VIRUS ISOLATION

Virus isolation is time-consuming and expensive, but it is a sensitive method for identifying viruses. Virus isolation is performed in cell culture. A variety of specimens can be tested, including nasopharyngeal, conjunctival, and tracheal swabs, TTAs, BALFs, and a variety of respiratory tract tissues that can be obtained at postmortem examination. Fluids, tissues, and swabs may be frozen; alternatively, swabs and tissue specimens may be placed in a viral transport medium and kept refrigerated until arrival at the diagnostic laboratory, preferably within 24 hours. BRSV does not appear to survive freezing or transport well, and it is important that specimens be inoculated onto cell cultures as soon as possible. In general, better success at virus isolation is obtained when specimens are collected in the acute phase of disease. Chances of successful isolation may be improved by sampling asymptomatic animals that are in close contact with affected animals. These animals may be in an incubation phase of infection. Some viruses appear to be more difficult to isolate than others. For example, BRSV is very difficult to isolate by routine procedures, and other diagnostic procedures (discussed later) should be performed in conjunction with attempts at virus isolation. During isolation procedures, viruses are detected by production of cytopathic changes in cell monolayers. Viral identification is accomplished by a variety of procedures such as neutralization with specific antiserum, FA staining, immunoperoxidase staining, and examination by electron microscopy and immunoelectron microscopy. An immunoperoxidase monolayer assay has been developed for detection of BVDV and is in routine use for screening serum samples for detection of cattle persistently infected with BVDV.

DETECTION OF VIRAL ANTIGENS

Immunofluorescence is a rapid method for identification of specific respiratory viruses. Antemortem identification can be made from conjunctival or nasal smears and from cells obtained by tracheal lavage or BAL. Postmortem identification can be made from frozen tissue sections prepared from a variety of respiratory tract tissues.

Another technique that is used to detect viral antigen in tissues is immunoperoxidase staining, which is most often carried out using formalin-fixed tissue. This is a very useful procedure that allows histologic examination of tissues in conjunction with immunologic identification of the causative agent.

Antigen capture enzyme immunoassay (EIA) provides a rapid means for detection of respiratory viruses. These tests can be performed on fluids obtained from the respiratory tract. Commercially available antigen capture EIAs are available for diagnosis of human RSV infections in infants and young children that are also capable of detecting BRSV,⁴²¹ and these are in use in some veterinary diagnostic laboratories. The same technique has been developed for the detection of BVDV and is in use for screening serum samples to detect cattle persistently infected with BVDV.

DETECTION OF VIRAL NUCLEIC ACIDS

The nucleotide sequence has been determined for the genome or partial genome for many of the ruminant respiratory viruses. Testing for viral nucleic acid by PCR (for DNA viruses) or RT-PCR (for RNA viruses) is increasingly more widely available at veterinary diagnostic laboratories. Although they are not currently in routine use, the possibility exists of using nucleotide probes for the detection of these viruses in tissue samples. One benefit of using nucleic acid detection to identify pathogens is that the pathogen does not have to be alive to be identified; this can be a particular benefit for relatively fragile viruses such as BRSV.

SEROLOGIC DIAGNOSIS

Retrospective diagnosis of viral infections can be made by determination of antibody titers in paired sera from individual animals. The first sample is collected in the acute phase of the disease, and the second is collected 2 to 4 weeks later (“convalescent sample”). In a respiratory disease outbreak multiple animals should be tested to achieve a serologic diagnosis; it is typical for seroconversion to be identified in only a subset of animals tested in any outbreak. Serologic diagnosis is made by demonstrating a fourfold increase in antibody titer in the convalescent sample as compared with the acute sample; a fourfold fall in titer also indicates recent infection. Because day-to-day variation in results of tests used for serologic diagnosis is typical, the acute and convalescent samples should be run by the laboratory on the same day. Thus the acute samples can be stored in the freezer by the local veterinarian and shipped together with the convalescent samples.

