Pneumonic mannheimiosis and pasteurellosis of cattle

Previous author: D C Hodgins and P E Shewen

Current authors:
Anthony W. Confer, DVM, PhD, Diplomate ACVP,Regents Professor & Sitlington Endowed Chair, Oklahoma State University, Stillwater, Oklahoma, USA
J D, TAYLOR, Professor, DVM, MPH, PhD, DACVIM (LA), DACVPM, Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, United States

Introduction

Pneumonic pasteurellosis by definition refers to infection of the lung(s) with organisms of the genus Pasteurella.³¹ The term pneumonic pasteurellosis has served conveniently since the 1960s^{29, 220} as a means of speaking collectively of pneumonias caused by Pasteurella haemolytica and Pasteurella multocida without committing oneself as to the relative importance of the two agents. With the reclassification of P. haemolytica biotype A strains as Mannheimia haemolytica,¹¹ pneumonic pasteurellosis is an inappropriate name for pneumonia caused by both agents; however, its use is still widespread. The terms pneumonic mannheimiosis and pneumonic pasteurellosis should be used to separate the diseases caused by the two bacteria, M. haemolytica and P. multocida, respectively.

Although these organisms can cause disease in young calves (as a component of enzootic pneumonia of beef, dairy, and veal calves,^{5, 92, 148, 276} pneumonic mannheimiosis and pasteurellosis are a far greater problem in recently weaned beef calves shortly after entry to feedlots or after long shipments of various kinds as a component of ‘shipping fever’ or undifferentiated bovine respiratory disease (BRD).^{138, 184, 190, 192, 290} Economic losses to the North American feedlot industry due to respiratory disease have been estimated to be as high as one billion dollars annually,²⁸³ and losses to the beef industry in the UK have been estimated at 70 million pounds annually.^{135, 206} Morbidity rates of 15 to 45 per cent and mortality rates of 1 to 5 per cent are common in newly received feedlot calves;¹⁴⁴ it is estimated that 75 per cent of the morbidity¹²⁵ and 50 to 60 per cent of the mortality⁷⁸ are attributable to respiratory disease. The major bacterial pathogen involved in beef cattle respiratory disease is M. haemolytica, whereas P. multocida is less frequently involved, but is often the major pathogen in young dairy calf pneumonia.^{189, 278} In spite of continuing intensive research to develop efficacious vaccines and improved management programmes to prevent pneumonic pasteurellosis in feedlot cattle, success to date has been limited and control of bovine bacterial pneumonia still relies heavily on antibiotics as preventative measures and for treatment.²¹

Aetiology

Mannheimia haemolytica and P. multocida are Gram-negative, non-motile, non-spore-forming, fermentative, oxidase- positive, facultative anaerobic short rods or coccobacilli of the family Pasteurellaceae.^{117, 217} Bipolar staining can be demonstrated using Wright's stain. Both grow best in media supplemented with serum or blood; M. haemolytica grows on MacConkey agar, but P. multocida does not. After 24 hours’ incubation on bovine or ovine blood agar plates, colonies of M. haemolytica are round and greyish, with a variable area of ß haemolysis, which can be small, requiring scraping of the colony from the agar to visualize. Colonies of P. multocida are generally round, greyish and non-haemolytic with more heavily encapsulated strains appearing mucoid.^{117, 217, 224}

Mannheimia haemolytica was originally named Pasteurella haemolytica, and two biotypes, A and T, along with 17 serotypes and numerous untypable strains were identified.^{88, 251} In 1990, biotype A strains were found related by DNA homology, and biotype T strains were related; however, biotype A and T strains had little genetic relationship.²⁷ Biotype T strains became Pasteurella trehalosi and later Bibersteinia trehalosi.^{28, 252} Through DNA–DNA hybridization and 16S rRNA sequencing, all but one of the A biotypes were designated M. haemolytica. (Angen et al., 1999) Therefore, M. haemolytica consists of the previous P. haemolytica biotype A Serotypes 1,2,5-9, 12-14, 16 and 17.¹⁴² Because all M. haemolytica serotypes are derived from biotype A, the designation of M. haemolytica serotypes as A1, A2, etc., often continues, even though it is redundant to include the biotype designation. Serotypes 1 and 6 are the most commonly isolated from BRD.²²⁴

Pasteurella multocida has been classified into 5 serogroups (A, B, D, E and F) based on capsular polysaccharide antigen and 16 serotypes (1-16) based on lipopolysaccharide.^{39, 227} Most P. multocida isolated from bovine respiratory disease are A serogroup, with A:3 being the most common.⁶⁶

The importance of M. haemolytica and P. multocida in pneumonia of feedlot cattle was suspected in early studies because of their frequent isolation from clinical cases and necropsy specimens. Doubts arose, however, as to whether these agents were primary pathogens, due to difficulties in reproducing clinical disease and pulmonary lesions experimentally and because bacterins did not mediate protection. Identification of numerous pathogenic bovine respiratory viruses that cause lesions or impair clearance of bacteria from the lower respiratory tract encouraged the view that infection with viruses or perhaps Mycoplasma spp., especially Mycoplasma bovis,¹⁰² was a necessary prelude to pneumonia with M. haemolytica or P. multocida. Bovine herpesvirus 1 (BoHV) that is also called infectious bovine rhinotracheitis virus,¹³⁰ parainfluenza-3 (BPIV-3) virus,¹⁶⁵ bovine respiratory syncytial virus,²⁶⁸ bovine virus diarrhoea virus,^{164, 209, 210} and more recently bovine coronavirus^{160, 260, 103, 159} have been implicated as predisposing to bacterial pneumonia. Challenge models employing primary infection with BoHV or BPIV-3 virus followed by M. haemolytica or P. multocida have been used in studies of pathogenesis and vaccine efficacy.^{43, 83, 126, 127} It was demonstrated, however, that fibrinous pneumonia could be induced in calves using logarithmic growth phase M. haemolytica or P. multocida alone,^{6, 89, 90, 98, 202} when sufficient numbers of bacteria (~5 x 10⁹ colony-forming units) are delivered to the lungs by intratracheal or transthoracic routes in non-immune calves.²⁴⁴ In addition, an exotoxin (leukotoxin) specific for ruminant leukocytes was demonstrated in M. haemolytica, ^{47, 96, 140, 238, 239, 240} establishing that bacterium as a primary pathogen in shipping fever pneumonia. Research has focused on M. haemolytica serotype 1 (S1) as the serotype most commonly isolated from cattle with pneumonia, although S6 is involved approximately 20 per cent of the time.^{86, 143, 192, 198, 215, 281} In addition, S1 is the dominant serotype in the nasal passages of feedlot calves with acute respiratory disease.⁸⁶

