonia later in the feeding period, different proportions of these organisms were isolated. Specifically, M. hemolytica, H. somnii and M. bovis represented 40%, 30% and 90% of agents detected in lesions at necropsy.(booker et al 2008) Fulton, et al., (2009) in a one year study of fatal respiratory disease in feedlot animals demonstrated the mean days until disease onset FDO) for BRD when M. hemolytica was isolated to be 19 days on feed, whereas when M. hemolytica was not isolated, when FDO was 33 days.(fulton et al 2009) Mean number of days until disease onset (FDO) when H. somnii was cultured was 13 days, when H. somnii was not cultured FDO = 31 days.(fulton et al 2009) When M. bovis was cultured from lungs, mean FDO = 70 days, whereas when M. bovis was not cultured FDO = 29 days on feed.(fulton et al 2009) This article went further to characterize relationships between viral, bacterial etiology and lung pathology, day of disease onset, treatment interval, treatment number, number of different antibiotics, and days until death. Significant correlations between positive M. hemolytica culture and positive virus isolation and BRSV, BVDV and BHV-1 were observed. One could assume that acute onset fatal pneumonias are associated with viral and M. hemolytica infections, whereas P. multocida and M. bovis are differ temporally from acute pneumonias.(fulton et al 2009) In contrast, early pneumonia associated with H. somnii was highly correlated with M bovis culture.(fulton et al 2009) Similar 4

5 correlations were observed when comparing infectious agent and lesions observed at necropsy.(fulton et al 2009) References Booker CW, Abutarbush SM, Morley PS, Jim GK, Pittman TJ, Schunicht OC, Perrett T, Wildman BK, Fenton RK, Guichon PT, Janzen ED (2008a), Microbiological and histopathological findings in cases of fatal bovine respiratory disease of feedlot cattle in Western Canada, Can.Vet.J. 49: Czuprynski CJ, Leite F, Sylte M, Kuckleburg C, Schultz R, Inzana T, Behling-Kelly E, Corbeil L (2004), Complexities of the pathogenesis of Mannheimia haemolytica and Haemophilus somnus infections: challenges and potential opportunities for prevention?, Anim Health Res.Rev. 5: Czuprynski CJ, Welch RA (1995), Biological effects of RTX toxins: the possible role of lipopolysaccharide, Trends Microbiol. 3: Fulton RW, Blood KS, Panciera RJ, Payton ME, Ridpath JF, Confer AW, Saliki JT, Burge LT, Welsh RD, Johnson BJ, Reck A (2009a), Lung pathology and infectious agents in fatal feedlot pneumonias and relationship with mortality, disease onset, and treatments, J.Vet.Diagn.Invest 21: Leite F, Kuckleburg C, Atapattu D, Schultz R, Czuprynski CJ (2004), BHV-1 infection and inflammatory cytokines amplify the interaction of Mannheimia haemolytica leukotoxin with bovine peripheral blood mononuclear cells in vitro, Vet.Immunol.Immunopathol. 99: Panciera RJ, Confer AW (2010a), Pathogenesis and pathology of bovine pneumonia, Vet.Clin.North Am.Food Anim Pract. 26: Tegtmeier C, Angen O, Ahrens P (2000), Comparison of bacterial cultivation, PCR, in situ hybridization and immunohistochemistry as tools for diagnosis of Haemophilus somnus pneumonia in cattle, Vet.Microbiol. 76: