Endotoxin and Disease in Food Animals

8/14/2019 Endotoxin and Disease in Food Animals

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nellosis in cattle are most severe in confinement-raiseddairy calves at 1 to 10 weeks of age.9,10Although salmo-nellosis is usually described as being confined to the gas-trointestinal tract, most calves develop bacteremia withspread of the infection to liver, lungs, bone marrow, and

central nervous system.In older cattle, shipping fever pneumonia (SFP) oc-curs in feedlot animals; 75% of cases develop duringthe first 45 days that the cattle are housed at the feedlotfacility. The disease process is apparently caused by acomplex interaction among stressors, viruses, and bac-teria that have an endotoxin component in the cell

wall. The primary bacterial isolates of shipping feverpneumonia are Pasteurella hemolytica, P. multocida,and some Pseudomonas species.16 The capsules of P.hemolytica, P. multocida, and Haemophilus somnuscontain lipopolysaccharide (endotoxin). The release of

the endotoxin molecule induces several events, includ-ing initiation of complement and coagulation cascadesand recruitment of activated neutrophils and macro-phages. Pasteurella hemolyticaproduces a protein cyto-toxin that is lethal to these macrophages and neu-trophils; enzymes that can destroy tissue are thusreleased into the microenvironment. In addition, reac-tive oxygen intermediates are produced that are capableof destroying neutrophils and surrounding tissue.

Coliform mastitis, another disease process initiatedby gram-negative opportunists, can be devastating todairy production units. The process, which primarily

develops during the first 100 days of lactation but mayoccur at any stage of lactation or during the dry period,encompasses all degrees of severity from peracute tosubclinical. 17 The bacteria most frequently isolatedfrom this form of bovine mastitis include E. coli, En-terobacter aerogenes, and Klebsiella pneumoniae. Othergram-negative organisms that are less commonly isolat-ed include Pseudomonas aeruginosa, P. multocida, andSerratia marcescens. The resultant bacterial growth inthe mammary gland can cause serious local and sys-temic consequences.1821

CLINICAL SIGNS ASSOCIATEDWITH DISEASE: MEDIATOR SHOCKMorbidity and mortality associated with gram-nega-

tive bacterial sepsis are apparently the consequences ofhost reaction to bacterial cell wall components (e.g., en-dotoxin, the lipopolysaccharide cell wall component ofgram-negative bacteria).2224 The following endogenousand exogenous factors, however, have been linked to thepathophysiology of sepsis and mediator shock: (1) endo-toxin from gram-negative bacteria; (2) peptidoglycanand exotoxins from gram-negative bacteria; (3) endotox-in-binding proteins and receptors; (4) bactericidal pro-

teases; (5) release of cytokines, histamine, bradykinin,and arachidonic acid metabolites; (6) complement acti-vation; and (7) endothelium-derived adhesion molecules.

The arachidonic acid metabolites originate in the cy-clooxygenase and lipoxygenase pathways. Members of

the cyclooxygenase pathway and their biologic activitiesinclude PGE2 (vasodilator), PGF2 (vasoconstrictor),thromboxane A2 (vasoconstrictor and promoterof platelet aggregation), and PGI2 (vasodilator andinhibitor of platelet aggregation). Members of the lipoxy-genase pathway (leukotrienes) include 5-hydroxyeico-satetraenoic acid (5-HETE) and leukotrienes (LT) A4,B4, C4, and D4. These compounds are potent bron-choconstrictors and vasoconstrictors, elicit plasma exuda-tion, are chemotactic for leukocytes, and are involved inmicrothrombus formation.