Although P. multocida has been shown to induce pneumonia when delivered to the lungs in large numbers,⁶ pulmonary lesions associated with this organism are usually not those of fulminating fibrinous pneumonia.^{139, 220} Fibrin and necrotic foci can be present; however, lesions are more typically suppurative bronchopneumonia, and as with both bacteria, severity of lesions may be somewhat strain dependent.^{6, 66, 67, 201} Pasteurella multocida has, therefore, been relegated to a secondary role in pneumonia of feedlot calves,^{56, 269, 289} although it may be relatively more important as a primary pathogen in disease of young dairy calves.^{78, 189, 278}

Epidemiology

Epidemiological studies of pneumonic pasteurellosis in feedlot calves have been hampered by the difficulty of distinguishing, at the clinical diagnosis level, respiratory disease caused by M. haemolytica or P. multocida from that caused by other bacterial and viral agents.²⁶⁵ This has led to the use of the term ‘undifferentiated bovine respiratory disease’,^{119, 178, 279, 291} more simply “bovine respiratory disease complex”,^{12, 106, 175} or even “undifferentiated fever”.^{236, 273} Case definitions of clinical respiratory disease have been general²⁸⁵ and subjective.²²¹ Clinical diagnosis of BRD also lacks sensitivity in identifying affected animals. A meta-analysis found an estimated pooled sensitivity of clinical diagnosis of 0.27, with a 95 per cent credible interval of 0.14 to 0.92.²⁷¹ Because of this difficulty in differentiating causative agents or even disease processes, studies may rely upon total morbidity as an outcome measure in field studies.¹⁶⁷ Even this approach may underestimate the incidence of BRD, as many untreated cattle demonstrate lung lesions at slaughter.²⁸⁸ Mortality (either overall or respiratory specific, based upon necropsy findings) is more objective than morbidity, but does not identify all affected cattle. Mortality is likely not sensitive enough to facilitate study of most variables of interest. In addition to assessing morbidity and mortality, studies examining efficacy of products or interventions in controlling BRD may also examine production variables, such as average daily gain, feed efficiency, and cost-benefit analysis. Historically,³⁰ the stresses of weaning, adverse weather conditions, change in feed,^{173, 174} transportation, and mixing of cattle from diverse sources^{173, 174} have been considered to contribute to the high incidence of respiratory disease observed in recently weaned and assembled feedlot calves. The close association of these events in time has complicated efforts to identify causal relationships. Numerous studies have been conducted to attempt to elucidate the relationship of these practices with BRD, often yielding conflicting or inconclusive results. Weaning prior to shipment appears to be more important than vaccination in preventing BRD.²⁵⁸ Shipment is clearly associated with disease occurrence, but no clear association has been found regarding distance of transport, method, or location within transport trailer.²⁶⁵ Seasonal variation is commonly noted, but this may be confounded by a variety of factors, including typical management practices that result in large numbers of freshly weaned calves being marketed in the autumn. No clear or compelling association can be identified with weather, either. Commingling of calves from multiple sources appears to increase BRD risk, as seen in several studies.^{223, 232, 258}

Higher BRD morbidity and mortality are commonly associated with lighter weight at purchase/arrival, which is assumed to correlate with younger age.¹⁷ Bovine respiratory disease (regardless of aetiology) onset within a population of calves coincides with a typical incubation period of common infectious agents (7 to 10 days after initial stressors), with a peak around two weeks after arrival.²²² If calves become ill or die more abruptly than that, it is likely they were incubating disease prior to arrival. Historically, morbidity and mortality begin abating soon thereafter, with median time of mortality being approximately three weeks after arrival.²²² For unknown reasons, however, there appears to have been a shift in epidemic curves since the 2000s, with certain classes of cattle having a relatively large percentage of BRD cases occurring later in the feeding period.¹⁸ Heifers are at a modestly increased risk for BRD as compared to steers.¹⁶³ Bulls that are castrated after arrival at the feedlot are also at greater risk of BRD than steers castrated and healed prior to purchase.²²⁵

It has been questioned whether pneumonic mannheimiosis and pasteurellosis in feedlot calves should be considered highly contagious diseases.²⁶⁹ Although morbidity rates as high as 69 per cent have been reported in the first weeks after feedlot arrival,¹⁴⁴ it has been observed that fibrinous pneumonia does not sweep through the feedlot like an epidemic but centres on certain pens.²⁶⁹ This would suggest that characteristics of the calves in the various pens rather than mere exposure to M. haemolytica are critical in determining disease outcomes. In an experimental study, 50 per cent of non-challenged control calves (naive to M. haemolytica) in contact with animals challenged with M. haemolytica developed clinical signs of pneumonic mannheimiosis and responded serologically,⁹⁸ but it is unclear how well this reflects transmission under field conditions. The question of transmissibility was reviewed by, TAYLOR et al 2010²⁶⁶ where evidence both for and against transmissibility was found. More recent molecular characterization techniques have shown limited dissemination of clonal strains of M. haemolytica throughout the nasopharyngeal microflora within a large population.¹⁵¹ Molecular approaches have also found certain strains are more commonly associated with BRD (perhaps indicating increased virulence compared to other strains).¹⁵⁰ Despite the value of this finding, it is unlikely that hyper-virulent vs. less virulent bacterial strains is a notable variable in defining the epidemiology of BRD.

Most recently, molecular studies have focused on the bovine respiratory microbiome with respect to what are the normal nasal, nasopharyngeal, and tracheal microbial flora and what influence various procedures, stresses, age, and feeding period have on that flora. Several studies found differences in the microbiome of calves that remained healthy compared to calves treated for clinical BRD.^{177, 272} Numerous challenges remain in interpreting or utilizing such results. For example, what considerations are most important - the degree of alteration in the microbiome, the rapidity of changes, or presence (or absence) of certain critical species? Study of the nasal and nasopharyngeal microbiome in beef calves from the time of first processing on the ranch to 40 days after feedlot arrival or throughout the feeding period demonstrated that changes occurred in the microbiome during progression of the study.¹⁷⁶ They concluded that although there were changes in the flora, individual animal variation prevented any conclusions concerning disease potential. Additional questions include how stressors impact the microbiome. Another recent study found no significant influence of transportation or commingling of cattle on composition of the nasopharyngeal or tracheal microbial flora.²⁶⁴ In contrast, a single injection of oxytetracycline or tulathromycin upon entry to the feedlot resulted in measurable changes in nasopharyngeal microbiota.¹²³ Those same authors found distinct differences in nasopharyngeal and tracheal microcolonies in healthy cattle and pen-mates with pneumonia with a higher abundance of M. haemolytica and P. multocida in pneumonic compared to healthy cattle.²⁷² This field of study shows great promise for further understanding pathogenesis and epidemiology; however, it is still in its infancy. 

Pathogenesis

The vast majority of studies of the pathogenesis of pneumonic mannheimiosis/pasteurellosis have been in the context of M. haemolytica. It has not been clearly demonstrated whether similar processes are responsible for disease associated with P. multocida.

Stress-related factors such as weaning, adverse weather conditions, change in feed, transportation over long distances, and mixing of cattle from various sources have long been associated with pneumonic mannheimiosis and pasteurellosis in feedlot calves.^{30, 76, 267} Numerous studies have attempted to clarify the induced pathogenic mechanisms. Cold stress (chilling of calves with cold water) increases plasma cortisol levels transiently, but does not affect histamine or bradykinin levels.²⁴⁸ Enhanced proliferation of M. haemolytica in the nasopharynx of calves following an abrupt change in climate from cold and dry to warm and humid has been noted, and that may be related to the effects of stress-related chemicals such as epinephrine on M. haemolytica biofilm dispersal.^{136, 208} Transporting recently weaned calves leads to the elevation of plasma cortisol levels for three days or more and depressed lymphocyte blastogenic responses.⁷⁷ Transporting heifers during high ambient temperatures increased plasma cortisol and modified behaviour.²⁶⁷ Decreases in serum complement activity as calves move from the auction market to the feedlot have been documented.²¹⁶ Transportation and weaning stress decreased the number of T lymphocytes, shifted dominant immune responses from TH1 to TH2, and caused neutrophilia due to release of immature neutrophils from the bone marrow, decreased neutrophil margination along endothelial lining of vessel walls, and a decrease in neutrophil apoptosis.⁷² The effects of mixing of calves (during transportation to the feedlot or after sorting at the feedlot) on the prevalence of respiratory disease may result from the stresses of interacting with strange calves, or may reflect increased opportunities to contact infectious agents.¹²⁸ The relative importance of these influences continues to be debated.²²³

Both M. haemolytica and P. multocida constitute part of the normal flora of the nasopharynx of healthy calves, where they exist in polysaccharide biofilms,^{32, 33} but may be undetectable or detected in low numbers by routine culture.^{20, 79} Although these pathogens are present in the nasopharynx, recent studies indicate their absence from the paranasal sinuses.¹⁹³ Changes in the flora of the nasopharynx of calves from before weaning until after arrival at the feedlot have been investigated, especially in recent years using metagenomics.^{122, 292} In one study, isolation of M. haemolytica was infrequent from nasal swabs collected at the farm of origin, but increased at auction markets, and was quite marked after arrival at the feedlot.⁸⁶ Serotyping of the isolates indicated that M. haemolytica S2 was most common on the farm, but serotype S1 predominated in nasal swabs from calves in the feedlot and from lung cultures from fatal cases of respiratory disease. Currently, studies of M. haemolytica using genotyping of isolates are being conducted, which may provide a better understanding of colonizing, pathogenic M. haemolytica.  A recent study demonstrated prevalence of various M. haemolytica serotypes in European cases of BRD to be similar to that in North American BRD in that S1 was present in 59 per cent, S6 present in 22 per cent and S2 in 18 per cent of cases.⁹ Overall, culture of nasopharynx samples from calves upon arrival in a feedlot is of limited value.

Several studies have investigated serotypes of M. haemolytica isolated from cattle in sub-Saharan African countries. The examination of 48 isolates from primarily healthy cattle in Kenya revealed a predominance of serotypes S1and S2.¹⁹⁴ A progressive shift in nasal flora from more frequent isolation of serotype S1 to more frequent isolation of S2 was noted in a group of heifers during transportation. Of 96 isolates from diagnostic specimens from cattle in South Africa, 30 per cent were untypable, and serotype S1 was isolated from 40 per cent of cases.¹⁹⁸ Serotypes 2, 6, 23, 24 were also represented.

Tonsillar tissue, specifically, has been identified as a reservoir for M. haemolytica.^{81, 85} Calves may be negative for M. haemolytica on culture of nasal swabs, but positive on culture of the tonsils.⁸⁴ Not only does the frequency of isolation of M. haemolytica S1increase as calves move to the feedlot, but the number of bacteria also increases rapidly.⁷⁹ When high numbers of M. haemolytica are present on the nasal mucosa of calves, the bacteria are inhaled into the lungs (although they are not present in exhaled air).¹⁰³ In healthy calves, lung clearance of inhaled M. haemolytica is highly efficient, with the elimination of 90 per cent of an administered dose within four hours.¹⁵⁹