Because infections in young ruminants can occur in the presence of passively derived antibodies, seroconversion might not always occur during outbreaks of bronchopneumonia involving young animals.⁴²² This problem may be overcome by inclusion of older individuals in contact with the younger animals in the population sampled, which are likely to have lost passively derived antibody to these viruses and will be more likely to seroconvert. Also, BRSV antibody levels appear in some instances to peak at the onset of severe disease, and a decreasing antibody level is seen on paired serologic analysis rather than a rising level. Serologic testing of normal appearing, in-contact cattle that may be in early stages of infection may be helpful in demonstrating seroconversion to BRSV. A wide variety of serologic procedures is available for antibody determinations, but most laboratories use a microtiter serum neutralization test (also known as virus neutralization test) for IBRV, BVDV, PI3, and BRSV. It is important to remember that serum neutralization tests take several days to run. Some laboratories are beginning to use more rapid procedures such as ELISA for determination of serum antibody titers. Through use of an isotype-specific ELISA, diagnosis of BRSV can be achieved with a single serum sample by measurement of IgM levels⁴²³; similar tests could be developed for other pathogens, but these are unlikely to be widely available. A hemagglutination-inhibition test can also be used for PI3 and respiratory coronavirus.

DETECTION OF BACTERIAL ANTIGENS OR NUCLEIC ACIDS

It is increasingly common for diagnostic laboratories to use IHC for identification of bacteria in formalin-fixed tissues. This technique offers many advantages, including correlation of the pathogenic organism with the lesion and detection of pathogens not found on bacterial culture because of overgrowth of other organisms such as A. pyogenes or P. multocida. The use of PCR for identification of bacterial agents in a variety of samples is also increasingly available. The veterinarian is encouraged to contact the diagnostic bacteriologist at the local diagnostic laboratory or check the laboratory website for information regarding which tests are available.

SEROLOGIC TESTING FOR BACTERIAL PATHOGENS

Diagnosis of infection with bacterial pathogens can be attempted as described earlier for viral pathogens. However, the use of serologic tests for identification of infection by bacterial respiratory pathogens has mostly been limited to use in research. Thus these tests are not likely to be widely available for clinical use.

ANTIMICROBIAL THERAPY

The basic foundations of antimicrobial therapy for bacterial bronchopneumonia are treat early enough, treat long enough, and treat with the appropriate antimicrobial agent. Because there are currently many effective products marketed for the treatment of important bacterial respiratory pathogens in cattle, treating early enough is perhaps more important than what is used for therapy. It should be remembered that a major reason for treatment failure is the presence of a lesion that is too far advanced for successful therapy. If lesions becomes too far advanced, the antimicrobial agents will have difficulty reaching walled-off areas of necrosis and suppuration; moreover, the regenerative response will not be able to return this tissue to normal lung parenchyma.

Although antibacterial agents for the treatment of bacterial bronchopneumonia may reduce losses caused by fatality and retarded growth, they do not serve as a substitute for preventive management practices. Cattle requiring treatment do not perform as well as those that have not needed treatment. However, cattle requiring only one treatment perform better than those that require two or more treatments⁴²⁴; this further emphasizes the need for treating early enough with an effective antimicrobial, because animals with treatment failure will have suboptimal performance.

The precise temperature used to determine whether animals need treatment depends on the balance between the costs of overtreatment (drugs and labor) and undertreatment (treatment failures and mortality.) This temperature may vary depending on the animal type. The cutoff commonly used for feedlot cattle is 104° F to 104.5° F (40° C to 40.3° C), but 103.5° F (39.7° C) may be more appropriate for calves. This recommendation is based on the long-term effects that ECP has been shown to have on growth rate, age at first calving, culling before calving, and culling after calving, indicating that ECP can have long-lasting effects if not properly treated with early antibiotic therapy. When outbreaks of respiratory disease occur, surveillance of the affected group must be increased to ensure early detection of diseased animals.

Treatment of sufficient duration can be achieved only if the response to therapy is monitored. Therapy should be continued for at least 48 hours after clinical signs of fever, dyspnea, and toxemia have abated. Many of the antimicrobial drugs labeled for use in the treatment of pneumonia in cattle provide multiple days of therapeutic drug concentrations in lung tissue after only a single injection. These products decrease the time and stress associated with daily treatment; they also make it easier for feedlots to return animals to home pens rather than keeping them in hospital pens, which seems to be associated with poorer responses by treated animals.⁴²⁵ Frequently, antibiotics are evaluated over a 3-day treatment period, with cases failing to demonstrate a normal body temperature after 3 days being classified as nonresponders; a different class of antimicrobial should be administered to nonresponders.