Variations in the biologic activity of endotoxins have

been observed. These differences relate to the presenceof lipid-Aassociated protein, aggregation, polysaccha-ride composition, culture conditions, and the source ofthe organism. Many of the clinical signs observed inconjunction with gram-negative bacterial disease havebeen reproduced experimentally by administering puri-fied endotoxin (also known as lipopolysaccharide) invarious doses and by various routes. The effects oflipopolysaccharide on host cells (e.g., macrophages,platelets, and endothelial cells) and on the release of in-flammatory mediators also influence the clinical signsobserved at various stages of the disease process. For

example, the severity of inflammatory responses afterlipopolysaccharide challenge has been demonstrated tovary directly with receptor numbers on the macrophage(which can vary among animals).25

The general effects of endotoxins are well chronicledand reportedly include lethargy, respiratory distress, tran-sitory hyperthermia followed by hypothermia, decreasedsystemic blood pressure, increased heart rate followed bydecreased cardiac output, diarrhea, changes in blood cellcounts, and alterations in the blood coagulation system.Some of the more specific physiologic and pathologic re-actions are lymphopenia followed by lymphocytosis, neu-

tropenia followed by leukocytosis, hyperglycemia fol-lowed by hypoglycemia, depletion of liver glycogen,anabolic and catabolic responses in protein metabolism,localized and generalized Shwartzman reactions (i.e., localthrombosis formation and/or general disseminated in-travascular coagulation with bilateral renal cortical necro-sis), induction of transitory tolerance to further endotoxininsults, and altered reproductive performance (see thebox).

The classical and alternative complement pathways areactivated, resulting in generation of anaphylatoxin andmany secondary local and systemic effects. The intrinsic

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and extrinsic pathways of theclotting system also are acti-vated, expression of tissuefactor is enhanced, and dis-seminated intravascular coag-

ulation may ensue. Plateletsaggregate and sequester invarious capillary locations andsecrete their mediators. Neu-trophils respond by produc-ing inflammatory mediators(prostaglandins or leuko-trienes) and oxygen radicals.Macrophage function is en-hanced, and the cells secretecytokines. Comprehensivediscussions of the pathophysi-

ologic effects of endotoxins inruminants are available in theliterature.26,27

ANTIBIOTIC THERAPYAND ENDOTOXINRELEASE

Antibiotic-induced releaseof endotoxin has been ofclinical and research interestfor some time. A 3- to 78-fold increase in the total con-

centration of endotoxin invitro and in vivo has been re-ported.28,29 There is appar-ently considerable overlapbetween the effect of-lac-tam antibiotics and non-lactam antibiotics, with anunexplained delay betweenthe lethal activity of antibi-otics and the release of endo-toxin. The lytic and nonlyticrelease of endotoxin thus

must be considered in thepathogenesis of disease andwill influence the therapeuticefficacy of antiendotoxintherapy. Scientific research isnecessary concerning this

topic in food animals.

ENDOTOXINS, EXOTOXINS,AND ENTEROTOXINS

Endotoxins are heat-stable lipopolysaccharidelipoprotein complexes that may be released during cell

growth and bacterial lysis as part of the outer membraneof gram-negative bacteria. The release of this compoundresults in the initiation of mediator cascades (e.g., releaseof cytokines, serotonin, histamine, bradykinin, andarachidonic acid metabolites) that culminate in the clas-

sical clinical signs mentioned. Although it is a strong py-rogen in the host, endotoxin is weakly toxic, rarely fatalcompared with exotoxins, and a relatively poor immuno-gen. No toxoid preparation, in the classical scientific def-inition, is provided in most vaccine preparations of thismolecule. The appropriate definition of a toxoid dictatesthat the endotoxin molecule in the preparation be treat-ed by chemicals or heat in such a way as to eliminate thetoxic qualities while retaining the antigenic properties.These data are often unavailable to the public.

Exotoxins are heat-labile proteins excreted by certaingram-positive or gram-negative bacteria. The molecules

possess a specific mode of action (e.g., cytotoxin, entero-toxin, or neurotoxin) with defined actions on cells or tis-sue. Exotoxins are highly toxic and often result in a fataldisease process. Compared with endotoxins, these bacte-rial proteins are highly immunogenic and stimulate theproduction of neutralizing antibody (antitoxin). Treatingthe protein toxin with formaldehyde eliminates its toxici-ty without destroying the immunogenic properties.Formaldehyde treatment of endotoxin does not make thelipopolysaccharide molecule a toxoid as strictly defined.Exotoxins reportedly do not produce fever in the host.