Infection with BPIV-3 virus or BoHV-1 can lead to the proliferation of M. haemolytica in the nasopharynx of calves that had previously reduced their numbers of M. haemolytica to undetectable levels.⁷⁹ Virus infection can mediate colonization of the nasal passages by M. haemolytica or P. multocida  even in the presence of detectable titres of antibodies in serum and nasal secretions.^{83, 93} Exposure of bronchial epithelial cells to BoHV-1, M. haemolytica , or both causes marked inductions of genes responsible for inflammatory processes.¹⁹⁵ Increased elastase activity in the mucus of the nasal passages was documented in calves following experimental infection with BoHV-1, and preceding colonization by M. haemolytica.^36,23 Elastase may act by cleaving fibronectin on the surface of epithelial cells, permitting colonization by Gram-negative bacteria.^{20, 36} Pasteurella multocida outer membrane protein OmpA has been shown to enhance colonization by binding to fibronectin.⁶⁵ Infection with BPIV-3 virus leads to impaired clearance of bacteria from the lungs.¹⁶⁵ Bovine herpesvirus 1, BPIV-3 virus and bovine virus diarrhoea virus have been shown to impede ciliary activity of tracheal epithelial cells in vitro.²³⁰ The roles of viral-bacterial synergism²⁸⁹ and other mechanisms in the pathogenesis of pneumonic pasteurellosis have been reviewed.^{20, 283}

There is experimental evidence that neutrophils play a considerable role in the induction of lung lesions following infection with M. haemolytica. Calves depleted of neutrophils before challenge with live M. haemolytica have minimal or reduced lung lesions.^{35, 249} The contents of primary and secondary granules, as well as cytosolic enzymes, are released from bovine neutrophils following exposure to live M. haemolytica or its leukotoxin, mediating acute lung injury.²⁸⁰ Pulmonary intravascular macrophages and alveolar macrophages are also important mediators of inflammation in early lung lesions.²⁸²

Multiple products and components of M. haemolytica S1 have been proposed as virulence factors, including adhesins,^{124, 149} capsular polysaccharide,^{38, 58, 60} fimbriae,^{186, 187} iron-regulated outer-membrane proteins,^{94, 185, 256} leukotoxin,^{96, 240, 241} lipopolysaccharide,⁵⁷ lipoproteins,^{61, 196} neuraminidase,^{87, 262, 263} a serotype-specific antigen,^{100, 162} sialoglycoprotease,^{1, 156} IgA protease,  and transferrin binding proteins.^{13, 50, 199, 211, 247} The adhesin protein, capsular polysaccharide, fimbriae, sialoglycoprotease and neuraminidase may have roles in the attachment of M. haemolytica and its colonization of cells of the respiratory tract of calves.^{20, 186, 188, 283} The capsular polysaccharide also has anti-phagocytic properties,⁴¹ and increases directed migration of neutrophils.⁶² The sialoglycoprotease, by cleaving bovine IgG1 or host cell surface proteins, may reduce the effectiveness of opsonizing antibodies and enhance colonization.¹⁵⁵ Transferrin-binding proteins and other iron-regulated proteins enable M. haemolytica to proliferate in vivo in spite of the low iron environment normally maintained by the host. Lipopolysaccharide as an inducer of inflammation has a central role in the development of vascular lesions in lung tissue and activation of proinflammatory mediators.^{245, 246, 283} Leukotoxin has multiple effects on bovine leukocytes, mediating cell death by both cytolytic⁴⁶ and apoptotic mechanisms.^{157, 259} Lower concentrations of leukotoxin inhibit lymphocyte (blastogenic) responses¹⁷¹ and reduce the chemiluminescent and bactericidal responses of phagocytic cells.^{42, 55} Lytic effects on platelets probably contribute to the exudation of fibrin and formation of thrombotic lesions in infected lung tissue.⁴⁸

In summary, colonization (or recolonization) of the upper respiratory tract of calves by M. haemolytica S1 may occur rapidly during the process of weaning, marketing, transportation and admission to a feedlot. Environmental factors and/or viral infection may facilitate the dramatic increase in population of M. haemolytica in the nasopharynx. Inhalation of M. haemolytica in increased numbers, in association with stress or virus-associated impairment of bacterial clearance, permits rapid proliferation of the organism in the lungs. The influx of neutrophils in response to the presence of lipopolysaccharide and capsular polysaccharide is followed by lysis of these cells due to the effects of leukotoxin, with the release of the contents of primary and secondary granules. This event, in combination with inflammatory effects due to lysis of platelets by leukotoxin and the effects of lipopolysaccharide and leukotoxin on alveolar and intravascular macrophages, leads to vascular damage, exudation of fibrin, the development of oedema in the alveoli and interlobular septa, and the accumulation of fluid and fibrin in the thoracic cavity. The compromising of the vascular supply soon leads to necrosis of affected areas of lung parenchyma.

Pasteurella multocida virulence factors and respiratory pathogenesis are less understood than those associated with M. haemolytica.^{66, 112} Suppurative bronchopneumonia occurs when bronchial colonization with P. multocida initiates suppurative bronchitis with progressive spread along airways resulting in an obviously bronchiole-centered lesion within each lung lobule.  Isolates associated with BRD are usually serogroup A, whereas serogroups B and E are associated with ruminant haemorrhagic septicaemia. Serogroup D strains, as well as some serogroup A strains, can produce a cytolytic toxin, Pasteurella multocida toxin (dermonecrotic toxin) that is associated with atrophic rhinitis of pigs.⁴⁰ In the past, toxigenic serogroup D isolates were rarely associated with bovine respiratory disease.  However, in a recent study from Spain, toxigenic serogroup A and D strains were isolated from pneumonia in sheep.⁴⁴ Strains of P. multocida serogroup A that are heavily encapsulated have been shown to resist phagocytosis and killing by bovine neutrophils.¹⁷⁰ Lipopolysaccharide of P. multocida has carbohydrate moieties that are similar to the carbohydrate component of host glycoproteins, making it likely that LPS mimicry of host molecules could play a role in the survival of P. multocida in the host.¹¹¹ In vivo studies in mice demonstrated that P. multocida LPS and outer membrane proteins interact with TLR4 and CD14, stimulating release of numerous proinflammatory cytokines.²¹³ In a dose- and time-dependent manner, P. multocida LPS can also stimulate leukocyte proliferation and leukocyte death via mitochondrial dysfunction and caspase activation.²⁰⁴ Expression of various genes for adhesins, outer membrane proteins OmpA and OmpH, iron-regulated membrane proteins, and haemoglobin-binding proteins have been shown to be different between virulent and less virulent P. multocida strains and among strains from different hosts.^{74, 212, 213, 242, 243}  