Although a 3-day course of antimicrobial therapy for bronchopneumonia was for many years standard operating practice, particularly in the treatment of feedlot cattle, the view is increasingly held that treatment for a longer duration may be more appropriate. This is particularly true for pneumonia caused by Mycoplasma bovis in dairy calves or feedlot cattle, which seem to respond better to treatment for at least 7 to 10 days.^359,395 Although treatment for 7 to 10 days would be extralabel for many antibiotics, at least three products currently marketed have been shown to provide therapeutic drug levels for at least 7 days when used at dosages recommended on the label (see Table 31-10). Unfortunately there is little research evaluating the effect of treatment duration on long-term outcome in ruminants with bacterial bronchopneumonia, so it is difficult to make evidence-based recommendations regarding exactly how long antibiotics should be administered. Determination of therapeutic response by evaluation of general appearance without regard to restoration of normal body temperature has been shown to result in high relapse rates. A typical decision tree for treating feedlot cattle with antibiotics is shown in Fig. 31-63, but protocols such as these may be modified as more information about the use of long-acting antimicrobials is obtained from field research.

Fig. 31-63 Decision tree for antibiotic treatment of feedlot cattle.

Selection of the appropriate antibiotic tends to be what most veterinarians focus on when treating respiratory disease because this is the aspect of therapy over which they have the greatest control. Factors such as cost, route of administration, treatment interval, drug labeling, necessity of extralabel doses, and withholding times quickly cull a number of antibiotics, leaving a short list of suitable alternatives for use as first-line antimicrobial agents. Antibiotics that are associated with severe injection site reactions such as erythromycin or those associated with complications of administration such as balling gun injuries with oral boluses are often avoided. Only antibiotics that are licensed and effective at label doses should be considered for routine use in food animals. Table 31-10 lists the approved antimicrobials for treating respiratory disease in cattle. If data regarding the MIC of bacteria isolated from animals before treatment with antimicrobials are available, the dose or duration of therapy can be rationally modified, but it is imperative that proper withdrawal times be observed when antimicrobials are used in an extralabel fashion. At the time of this writing, the Food Animal Residue Avoidance Databank (FARAD; www.farad.org or 1–888-USFARAD) is an invaluable resource for veterinarians who need to identify withdrawal times for drugs administered to food animals at extralabel dosages. The use of MIC data requires some understanding of the pharmacokinetics of the drugs in question; published information is available regarding interpretation of MIC data, or veterinarians can contact FARAD or the diagnostic bacteriologist at their local diagnostic laboratory for assistance.

Determining the antimicrobial sensitivity patterns or MIC data for causative agents such as M. haemolytica in the case of bacterial bronchopneumonia can be difficult. The best information is that gained from bacterial culture and susceptibility testing of animals subjected to necropsy before receiving any antimicrobial therapy; however, producers may be reluctant to allow necropsy of animals that have never been treated. Once an animal has been treated, any antimicrobials administered can bias the results of susceptibility testing of bacteria later cultured from the animal. Many bacteria, including M. haemolytica, can develop plasmid-mediated multiple antimicrobial resistance by bacterial conjugation so that, for example, exposure to oxytetracycline may induce resistance not only to oxytetracycline, but also to penicillin. Therefore, M. haemolytica recovered from cattle treated with antibiotics will have a different sensitivity pattern than M. haemolytica cultured from untreated cattle. This is especially important when reviewing publications reporting antimicrobial susceptibility of M. haemolytica isolates cultured at diagnostic laboratories, because these results will most often be from cases that have been treated with antimicrobial agents before death. The findings of these studies may be looked at as a worst-case scenario demonstrating antimicrobial agents for which acquired resistance is rarely or never a problem, versus those for which acquired antimicrobial resistance occurs commonly. In general, resistance to many drugs used for the treatment of bovine pneumonia has been identified when M. haemolytica isolates from cattle treated with antibiotics before death are evaluated.

