Role of etiological agents

The role of the etiological agents in the cause of acute undifferentiated respiratory disease in cattle has been controversial and often uncertain because the major pathogens of bovine respiratory disease are ubiquitous in clinically normal animals. The disease is considered to be the result of the effects of stressors causing immunosuppression, which allows colonization of the respiratory tract by opportunistic pathogens. The spectrum of the immune status of the animals is also a major factor. Animals vaccinated well before natural infection will usually be immune to specific pathogens. Animals that have had the natural infection and have adequate humoral immunity, or cell-mediated immunity in the case of some infections, will be immune to clinical disease.

Many epidemiological studies of bovine respiratory disease have attempted to correlate the level of serum antibodies in feedlot calves on arrival at the feedlot and over the first 30–50 days of the feeding period with morbidity and mortality due to bovine respiratory disease. A low level of antibody to a specific pathogen on arrival followed by significant seroconversion in animals that develop bovine respiratory disease in the first few weeks of the feeding period suggest that the pathogen was an important pathogen in the cause of cases of the disease. Conversely, those animals with a high level of antibody on arrival that do not develop bovine respiratory disease are considered immune. However, some animals with low levels of antibody may remain normal and seroconvert during the early part of the feeding period.

Feedlot cattle commonly seroconvert to the viruses of infectious bovine rhinotracheitis (IBRV), parainfluenza-3 virus (PI-3V), bovine virus diarrhea virus (BVDV), and bovine respiratory syncytial virus (BRSV),³ and to Mycoplasma bovis and Mycoplasma dispar, within the first month after arrival.⁴ Seroconversion to these pathogens occurs both in animals that develop respiratory disease and those that remain normal within the same group, but the relative importance of each agent and their causative nature is controversial. Seroconversion to M. haemolytica cytotoxin, BRSV and BVDV were predictive of approximately 70% of all respiratory disease cases in Ontario feedlots.³ Calves arriving in Ontario feedlots with high serum antibody levels to Histophilus somni (formerly Haemophilus somnus) had less bovine respiratory disease than calves with lower levels.⁵

Many respiratory pathogens that could cause disease are present in both individuals and groups of feedlot cattle after they are mixed and during outbreaks of bovine respiratory disease.³ Which ones are most important and causing disease is a major question. It has been suggested that undifferentiated bovine respiratory disease in weaned beef calves entering a feedlot is not a contagious disease and that, while respiratory pathogens may be necessary causes of the disease, they are not sufficient causes.³ This suggests that groups of animals experiencing a high incidence of bovine respiratory disease have been highly stressed and that it may be more important to identify and prevent the environmental and managemental risk factors.

The relationships between bacterial and viral antibody titers and undifferentiated fever and mortality in recently weaned beef calves in western Canada were examined.⁶ Feedlot calves are commonly exposed to M. haemolytica, H. somni, bovine herpesvirus (BHV)-1 G-IV glycoprotein, BVDV, M. bovis, and Mycoplasma alkalescens in the early feeding period.⁶ Seroconversion to M. haemolytica antileukotoxin was associated with a decreased risk of undifferentiated fever. Higher arrival BVDV antibody titer was associated with a decreased risk of undifferentiated fever. Higher arrival H. somni antibody titer and increases in H. somni antibody titer after arrival were both associated with a decreased risk of undifferentiated fever. The odds of overall mortality (OR 5.09) and hemophilosis mortality (OR 11.31) in clinical cases were higher than in the controls. In summary, protective immunity to M. haemolytica antileukotoxin H. somni, BHV-1 G-IV glycoprotein, BVDV, and Mycoplasma spp. may be necessary to reduce the occurrence of undifferentiated fever.

The association between exposure to H. somni and M. haemolytica and the risk of acute UBRD was examined using serological evidence of exposure and a vaccine field trial.⁷ Vaccination with H. somni in combination with M. haemolytica and with M. haemolytica alone reduced the risk of UBRD. There was no association between serological evidence of concurrent exposure to M. haemolytica and UBRD occurrence. Treated animals tend to have lower titers to H. somni compared to untreated animals.

Chronic, antibiotic-resistant pneumonia, sometimes with polyarthritis, occurs in feedlot cattle in western Canada.^8,9 M. bovis, BVDV, and H. somni are commonly found in the tissues at necropsy. This coinfection suggests the possibility of synergism between the BVDV and M. bovis in the pneumonia with the arthritis syndrome.

BVDV has been identified as a contributor to respiratory disease in feedlot calves. On arrival in feedlots, 39% of animals were seropositive for BVDV, and those animals treated for UBRD had larger titer increases to the virus than nontreated animals.¹⁰ The virus has been demonstrated by experimental infections of the respiratory tract, isolation of the virus and/or identification of BVDV antigen in tissues and demonstration of active infection through seroconversion in groups of cattle with bovine respiratory disease. BVDV-1b strains have been associated with acute pneumonia in commingled calves that were not vaccinated with BVDV vaccines, and in which M. haemolytica and P. multocida were also present in the pneumonic lesions.¹¹ Experimental infection of seronegative and immunocompetent calves with BVDV type resulted in primary respiratory disease.¹²

Bovine coronavirus (BCV) has been implicated as a cause of UBRD based largely on the isolation of the virus from the nasal cavities of cattle with respiratory disease. However, based on seroepidemiology of BCV titers in feedlot cattle, although higher antibody titers to the virus were associated with a decreased subsequent risk of treatment for UBRD, there was no association between evidence of recent infection (titer increase) and the occurrence of UBRD.¹³ Other studies have shown that BCV infections are not associated with an increased risk of treatment for UBRD.¹⁰

BCV is widespread in the cattle population and can be isolated from nasal swabs from cattle with bovine respiratory disease. The virus can be found in the feces and nasal swabs of recently arrived feedlot cattle and calves with and without clinical signs of bovine respiratory disease.¹⁴ Exposure to BCV prior to arrival in the feedlot is common, with 90% of animals being seropositive on arrival.¹⁰ BCV can be isolated from feedlot cattle in many different locations and most cattle seroconvert to the virus during the first 28 days after arrival in the feedlot.¹⁵ Cattle shedding the virus from the nasal cavity and developing an antibody response to the virus were 1.6 times more likely to require treatment for respiratory disease than cattle that did not shed the virus or develop an immune response. Cattle that shed the virus from the nasal cavity were 2.2 times more likely to have pulmonary lesions at slaughter than cattle that did not shed the virus.¹⁶ In natural outbreaks of shipping fever, more than 80% of affected cattle shed BCV at the beginning of the epidemic when the M. haemolytica infection rate was low.¹⁷

Intranasal vaccination of backgrounded feedlot cattle with a BCV vaccine reduced the risk of bovine respiratory disease.¹⁸ Vaccination had the greatest effect on calves with intranasal BCV, and on those with antibody titers less than 20, on entry.

The role of BCV in epidemics of shipping fever pneumonia in cattle was examined by the collection of nasal swabs and serum samples prior to the onset of the epidemic, during the course of the illness and after death when necropsies were done and samples of lung tissues were examined.¹⁹ Respiratory BCV (RBCV) was isolated from the nasal secretions before and after transport, from lung tissues of those cattle that died early in the epidemic but not later. Pasteurella spp. were isolated from all cattle that had severe pneumonia. All cattle were immunologically naive to both infectious agents at the onset of the epidemic but those that died after day 7 had rising antibody titers to RBCV and M. haemolytica. In contrast, the 18 clinically normal and RBCV isolation-negative cattle had high HAI antibody titers to RBCV from the beginning, while their antibody responses to M. haemolytica were delayed. Application of Evan’s criteria for causation were applied to the findings identified RBCV as the primary inciting cause in the epidemics. Because of the multifactorial nature of bovine respiratory disease, the criteria used are as follows.

Clinical case definition

The most important part of the clinical and epidemiological examination is to determine the case definition, which includes the following questions.

Occurrence

Bovine respiratory disease occurs under many different situations, including all age groups, feedlot animals kept outdoors, housed dairy calves, nursing and recently weaned beef calves, dairy and beef cattle heifers, and adult lactating dairy cows. Epidemics of acute respiratory disease have been described in dairy calves from birth to 6 months of age.^24,25 Outbreaks of BRSV can occur in dairy cattle heifers and adult dairy cattle.²⁶

Pneumonic pasteurellosis is most common in recently arrived feedlot calves. In calves 3–5 weeks after arrival in the feedlot, H. somni pleuropneumonia may be more likely. Acute interstitial pneumonia (pasture-induced) is the most likely diagnosis when confronted with an outbreak of acute respiratory disease in mature beef cattle that have been moved from a summer pasture to a lush autumn pasture within the last 4–10 days. Acute pulmonary disease in a few head of feedlot animals several weeks or months after arrival in the lot is probably an acute interstitial pneumonia, which may be associated with 3-methlyindole (3MI) metabolites.²⁷

Risk factors

The risk factors that have been identified in outbreaks of respiratory disease in feedlot cattle include the purchase of cattle from auction markets, whereby cattle arrive at the feedlot over an extended period of time, and mixing of cattle from many different sources.³ An epidemiological study of fatal fibrinous pneumonia in auction-market-derived feedlot calves in western Canada revealed that peak mortality occurred approximately 16 days after arrival at the feedlot.²⁸ The risk of fatal fibrinous pneumonia was consistently greater for calves entering the feedlot in November, shortly after the auction sales had peaked, when the feedlot was reaching capacity.²⁹ Mixing of calves from different farms was considerable, with a median of two calves per farm on truckloads arriving at the feedlot. Increased mixing at the auction markets was associated with increased fatal disease risk. The distance calves were transported by truck from the auction markets to the feedlot was not associated with fatal disease risk.³ When the incidence of fatal fibrinous pneumonia was high, the disease clustered within truckloads or pens. Risk factors positively associated with disease clustering included increased mixing of calves from different farms at the auction markets, month of purchase, number of calves passing through the auction markets, and weather conditions at arrival.^28-31

Transportation of feedlot calves increases serum concentration of oxidative stress biomarkers, which are related to episodes of bovine respiratory disease.³² Transportation stress significantly decreases serum total antioxidant capacity and increases malondialdehyde concentrations in steer calves.³³ It is proposed that stressors such as marketing (through an auction barn) and transportation to the feedlot precipitate oxidative stress, which reduces the antioxidant defense capacity and increases total body lipid peroxidation, resulting in increased susceptibility to bovine respiratory disease. These biomarkers may be useful to measure the oxidative stress of transported cattle. There is some experimental evidence that acidogenic diets and ketoacidosis may affect lymphocyte function, which may affect vaccine efficacy.³⁴

The literature on how the adequacy of diets of recently arrived feedlot cattle may affect their health and immunity has been reviewed.³⁵ Diets for newly arrived stressed beef cattle must be formulated to compensate for decreased feed intake and known nutrient deficiencies.

The literature on the risk factors for bovine respiratory disease in dairy heifers and the effect of the disease on productivity has been reviewed with relevance to commercial dairy farming in the Netherlands.²⁶ Bovine respiratory disease in dairy heifers increases the risk of mortality directly after the disease episode by up to six times, reduces growth during the first 6 months of life by up to 10 kg, and increases the likelihood of dystocia after first calving. Both herd size and other diseases in dairy heifers are clearly associated with the risk of bovine respiratory disease. Season and colostrum feeding are important. The most important risk factors for mild and severe pneumonia in dairy calves aged birth to 3 months were inadequate air circulation and the purchase of cattle.²⁴

An epidemic of acute respiratory disease associated with BRSV occurred during the winter and spring of 1995 in Norway.³⁶ Data from 431 cattle herds were collected. The risk of acute respiratory disease occurring in cattle was related to herd size and type of production and an expressed interaction between these two variables. The risk of a herd outbreak in a mixed herd of 20 animals was estimated to be 1.7 times greater than in a dairy herd, and 3.3 times greater than in a beef herd of comparable size. On increasing herd size to 50 animals, the risk increased 1.3-fold for a mixed herd, 3.3-fold for a dairy herd and 2.1-fold for a beef herd, compared to a risk for a corresponding type of herd of 20 animals. The disease spread initially from one location to another during the first 6–9 weeks; the rate of transmission between neighboring farms seemed to be higher than for the other districts included in the study. It was hypothesized that one common source of infection was involved in the outbreak and the case herds were clustered in time as well as spatially.³⁷ The average daily milk loss was estimated to be 0.70 kg per cow for 7 days after a herd outbreak compared with the period one week before.³⁸

Bacterial culture and antimicrobial sensitivity

Nasal swabs taken from clinical cases before treatment often yield a pure culture of pasteurellas but M. haemolytica biotype A serotype 1 is the most common isolate obtained from cattle with acute pneumonic pasteurellosis. The same serotype can usually be isolated from in-contact and apparently healthy calves. The antimicrobial sensitivity of the pasteurellas isolated can be done, but interpretation of the results is often difficult because it is not known whether the isolates from nasal swabs represent the organisms causing the lesions. Significant differences may exist between the antimicrobial sensitivities of isolates from nasopharyngeal swabs and those from the lung tissues. Thus it is not yet possible to recommend routine culturing and antimicrobial sensitivity determination of pasteurellas from nasal cavity or nasopharyngeal mucus from cattle with acute bovine respiratory disease. At the individual animal level, nasopharyngeal swabs and bronchoalveolar lavage reveal only moderate agreement; at the group level the isolation rates of various organisms are similar. In healthy calves monitored from the farm to the feedlot there was no relationship between the nasal flora and pulmonary lesions. The results of antimicrobial susceptibilities of bacterial pathogens isolated from the lung tissues of cattle with pneumonia over a period of years may provide some indication of trends in antimicrobial sensitivities but the results are not useful in making decisions about the selection of antimicrobial-affected animals.⁴⁰

The literature on the principles of antimicrobial susceptibility testing of bacterial pathogens associated with bovine respiratory disease has been reviewed.⁴¹ Two different methods are used. The Kirby– Bauer method is the traditional in vitro test of bacterial susceptibility or resistance to antimicrobials, which uses a disk containing a standardized concentration of an antimicrobial. Bacteria grow or fail to grow surrounding the disk, and results are interpreted as resistance or susceptibility of the bacteria to certain antimicrobials. The serial-dilution testing uses a broth or agar medium with selected dilutions of antimicrobials in 1:2 dilution steps. Results are expressed as susceptible, intermediate susceptibility or resistant and also as minimum inhibitory concentrations (MICs), which are considered more reliable. The MIC is defined as ‘the lowest concentration of an antimicrobial that prevents visible growth of a microorganism in agar or broth dilution susceptibility test’.