Clinical signs

Clinical signs in calves following experimental challenge with M. haemolytica or P. multocida closely resemble those occurring in feedlot calves with pneumonic mannheimiosis/pasteurellosis;^{6, 90, 98, 244, 286} effects due to M. haemolytica are generally more severe than those due to P. multocida.⁵ Observed signs in calves challenged by the intratracheal route include depression (drooping ears, reluctance to move),⁹⁸ inappetance,^{284, 286} increased respiratory rate and effort, moist rales on lung auscultation with occasional moist coughing,⁹⁰ and recumbency.²⁸⁴ A serous to mucoid or purulent nasal discharge may be present.²⁸⁶ Rectal temperatures over 40°C are common⁶ and may be as high as 41,5 °C.²⁸⁶ The naturally occurring disease in feedlot calves may be acute and fulminating, with calves dying before they are detected as ill by feedlot personnel²⁶⁹ or taking a more chronic course.^{79, 289} Increased lachrymation is common, and mucopurulent nasal discharges may result in encrusted muzzles.²⁸⁹ Dyspnoea in severe cases may lead to oral breathing²⁸⁹ with an expiratory grunt.²¹⁹ Calves may adopt a distressed stance, with elbows abducted and neck extended.²⁸⁹ Moist rales may progress to dry rales and pleuritic friction rubs.²¹⁹ During a disease outbreak up to 20 per cent or more of calves that appear clinically normal may have fever of 40 °C or more; some of these will progress to be patently ill, while the rest will recover without treatment.²¹⁹

Pathology

It is common to culture or detect with multiplex PCR multiple infectious agents in pneumonic bovine lungs.^{91, 152, 166, 287, 294} The lesions associated with pneumonic mannheimiosis have been reviewed^{40, 201, 220, 289} and are basically those of fibrinous pleuropneumonia (Figure 1). Commonly, the cranioventral one- to two-thirds of the lung are bilaterally consolidated and of firm and heavy consistency (hepatization). Lobules in the affected areas are red, grey, or nearly black, and in a spectrum of stages of the pneumonic process, imparting an appearance to those areas that have been described as ‘marbled’ (Figure 2).²²⁰ A clear separation exists between pneumonic and non-pneumonic areas of the lung. Acute fibrinous or serofibrinous pleuritis often accompanies the pneumonic lesions, with sheets of fibrin loosely or firmly adherent to the parietal and visceral pleura and/or pericardium. Large volumes of straw-coloured thoracic fluid are occasionally encountered.²²⁰ Oedema and deposits of fibrin distend the interlobular septa in affected areas and interlobular lymphatic thrombi may be visible. In more chronic lesions, numerous areas of coagulative necrosis are present,^{220, 289} delimited by pale fibrous tissue. This fibrous capsule becomes progressively thicker with time in calves surviving the acute disease process.³ Fibrin deposits in the pleural cavities may become organized to form extensive fibrous adhesions.

Figure 1 Severe, acute fibrinous pleuropneumonia in a calf with Mannheimia haemolytica infection

Figure 2 Close-up view of red and grey hepatization of the lungs

Figure 3 ‘Streaming macrophages’ in the affected lung of a bovine

Gross lesions of pneumonic pasteurellosis are most commonly seen in BRD of young dairy calves and most often associated with P. multocida infection though other respiratory bacteria may also produce the lesion.^{10, 40, 66, 201} Suppurative bronchopneumonia occurs when bronchial colonization of bacteria initiates suppurative bronchitis with progressive spread along airways resulting in bronchiole-centered lesion within each lung lobule.  The pneumonia is bilateral, cranioventrally distributed, and moderately firm.  In acute lesions, affected lobes are fairly uniform in colour varying from pink, pink-grey, dark red, red-grey, or grey with minimal to mild interlobular septal oedema.  On cut surface within lobules, there are variably-sized, partially discrete tan to grey foci indicative of a pattern of bronchiolar and peribronchiolar inflammation from which purulent to mucopurulent exudate can often be expressed. Pleuritis is usually not present; however, if present, it consists of small foci of pleural dullness to small clusters of fibrin strands.  Remaining areas of lobules are pink to dark red representing various amounts of inflammation, congestion, and atelectasis. 

Histological lesions of pneumonic mannheimiosis vary with the stage of progression of the disease. In experimental cases, neutrophils, macrophages, oedema and fibrin are prominent in the alveoli by six hours post-inoculation.⁴⁵ Subsequently, oedema, fibrin and congestion or haemorrhage become more prominent in the alveoli. At a later stage, ‘swirly’ or ‘streaming’ or ‘oat-shaped’ dark-staining macrophages with pyknotic, hyperchromatic nuclei are typically found in the alveoli (Figure 3).^{220, 289} Large areas of coagulative necrosis, often involving nearly entire lobules, surrounded by degenerating and intact leukocytes and fibrin are often present. Thrombosis of septal lymphatic vessels is present in severe cases.²²⁰ Arterial thrombosis is often present in more subacute to chronic lesions.⁴⁰

Histologic lesions of pneumonic pasteurellosis are classical, suppurative bronchopneumonia characterized by bronchioles and adjacent alveoli distended with degenerating and viable neutrophils, fibrin, and protein-rich oedema.^{40, 68} Segmental necrosis of bronchiolar epithelium may be present along with intra-alveolar haemorrhage. Over time, macrophages and lymphocytes increase within bronchioles and alveoli. Foci of necrosis may occur within affected alveoli, which may progress into foci of abscessation.