Sensitivity testing using isolates from clinical cases raises questions regarding the best site for sample collection. Antibacterial sensitivities of isolates cultured from nasal swabs may not represent sensitivities of organisms causing pneumonia. This is surprising, because pneumonia usually is preceded by multiplication of bacteria such as M. haemolytica in the upper respiratory tract, and the nasopharynx serves as the source of bacteria colonizing the lungs. Nevertheless, there are discrepancies between antimicrobial sensitivities of bacteria isolated from nasal swabs and clinical outcome. Specimens for sensitivity testing should be collected from pneumonic lung, tracheal swabs, or TTAs collected from cattle before treatment whenever possible.

The choice of which drug to use can also be based on records of efficacy for animals treated in the past. Producers who keep accurate records of drugs used, with results of treatment responses, relapses, and chronic cases, may select first-line antibiotics based on historical performance of a drug. This may be the best approach to antimicrobial selection. A final method of choosing a first-line antimicrobial drug is reliance on published treatment trials. Published trials give comparisons between among responses for various antibiotics in cattle with naturally occurring bacterial bronchopneumonia. The outcomes for these trials are often expressed as both health and production values. When evaluating published treatment trials that use cases of naturally occurring bacterial bronchopneumonia, it is important to realize that the results may not be applicable to the cattle and pathogens outside the operation where the trial was carried out, but if the trial was well designed, it should provide useful comparisons. The characteristics of a well-designed field trial are discussed later in the section on vaccination (p. 641).

Mass medication with antibiotics at full therapeutic doses during an outbreak of feedlot cattle pneumonia dramatically curtails the daily number of new cases and improves feed consumption. In the acute stages of an outbreak, whatever drug is chosen should be given by injection; therapeutic levels cannot be reliably maintained by administering drugs in feed or water. Bronchopneumonia cases that occur after administration of mass medication have an increased possibility of being resistant to therapy with the antimicrobial used in mass treatment and have a greater than usual resistance to other antimicrobials. Thus mass medication should not be a standard practice but is warranted to control severe outbreaks of pneumonia. It is important to base a decision to mass medicate on measurable criteria. Some feedlot veterinarians implement mass medication when the pull rate of sick animals is 10% on any 1 day or is 25% over a 3- to 5-day period. A sudden drop in feed consumption, especially in high-risk cattle, is another situation in which mass antibiotic medication should be cost-effective. Long-acting antibiotics have extended withdrawal times to slaughter. It is of critical importance that animals that receive them are properly identified and that the withdrawal times are observed.

The same principles of therapy described previously apply to the treatment of sheep and goats.²²⁰ Unfortunately, fewer drugs are labeled for the treatment of sheep and goats as compared with products used for cattle. Drugs labeled for use in sheep and goats are listed in Table 31-10. Note that whereas tilmicosin (Micotil 300, Elanco Animal Health) is labeled for use in sheep, fatal reactions to tilmicosin have occurred in goats treated with this drug. Goats should not be treated with tilmicosin. Long-acting tetracycline at 10 mg/kg is very effective against experimental M. haemolytica infections in sheep. Administration of tetracycline subcutaneously is effective and less painful than IM injection. It is imperative to ensure that producers are given an appropriate meat and milk withdrawal time when antimicrobials are administered to sheep and goats at extralabel dosages; this is a particular concern in feedlot lambs or goats and in lactating dairy sheep or goats, from which products may enter the food chain in a relatively short time after treatment.

ANTIINFLAMMATORY THERAPY

Favorable responses to treatment with corticosteroids and antihistamines have been reported from field outbreaks of BRSV infection. However, corticosteroids should not be used indiscriminately in the treatment of respiratory disease because of the potential for immunosuppression. Corticosteroids may have a place in treatment of respiratory diseases such as necrotic laryngitis or tracheal edema syndrome of feedlot cattle.⁹⁰ It is unlikely that a single administration of a glucocorticoid will have a detrimental effect on the immune system of cattle. The dose for dexamethasone in cattle is 0.05 to 0.2 mg/kg IM or IV, and the dose for isoflupredone acetate is 10 to 20 mg IM. Treatment with corticosteroids may cause recrudescence of BHV-1 infections.