It is important to adhere to standards set by the National Committee on Clinical Laboratory Standards/Veterinary Antimicrobial Susceptibility Testing Subcommittee (NCCLS/VASTS). Veterinary-specific breakpoints are determined by the NCCLS/VASTS through a consensus process based on reviewing pharmacokinetic, MIC, zone-diameter scattergram and clinical trial data relating to an antimicrobial application. The subcommittee selects MIC breakpoints and zone-interpretative criteria that best fit the definitions of susceptible, intermediate susceptibility and resistant.⁴¹

The most veterinary-specific breakpoints for pathogens in bovine respir-atory disease have been determined for five antibiotics: ceftiofur, enrofloxacin, florfenicol, spectinomycin, and tilmicosin.⁴¹ The breakpoints for oxytetracycline and chlortetracycline are adapted from human breakpoints developed for tetracycline.⁴¹

Virus isolation or detection

Nasal swabs may be submitted for isolation or detection of viruses such BVH-1, BRSV, bovine coronavirus.

Serology

Serum samples may be submitted for determination of the levels of specific antibody to suspected viral causes of the bovine respiratory disease. Paired acute and convalescent serum samples from both affected and normal animals in the herd are desirable. In a group of animals in a feedlot, or dairy or beef cattle herd, serology for a specific etiological agent may be followed over a period of time to determine seroconversion and its relationship to occurrence or absence of clinical disease.

Hematology

Plasma fibrinogen concentrations are elevated, paralleling the increase in body temperature, and are a more reliable indication of the presence of the lesion than clinical assessment. Young cattle with clinical signs of acute respiratory disease, a fibrinogen concentration greater than 0.7 g/dL, and a temperature greater than 40°C (104°F) are likely to have pneumonic pasteurellosis. Leukocyte counts are of little value, as a leukocytosis and neutrophilia occur in some animals but in others there may be a neutropenia or no significant change. Acute phase proteins are increased within 24 hours following experimental intratracheal inoculation of M. haemolytica into calves. The availability of a rapid test for acute-phase proteins could assist in the field diagnosis of the disease and its possible differentiation from similar diseases.

Interpretation of results of clinical pathology and necropsy findings

A large body of information has been generated on the microbiology, and more recently molecular microbiology, of specific pathogens associated with bovine respiratory disease but only a small amount is applicable clinically. Insufficient effort has been directed towards integrating the information and applying it to the effective control of respiratory disease on the farm. Ideally, investigations of outbreaks of bovine respiratory disease should consist of in-depth examinations of a representative sample of the affected group and normal in-contact animals using a multidisciplinary approach involving clinical, epidemiological, and laboratory investigation. These procedures, especially those requiring detailed virological and serological examinations, are expensive and in the light of the economic status of cattle industries not likely to be lightly borne. But it will only be when such a multidisciplinary approach is brought to bear on bovine respiratory disease that we will improve our position with respect to knowing what actually occurs in outbreaks of the disease. Of paramount importance is the identification of risk factors, which, if valid, gives the clinician a powerful clinical tool for the clinical management and control of respiratory disease in cattle. Of even greater importance is the necessity for the clinician to visit the farm and conduct those clinical and epidemiological investigations that are necessary to solve the problem and to monitor the problem and the herd until recovery occurs.

Mass medication or metaphylaxis

The parenteral administration of antimicrobials to each animal as a form of mass medication may assist in the reduction of morbidity and mortality rates due to respiratory disease. The use of long-acting oxytetracycline at a dose of 20 mg/kg BW intramuscularly to feedlot cattle on arrival significantly reduced morbidity and mortality rates. The combined use of long-acting oxytetracycline at a dose of 20 mg/kg BW intramuscularly on arrival followed by the oral administration of 25 g of sustained-release sulfadimethoxine on day 3 resulted in a 90% reduction in treatment days per calf purchased. Tilmicosin, given at a dose of 10 mg/kg body weight subcutaneously to calves on arrival in the feedlot or 72 hours later, can significantly reduce the morbidity rate due to respiratory disease and improve the rate of gain.⁴⁶

A formulation of long-acting oxytetracycline (300 mg/mL) at a dose of 30 mg/kg BW intramuscularly is superior to the standard formulation of long-acting oxytetracycline (200 mg/mL) given at 20 mg/kg BW.⁴⁷ The 300 mg/mL preparation of oxytetracycline is also more cost-effective than tilmicosin.⁴⁸

Mass medication of cattle on entry into feedlots in Australia with tilmicosin at 10 mg/kg BW grew 0.08 kg/d faster than cattle medicated with oxytetracycline at 20 mg/kg BW and nonmedicated cattle.⁴⁹ There was no significant difference in growth rate between oxytetracycline-medicated cattle and those not medicated on entry into the feedlot. Cattle medicated with tilmicosin had fewer treatments for all illnesses compared with cattle not given an antibiotic on entry to the feedlot and compared with cattle mass-medicated with oxytetracycline. Tilmicosin induces apoptosis in pulmonary neutrophils, leading to a reduction in leukotriene B4 synthesis, thereby reducing further amplification of the inflammatory injury of bovine respiratory disease. Preshipment medication with tilmicosin are not more effective than mass medication on arrival.⁵⁰

The mass medication of feed supplies of newly arrived feedlot cattle has been investigated as a method of reducing the morbidity and mortality due to respiratory disease. The provision of chlortetracycline in the feed at a rate of 1, 2, or 4 g per head daily during the 2-week period after arrival reduced the number of calves that required treatment for respiratory disease.

Management of risk factors

As a general outline for the control of bovine respiratory disease the following factors are considered as contributing to disease and their effects must be minimized with suitable management and disease prevention techniques.

Presale vaccination programs are designed to establish an effective immune response to common respiratory tract pathogens well in advance of any natural exposure that may occur while calves travel through the auction market or after they arrive in the feedlot. These programs usually require calves to be castrated, dehorned, and vaccinated against IBRV, PI-3V, BRSV, and BVDV. Some programs also require vaccination against H. somni and M. haemolytica. Presale conditioning programs involve these procedures but also include weaning and nutritional components. Most such conditioning programs require calves to be weaned and adjusted to a roughage and concentrate diet for at least 30 days prior to sale.

Presale vaccination and conditioning programs have increased and decreased in popularity since their introduction in the 1970s. Producers tend to be reluctant to adopt these practices, because there is no assurance they will be rewarded, in terms of price premiums, for their efforts. However, the establishment of special auctions in Ontario that feature large numbers of vaccinated or conditioned calves resulted in an increased interest in these management practices. Producers selling lots of vaccinated or conditioned feeder calves through special auctions received a premium sale price compared with lots of feeder calves sold through conventional auctions.⁵¹ Vaccinated and conditioned calves were less likely to receive treatment for bovine respiratory disease during the first 28 days in the feedlot; but there was no difference in mortality.⁵² Calves that received antimicrobials on arrival at the feedlot had a reduced risk of treatment for bovine respiratory disease compared with calves that did not.