Diagnosis and differential diagnosis

Ante mortem diagnosis of BRD is typically based upon signalment, history, and clinical signs. For recently weaned, newly received feedlot calves, antibiotic treatment is usually initiated based on clinical signs without awaiting an aetiological diagnosis, because of the high incidence of pneumonic mannheimiosis and pasteurellosis in this class of calves and the expected rapid progression of disease signs.^{105, 219} Suspicion increases with increasing epidemiological risk factors, as outlined above. History is often incomplete, as calves are typically purchased at auction markets and commingled, with no knowledge of prior management practices. Various clinical scoring systems have been devised, with the most common using a combination of criteria involving evaluation of depression/mental obtundation; appetite (manifested as rumen fill, as well as approach to bunk when feed is delivered); respiratory signs (including nasal discharge, coughing, respiratory effort, and dyspnoea), and body temperature (with varying definitions of fever, depending upon type of cattle, time of day, geographic location, and season).²⁵⁸ While these criteria are in no way specific to bacterial pneumonia, antibiotics are commonly administered even when a viral agent is suspected, in order to control secondary bacterial infections.¹⁰⁵

More detailed examination of the respiratory tract has historically not been practised, since, in general, BRD is easy to distinguish from more discrete feedlot health issues (such as lameness, bloat, “bullers,” etc.). The exception to this is ruminal acidosis, which may mimic many of the non-respiratory signs, and even some respiratory signs (as the respiratory tract assists in acid-base regulation). This overlap of clinical signs can complicate BRD diagnosis, both in production and research settings.²²⁶ Clinical BRD diagnosis can be enhanced by detecting elevated serum  acute-phase proteins, particularly haptoglobin, and thoracic ultrasound evaluation.¹⁸² Culture of nasal swabs is of doubtful diagnostic value due to the high numbers of M. haemolytica present in the nasopharynx of newly arrived feedlot calves regardless of their health status,⁷⁹ and the lack of correlation between nasal and lung isolates in individual calves.⁴ Bronchoalveolar lavage along with bacterial culture or multiplex PCR can give a better assessment of bacteria involved in pneumonia.²⁸⁷ Evaluation of results from antimicrobial susceptibility testing of isolates from affected lung, especially from untreated cases, may provide useful information for therapeutic decisions for the rest of the group.⁸⁰ However, the correlation of susceptibility to clinical outcome is unclear.¹⁵³

Other respiratory conditions that may be mistaken for pneumonic mannheimiosis/pasteurellosis include pneumonia due to Histophilus somni or Mycoplasma spp. infection as well as bovine respiratory syncytial virus, BoHV-1 (or other viruses infecting the respiratory tract), interstitial pneumonias, and sporadic conditions, such as lung abscesses and aspiration pneumonia.^{105, 219} The finding of fibrinous or fibrinopurulent bronchopneumonia on necropsy is highly suggestive of pneumonic mannheimiosis, although H. somni, also a member of the family Pasteurellaceae, can cause fibrinous lesions.^{79, 105} For a definitive diagnosis, culture or multiplex PCR of affected lung tissue is required.^{7, 287, 294}

Control

Pneumonic mannheimiosis or pasteurellosis appears to largely be a management disease resulting from incompatibility between the biology of calves (and their microbiota) and the managing and/or marketing systems of humans. Calves that move directly from a ranch into feedlots without moving through sales yards, and without mixing with calves from other sources, can be expected to suffer notably lower morbidity than calves undergoing commingling, extended and/or repeated transport, or other stressors. While vaccines and antibiotics can be useful in controlling pneumonic mannheimiosis or pasteurellosis, basic changes in when and how calves are weaned, sold, and transported to feedlots would have a profound impact on the prevalence of disease. Despite this recognition, much uncertainty remains in understanding all contributing causes of BRD, and thus how to truly control its occurrence. One of the most consistent features of BRD is the enormous variability that can occur across operations following similar procedures, or even from year to year on the same operation.^{141, 253} Thus, while producers should be encouraged to castrate at a young age, vaccinate, wean on the farm/ranch of origin, and perform other tasks commonly referred to as preconditioning, they should be warned that unexpected morbidity may still occur.

Antibiotics

Use of oral antimicrobials (either in feed or in water) to treat, control, or prevent BRD has been extensively examined. Products available for these purposes in the United States (US) include oxytretracycline alone, sulfadimethoxine (and other sulfa compounds) alone, oxytetracycline and sulfamethazine in combination, oxytetracycline and neomycin in combination, and tilmicosin. Evidence for efficacy of most of these products is minimal, and the regulatory environment in the EU and the US makes oral antimicrobials more difficult to justify and utilize.

Injectable antibiotics are employed extensively in the feedlot industry in North America in attempts to prevent and treat pneumonic mannheimiosis, pasteurellosis, and other infectious diseases not distinguished from pneumonic pasteurellosis by feedlot personnel. Antibiotics are rarely selected on the basis of in vitro sensitivity of isolates from nasal or pharyngeal swabs. Isolates from these sources may not accurately reflect organisms present in the lower respiratory tract of the same animal.⁴ Necropsy specimens from calves treated with antibiotics also do not necessarily provide relevant information as to the antibiotic sensitivities of the organisms initiating the pneumonia, and may not be related to treatment history.¹⁵³

In most published studies examining the efficacy of antibiotics against disease in feedlots no attempt to distinguish pneumonic mannheimiosis or pasteurellosis from respiratory conditions caused by other bacteria or by viruses is made.^{158, 178, 279} The term ‘undifferentiated fever’ has been considered synonymous with ‘BRD complex’ by some workers.¹³¹ Thus a succession of antimicrobial drugs have been examined for efficacy against undifferentiated respiratory disease under field conditions, including penicillin,^{24, 178} oxytetracycline,^{24, 108, 178} trimethoprim/sulfadoxine,^{24, 108, 178} ampicillin,^{26, 158} tilmicosin,^{101, 119, 235} florfenicol,^{119, 131, 158} ceftiofur,^{114, 115} enrofloxacin,^{200, 233},^{75, 231} tulathromycin,^{145, 146},⁸ gamithromycin,^{161, 229} and others. Although many of these antimicrobials historically had some degree of efficacy for treatment of bovine respiratory disease, with the wide array of products now available there is little indication for use of penicillin, ampicillin, and sulphonamides. Resistance to oxytetracycline is quite prevalent among M. haemolytica and P. multocida, limiting its efficacy, as well.²⁷² The efficacy of labelled antimicrobials for treatment of BRD is extensive and compelling.⁷⁰ More controversial is the metaphylactic use of antimicrobials. Metaphylaxis is defined as the administration of parenteral antimicrobials to a population of animals based upon a threshold of morbidity or presence of characteristics that suggest high risk for BRD. Many of the products labelled to treat BRD are also labelled for metaphylactic usage. While the utility of metaphylaxis varies notably with the class of cattle and morbidity that occurs in the untreated controls, it is clear that metaphylaxis reduces overall morbidity and mortality.^{21, 70} Concern exists regarding, and research continues in examining, the role of metaphylaxis in stimulating antimicrobial resistance, both in BRD pathogens and in other microorganisms.  