NSAIDs such as acetylsalicylic acid (aspirin), flunixin meglumine, and ibuprofen have been reported to be beneficial in the treatment of respiratory disease in ruminants. Aspirin (100 mg/kg every 12 hours) is approved for use in cattle, as is flunixen meglumine (1.1 to 2.2 mg/kg IV either as a single dose or divided into two doses at 12-hour intervals). Flunixin meglumine administered intravenously at 2.2 mg/kg to calves with pneumonia induced by PI3 virus results in a marked improvement in clinical signs and reduction in lung consolidation.⁴²⁶ However, the use of flunixin meglumine may not be cost-effective in large numbers of animals. It is important to remember that flunixin meglumine is approved only for IV use; administration via the IM or SC route can result in violative residues in tissues if longer withdrawal times are not observed. Phenylbutazone, which has been used in the past for antiinflammatory effect in ruminants, is now illegal to use in lactating dairy cattle, and because of prolonged tissue levels found in treated cattle its use is discouraged in all food animals.

Unlike corticosteroids, NSAIDs do not impair immune function. The clinical responses of calves with either experimental or naturally occurring pneumonic pasteurellosis are markedly improved by adding flunixin meglumine to tetracycline therapy. In contrast, supplementation of antibiotic therapy with corticosteroids usually results in poorer responses, more relapses, and prolonged illness, although there is still some controversy over the use of corticosteroids for treatment of pneumonia. Because of the potential for renal toxicity with NSAIDs, dehydrated animals should be rehydrated before administration of these drugs. Care should also be taken not to overdose with NSAIDs or use them for prolonged periods, because they may also result in abomasal ulceration.

There has been little work done to evaluate the use of antihistamines as an ancillary treatment for bovine respiratory disease. Tripelennamine HCl is labeled for cattle at a dose of 1.1 mg/kg, which can be repeated in 6 to 12 hours if needed.

Tilmicosin has been suggested to have antiinflammatory effects in cattle because of the effect of the drug to induce apoptosis in leukocytes, which could theoretically decrease inflammatory responses in treated animals.⁴²⁷ However, the concentrations of tilmicosin used in this study were quite high relative to concentrations obtained in treated animals, and a later study of the effect of tilmicosin on the function of leukocytes taken from treated cattle showed no effect.⁴²⁸

ANTIVIRAL AND IMMUNOMODULATING THERAPY

Because viral respiratory infections predispose to development of secondary bacterial infections, antibiotic therapy is indicated to prevent or limit the development of bacterial pneumonia in animals with viral respiratory tract disease. Few antiviral drugs are available in human medicine, and none of these is in routine use in veterinary medicine for the treatment of viral respiratory disease in ruminants. Interferon has potential as an immunomodulating and antiviral drug in the prevention and treatment of viral respiratory disease. Human leukocyte interferon has been shown to decrease morbidity associated with shipping fever, but the therapy has not become widely used. Levamisole and isoprinosine have been used in attempts to stimulate the bovine immune system with equivocal success and cannot yet be recommended as supportive treatments.⁴²⁶ It is important to recognize that the immunostimulatory benefits of levamisole occur at doses in the 2- to 3-mg/kg range, compared with the anthelmintic dose of 6 mg/kg. A decreased immune response has been observed after an 8-mg/kg dose of levamisole. High doses of vitamin C (1 g/45 kg; 1 g/100 lb) have been shown to enhance the activity of bovine neutrophils and reverse dexamethasone-induced suppression of neutrophil activity.⁴²⁹ Isoprinosine has been evaluated as an immunomodulating drug for treatment of bovine respiratory disease and has shown some potential on the cellular level.⁴²⁶

SUPPORTIVE THERAPY

Supportive treatment of any kind will relieve stress, thus fostering the resistance of the patient, a very important component of the successful therapy of pneumonia cases. Sick animals should be provided shelter that protects them from rain, cold, wind, and hot sun. They should not be crowded, and the best-quality feed and clean water should be easily accessible. Mineral and vitamin deficiencies should be corrected with the use of injections or oral preparations if necessary. An IM vitamin A injection is considered useful adjunctive therapy by some veterinarians treating ruminants with bronchopneumonia.

ENZOOTIC CALF PNEUMONIA

ECP has traditionally been described as affecting calves from 2 to 6 months of age; however, prospective studies examining cohorts of calves have found calves may be affected with ECP as early as 2 weeks of age.⁴³⁰ Slaughter surveys of dairy calves 4 to 14 days of age have found ECP to be the second most common cause of slaughter condemnation.⁴³¹ Virtala and colleagues⁴³⁰ found that veterinarian-diagnosed ECP occurred at a younger age than did caretaker-diagnosed ECP. As a whole, these studies suggest that ECP may start much earlier than previously recognized.

