THE CANADIAN VETERINARY JOURNAL

LA REVUE VETERINAIRE CANADIENNESeptember-septembre 1974

SYMPOSIUM ON IMMUNIZATION OF CATTLE AGAINSTTHE COMMON DISEASES OF THE RESPIRATORY TRACT

On November 9, 1973 a symposium was

held at the University of Saskatchewan andwas sponsored cooperatively by the WesternCollege of Veterinary Medicine, the ExtensionDivision of the University of Saskatchewanand Connaught Laboratories, Toronto.The objective of the symposium was to

bring together some of the available informa-tion on the various aspects of respiratory tract

disease of cattle with a view to providing theveterinary practitioner with the informationnecessary to make rational recommendationsfor the control of respiratory tract disease incattle.

Dr. 0. M. Radostits was Chairman andtakes pleasure in bringing you these paperswhich were presented at the symposium.

THE BOVINE RESPIRATORY DISEASE COMPLEX

L. E. Lillie*

INTRODUCTION

THE BOVINE RESPIRATORY DISEASE COMPLEX

(BRDC) consists of at least three clinicalentities, as well as several additional diseaseswhich affect the respiratory tract secondarilyor as part of a more generalized disease (2).The three clinical entities are: 1) Enzooticpneumonia of calves, 2) "Shipping fever"complex and 3) Atypical interstitial pneu-

monia. Each of these groups consists of rela-tively well defined clinical and pathologicalsyndromes. However, each is also charac-terized by a complex often poorly understoodaetiology and difficult clinical control.

Enzootic pneumonia of calves is an entityfrom which numerous viral and bacterialagents have been isolated (45), includingParainfluenza 3 virus (PI-3) (24, 44, 88, 97),Adenovirus (22, 42, 59), Chlamydia agents(66, 87, 96), Rhinovirus (9), Reovirus (50,51), Enterovirus (23), Herpesvirus (63),Mycoplasma (31, 33), and a variety of more

conventional bacteria, usually Pasteurella spp.

These diseases tend to occur in the first six

'Veterinary Services Branch, Manitoba Depart-ment of Agriculture, Agricultural Services Com-plex, University of Manitoba Campus, Winnipeg,Manitoba R3T 2N2

months of life often in enclosed crowded con-

ditions where ventilation and humidity are

inadequate. The acute uncomplicated diseasesproduce more or less different pathologicalchanges and clinical illnesses which are occa-

sionally severe and fatal, but which more oftenare mild and transient. The sequelae of con-

solidation, bronchiectasis, purulent or obstruc-tive bronchiolitis, secondary bacterial infec-tions, and lung abcessation appear to becommon to many of these agents and pre-

dispose to ill thrift and further lung diseases inlater life.The "shipping fever" complex of diseases

are the acute diseases of adult life in dairy,feedlot or cow-calf operations. The principalconstituents of this group are infectious bovinerhinotracheitis (IBR) and pneumonic pas-

teurellosis. It is with this group of diseasesthat the symposium is concerned and sub-sequent discussion will be restricted to them.The third group of diseases consists of the

atypical or hypersensitivity pneumonias. It hasbeen our experience that this group of diseasesis becoming more prevalent and it is a signifi-cant cause of death, particularly in beef cattle.

While accurate statistics are difficult toobtain the BRDC remains as the most signifi-cant cause of morbidity and mortality in

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cattle, other than diseases of newborn calves.From 40% to 80% of all cattle diseases involvethe respiratory system (40, 41, 43, 46). Evena conservative estimate of losses to the Cana-dian cattle industry would run into manymillions of dollars annually. A 1967 sym-posium on the BRDC (2) was held for thefollowing reasons: 1) respiratory diseases ofcattle continue to be widespread and costly tocattlemen, 2) preventive measures and man-agement practices as generally applied havenot been entirely successful, 3) recognition ofa number of causative or potentially causativeagents has complicated understanding andcontrol and 4) development of a variety ofimmunizing agents has created a need todetermine optimal methods of application.

These reasons continue to be valid. Anypractitioner or research worker hoping tounderstand the respiratory disease complexmust synthesize the practical aspects of man-agement, genetics, economics and clinicalmedicine with the basic sciences of immu-nology, pathology, microbiology or virology.In the herd and in the individual animal, thetype of disease manifested and the severity,duration and distribution of the disease willresult from the integrated action of infec-tious agents, host resistance and environmentalstresses. Each of these factors must be takeninto account in any serious attempt at preven-tion, treatment, control or eradication of theBRDC, or of its components.

The Pathogenesis of Respiratory Disease: AConundrum

Infectious diseases of the respiratory systemresult from the interaction of the host, theparasites and the host's environment. In someinfectious diseases the relationship of host andparasite is relatively simple and direct. If theparasite is killed, removed or otherwise neu-tralized the disease will not occur irrespectiveof any other factors. IBR is an example of thistype of condition. IBR was originally identi-fied as a respiratory problem. However, sub-sequent investigation has shown that thisubiquitous virus can affect many body sys-tems (49, 61, 62, 73, 78, 99). If the virus ofIBR can be destroyed, the cattle populationisolated from the virus or a successful im-munization procedure developed, then thedisease would cease to exist. The significantunknown in the control of this type of con-dition continues to be the bovine immunesystem (68, 91, 96).

In other infectious diseases the relationshipis more complex. Coliform diseases of neo-nates, clostridial toxaemias of ruminants and

the pasteurellosis are examples of diseases inwhich the organisms involved are present socommonly in the body that they can be con-sidered part of the autocthonous flora. Pas-teurellae, for example, have been shown byMagwood, Collier and others to be part of thenormal nasal flora of cattle but not part of thenormal lung flora (18, 19, 32, 57, 93).

Under enviroumental conditions deleteriousto the host animal, often referred to as stress,these organisms (or specific strains of them),multiply rapidly and become dominant in theorgan in which they reside. Then either theyor their products are transported to other areasof the body and may induce severe and oftenfatal diseases. Control of this type of condi-tion involves elucidation of the complex inter-relationship of the environment, the agentsinvolved or associated with the disease and theresponse of the host animal.

Environmental FactorsThe economics of the beef cattle industry

(and to a lesser extent the dairy cattle indus-try) dictate that large numbers of cattle bemoved long distances at a time of year whenthe climate is changeable and often severe.Many Canadian beef cattle are born andraised on western ranges and then shipped tofeedlots near the great population centres inthe east, a distance of 1500 miles or more.Others are subjected to similar, if less lengthymovements to feedlots in western Canada orthe midwestern United States. During thisshipment the cattle may be subjected tocrowded conditions, exhaustion, irregular feed-ing and watering, climatic changes, and sickcattle. They may have gone through one ormore stockyards or sales barns. They mayhave been restrained, bled, tagged, herded,penned, culled, weighed, vaccinated, injectedwith antibiotics (often by rough, hurried oruntrained hands), bought or sold (perhapsseveral times) or otherwise handled. Theymay be moved off boxcars and onto trucks forfurther transit to feedlots. Once on the feedlot,they may be mixed with large numbers ofother cattle from many sources and perhapsintroduced a little too quickly to feedlotrations. In short, these animals may have beensubjected to intensive stress for periodsranging from several days to several weeks.The anxiety of being continually handledduring shipment alone may well be sufficientstress to severely retard body defence mech-anisms. This mental stress, coupled with theintense physical stress due to usually primitiveand occasionally cruel conditions of shipment,might make one wonder not why some of

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these animals become ill, but rather why allof them do not. Many of the debilitating con-ditions to which cattle are subjected duringshipment have been shown to retard thenatural defence mechanisms of the lung andprobably most of them do (6, 47, 53, 55, 79,80, 81). Dusts (11, 28), cold (65), suddenand extreme changes of temperature and rela-tive humidity, dehydration (6), hypoxia (29),cortisone, endotoxin (54, 90), cold coupledwith wetness, acute metabolic upsets (e.g.acidosis) (27), prior exposure to viruses (84)and the species of bacteria to which the lungis exposed (29) all have been shown to affectthe clearance of inhaled bacteria by the lungin a measurable and usually inhibitory way.

It should be pointed out that pasteurellosiswill also occur in cattle maintained underoptimal conditions. Curtis (22) followed bullsbeing moved short distances for feed-gainstudies in an R.O.P. (Record of Production)test station. "Shipping fever" was diagnosedclinically in eleven of forty-four bulls. How-ever, due to the fact that management condi-tions were optimal, the diagnosis was madeearly and adequate therapy was administeredrecovery occurred in all cases (three cases alsoresponded after relapses) with no loss ofweight or significant reduction in averagedaily gain. These observations do not in anyway discredit the role of debilitating condi-tions in the pathogenesis of this disease butrather illustrate that the disease is severeenough that even slight alteration in normalactivity may help to induce it and that, pro-vided management conditions are optimal andmedical care prompt and competent, the sys-temic effects of the disease may be kept to aminimum.

Besides the effects of shipment on pul-monary defence mechanisms, the convergence,shipment and redispersal of these animals pro-vides an ideal opportunity for the spread ofpathogenic agents. As pointed out below acertain percentage of normal (i.e. not clini-cally affected) animals carry Pasteurella mul-tocida and Pasteurella haemolytica as part ofthe normal nasal flora (57). During and aftershipment the numbers of P. haemolytica in-crease (89). It seems probable that dropletnuclei are produced during the low moistcough associated with the disease and perhapsalso during the laboured respirations (94).Increased nasal exudates may also serve tocontaminate feed and water containers, saltblocks and other common facilities. That sucha spread of P. haemolytica does occur wasnoticed by Carter (13) who found that"shipping fever" was present in the Toronto

Stockyards only when western cattle weremoving through and that local cattle whichhad not been subjected to abnormal conditionswould develop "shipping fever" when exposedto cattle which had been shipped.

Thus it appears that the environmental fac-tors associated with shipment of animals serveto: 1) reduce the resistance of cattle to in-fection and probably severely impair the res-piratory defence mechanisms and 2) exposelarge numbers of cattle to viral agents and toPasteurellae of increased numbers and viru-lence. As well the lung performs many non-respiratory functions within the organism whichare not often considered when treating a respir-atory disease. These non-respiratory functionsinclude filtration, acting as a blood reservoir,water, electrolyte and pH balance, tempera-ture regulation, elimination of volatile chemi-cal products and synthesis of required chemi-cal products (36). Loss of lung function as aresult of respiratory disease means loss of bothrespiratory and non-respiratory functions.Management of respiratory disease thus im-plies management of a diseased organism notjust a diseased lung.

Infectious AgentsMany infectious agents have been impli-

cated in the pathogenesis of "shipping fever."However, the two agents which have occupiedthe attention of the more recent workers arePI-3 virus and P. haemolytica. The Herpesvirus of infectious bovine rhinotracheitis(IBR) in spite of its ubiquitous distributionand multiple clinical manifestations has usuallytended to produce a separate and distinctclinical respiratory disease.

Gale isolated PI-3 from clinical "shippingfever" and designated it the SF4 strain ofPI-3 (25). Hoerlein measured the serumantibodies against PI-3 virus in feeder calves(39). He found that 68.6% of the animalsdeveloped significant (i.e. four-fold increaseor more) titres against PI-3 virus. Burroughsattempted to isolate IBR virus and PI-3 virusfrom feedlot cattle (12). He found that insummer 4.5% of the new arrivals yieldedvirus and 15.8% of the clinically affectedanimals also yielded virus. In winter 13.5% ofnew arrivals yielded virus while 66.6% ofclinically affected animals did so. The ratioof virus isolated was IBR virus to PI-3 virus as1 is to 1.55. Curtis in a more individual studyfound that 29.6% of the bulls he studied hadPI-3 titres on arrival at an ROP test stationand that the remainder developed titres within6 weeks. (21). Nine bulls with "shippingfever" developed titres between the acute and

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convalescent samples. In spite of the wide-spread titres the virus was only isolated in 2of 147 attempts. Thomson, Benson, and Savanfound equal serum titres in both sick and wellanimals (89).

It is possible that PI-3 virus plays some rolein "shipping fever". The virus is certainlywidespread and common. However, conclusiveproof of its pathogenicity is lacking (24, 97).This virus is capable of inducing a specificproliferative giant cell pneumonia in veryyoung calves and may contribute to the rathernon-specific lesions of enzootic pneumonia ofcalves. It has been demonstrated that in miceinfluenza virus (also a Myxovirus) does sig-nificantly inhibit the clearance of bacteria bythe respiratory tract if the virus infection pre-cedes the bacterial infection by 7-10 days(86). The specific effects of PI-3 virus on theciliated respiratory epithelium and on thealveolar macrophage of the cow need to bedetermined (16). In a recent study Gilka andThomson found that PI-3 virus did not affectthe ability of the bovine lung to clear inhaledP. haemolytica after the first day in calveswhich had serum antibody to P. haemolytica(90).

P. haemolytica is a gram negative cocco-bacillus haemolytic on beef blood agar andcontaining a number of subtypes within thespecies. The smooth colonial variant of bio-chemical Type A serotype 1 is almost alwaysassociated with bovine respiratory disease (7,14, 15). P. haemolytica is part of the normalnasal flora of many cattle and like Escherichiacoli and Clostridium perfringens, certainstrains multiply and become dominant underaltered environmental conditions.

The question arises as to how P. haemolyticamultiply in the nasal cavity and are trans-ported to the lung. The bovine lung is notsterile but carries a small transient burden oforganisms mainly Bacillus spp. and Micro-coccus spp. originating in inhaled ruminalgases and environmental dusts (64). Pas-teurellae are not part of this normal lungburden. Several possible mechanisms existwhereby this might occur:

1. The inhalation of droplet nuclei (95). Itseems likely that droplet nuclei would beproduced in the exhaled air from animalscarrying large numbers of bacteria on thenasal mucosa. Further the low moist coughassociated with this disease might also producedroplet nuclei. Inhaled aerosolized bacteria(Staphylococcus aureus and P. haemolytica)are deposited in the bovine lung (56). Againstdroplet nuclei as a sole cause of nose to lungtransfer is the fact that lesions in the natural

disease are virtually always anteroventral indistribution. Droplet nuclei on the other handare distributed fairly evenly throughout thelung. It is possible that exudates induced bybacteria in the posterodorsal aspects of thelung might drain to the dependent lobes. If sosome evidence of this flowing exudate shouldbe demonstrable. A flowing pattern is oftenevident in histological sections of pasteurellosislungs. However, whether or not this is respon-sible for the anteroventral distribution of thelesion is not clear.

Wright considered that "droplet nuclei com-prise an important state of airborne infection"(98). Gray studied the relationship of num-bers of P. haemolytica in the nasal cavity tonumbers of bacteria in the tracheal air (30).He found that when P. haemolytica colonizedthe nasal cavity they could also be found inthe tracheal air; 47.8% of the inhaled bacteriawere in droplet nuclei 1-5 mm in size; a sizeoptimal for deep lung penetration.

It is clear that the lung is exposed to P.haemolytica as droplet nuclei at the time ofincreased number in the nostrils. However,the distribution of the lesions mitigates againstdroplet nuclei as the sole form of pulmonaryinfection. It seems more logical to incriminatedroplet nuclei as the method by which Pas-teurellae are spread from animal to animal,(i.e. from nasal cavity to nasal cavity).