Enterotoxins are exotoxins that specifically affect the

small intestine, causing changes in intestinal permeabil-ity that lead to diarrhea. The substantial diarrhea ob-served in patients with cholera is due to the action ofthis type of toxin and is commonly caused by food-poisoning microorganisms.

ESCHERICHIA COLI0157:H7 AND VEROTOXINSDuring the winter of 1993, a severe outbreak of food-

borne human disease in the Pacific Northwest waslinked to microbial contamination of ground beef withE. coli0157:H7.30 The outbreak occurred in several lo-cations, and the number of cases reached 400. Of these,

125 patients were hospitalized. At least 29 patients de-veloped acute renal failure, and all but 8 of these re-quired hemodialysis. Three young children died. Al-though this outbreak received deserved public attention,it is not unique. Escherichia coli0157:H7 was first iden-tified in 1982, when it was determined to be the causeof a multistate outbreak of hemorrhagic colitis associat-ed with hamburger patties sold by a national fast-foodchain.31 Other recent outbreaks ofE. coli0157:H7related disease have been associated with contaminatedapple cider, unpasteurized milk, mayonnaise, and mu-nicipal water supplies.

Food Animal The Compendium January 1996

A N T I B I O T I C - I N D U C E D R E L E A S E s A N T I E N D O T O X I N T H E R A P Y s H E A T - L A B I L E P R O T E I N S

Effects of

Endotoxins

General

s Lethargys Respiratory distress

s Transitory

hyperthermia followed

by hypothermia

s Decreased systemic

blood pressure

s Increased heart rate

followed by decreased

cardiac output

sDiarrhea

s Changes in blood cell

counts

s Alterations in the blood

coagulation system

Specific

s Lymphopenia followed

by lymphocytosis

s Neutropenia followed

by leukocytosis

s Hyperglycemia

followed by

hypoglycemia

s Depletion of liver

glycogen

s Anabolic and catabolic

responses in protein

metabolism

s Schwartzman reactions

s Transitory tolerance to

further endotoxin

insults

s Altered reproductive

performance


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Because some of the most significant clinical eventshave involved contaminated meat, the public view offood-borne disease and the safety standards required toprevent its occurrence has changed. Veterinarians shouldbe active in improving on-farm, preharvest, food safety

quality assurance programs to prevent contamination ofmilk and meat by pesticides, herbicides, hormones, an-tibiotics, and microbes.

The vast majority of strains of E. coli isolated fromfeces are part of the normal intestinal flora. They playan important role in maintaining optimum intestinalphysiology. In this group of bacteria, however, arestrains that are pathogenic and cause diarrhea. Strainsthat cause diarrhea do so by mechanisms that have re-sulted in the following classifications: enteropathogenic(EPEC), enterotoxigenic (ETEC), enteroinvasive(EIEC), and verotoxigenic (VTEC).32 Canadian inves-

tigators have demonstrated that toxins produced bystrains of E. coli serotype 0157:H7 are cytotoxic forvero cells; hence the term verotoxins. In addition, isola-tion of the pathogen was closely related with hemor-rhagic colitis (HC) syndrome in humans.

Two clinically important verotoxins produced by E.coli (VT1 and VT2) are members of a family of manysimilar cytotoxins. The verotoxins are subunit toxins con-stituted by an A (active) subunit and several B (binding)subunits. The verotoxins bind to the receptor on the sur-face of an intestinal cell via the B subunit. The A subunitis then taken into the cell and cleaved to an active frag-

ment that inhibits cellular protein synthesis. Escherichiacoli0157:H7 is often the most frequent serotype ofVTEC isolated. The reported predominance of serotype0157 is undoubtedly biased by the wide use of methodsadapted only for this serotype. More than 57 otherserotypes that produce verotoxins have been described.33

A German study used a common biotechnologytechnique (DNADNA colony hybridization usingspecific gene probes for VT1 and VT2) to examine2100 E. colistrains from the feces of healthy animals.Ten of 82 milk cows, 20 of 212 beef cattle, and 5 of 75pigs reportedly carried genes for VT1 and/or VT2.