Pneumonia of dairy calves occurs both as endemic disease and as outbreaks (epizootics) of respiratory disease. Chronic endemic disease is the most common manifestation of this disease, and as a result pneumonia of dairy calves is commonly called enzootic calf pneumonia. The distinction between enzootic and epizootic calf pneumonia is important in reference to etiology because different causes are more important in each form of the disease.

Waltner-Toews, Martin, and Meek⁴³² determined from producer diagnosis that 15% of Ontario Holstein dairy calves were treated for pneumonia before weaning. Curtis, Erb, and White⁴³³ reported that Holstein calves in New York had a crude incidence risk of 7.4% for respiratory tract illness, as diagnosed by the farmer. Sivula and colleagues⁴³⁴ found that 7.6% of 845 Minnesota dairy calves were diagnosed by producers as having pneumonia. Van Donkersgoed and colleagues⁴³⁵ found that the risk of pneumonia in Saskatchewan dairy calves was 39% as diagnosed by the farmer and 29% when the pneumonia was veterinarian diagnosed. Virtala and colleagues⁴³⁰ found that the risk of pneumonia was 11% in New York dairy calves when diagnosed by producers and 25.6% when diagnosed by a veterinarian.

Mortality rates reported for ECP vary from 1.8%^434,435 to 4.2%.⁴³⁰ Case fatality rates reported for calves with ECP range from 2.2% to 9.4% and vary with the sensitivity of the initial detection method (veterinarian versus producer).⁴³⁰

Pneumonia accounts for a significant proportion of the mortality (proportionate mortality) in dairy calves raised on dairy farms. Pneumonia accounted for 24% of deaths in New York calves⁴³⁰ and 30% in Minnesota calves.⁴³⁴ In one study examining Ontario veal calves raised in veal barns, pneumonia accounted for 52% of mortality in 4863 calves on six farms.⁴³⁶ Producer accuracy in diagnosing causes of mortality was examined by Sivula and colleagues.⁴³⁴ Producers were found to be moderately accurate but often listed the cause of death as unknown. This emphasizes the importance of laboratory confirmation of cause of death over producer diagnosis.

SHIPPING FEVER

Despite the undisputed economic importance of the disease, surprisingly little has been established regarding the behavior of pneumonic mannheimiosis or shipping fever at the population level, and even the question of whether the disease is truly contagious has yet to be answered from the epidemiologic perspective. Reviews of the literature from North American feedlot studies before 1985 found that published measures of morbidity in calves ranged from 0% to 69%, whereas measures of population mortality ranged from 0% to 15%. Incidence of disease was found to peak within 3 weeks of calves arriving at the feedlot. In view of the lack of uniformity in methods used to define cases of respiratory disease and calculate disease incidence, however, these data may not be reliable. In most of the studies the crude measures of total morbidity and total mortality were used as outcomes, and case definitions for these were often highly variable or absent. This lack of uniformity with respect to case definition and nomenclature, along with the inherently subjective nature of morbidity assessment, makes it difficult to draw legitimate comparisons among reports. One observational study specifically addressing epidemiology of fibrinous pneumonia (the classic lesion of shipping fever caused by M. haemolytica) was conducted by Ribble and colleagues.³⁰⁵ Because of the difficulty and expense inherent in making definitive diagnoses of the causes of illness and death among feedlot cattle, most epidemiologic studies have used crude (total) mortality as an estimate of death losses caused by shipping fever, and treatment rate as a measure of respiratory morbidity. The results of several necropsy surveys and the previously cited epidemiologic study, however, indicate that crude mortality is unreliable as a surrogate measure of fibrinous pneumonia mortality and may lead to erroneous conclusions regarding risk factors contributing to this important disease.