Vaccines

While vaccines are available for the control of acute respiratory disease associated with IBRV, PI-3V, and Pasteurella spp., there are almost no reports available of their efficacy determined under scientifically designed field trials. Based on current immunological technology, efficacious vaccines are considered to be feasible. The vaccines have been evaluated by experimental challenge of vaccinated animals with specific pathogens in a laboratory environment. However, there is little scientific evidence available that the vaccines are protective against acute UBRD as it occurs in the ‘real world’ situation. Preshipment vaccination of beef calves 3 weeks prior to weaning with vaccines containing IBRV, PI-3V, Pasteurella spp., and H. somni did not reduce the incidence of UBRD compared to those unvaccinated.

Pasteurella bacterins and respiratory viral vaccines have been used extensively in an attempt to control bovine respiratory disease. Many veterinarians and feedlot owners maintain that vaccination against respiratory disease is an essential component in their disease prevention programs, both to prevent specific disease of the respiratory tract such as clinical infectious bovine rhinotracheitis and to reduce losses due to respiratory disease in the first few weeks after arrival. However, a review of the literature on the efficacy of the vaccines available for the control of bovine respiratory disease concluded that there are few documented data to support the use of vaccines against respiratory disease under feedlot conditions. Efficacy refers to the ability of the vaccine to reduce overall treatment rate and/or increase weight gains economically.

In North America a large number of bacterial and viral vaccines are available for the control of bovine respiratory disease. There are single antigen or multiple antigen vaccines, modified live virus or inactivated virus vaccines containing one or more of the following antigens: M. haemolytica, H. somni, IBRV, PI-3V, BRSV, and BVDV. There are many multiple antigen vaccines containing combinations of the respiratory viruses, BVDV, H. somni, and M. haemolytica. In western Canada, it is more cost-effective to vaccinate auction-market-derived, fall-placed feedlot calves with a multivalent viral vaccine containing IBR, PI-3, BVD, and BRS viruses than a single univalent viral vaccine containing IBRV only.⁵³

Occurrence

Pneumonic pasteurellosis is a common disease of young growing cattle in Europe, the UK, and North America. In Canada and the USA the disease occurs most commonly in recently weaned beef calves 6–8 months of age shortly after being placed into feedlots in the fall of the year. Nursing beef calves, yearlings, and mature dairy and beef cows may also be affected, but less frequently. Pneumonic pasteurellosis, also known as shipping fever, is an entity within the bovine respiratory disease complex, characterized clinically by acute bronchopneumonia with toxemia and pathologically by lobar, anteroventrally distributed, exudative pneumonia in which fibrin is usually a prominent part of the exudate and fibrinous pleuritis is common.

Morbidity and mortality

The morbidity may reach 35%, the case-fatality rate may range from 5–10%, and the population mortality rate may vary from 0.75–1%. However, these morbidity and mortality data may not be reliable because of wide variations in the methods used to calculate disease incidence and prevalence. A review of the literature of morbidity and mortality rates and disease occurrence in feedlot cattle in North America found deficiencies in the epidemiological data available from feedlots.⁶ Case definitions of clinical cases are often poorly defined. A summary of 14 comparable studies containing disease incidence rates in calves in the first few weeks following arrival in feedlots found wide variations in how the disease definitions and statistics were used. The incidence of morbidity ranged from 0–69% with most reports between 15% and 45%. The population mortality rate ranged from 0–15% with most reports between 1% and 5%. The peak incidence of disease occurs within the first 3 weeks after arrival of the calves in the feedlot. The most common clinical and pathological diagnosis was respiratory disease, often described as shipping fever.

In order to make valid assessments of morbidity and mortality rates, it is imperative that case definitions are stated clearly, the population at risk is precisely measured and the period of observation is stated or incorporated into the rate.⁷ The morbidity rates quoted for bovine respiratory disease are actually treatment rates based on treatment of animals that appear depressed, have a fever and have no signs to suggest disease of a body system other than the respiratory tract. Systematic methods of data collection from the customized records of large feedlots are now available⁸ and have been validated by the National Animal Health Monitoring System.⁹

An observational study of the epidemiology of fatal fibrinous pneumonia in feedlot calves purchased from auction marts in western Canada and placed in a commercial feedlot between September 1 and December 31 over a 4-year period identified some valid information.¹ Peak fibrinous pneumonia occurred approximately 16 days after arrival at the feedlot; the median number of days between arrival and the first treatment of fatal fibrinous pneumonia cases varied from 3–8 days. The fatal fibrinous pneumonia mortality varied 11-fold (0.25–2.73%) between years. The fatal fibrinous pneumonia proportionate mortality varied from 10–57%. Fully 75% of the calves that died of fibrinous pneumonia already were sick within 2 weeks after arrival.¹ When the incidence of fatal fibrinous pneumonia was high (greater than 2%), the disease clustered, either within certain truckload groups of calves or within certain pens, or within both.¹⁰ Clustering could have been due to contagious factors, noncontagious factors, or both.

Economic importance

Pneumonic pasteurellosis is a major cause of economic loss in the feedlot industry. It is responsible for the largest cause of mortality in feedlots in North America. In addition to the death losses, the costs of treatment (which include the personnel involved in the detection and actual treatment, the drugs used and the vaccines) are considerable. While it has been assumed that there is a loss of production following the illness, this has not been documented. In fact, because of compensatory regrowth in animals that have recovered there may be no correlation between average daily gain, feed conversion and treatment.

Risk factors

Immune mechanisms

Calves that have recovered from the experimental disease are resistant to naturally occurring disease. Numerous M. haemolytica antigens may stimulate the immune response and resistance to disease. These antigens include capsular polysaccharide, leukotoxin, and surface antigens, including iron-regulated proteins,²³ a serotype-specific outer membrane protein, and several other antigens that are less well defined. High antibody responses to M. haemolytica surface extract proteins are correlated with resistance to experimental pneumonic pasteurellosis. Resistance to experimental challenge with the organism correlates directly with serum cytotoxin neutralizing titers. Cattle dying from pneumonic pasteurellosis may have lower levels of cytotoxin neutralizing antibody than animals from the same group dying from other causes. Aerosol exposure of calves with M. haemolytica results in the development of toxin neutralizing antibodies in pulmonary lavage samples and an accompanying increase in serum neutralizing titer. Since aerosol exposure of calves to viable M. haemolytica elicits a protective immune response characterized by enhanced clearance of the organism from the lung and by protection against fibrinous pneumonia, it is possible that the presence of pre-existing antibodies to the leukotoxin in the lungs may provide immunity by protecting phagocytic leukocytes from the leukotoxin and by promoting phagocytosis and intracellular killing of the organism.

Passive immunization with antibodies to whole M. haemolytica or leukotoxin-containing supernatants provides protection against experimentally induced pneumonic pasteurellosis similar to the protection provided by active immunization with these antigens.²⁴ In contrast, antibodies to lipopolysaccharide provided little protection against challenge.

Cattle exposed to live organisms produce antibodies to both cell surface antigens and cytotoxin, whereas exposure to the killed vaccine results in the production of antibodies primarily to cell surface antigens.