Emergence of antimicrobial resistance among M. haemolytica and P. multocida since the early 2000s has complicated treatment recommendations. Antimicrobial resistance is generally much higher in bacterial isolates obtained from calves previously treated for BRD than from those collected from untreated calves.^{69, 168} Nonetheless, it is unclear how much resistance contributes to treatment failure; for example, there is often less-than-perfect concordance between antimicrobials used to treat calves and the resistance profiles seen in pathogens recovered from those calves.¹⁵³ Thus, the question remains unanswered whether resistance is what allowed the organisms to persist and ultimately cause death, or if the cattle were at great risk of death due to other causes, and resistance simply emerged in them as a result of selection pressure. There is evidence that resistance can disseminate throughout a group of cattle via integrative conjugative elements (ICE).¹⁹⁷ These findings suggest that antibiograms of isolates from untreated cattle, if available, may be useful in guiding treatment decisions for other members of the group.

Vaccines

Vaccines intended for prevention of respiratory disease in feedlot cattle have been manufactured for nearly 100 years.¹⁹⁰ Numerous commercial M. haemolytica and P. multocida vaccines are available worldwide. Evaluation of vaccine efficacy in calves against M. haemolytica and P. multocida requires controlled studies involving challenge with virulent bacteria; however, there are difficulties associated with those studies  in part because of problems in defining objective outcome measures,²²¹ and because of difficulties in achieving adequate group sizes to obtain acceptable statistical power.²⁸⁵ Comparison of experimental vaccination data from various published studies is complicated by variations in challenge methods used.⁵¹ Vaccine efficacy is also difficult to establish in field studies in part because morbidity and mortality rates, infectious agents and stressors, and genetic makeup of cattle vary widely among studies.^{222, 275} A single field trial is considered inadequate to assess the economic impact of a particular vaccine on respiratory disease in feedlots.²⁸⁵ Mannheimia haemolytica and P. multocida vaccines have been reviewed, and efficacy of commercial vaccines has been assessed retrospectively.^{51, 66, 154, 205}   

Early bacterins were prepared from cultures of Bacillus bovisepticus (which has since been divided into the species M. haemolytica and P. multocida; following field trials their efficacy was questioned¹⁸¹ or they were found to have detrimental effects.⁷⁶ More recently, bacterins prepared from M. haemolytica have been reported to have no clear beneficial effect,^{107, 172} or to have detrimental effects and for the most part are no longer commercially available.^{90, 234, 284}Pasteurella multocida bacterins, however, are still in use, but there is little evidence of efficacy.⁵¹

Live M. haemolytica vaccines have been investigated^{19, 190} and marketed,¹¹⁸ but protection studies have yielded variable results, and one report found septicaemia of the previously marketed M. haemolytica  vaccine strain in calves.^{191, 214, 250, 293} Use of antibiotics in cattle vaccinated with live M. haemolytica (within seven days after or three days before vaccination) is not recommended, due to inhibitory effects on vaccine bacterial replication.¹¹⁸ The widespread use of antibiotics in calves arriving at feedlots makes the use of live bacterial vaccines impractical. Recently, the live streptomycin-dependent M. haemolytica and P. multocida vaccine that has been in use parenterally for many years was approved for both parenteral and intranasal vaccination.²⁵⁵

Identification of the importance of the leukotoxin produced during logarithmic phase growth in the pathogenesis of pneumonia^{96, 238, 240} led to the development of a commercial, cell-free, M. haemolytica S1culture supernatant vaccine.^{237, 241} In experimental trials using two doses of vaccine at an interval of 21 days, efficacy against moderate to severe pneumonia ranged from 60 to 70 per cent.²³⁷ Results from field trials were variable.^{22, 134, 270}

Numerous other antigens of M. haemolytica have been documented in logarithmic phase culture supernatant, including surface antigens involved in agglutination reactions,²⁴¹ capsular polysaccharide,⁶⁰ lipoproteins,⁶¹ outer membrane proteins,¹³ and sialoglycoprotease,¹ and may contribute to vaccine efficacy. Numerous immunogenic outer membrane proteins and lipoproteins have been demonstrated and may contribute to immunity against M. haemolytica. These include PlpE, OmpA, Gs60, Serotype 1- specific antigen, and transferrin binding proteins.^{14, 15, 52, 169, 183}

Since the initial M. haemolytica subunit vaccine, various companies have introduced other subunit or subunit-enriched vaccines consisting of outer membrane extracts,²⁵⁷ or extracted antigens enriched with recombinant leukotoxin,^{19, 274, 275, 277} or a bacterin with added culture supernatant antigens.^{19, 257} In 1999, a vaccine based on antigens expressed under iron-limiting conditions was licensed.^{71, 99} Serological responses to selected commercial M. haemolytica vaccines have been compared.^{52, 54, 257} Field studies with bacterin-toxoid vaccines demonstrated variable results, although positive effects on mortality or morbidity were seen in some studies.^{82, 167, 277}

Recent studies have focused on the induction of local immunity in the nasopharynx to M. haemolytica by mucosal delivery of antigen, thereby reducing colonization. Viral vectors replicating in the upper respiratory tract and expressing antigens of M. haemolytica,^{19, 25} oral administration of M. haemolytica antigens encapsulated in alginate microspheres,³⁴ recombinant outer membrane proteins and leukotoxin^{16, 53} and oral administration of modified live M. haemolytica have been studied.³⁷ None of those were commercialized.