2. The retrograde drainage of infectedexudates from the nasal cavity to the lungs.Wright has stated that materials suspended ina liquid phase and dropped into the noses ofsome experimental animals will find their wayin a matter of minutes into the deepest portionof the lung (98). With liquid penetration thenormal defense mechanisms are overwhelmedby the large concentrated dosage of infectedmaterial. Apparently the accumulation of bac-teria-laden liquid in the suprapharyngeal por-tions of the respiratory tract (such as mightoccur with profuse mucus production as aresponse to irritation of the nasal mucousmembrane) may overwhelm the subpharyn-geal portion. In pasteurellosis the numbers ofbacteria increase markedly and increasedmucus production does occur. The exudate ismoved by ciliary activity to the suprapharyn-geal area. Wright states that the subpharyn-geal region may be overwhelmed in normalanimals. It is possible that under the debilitat-ing conditions of transit, the subpharyngealdefenses will be even more susceptible toattack. It may also be that, due to dehydration(a common condition in shipped cattle), themucucilliary tracheal elevator is inhibited.Thus infected exudates, once passed the

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pharynx would face little opposition on theirtrip to the lung.

Infection by retrograde tracheal drainageof infected nasal exudates would be consistentwith the dependent, anteroventral distributionof the lesions of pasteurellosis. However, nostudy has yet been carried out on trachealdrainage of infected exudates in cattle or onthe inhibition of the mucuciliary trachealelevator under the environmental conditionsof transit.

3. Lymphatic drainage. Lymphatic drainageis thought to occur in the spread of infectionfrom the lymphadenitis of strangles in thehorse to the pleural cavity to produce an em-pyema. This has not been demonstrated incattle.

4. Haematogenous spread. P. haemolyticais not usually found in the blood of pneumoniccattle. The disease is not considered to besepticaemic.A characteristic bacteriological finding in

"shipping fever" lungs is massive numbers ofP. haemolytica often in pure culture. Thepathogenic properties of P. haemolytica arenot well described. What characteristic of P.haemolytica induces the typical serofibrinousresponse, or is this response in fact a charac-teristic of the host animal? Is the pathologicalpicture a function of the infectious agent orthe host? Wessman in a study of P. haemoly-tica isolated from the respiratory tract ofcattle concluded that strains of P. haemolyticafrom healthy cattle may differ from those of"shipping fever" cases (92). The fact that P.haemolytica can be transferred from stressedcattle to nonstressed cattle and produce clini-cal disease suggests that the virulence of theorganism may be enhanced perhaps by theproliferation of more resistant strains. Therequirements of P. haemolytica for oxygenand enriched medium have been described(93). It seems that the lung provides an idealmedium for the growth of P. haemolytica.

Biberstein and Thompson concluded thatthe pathogenic process of P. haemolyticaconsists of a build-up in the host of a bacterialpopulation that will be toxic (8) and that thevirulence of strains of P. haemolytica is due totheir ability to grow rapidly from a smallinoculum to a toxic concentration.

Rebers, Heddlestone and co-workers carriedout extensive studies on P. multocida("haemorrhagic septicaemia" strains), a re-lated organism. They have isolated a heatstable particulate, antigenic lipopolysacharrideprotein complex from virulent encapsulatedstrains (69, 70, 71, 75). This fraction wastoxic and lethal to lab animals and conferred

a high degree of immunity. It was toxic tocalves and produced shallow rapid breathing,depression, salivation, lacrimation, diarrhoea,coma, and death. These workers concludedthat this fraction was similar to endotoxin.

Endotoxin is a toxic cell wall fraction of allgram negative bacteria (10). Endotoxins actsystemically to produce fever, sweating, weak-ness, and generalized aches. The pyrogeniceffect of endotoxin is due to a direct action onthe circulation of the hypothalmus resulting inslowed systemic circulation and reduced heatradiation. Endotoxin in high doses can producecoma and death due to acute circulatory col-lapse or pulmonary hypertension (72, 74, 75,86).The growth curve of P. haemolytica shows