The experimental lung challenge of calves with formalin-killed P. multocida does not provide subsequent protection to challenge with live P. multocida.²⁵

Method of transmission

Transmission of pasteurellas probably occurs by the inhalation of infected droplets coughed up or exhaled by infected animals, which may be clinical cases or recovered carriers in which the infection persists in the upper respiratory tract. M. haemolytica and P. multocida are highly susceptible to environmental influences and it is unlikely that mediate contagion is an important factor in the spread of the disease. When conditions are optimal, particularly when cattle are closely confined in inadequately ventilated barns, or when overcrowded in trucks and trains, or held for long periods in holding pens in feedlots, the disease may spread very quickly and affect a high proportion of the herd within 48 hours. In animals at pasture, the rate of spread may be much slower.

Colonization of upper and lower respiratory tracts

Considerable research has centered on determining how the pasteurellas, which are part of the normal flora of the upper respiratory tract, colonize first the upper respiratory tract then the lower respiratory tract. Under normal conditions the bovine lung is relatively free of pasteurellas because of an effective lung clearance mechanism. The current hypothesis is that a combination of a viral infection of the respiratory tract and/or devitalizing influences from transportation, temporary starvation, weaning, rapid fluctuations in ambient temperature, the mixing of cattle from different origins and the excessive handling of cattle after arrival in a feedlot can all collectively promote an increase in the total numbers and virulence of pasteurellas in the nasopharynx, which then enter the lung. In clinically normal cattle, M. haemolytica are present in low numbers in the tonsil and nasal passages and those that are isolated are predominantly biotype A serotype 2 which is rarely associated with shipping fever. Exposure of healthy cattle to stressors such as viral infection, change in management practices and environmental changes leads to an explosive growth and selective colonization by M. haemolytica A 1 in the upper respiratory tract.

The experimental intranasal exposure of calves to a leukotoxin-deficient M. haemolytica elicits an increase in the serum antibody titers against the organism and decreased colonization of the nasopharynx by wild-type M. haemolytica.²⁷ This could allow an immune response to develop before transportation and offer protection from nasopharyngeal colonization and pneumonia by wild-type M. haemolytica.

Under normal conditions, alveolar macrophages will effectively clear pasteurellas from the alveoli by phagocytic mechanisms. When the large numbers of organisms enter and colonize the lung they interact with alveolar macrophages. Neutrophils enter the lung within the first few hours after bacterial inoculation.

Bovine alveolar macrophages release superoxide anion when exposed to M. haemolytica and the response is dependent on the presence of opsonizing antibody and the quantity of organisms presented to the phagocyte.²⁸ This may have a major role in the pathogenesis of the acute lung injury associated with pneumonic pasteurellosis. It is an important mechanism by which this phagocyte can initiate microbicidal activity and may provide clues to further study of the defense mechanisms of the lung.

Virulence factors and cellular and humoral reactions

The lung injury caused by the organisms after entry into the lung is dependent on important virulence factors.

Four virulence factors have been associated with M. haemolytica:

The interactions of these virulence factors contribute to the pathogenesis of the disease.^23,26 Fimbriae enhance the colonization of the upper respiratory tract. The polysaccharide capsule of the organism inhibits complement-mediated serum killing as well as phagocytosis and intracellular killing of the organism. The capsule also enhances neutrophil-directed migration and adhesion of the organism to alveolar epithelium. The lipopolysaccharide or endotoxin can alter bovine leukocyte functions and is directly toxic to bovine endothelium. It also modifies cardiopulmonary hemodynamics and elevates circulatory prostanoids, serotonin, cAMP, and cGMP. The organism induces morphological alterations in bovine pulmonary endothelial cells, the effects of which can be partially inhibited by indomethacin.²⁹ Tissue factor is involved in intra-alveolar fibrin deposition and coagulopathy associated with pneumonic pasteurellosis in cattle.³⁰

The migration and activation of neutrophils in inflamed tissue are regulated by a complex network of interactions among cytokines, leukocytes, vascular endothelium, cellular adhesion molecules, and soluble chemotactic factors.²⁶ The inflammatory cytokines tumor necrosis factor alpha, interleukin (IL)-1 beta, and IL-8 play a central role in the initiation and orchestration of these interactions.^23,26 IL-8 is the dominant cytokine expressed within the lungs during the acute phase of pneumonic pasteurellosis.³¹

Neutrophil-mediated inflammation in cattle with pneumonic pasteurellosis contributes to the development of severe disease rather than effective clearing of invading M. haemolytica. Leukotoxin is one of the major virulence factors of M. haemolytica responsible for impaired function of neutrophils.

The lipopolysaccharide or endotoxin of M. haemolytica is capable of causing direct injury to bovine pulmonary arterial endothelial cells, which may be a contributing pathogenetic mechanism. Endotoxin interacts with numerous cell types and humoral mediator systems, resulting in widespread injury to the lung. Endotoxin can readily cross the alveolar wall either from the air or blood and interact with cells and humoral mediators. The endotoxin can be found in the neutrophils in the alveolus, interstitial tissue, and capillary lumen; in intravascular, interstitial, and alveolar macrophages; in endothelial cells; and on alveolar epithelial cell surfaces.²³ The interaction of endotoxin with cells leads to cell activation and death.

Leukotoxin is produced by all known serotypes and is a heat-labile protein exotoxin, a pore-forming cytolysin that affects ruminant leukocytes and platelets. The bacterium produces the leukotoxin, with maximum production occurring during the log phase of growth, peaking after 6 hours of incubation. Following the inhalation of M. haemolytica into the lung there is an accumulation of neutrophils that, when destroyed by leukotoxin, result in the release of proteolytic enzymes, oxidant products, and basic proteins, which degrade cellular membranes, increasing capillary permeability, which results in fluid accumulation in the interstitium of the alveolar wall, alveolar wall necrosis, and pulmonary edema. Leukotoxin also induces histamine release from bovine mast cells.³² The importance of the neutrophil is supported by experimental evidence that depletion of blood neutrophils in calves made the animals much less susceptible to pulmonary injury following intratracheal inoculation of M. haemolytica.

Exposure to low concentrations of M. haemolytica leukotoxin in vitro induces apoptosis in bovine leukocytes.³³ Apoptosis is a process of cell death distinguished from necrosis by various morphological and biochemical criteria. These include chromatin collapse with subsequent chromatin margination in crescent-shaped masses around the periphery of the nucleus, blebbing of the cytoplasmic membrane, and internucleosomal cleavage of DNA into nucleosome-sized fragments. This may represent an important mechanism by which M. haemolytica overwhelms host defenses.

Tilmicosin, a very effective antibiotic for the treatment of pneumonic pasteurellosis, induces apoptosis in neutrophils, which results in reduced levels of the potent proinflammatory mediator leukotriene B₄ in lung fields of infected calves treated with tilmicosin. The tilmicosin-induced apoptosis in neutrophils directly enhances phagocytic removal of these cells by macrophages.^33,34

Supernatants of the organism can also cause rapid cytolysis of platelets. The genes that code for the synthesis and secretion of the leukotoxin have been cloned. It is a highly immunogenic protein that is produced by all 15 serotypes of M. haemolytica. Antiserum raised to the 105 kDa protein neutralizes its leukotoxic activity. Cattle with high leukotoxin antibody titers have higher survival rates in natural and experimental cases of pneumonic pasteurellosis than animals with low antibody titers. The development of efficacious vaccines will probably depend on using leukotoxin antigens and bacterial surface components to elicit maximum resistance against pneumonic pasteurellosis. Assay tests for determination of cytotoxin neutralizing antibody titers in cattle sera are described. There is positive correlation between ELISA titers to cytotoxin and protection to experimental pneumonic pasteurellosis.