In the observational study of fatal fibrinous pneumonia conducted by Ribble and colleagues in 1995,³⁰⁵ risk factors specifically associated with shipping fever mortality in western Canadian feedlot calves were investigated. Data were collected on all 58,885 spring-born calves entering a single feedlot in southwestern Alberta between September 1 and December 31 over a 4-year period (1985 to 1988). The vast majority of calves were purchased from auction marts throughout western Canada and transported to the feedlot by truck. A complete necropsy was performed on all dead cattle within 24 hours of death, and a gross diagnosis recorded. Cases were assigned a diagnosis of fatal fibrinous pneumonia on the basis of pathologic evidence of acute fulminating lobar bronchopneumonia with fibrinous exudate, and data from each year were analyzed separately. Crude mortality ranged from 2.44% to 4.78%, whereas the mortality caused specifically by fibrinous pneumonia varied more than tenfold (0.25% to 2.73%) between years. Proportionate mortality caused by fibrinous pneumonia ranged from 10% to 57%, and this large annual variation was interpreted as evidence that crude mortality should not be used as a measure of fibrinous pneumonia mortality in epidemiologic studies. Epidemic curves constructed for each of the 4 years showed that peak mortality occurred approximately 16 days after arrival at the feedlot and that at least 50% of fibrinous pneumonia mortalities occurred within 3 weeks of arrival. Epidemic curves using the time of first treatment for all cases that eventually died of fibrinous pneumonia revealed that peak fatal disease onset occurred within 8 days of arrival and that 75% of fibrinous pneumonia mortalities were already sick within 2 weeks of arrival. The consistent onset of fatal disease in calves within days of their arrival at the feedlot indicates that the disease process may have been well underway in affected calves before their installation in a home pen, and that preventive measures should be implemented at the time of arrival, or possibly even before. In one of the study’s most important findings Ribble and colleagues³⁰⁵ demonstrated that when the incidence of fatal shipping fever was high (greater than 2%), the disease clustered within truckload groups of calves and also, in 1 year, within pens. This was contrary to the conclusions of other studies and lends credence to anecdotal reports from feedlot owners that shipping fever mortality is not randomly distributed in calves throughout the feedlot, but may often be abnormally high in individual truckloads or pens, indicating a contagious nature to the disease.

Although H. somni can also cause fibrinous bronchopneumonia in feedlot cattle, epidemiologic curves evaluating the day of first treatment of calves ultimately dying of disease caused by H. somni are distinct from epidemic curves of cattle dying of fibrinous pneumonia caused by M. haemolytica. The median days after arrival for the onset of fatal disease caused by H. somni is 28, as opposed to 8 days after arrival for fatal fibrinous pneumonia.^345,346

BRONCHOPNEUMONIA OF ADULT CATTLE

Although anecdotal reports indicate that adult beef or dairy cows can experience outbreaks of bronchopneumonia that can have high morbidity and an important impact on milk production (in dairy herds), very little is published in the veterinary research literature regarding the problem. Outbreaks of significant respiratory disease with notable mortality caused by BRSV infection have been described in individual herds of adult dairy cattle.^149,150 Respiratory disease and decreased milk production in adult dairy cows was associated with seroconversion to influenza virus and BRSV,²⁵³ but the authors could not confirm that influenza was contributing to clinical disease in the affected cows. The lack of research on respiratory disease in adult cows is likely a result of the fact that other diseases that affect reproductive performance and milk yield are of greater economic significance in this class of cattle, but the few published descriptions of respiratory disease outbreaks confirm that the problem can on occasion be of major importance to individual herds. Little research has investigated the effects of infectious respiratory disease in adult cattle on productivity.

BRONCHOPNEUMONIA OF SHEEP AND GOATS

Little information has been published regarding the epidemiology of bronchopneumonia in sheep and goats. The 2001 National Animal Health Monitoring System (NAHMS) survey of producers indicated that 7% of death in adult sheep were due to respiratory disease, whereas 12% of lamb deaths were due to respiratory disease.⁴³⁷ Feedlots reported that shipping fever pneumonia accounted for 13% of feedlot lamb deaths, and other respiratory disorders accounted for 29% of lamb deaths.⁴³⁸