Several of the serotyped isolates have been described tobe pathogenic in humans (0157:H7, 082:H8, 0116,0113, 0126, and 091).34

In a portion of the National Dairy Heifer EvaluationProject conducted by Veterinary Services (USDA/

APHIS), 6894 heifer calves in 1068 dairy herds weresampled in 28 states. The study reported a prevalence ofisolation ofE. coli0157:H7 in calves of 3.6 per 1000.Escherichia coli0157:H7 was found among calves from2 weeks to greater than 12 weeks of age; however, no cul-ture-positive feces were found among 633 calves sampledduring the first week of life. Culture-positive calves were

present in all regions of the United States; the herdprevalence was estimated at 5%.35 No information wasreported concerning the capability of these isolates toproduce verotoxins.

VACCINES AND ENDOTOXIN CONTENTTraditional gram-negative vaccine preparations havebeen plagued by problems of adverse reactions in thehost species, thus earning the distrust of many veterinari-ans and producers. The Limulusamebocyte lysate (LAL)test was used to determine endotoxin levels (endotoxinunits [EU/ml]) present in commercial vaccine prepara-tions. The usual conversion of 5 EU/ng of endotoxin ap-plies to all of the figures in this report. Commercialgram-negative immunogens contain thousands ofEU/ml of vaccine and may contain millions of EU/ml offree endotoxin, as measured by the LAL (Table I).

Because the pyrogenic threshold for pharmaceuticalcompounds is 5 EU/kg body weight, the maximum tar-get amount in a 700-kg cow would be 3500 EU. No py-rogenic thresholds have been established for food animalsrelated to vaccine administration. Many of the immu-nization schedules used today in food animals may exceedthe target amount set in the pharmaceutical compoundexample. As producers become more aware of the adversereactions that may result from immunization protocols,the veterinarian in charge of herd health programs mustbe aware of the endotoxin levels in the vaccines being ad-ministered. For example, the veterinarian may need to

have the products tested and then weigh safety and effica-cy considerations in selecting the immunogen to be ad-ministered or the frequency of vaccine administration. Todate, no published research studies have assessed either ofthese strategies using commercial vaccine preparations.

EXPERIMENTAL FINDINGS An experiment of importance to the dairy industry

involved the administration of commercially availableimmunogens to lactating dairy cattle and the effect ofthis practice on milk production during the next fewdays (Table II). The immunogens were administered

via the dose and route recommended by the manufac-turer and were administered alone or in combinationwith the other two vaccines. The subjects were lactatingHolstein cows in the first to third lactation and 10 to75 days in milk.

Although there were no overt signs of mediator shockduring the first 5 days after vaccination, injection siteswelling was noted with each vaccine. The dairy wasequipped with a computerized system to monitor milkproduction of each cow twice daily throughout lactation.Some of the subjects experienced a decrease in milk pro-duction compared with their baseline values (Table III).


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able (e.g., micromethod, mi-crotechnique, microdilution,and LAL-bead). In perform-ing the gel-clot assay, a smallamount of LAL solution is

added to an equal volume ofsample or standard solution.If a gel-clot is formed afterappropriate incubation, theassay is scored positive. Theturbidimetric method isan extension of the gel-clotsystem. The turbidimetricreagent contains enough co-agulogen to form a turbid so-lution (not a gel-clot) whencleaved by clotting enzyme.

The amount of turbidityformed is proportional to theamount of active clotting en-zyme and is thus proportionalto the amount of endotoxinpresent in the test solution.