Experimental pneumonic pasteurellosis

In an attempt to understand the pathogenesis of shipping fever pneumonia the experimental disease has been reproduced using several different methods: the most commonly used is the sequential aerosol infection of calves with either the PI-3 virus or the IBR virus followed by an aerosol of M. haemolytica 3 days or more later.^35,36 Exposure of calves to aerosols of PI-3V followed by M. haemolytica at intervals of 3–13 days later results in a purulent bronchopneumonia. The virus interferes with the lung clearance of M. haemolytica when an aerosol of the bacteria is given 7 days following the viral infection. There is little interference after only 3 days and a moderate degree at 11 days.

Pneumonic pasteurellosis similar to the naturally occurring disease can be reproduced experimentally by exposing calves sequentially to aerosols of BHV-1 and M. haemolytica 4 days apart.^35,36 The virus infection partly destroys the clearance mechanism of the respiratory tract epithelium and exacerbates the subsequent M. haemolytica infection.³⁵ Both antigens can be detected by immunohistochemical methods in the bronchoalveolar fluid cells.

The viral–bacterial synergism is associated with the release of cytokines, which attract more leukocytes and increase leukocyte expression of CD11a/CD18. In this experimental model, vaccination of the animal against the virus before challenge with the viral–bacterial aerosol sequence is protective. The interaction between the IBR virus and M. haemolytica can persist for up to 30 days after infection with the virus. A sequential aerosol infection of IBRV and P. multocida, or P. multocida alone, can also result in pneumonia. Experimental in vitro studies indicate that IBRV infection does not have a direct effect on the ability of neutrophils to phagocytose M. haemolytica but rather that there is an indirect effect, perhaps through the release of mediators that have an effect on phagocyte function. Large amounts of interferon are produced throughout the course of IBRV infection, which reduces chemotaxis and elevates oxidase activity by bovine neutrophils.

Pneumonic pasteurellosis can also be reproduced by transthoracic intrapulmonic infection of unstressed, conventional calves with only M. haemolytica or P. multocida, endobronchial inoculation intratracheal challenge, or intranasal inoculation of calves with the organism without a preceding viral infection. The intratracheal injection of P. multocida biotype A:3 into 8-week-old calves results in clinical and pathophysiological findings characteristic of bovine pneumonic pasteurellosis and gross pathological and microscopic changes similar to field cases.⁵ Concentrations of the acute phase proteins haptoglobin, serum amyloid-A and alpha-1 acid glycoprotein increased, suggesting a role for these proteins as markers of the onset of and progress of the disease.

The intratracheal instillation of live M. haemolytica into conscious calves results in acute cardiovascular changes consisting of two systemic hypodynamic and pulmonary vasoconstrictive phases.³⁷ Injection of metrenperone (a 5HT₂ receptor antagonist) 2 hours after inoculation abolishes the late increases in pulmonary arterial pressure and pulmonary vascular resistance.²⁸

Synergism between pathogens

Experimentally, synergism may occur between M. haemolytica and M. bovis in producing pneumonia in gnotobiotic calves and not in conventional calves.

The role of BVDV in outbreaks of pneumonic pasteurellosis is uncertain. In one study the virus did not impair the pulmonary clearance of M. haemolytica. In a different study the endobronchial inoculation of calves with the virus and M. haemolytica sequentially 5 days apart resulted in a severe fibrinopurulent bronchopneumonia and pleuritis involving up to 75% of the total lung volume. Endobronchial inoculation of the organism only caused a localized noninvasive lesion in the lungs.

In summary, pneumonic pasteurellosis can be reproduced experimentally without a preceding virus infection, and it is likely that the naturally occurring disease can also occur without a preceding viral infection.

The terminal lesion is an acute fibrinous pleuropneumonia. The ventral aspects of the apical and cardiac lobes of the lungs are most commonly affected; in advanced cases a greater portion of the lung becomes affected and other lobes of the lung become involved. Consolidation of affected lobes results in loud breath sounds, and the exudative nature of the lesion causes crackles. The pleuritis causes thoracic pain and pleuritic function rubs. Death is due to hypoxemia and toxemia. Complications include pulmonary abscessation, chronic pleuritis with or without pleural effusion, bronchiectasis, pericarditis and, rarely, congestive heart failure due to cor pulmonale.

Feedlot

In the feedlot, the disease usually occurs within 10–14 days after the animals have been stressed or have arrived in the feedlot. It may occur within 1 day after arrival if the animals have been incubating the disease prior to arrival. Animals found dead without any previous warning signs may be the first indication of an outbreak in which many weaned beef calves are obviously affected and some are in the incubation stages of the disease.

When viewed from a distance, affected cattle are depressed and their respirations are rapid and shallow. There may be a weak protective cough, which becomes more pronounced and frequent if they are urged to walk. Those that have been ill for a few days will appear gaunt because of anorexia. A mucopurulent nasal discharge, a crusty nose, and an ocular discharge are common. Although affected cattle are anorexic, they may continue to drink maintenance amounts of water, which may be useful in mass medication of the water supplies.

When the disease has been diagnosed in a group or pen of animals, and new cases are occurring daily, those that are in the earliest stages of the disease are not obviously ill when examined from a distance. If the entire group of animals is put through a chute and examined closely, up to 20%, or even more, of apparently normal animals may have a fever ranging from 40–41°C (104–106°F) and no other obvious clinical abnormalities. Auscultation of the thorax of some of these subclinical cases will reveal rapid shallow respirations and an increase in the loudness of the breath sounds. These animals respond remarkably well to treatment. If not treated at this stage, they may progress to clinical cases within a few days or they may recover uneventfully.

Not all animals that appear depressed have significant lung disease that requires treatment. When the presence of a fever of 40°C, or higher, in animals which are depressed, is used to decide whether or not the animal has pneumonia and requires treatment, some animals are treated unnecessarily. This is a problem in large feedlots that process many ‘sick’ animals daily based on the clinical findings of depression and fever. Using depression and a fever, the sensitivity of detection of sick animals is high but the specificity is low and therefore more animals are treated than is necessary. Improvement of the accuracy of both the diagnosis and the selection of those animals that require treatment will require improvement in the accuracy of the identification of affected animals by visual observation, and the use of rapid and reliable clinical examination techniques of individual animals that can identify animals with evidence of pulmonary disease. Close physical examination techniques, such as auscultation of the lungs, have not been routinely used in feedlots because of the time required to examine individual animals and the perceived inaccuracy of the examination in making a clinical diagnosis.

Outbreaks of the disease in feedlots may last for 2–3 weeks or longer after the first index case, depending on the health status of the cattle when first affected. Outbreaks can be prolonged in feedlots that add groups of newly arrived cattle to an existing pen of cattle every few days in order to fill the pen to optimum capacity. The disease then occurs in each new group of cattle and may spread to previously resident cattle, perpetuating the disease for several weeks.