a sharp log phase of growth beginning atthree hours of incubation and reaching apeak at eight to 12 hours (92). This peak isfollowed by a phase of rapid decline accom-panied by lysis of cells and release of endo-toxin. If the growth of massive numbers of P.haemolytica in vivo is accompanied by asimilar rapid die-off and lysis of cells it wouldbe logical to assume a similar release of mas-sive quantities of endotoxin into the lung. Itshould be noted that, while several workershave demonstrated that P. haemolytica doesnot usually circulate (i.e. bacteraemia or sep-ticaemia does not usually occur) it is not yetclear whether toxemia occurs.The endotoxins of P. haemolytica have been

demonstrated by Keiss (48). He concludedthat endotoxin constitutes 12.25% of the dryweight of the organism and was a phos-pholipid-polysaccharide-protein complex. Thiscomplex was neutropaenic, pyrogenic, andtumor necrotizing. It produced a Shartzmanreaction and a generalized reticulo-endothelialreaction. Keiss found that quantitative differ-ences existed in the haemodynamic response ofdifferent species to the endotoxin but that theresponses were qualitatively similar. The toxicproperties were not necessarily neutralized byhomologous antibody. Keiss concluded that,"in the case of 'shipping fever' in cattle wherelarge numbers of P. haemolytica cells are pres-ent in pneumonic lungs, endotoxin effects,including death, may be expected." The clini-cal signs of "shipping fever", excluding theobvious hypoxia and dyspnea resulting fromloss of a large percentage of functional lungparenchyma, may be explained by endotox-icity.

Several further interesting observations areavailable on the effects of endotoxin on thelung. Snell found that an aerosol of E. coliendotoxin was rapidly absorbed and produced

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a prompt transient leukopenia followed by aleukocytosis and fever after one to two hours(86). After 24 hours it produced focal capil-lary haemorrhage, massive edema of alveolarwalls and infiltration of alveolar walls withlarge phagocytes, eosinophils and neutrophils.At 48 hours the septal oedema was reducedand marked proliferation of alveolar macro-phages was present. Snell described this effectas an acute self-limited interstitial pneumonitis.Rhoades et al exposed cattle to aerosols of P.multocida endotoxin and found that aerosolexposure constantly produced a multiple focalfibrinosuppurative pneumonia (75). Larsonand Schell studied the toxicity and antigenicityof "shipping fever" vaccines and concludedthat the present bacterins may produce tran-sient (four *to six hour) endotoxic shockespecially under transit stress; that is, thevaccine could actually reduce the host re-sistance rather than aiding it (52). They pro-duced a detoxified Pasteurella bacterin whichdid not have this noxious effect.

Experimental ReproductionMany questions still remain concerning the

pathogenesis of "shipping fever" mainly be-cause of the difficulty of satisfying Koch'spostulates. An erroneous attempt is sometimesmade to equate this disease to more conven-tional forms of infection rather than to suchopportunistic pathogens as E. coli. This wasrecognized as early as 1956 by Carter (13)who said,"When thinking about shipping fever it shouldbe remembered that we cannot necessarily drawan analogy between this disease and clear cutdiseases of one cause, like hog cholera and rinder-pest. One observation which indicates that ship-ping fever is not comparable with an epizootic isthe fact that shipping fever in the Toronto Stock-yards is almost non-existent when there are nowestern cattle passing through the yards. That is,without a continuous supply of susceptiblestressed animals, the disease disappears. Suchwould not be the case with our clear cut epizooticdiseases."

Early attempts to reproduce the diseasefailed to emphasize its multicomponent aeti-ology. The fact that Pasteurellae and PI-3virus could not reproduce the disease bythemselves prompted some workers to ques-tion their validity as pathogens. More recentlyattempts to reproduce the disease using bothbacterial and viral agents coupled with de-bilitating stresses have met with greater, butstill limited success.