The colorimetric methodrequires the mixing and in-cubation of test sample andreagent. A precipitate that isformed consists of turbid gel-clot material. The gel-clot pre-

cipitate is centrifuged, collect-ed, washed, and assayed bythe Lowry protein procedure.The amount of protein in theprecipitate is directly propor-tional to the amount of coag-ulogen cleaved by the activeclotting enzyme. A standard

curve can be constructed to determine the endotoxinconcentration in the sample.

The chromogenic method is similar to the turbidimet-ric assay system in that it is quantitative. The coagulogen

is partially or completely replaced by a chromogenic sub-strate. In a two-step method, the sample and LALreagent are incubated and the chromogenic substrate isthen added to the mixture. After incubation, the reactionis halted by the addition of an acid solution. The com-pleted reaction can be read via spectrophotometer.

The formats of LAL assays vary among manufacturersbecause of the combinations of constituents and relativeamounts of components in each product. There are manyversions of this test system; this brief discussion does notdescribe all endotoxin assays currently on the market.

In controlled conditions, the Limulusassay can be

This decrease ranged from 2 to 8 pounds per milking forat least 48 hours after the vaccines were administered.There were no statistical increases in milk somatic cellcounts for the group during the 5-day observation period.

THE LIMULUSASSAYMany LAL assay methods are available for assessing

the endotoxin content of body fluids, research reagents,pharmaceutical materials, and vaccine contents. Theseassays depend on the ability of endotoxin to coagulate aprotein isolated from the circulating amebocytes of thehorseshoe crab Limulus polyphemus. At least four centralmethods of the LAL are used in the endotoxin-testingarena: the gel-clot, turbidimetric (spectrophometric),colorimetric (Lowry protein), and chromogenic assays.

Several modifications of the gel-clot method are avail-


M I L K S O M A T I C C E L L C O U N T S s A S S A Y M E T H O D S s G E L - C L O T S Y S T E M

TABLE I

Comparison of Endotoxin Units in Some Commercially Available Vaccines

Vaccinea Endotoxin Content (EU/ml)b

UCD J5 Escherichia coliexperimental core antigen 100

Commercial J5 E. colicore antigen 1,825Salmonellacore antigen 5,470

E. colipilus vaccine 2,930,000

Lepto 5-way 52,500

Pasteurella hemolytica, P. multocida, 870,400

Salmonella typhimurium

Haemophilus somnus 117,000

BRC, Clostridium perfringens, E. coli 38,800S. typhimurium 2,975

S. dublin/typhimuriumbacterin 33,875

Campylobacter fetus, Lepto 5-way 155,000

P. hemolytica 97,200

IBR, PI3, H. somnus, P. hemolytica, P. multocida 226,500

C. fetus, H. somnus, Lepto 5-way 49,950

H. somnus, Lepto 5-way 414,250

Eight species ofClostridium 10.1C. perfringins, types C and D 0.51

IBR, BVD, PI3, Lepto 5-way 96,575

IBR, BVD, PI3 183,100

IBR, BVD, PI3, BRSV 143,000

IBR, BVD, PI3, BRSV (live virus) 2.4

IBR, BVD, PI3, BRSV (killed virus)c 3.9

IBR, BVD, PI3, BRSV (killed virus)c 11,500

aThe Limulusamebocyte lysate (LAL) values may vary from lot to lot of the vaccine preparation.bEndotoxin levels determined via LAL methodology by Associates of Cape Cod, Inc., WoodsHole, MA.

Abbreviations: UCD= University of California-Davis, BRC= bovine respiratory complex, IBR=infectious bovine rhinotracheitis, PI = parainfluenza, BVD = bovine virus diarrhea, BRSV=bovine rhinotracheitis syncytial virus.cProducts from different manufacturers.