The origin of the cattle also influences the severity and length of outbreaks. In well-nourished cattle originating from one ranch and maintained as a single group the morbidity may be less than 5% and the mortality nil. The outbreak will last only a few days and the cattle return to normal quickly. In cattle that have originated from a variety of sources and moved through saleyards and then commingled in the feedlot, the disease may persist for several weeks. In these situations, many animals are sick with the disease when they arrive at the feedlot. Some cattle will develop complications, never fully recover and are culled later.

Close physical examination

The relationships between clinical and pathological findings of disease in calves experimentally infected with M. haemolytica type A1 indicated that the respiratory rate, rectal temperature and clinical scores are significantly correlated with the extent of consolidation of the lungs.³⁸ The respiratory rate increased from 30 per minute up to 70 per minute as the percentage of lung consolidation increased from 10% to 50%.

The typical case of pneumonic pasteurellosis reveals a fever of 40–41°C (104–106°F), bilateral mucopurulent nasal discharge, gaunt abdomen with rumen atony, coughing, varying degrees of polypnea and dyspnea, and evidence of bronchopneumonia. In the early stages there are loud breath sounds audible over the anterior and ventral parts of the lungs. As the disease progresses these breath sounds become louder and extend over a greater area; crackles become audible, followed by wheezes in a few days, especially in chronic cases. Pleuritic friction rubs may be audible, although their absence does not preclude the presence of extensive adherent pleuritis. In severe cases or those of several days’ duration the dyspnea is marked, commonly with an expiratory grunt, although the respiratory rate may not be elevated.

The course of the disease is only 2–4 days. If treated early, affected cattle recover in 24–48 hours but severe cases and those that have been ill for a few days before being treated may die or become chronically affected in spite of prolonged therapy. Some cattle recover spontaneously without treatment.

A mild diarrhea may be present in some cases but is usually of no consequence. On an affected farm, calves may be affected with pneumonia and young calves may die of septicemia without having shown previous signs of illness.

Bacterial culture

Nasal swabs taken from clinical cases before treatment often yield a pure culture of pasteurellas, but M. haemolytica biotype A serotype 1 is the most common isolate obtained from cattle with acute pneumonic pasteurellosis. The same serotype can usually be isolated from in-contact and apparently healthy calves. The antimicrobial sensitivity of the pasteurellas isolated can be determined, but interpretation of the results is often difficult because it is not known whether the isolates from nasal swabs represent those causing the lesions. Significant differences may exist between the antimicrobial sensitivities of isolates from nasopharyngeal swabs and those from the lung tissues. Thus it is not yet possible to recommend routine culturing and antimicrobial sensitivity determination of pasteurellas from nasal cavity or nasopharyngeal mucus from cattle with acute shipping fever pneumonia. At the individual animal level, nasopharyngeal swabs and bronchoalveolar lavage reveal only moderate agreement; at the group level the isolation rates of various organisms are similar. In healthy calves monitored from the farm to the feedlot there was no relationship between the nasal flora and pulmonary lesions. There is some evidence that antimicrobial resistance is emerging among field isolates of M. haemolytica, and plasmid-mediated antimicrobial resistance is now known to occur.

Hematology

Plasma fibrinogen concentrations are elevated, paralleling the increase in body temperature, and are a more reliable indication of the presence of the lesion than clinical assessment. Young cattle with clinical signs of acute respiratory disease, a fibrinogen concentration greater than 0.7 g/dL and a temperature greater than 40°C (104°F) are likely to have pneumonic pasteurellosis. Leukocyte counts are of little value, as a leukocytosis and neutrophilia occur in some animals but in others there may be a neutropenia or no significant change. Acute phase proteins are increased within 24 hours following experimental intratracheal inoculation of M. haemolytica into calves. The availability of a rapid test for acute phase proteins could assist in the field diagnosis of the disease and its possible differentiation from similar diseases.

Samples for confirmation of diagnosis

Antimicrobial therapy

The recommendations for the treatment of bovine pneumonic pasteurellosis are based on clinical experience and the results of clinical field trials.

About 85–90% of affected cattle recover within 24 hours if treated with antimicrobials such as oxytetracycline, tilmicosin, trimethoprim–sulfadoxine, the sulfonamides, and penicillin. Broad-spectrum antimicrobials are used most commonly. One treatment is usually adequate and most economical for most cases but severely affected cattle or those that relapse require treatment daily, or even two to three times daily, depending upon the drug used, for up to 3–5 days.

Anti-inflammatory agents

Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are used by some veterinarians as an ancillary treatment for severe cases. The rationale is their anti-inflammatory effect but no data are available to support the field experience of some veterinarians that they are efficacious and economical.

Failure to respond

The causes of failure to respond to therapy include:

Management strategies

Vaccines

Chemoprophylaxis

Antimicrobials are used for the control of pneumonic pasteurellosis, particularly in cattle that have just been introduced into a feedlot.

Septicemic pasteurellosis of suckling lambs

This is a disease of young lambs associated with M. haemolytica biotype A. It occurs in lambs from 2 days to 2 months of age but presents most commonly at 2–3 weeks of age. The young lamb is highly susceptible to biotype A infections, which progress rapidly to a fatal septicemia. The organism is also a primary pathogen in goat kids. Septicemic pasteurellosis in suckling lambs may occur as an isolated disease but more commonly occurs in conjunction with pneumonic pasteurellosis, younger lambs succumbing to the former and ewes and older lambs to the latter. This disease probably does not warrant a separate classification but is kept separate because some outbreaks are manifest only with this septicemia in lambs.

There is a significant difference in the incidence of death from septicemic pasteurellosis in lambs between flocks that are infested with Ixodes ricinus and flocks that are Ixodes-free. It is believed that tick-borne fever can predispose to septicemic pasteurellosis¹ and lambs that die are usually 4–8 weeks of age.

A single intramuscular injection of 10 mg/kg tilmicosin or 20 mg/kg oxytetracycline is effective in preventing disease.²

P. multocida is a rare cause of septicemic disease in neonatal lambs but can occur with a high morbidity and high case fatality rate.³ Clinically, it presents with a syndrome resembling watery mouth with marked salivation, abdominal distension and a short clinical course. On postmortem examination there is excess peritoneal and pleural pericardial fluid. Prophylactic long-acting tetracycline at a dose of 100 mg per lamb has prevented further cases.