Corier in 1960 (20) using IBR virus and P.

haemolytica found that the use of both agentsdid not affect the severity of the illness butdid prolong its duration. He postulated sup-pression of leukocytes as the mechanism. P.multooida and P. haemolytica and PI-3 virushave also been used in various combinationsbut the results were unconvincing. Heddle-stone et al (35) administered PI-3 virus byaerosol, intratracheally and intramuscularly,followed by P. multodica, P. haemolytica orboth. He found that the virus, if administered24 hours prior to bacterial exposure, did po-tentiate the effects of the bacteria. Hetrickdemonstrated that PI-3 viral exposure 48hours before exposure to P. multocida pro-duced a febrile response and a respiratoryillness of varying severity in 2-3 days (38).He concluded that synergism had occurred.Saunders exposed cattle to P. haemolytica andstress with and without exposure to PI-3 virus(82, 83). A combination of both agents pro-duced transient increased temperatures, nasaldischarge, and proliferation of P. haemolyticain the nose. Matusuoko et al in immunizationstudies with cattle used aerosols of PI-3 virus,P. multocida, and P. haemolytica accompaniedby varying stresses (380C for 12 hours in aclosed room, trucking, spraying with water,leaving overnight on a truck) (58). They pro-duced depression, coughing, dyspnoea, nasaldischarge, and fever for 5 days after challenge.

Baldwin et al exposed normal and cholos-trum deprived calves to aerosols of PI-3 virusand P. haemolytica (5). PI-3 virus alone pro-duced mild signs of respiratory infection. P.haemolytica alone produced a mild infectionwith a febrile response. Together the twoagents produced extensive lung lesions (es-pecially if PI-3 virus was administered 24hours prior to P. haemolytica). More recentlyGilka measured the effects of previous ex-posure to PI-3 virus on the lung clearance ofcalves (90). He concluded that there waslittle inhibition of pulmonary clearance ofinhaled P. haemolytica after the first day incalves with a serum antibody titre to P.haemolytica.

Current ConceptsThe search for effective immunizing agents

has been underway for many years. Some ofthe early effort was not based on sound scien-tific evidence, was of questionable efficacy andremains contentious (34). Thus, the "haemor-rhagic septicaemia" bacterins have now beenremoved from the market. The danger remainsthat any product introduced with the promiseof reducing either IBR or pasteurellosis maybe seized upon by both producers and vet-

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erinarians as a panacea and expected to domore than is reasonable. It is clear that novaccine, however effective it may be undercontrolled circumstances can be expected tocompensate for gross errors of husbandry,environmental stress, inadequate nutrition, orsubclinical disease (2, 26, 43, 46, 66). Avaccine which may be quite reliable in ahealthy animal could quite easily invoke afull blown disease when administered im-properly or to an already compromised animal(77, 85). We must take care not to seek solu-tions to diseases only in the barrel of a syringe.

It is clear that solid progress in the controlof bovine respiratory disease will come onlywith an increased understanding of both therespiratory and immune systems of the cowand of the interaction of the host, parasitesand environment (1, 4, 26, 66). The recentwork of Thomson and his group at Guelphhas made considerable progress towardsunderstanding the effects of various deleteriousinfluences on the bovine respiratory tract(89). The importance of understanding theimmune system of the cow is underscored notonly by the emphasis placed on immunology atthis Symposium but also by the Colloquium onImmunity to Selected Infectious Diseases ofCattle sponsored last year by the Council onBiological and Therapeutic Agents of theAmerican Veterinary Medical Association (3).Each of us involved in bovine respiratory

disease work whether at the research, teach-ing, or clinical practice levels needs to ap-preciate the importance of understanding theproblem. Research in this area is hampered bya lack of funds. The enormous losses do notseem to generate a proportionate amount offunds to attempt to solve the problem. Re-search is slow and difficult because amongstother reasons there are substantial physicalproblems involved in working with cattle. Yetsignificant and solid progress is being made byworkers in this country and elsewhere and theirefforts need to be applauded, appreciated, andsupported. The practitioners amongst usmust recognize the importance of in depthknowledge of the three components of bovinerespiratory disease. It is discouraging to hearpractitioners indicate that papers being pre-sented are too research oriented or not prac-tical enough for them in one breath and thenwonder about the reasons why they experi-enced a vaccine failure in the next. It is notsufficient to know how much of which productto inject by which route for which particulardisease condition. Any practitioner adminis-tering any drug or biologic is ethically re-sponsible for understanding the variety of

effects which that product may have. Certainlyany product administered for the preventionor treatment of bovine respiratory diseasesrequires an understanding of both the immunesystem of the cow and the mechanisms ofrespiratory disease in the cow.