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used for direct detection ofcontaminating endotoxinsin many products and bio-logic fluids. Some cyto-kines , such as tumor

necrosis factor, may syner-gize with contaminatingendotoxins and other mi-crobial products at levelsthat cannot be reliably de-tected by the Limulus as-say.36 A negative Limulusassay thus is not sufficientevidence that endotoxinsare unrelated to the clinicalphenomenon being ob-served. Other cell wall

products (e.g., peptido-glycans, protein toxins, fungalpolyglycans, and mycoplasmal li-poglycans) are also capable ofefficiently inducing the cytokineproduction associated with clini-cal mediator shock.36

Peptidoglycans are potent acti-vators of cytokines and are foundin all bacterial cell walls.37 Thesecell wall products may be presentin vaccines, biologic fluids, or

commercial products and are notspecifically detected by theLimulusassay.

CONCLUSIONIn food animals, gram-negative bacteria are responsi-

ble for clinical conditions that range from simple diar-rhea to life-threatening meningoencephalitis. Currenttreatments and management practices are only moder-ately successful; a better understanding of the mole-cules responsible for the pathophysiologic changes asso-ciated with these disease processes is necessary. Various

experiments and clinical reports27

have supplied infor-mation necessary to begin the process of studying themediator-induced shock that develops during gram-negative bacterial disease. Because of animal health and

well-being and food safety issues, the ability to delivercost-effective treatment in patients with gram-negativebacterial disease and mediator-induced shock is ex-tremely important in food animal agriculture. In addi-tion, there must be continued efforts to prevent gram-negative disease via new immunogens and improvedmanagement practices.

In the Code of Federal Regulations (9 CFR), safety in

vaccines is defined as thefreedom from propertiescausing undue local or sys-temic reactions when usedas recommended or suggest-

ed by the manufacturer.In the same code, unfavor-able reactions are definedas overt adverse changes

which occur in healthy testanimals subsequent to initi-ation of a test and manifest-ed during the observationperiod prescribed in the testprotocol which are at-tributable either to the bio-logical product being tested

or to factors unrelated tosuch product as determined bythe responsible individual con-ducting the test. The experimentreported here indicates that, inclinical signs and milk produc-tion, vaccine administration pro-duced undue local and systemicreactions in certain individuals.The observations noted in thisfield demonstration indicate thatrigorous experimental investi-

gations should be designed toreevaluate the safety of food ani-mal vaccine preparations.

In spite of mandated safetyconsiderations in the manufacture of current food ani-mal immunogens, deaths and illnesses related to vac-cination occur daily. The new emphasis in food safetyregarding pathogen reduction and chemical residueavoidance should dictate that immunogens that createabnormalities in host defense or production parametersmust be identified. Although the endotoxin content ofa vaccine is only one of several risk factors in adverse re-

actions, attempts should be made to reduce the amountof endotoxin in vaccine preparations using currentlyavailable production technology. Veterinarians shouldroutinely reevaluate immunization protocols to mini-mize the exposure of animals to endotoxin.


C O L O R I M E T R I C M E T H O D s C H R O M O G E N I C M E T H O D s M E N I N G O E N C E P H A L I T I S

TABLE III

Cows with Milk Loss for at Least48 Hours After Vaccination

Trial Number of Number Vaccine Cows

1 A 2 of 5

2 B 1 of 5

3 C 2 of 5

4 Combination 2 of 5of 3 vaccines

TABLE II

Vaccine Immunogens andEndotoxin Units per Milliliter

Endotoxin

ContentVaccine Immunogens (EU/ml)

A Pasteurella hemolytica, 102,000P. multocida, Salmonellatyphimurium

B Salmonellacore antigen 5,470

C Infectious bovine 469,000rhinotracheitis, parainfluenza3,bovine virus diarrhea, bovinerhinotracheitis syncytial virus

About the AuthorsDr. Cullor and Mr. Smith are affiliated with the Dairy

Food Safety Laboratory, Department of Pathology,

Microbiology, and Immunology, College of Veterinary

Medicine, University of California, Davis, California.


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Endotoxin and Disease in Food Animals