Mastitis

M. haemolytica is recorded as a major cause of mastitis in ewes in Britain. It has been isolated from the udder of 20% of ewes with subclinical mastitis and from 40% of cases of acute mastitis.⁴ A variety of typed and untyped strains within biotype A are isolated and serotype A2 is commonly isolated from acute mastitis. The epidemiology of the disease is unclear. Infection may occur from the organism on bedding⁵ but the source of infection is more probably from the nose and mouth of the suckling lamb, which is supported by the observation that the prevalence of mastitis associated with this organism is less in dairy sheep than in conventional flocks.⁶ Experimental challenge studies show that strains vary in their pathogenicity for the udder.⁶

Pneumonic pasteurellosis affecting wildlife

Pasteurella and Mannheimia spp. have been isolated from a number of different species of wildlife but there has been particular concern with outbreaks of acute fatal pneumonic pasteurellosis that have occurred in Rocky Mountain and desert bighorn sheep (Ovis canadensis) following commingling with domestic sheep or feral goats.⁷ M. haemolytica, P. trehalosi, and P. multocida have been isolated. P. trehalosi serotypes are carried in the tonsils of healthy bighorn sheep⁸ but bighorn sheep are believed to be particularly susceptible to pathogenic biotype A strains acquired as a result of commingling with domestic sheep on range coupled with the stress of high densities and food shortage.^9,10 This association has raised environmentalist concerns for practices of communal grazing of domestic sheep with wildlife species. As with sheep, disease associated with these bacterial species in wildlife has not been prevented by vaccination with current vaccines.¹¹

Occurrence

The disease occurs in sheep of all ages and causes losses in sheep in most parts of the world, through both death and depression of weight gain. The seasonal prevalence varies regionally. In the northern hemisphere, outbreaks, as opposed to sporadic disease, are more prevalent in the late spring and early summer. In contrast, in New Zealand and Australia the disease is more prevalent in the late summer and fall, occurring in lambs associated with mustering or transport in hot weather.¹⁰

Lambs are most susceptible during the first few months of life and ewes are most susceptible at lambing.⁴ Outbreaks in lambs can have attack rates up to 40% and a population mortality up to 5%. Both ewes and lambs can be affected in the same outbreak. Outbreaks often start with sudden death in lambs from septicemic pasteurellosis and progress to pneumonic pasteurellosis in the ewes and also in the lambs as they get older. The loss of 400 of 1200 ewes from this disease over a 3-year period is recorded¹¹ and a mean flock population mortality of 2.49% has been calculated from 450 outbreaks in Britain.⁴

In housed lambs the majority of deaths occur over a 2-week period, 3–6 weeks after entry;¹² death losses in feeder and housed lambs are usually of the order of 5%¹⁰ but may be as high as 20%.

High mortality has occurred in goats kept in confined quarters after collection from a number of centers.

Experimental reproduction

Pneumonic pasteurellosis can be experimentally reproduced by challenge of specific-pathogen-free lambs with aerosols of M. haemolytica, either given alone or preceded by PI-3V or B. parapertussis challenge⁵ and by intratracheal inoculation.⁶

Environmental and pathogen risk factors

In sheep at pasture, the disease tends to spread slowly and the population mortality rate is lower than in feeder lambs maintained in small areas. Outbreaks in flocks at pasture are frequently associated with changes in climate or management and deleterious changes in environment. In range sheep, confinement for shearing, mating or supplementary feeding may precipitate an outbreak, and severe parasitism or rain and windchill, exposure to bad weather or sudden change in weather may also increase susceptibility,^6,13 with deaths starting within 2 weeks of the stress factor.

In housed sheep, risk factors for disease include commingling of animals from different sources, taking sheep to show fairs, drafty or poorly ventilated barns, transport and malnutrition.^3,14

Feedlot dust contains significant endotoxin and it has been postulated that inhalation of dust may be a predisposing factor in feedlot sheep. However, an experimental challenge study found no effect.¹⁵

PI-3V appears to be an important predisposing factor to pneumonic pasteurellosis in some outbreaks, based on serological evidence of concurrent infection with PI-3V during outbreaks of pasteurellosis in sheep.^8,16 Adenovirus may also predispose to naturally occurring and experimentally produced pneumonic pasteurellosis.^17,18

Samples for confirmation of diagnosis

Antibiotics

The use of long-acting tetracycline in the face of an outbreak is a common approach to control. At-risk animals are given the drug intramuscularly at a dose rate of 20 mg/kg BW. The treatment may be repeated at 4-day intervals. A controlled field trial of this procedure has shown it to be efficacious.²⁵ The feeding of broad-spectrum antibiotics, especially tetracyclines, to lambs in feedlots is a common method of preventing pneumonia in recently weaned lambs. However, there is no documented evidence of its efficiency.

Vaccination

There has been considerable activity in the development of vaccines for the control of pasteurellosis in sheep and goats; however, the development of an effective vaccine has proved elusive. Early studies showed that sheep that had recovered from infection were resistant to subsequent homologous challenge. Also, immune serum will protect against experimental challenge in specific-pathogen-free lambs.²⁶ Because M. haemolytica A2 is the most common isolate from pneumonic lungs of sheep and goats throughout the world, most research on vaccines for sheep and goats has focused on incorporating either a suitable isolate of M. haemolytica A2 or suitable antigens extracted from the serotype. Different antigen preparations have been used and, whereas most studies have shown that vaccination can give protection against homologous challenge, there is variable protection against challenge with other serotypes of M. haemolytica.²⁷ The approach has thus been to incorporate other serotypes in the vaccine, usually the ones that are common in the region of vaccine manufacture. However, despite the fact that vaccines thus developed can engender protection against experimental challenge with H. haemolytica in sheep and goats, they are not always effective in natural outbreaks and several studies show limited or no protection against natural disease in the field.^16,27-30 This may be because the relevant serotype is not in the vaccine formulation. There have been few controlled field studies of vaccination.³⁰ Vaccines containing concentrated components of organisms such as outer membrane proteins show potential for cross-serotype protection with experimental infections but remain to be proved in the field.³¹

Vaccines containing various serotypes of M. haemolytica stimulate antibody production in pregnant ewes and the lambs receive colostral antibody, which does interfere with the production of antibody by the lambs if they are vaccinated at an early age.

Another approach to control is the vaccination of lambs with PI-3V vaccines in addition to Pasteurella vaccination in an attempt to immunize lambs against challenge exposure with both this virus and H. haemolytica. The experimental vaccination of specific-pathogen-free lambs with an inactivated PI-3V vaccine provides protection against the combined effect of an experimental challenge with PI-3V and H. haemolytica, and field reports suggest that this vaccination is of value.^32,33

Occurrence

This is an important disease in regions of Britain; it occurs in Europe and the USA. While recorded as occurring in Australia or New Zealand it is not a significant disease in these countries.⁴ The disease occurs predominantly in weaned lambs 5–12 months of age. It occurs following some form of stress such as transport, marketing, or shearing; or coupled with a movement to better feed, which is often to turnips, rape, or alfalfa and crop aftermath grazing. In Britain it is a disease of sheep moved from hill and upland farms to lowland farms for fattening.

In North America it is a disease of feedlot lambs and occurs following a change from roughage to concentrate feeding.

In affected groups a population mortality up to 9% is recorded⁴ and in some areas septicemic pasteurellosis is the most common cause of death in lambs of this age group.³

Experimental reproduction

The disease has been reproduced by oral inoculation coupled either with rapid change in feed from 100% roughage to 90% concentrate or with drugs eliciting immunosuppression.⁵

Septicemic pasteurellosis

Clinical disease is seldom seen as the clinical course is often less than 6 hours and affected sheep are found dead. Affected sheep are dull, rapidly become prostrate, are toxemic, and may have a frothy bloody nasal discharge in the terminal stages.

Samples for confirmation of diagnosis

Vaccination

Immune serum will protect against experimental challenge in specific-pathogen-free lambs.⁶ However, despite the fact that vaccines have been developed that engender protection against experimental challenge, they are not always effective in natural outbreaks and several studies show limited or no protection against natural disease in the field.^6-8

Samples for confirmation of diagnosis