Veterinarians attending this symposium arefortunate in receiving presentations on the im-mune system of the cow, the mechanisms ofrespiratory disease of the cow, and severalpractical approaches to clinical problems.They also, I am sure, developed an apprecia-tion for scientists who are courageous enoughto work in this field and for the magnitude ofthe problems which must yet be solved. Theresearch workers, in turn, become reacquaintedwith some of the day to day problems of themen and women who are on the front linesand some of the approaches devised by thesepractitioners to handle difficult, clinical situa-tions. Out of such mutual dialogue comesmutual reinforcement, renewed enthusiasmand new ideas for handling bovine respiratorydiseases. The organizers of this symposium areto be commended for their initiative in pro-viding an opportunity for such a dialogue.

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3. ANON. Report of the panel of the collo-quium on immunity to selected infectiousdiseases of cattle. J. Am. vet. med. Ass. 163:718-787. 1973.

4. BAKER, J. A., M. J. C. APPEL and F. J.VOLENEC. Possibilities for prevention ofdisease in the future. J. Am. vet. med. Ass.152: 911-919. 1968.

5. BALDWIN, D. E., R. G. MARSHALL and G. E.WESSMAN. Experimental infection of calveswith myxovirus parainfluenza 3 and Pasteurellahaemolytica. Am. J. vet. Res. 28: 1773-1782.1967.

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8. BIBERSTEIN, E. L. and D. A. THOMPSON.Type specificity of immunity to Pasteurellahaemolytica infection in mice. J. comp. Path.75: 331-337. 1965.

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9. B6GEL, K. Bovine rhinoviruses. J. Am. vet.med. Ass. 152: 780-785. 1968.

10. BRAUDE, A. I. Bacterial endotoxins. Sci. Am.210: 36-41. 1964.

11. BRUNDELET, P. J. Experimental study of thedust clearance mechanism of the lung. Actapath. Microbiol. scand. Suppl. 175: 1-149.1965.

12. BURROUGHS, A. L. Viral respiratory infec-tions in commercial feedlot cattle. Am. J. vet.Res. 28: 365-371. 1967.

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ABSTRACT

Clearance of endotoxin from the blood ofcalves. M. G. Maxie (Ont. Vet. Coll., Guelph,Ont.).

Endotoxins, which are constituents of thecell walls of Gram-negative bacteria, appearto be of importance in the pathogenesis ofmany toxemic diseases of cattle. They maydirectly or indirectly cause fever, leukopenia,shock and death.

In order to clarify the effects of endotoxinson cattle, the clearance and organ distribu-tion of 51Cr-labelled Pseudomonas aeruginosaendotoxin was studied in nontolerant andtolerant calves. Tolerance (increased resist-ance to the toxic and pyrogenic effects ofendotoxin) was induced by daily intravenousinjections of endotoxin. Clearance of the sub-

lethal doses of endotoxin used was so rapid(99% of injected dose cleared within 3 min-utes) that an effect of tolerance on the clear-ance rate was not observed. The radioactiveendotoxin localized primarily in the lungs(50%) and liver (3%) and radioactivity wasexcreted mainly in the urine. Significant as-sociation of endotoxin with any of the circu-lating formed elements of the blood was notobserved. The characteristic fever, leukopeniafollowed by leukocytosis, tachycardia, dyspneaand shock following endotoxin injection wereobserved and were decreased in severity intolerant calves.

Research Rostrum of the Twenty-fifth Cana-dian Veterinary Medical Association AnnualConvention, Edmonton, Alberta 1973.

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