The protective antigens of P. multocida have received less attention, but outer membrane proteins,^{2, 64, 97} fimbriae,² capsular polysaccharide,² neuraminidase,²⁶¹ OmpA^{63, 95} and transferrin binding proteins² are candidate antigens for subunit vaccines for use in cattle.

Vaccines targeting viral agents of respiratory disease (BoHV-1, BPIV-3 virus, bovine respiratory syncytial virus, bovine virus diarrhoea virus) have been advocated¹⁹⁰ in the prevention of pneumonic mannheimiosis/pasteurellosis in feedlot animals, on the basis that immunity to viral agents could reduce susceptibility to bacterial invaders by preserving the integrity of mucosal barriers and bacterial clearance mechanisms.

In spite of advances in identification of relevant organisms and antigens for inclusion in vaccines, the impact of vaccination on morbidity and mortality in the feedlot remains limited.^{73, 172, 179, 180, 190} To a large degree, this may reflect the conditions under which cattle are vaccinated. Although many vaccine manufacturers recommend that stressed or recently shipped cattle should not be vaccinated,^{118, 129} most vaccines against respiratory disease are administered on arrival at feedlots.^{19, 22} In many cases, vaccination on arrival delivers vaccine antigens after infection has already taken place,¹⁹ making it impossible for the animal to mount a timely immune response. Vaccines containing antigens of multiple agents are common and interactions between vaccine products can occur. A modified live BoHV vaccine has been shown to suppress immune responses to a M. haemolytica vaccine administered at the same time.¹¹⁰ While recommendations and practices continue to evolve, the utility and appropriateness of vaccination at arrival has been questioned. Recent studies found benefit to delaying vaccination until calves have become acclimated to the feedlot (the amount of delay may vary from 10 to 30 days).^{104, 228} A meta-analysis, however, found no difference in vaccination at arrival vs. delayed.²⁵⁴  

The kinetics of immune responses to respiratory pathogens in calves from birth to weaning, and from weaning to the onset of feedlot respiratory disease have not been studied systematically. It is unclear what proportion of beef calves have been primed to antigens of M. haemolytica S1 by the time of weaning. In one field study it was found that a significant increase in serum antibody titres to M. haemolytica leukotoxin occurred after primary vaccination on arrival at the feedlot, suggesting that many calves had been primed by natural exposure and had mounted anamnestic responses after a single dose of vaccine.²⁷⁷ Following an experimental study in young Holstein calves, it was also concluded that a single dose of M. haemolytica vaccine was as efficacious as two doses in increasing serum antibody titres and in protecting against experimental challenge;⁵⁹ this again suggested priming by natural exposure. If most calves leave the ranch of origin primed by natural exposure, then secondary immune responses to the rapidly increasing numbers of M. haemolytica in the nasopharynx must be insufficient in many cases to control the disease process. For vaccination to be effective in these animals it must provide a more potent antigenic stimulus than that occurring naturally, and/or the stimulus must occur earlier. Some calves may reach weaning age immunologically naive to M. haemolytica S1.^{77, 120} If vaccination is to protect such naive calves, then management changes which allow earlier vaccination will be necessary.

Diversity of immune experience (e.g. calves immune to some respiratory pathogens, primed for anamnestic responses to others, infected and mounting an early primary response to some and naive to the rest) on feedlot arrival could contribute to the variable efficacy of particular vaccines.^{134, 270} If calves in a particular trial arrive at the feedlot with a high level of immunity to the pathogen targeted by the vaccine in question, then the perceived benefits of vaccination will be low, although morbidity with respiratory disease due to other pathogens could still be high. Serological findings have been published in conjunction with clinical findings in some vaccine studies,^{110, 277} but not in others.^{134, 270}

To summarise, commercial vaccines are available for most of the agents implicated in BRD, including viral and bacterial pathogens. In general, these vaccines are effective in generating immune responses, and can be an integral part of a BRD control programme. Nonetheless, it is critical to recognize that vaccination alone is not an efficacious BRD control programme.

Preweaning and preconditioning programmes

Programmes to prepare cattle for entry to feedlots by preweaning (weaning 14 to 28 days before shipment off farm) or preconditioning (preweaning, castration, dehorning, and vaccination with selected vaccines 21 to 45 days before shipment¹³⁷) generally reduce BRD morbidity and mortality, but can still produce variable results. ‘Certified Precondition for Health’ preconditioning programmes for beef calves have been established in numerous states of the US since the 1960s,^{113, 218} but have made only limited impact on the feedlot industry.¹³² A review of controlled experiments of preconditioned calves found an average reduction in morbidity of 23 per cent and a decrease in mortality of 0,7 percentage units.⁴⁹ The economic benefits to both cow/calf producers and feedlot operators of preconditioning have been questioned.^{49, 73, 132, 133, 137, 207} In general, economic benefits of preconditioning are derived from weight gain of calves during that time, rather than a premium collected at marketing.¹¹⁶

Accumulating evidence suggests that calves can be vaccinated successfully at a relatively young age in spite of persisting titres of maternal antibodies. Serum antibody responses to the leukotoxin and capsular polysaccharide of M. haemolytica S1 have been reported in dairy calves vaccinated at six and eight weeks of age with a commercial culture supernatant vaccine.¹²¹ The results obtained in beef calves vaccinated at three and five weeks of age,²⁷⁵ at one and two months of age,²⁷⁴ or at two months of age¹⁰⁹ with a commercial vaccine containing genetically attenuated leukotoxin with extracted antigens of M. haemolytica, have also demonstrated significant increases in serum antibody titres post-vaccination. Vaccination of calves against respiratory viruses, in the presence of maternal antibodies, may induce immune priming^{147, 203} with the potential for anamnestic responses after weaning. A management programme of vaccination at branding combined with revaccination within a day of weaning⁸⁴ could provide a means to maximize immunity by the time of feedlot entry, with minimal extra labour costs.

In conclusion, given the current marketing procedures used in cattle industries mannheimiosis/pasteurellosis pneumonia can be reduced and managed through use of vaccines, antibiotics and good management practices. However, even the most fastidious utilization of these tools seems unlikely to eliminate the condition.

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