ENZOOTIC CALF PNEUMONIA

The documented host and environmental risk factors of dairy and veal calf bronchopneumonia involve inadequate passive transfer of immunoglobulins, nutritional deficiencies, and adverse environmental conditions (Fig. 31-64). Calves are generally affected at less than 2 months of age. Successful passive transfer is the foundation of protection against pneumonia at this age and older and is effective except in situations in which the other risk factors are so severe that even calves with high concentrations of passively acquired immunoglobulins are at high risk. Successful passive transfer requires good-quality colostrum and adequate volume (4 L in the first 12 hours for 45-kg calves). In addition, regular herd vaccination, especially in dry cows, should increase the levels of specific antibody in calves, provided passive transfer is accomplished. Vaccination of calves may produce a protective immune response in calves that prevents or limits the severity of ECP from certain infectious agents. Historically it has been recommended that vaccination be delayed until maternal immunity has waned, but recent research indicates that calves can be primed for a protective immune response by vaccination in the face of maternal antibodies in at least some cases (see further discussion on p. 640).

Fig. 31-64 Path model for risk factors for enzootic calf pneumonia. Note: Risk factors in bold-faced rectangles indicate those that may be altered by management.

Nutritional problems that predispose to calf pneumonia include deficiencies of energy, protein, vitamins, or the minerals necessary for the immune response. Deficiencies of copper, selenium, zinc, manganese, iron, and vitamins A and E are of special concern. Dairy managers sometimes create energy and protein deficiencies by feeding calves a low volume of milk during the first few weeks of life to minimize the incidence of neonatal diarrhea.

The calf’s immediate environment affects the calf in a number of ways. Ambient temperature is an important factor affecting dairy calf health.⁴³⁹ Cold weather is especially detrimental to young calves, which have little body insulation. Increased humidity or precipitation in the calf’s environment worsens the calf’s ability to maintain thermal neutrality. Warm weather can also be undesirable, because young calves are capable of greater perspiration per pound of body weight than adults, and warm weather may predispose young calves to dehydration.⁴³⁹

The bacterial content of air in cattle barns can be as high as 10⁶ organisms per cubic meter.⁴⁴⁰ Disease incidence can be affected by length of pathogen survival time as an aerosol and the concentration of the pathogen in the air space. Humidity is an important limiting factor affecting pathogen survival. The optimum zone for limiting survival time of bovine pathogens is 55% to 75% relative humidity. Adequate fresh airflow into the calf’s environment is important in limiting humidity and reducing the concentration of noxious gases and pathogens. The flow of air should be from younger, more susceptible cattle to older, less susceptible cattle to limit moving pathogens from older cattle to younger cattle. Adequate fresh airflow and proper directional movement of air are important goals of ventilation.

Calf housing with overcrowding of calves or excessive stocking densities results in increased transmission of pathogens, especially if there is mixing of age-groups. Overcrowding also puts additional stress on the building ventilation through buildup of noxious gases and pathogens. Cleaning of calf crates with high-pressure water sprayers is associated with new cases of pneumonia several days later. Bates and Anderson⁴⁴¹ have recommended standards for ventilation, including building location, fan capacity and location, intake location and design, temperature regulation, air space needed and airflow directions, and acceptable humidity levels. Individual calf hutches that are properly located provide the calf with adequate fresh air free of pathogens and noxious gases and overcome many of the problems found with calf barns. Calves moved out of hutches can then be put into small groups (seven or eight calves) separated from older cattle through use of super hutches. Like the calf hutch the super hutch also serves to limit pathogen transmission and buildup of noxious gases in this susceptible group of calves. Alternatively, calves can be moved out of hutches and placed in pens in pole sheds provided groups are small (7 to 10 calves), air quality is good, and proper segregation from older age-groups is maintained. Standards of housing for calves are shown in Table 31-11.

Table 31-11 Standards for Adequacy of Ventilation of CalfHousing^434,441

Sivula and colleagues⁴³⁴ found that 80% of calf barns provided housing that failed to meet adequate standards of ventilation and housing⁴⁴¹ regardless of whether calves were housed individually or in groups. In addition, calf housing in which calves shared the same air space as adults never met the adequate standards of ventilation and housing.⁴³⁴ A much higher percentage of calf housing that used calf hutches met these adequate standards of ventilation and housing, and virtually 100% would have been adequate housing if the hutches had been positioned correctly.⁴³⁴ Calves raised in inadequate housing have significantly poorer growth rates than do calves raised in housing that is considered adequate,⁴³⁴ which emphasizes the importance of adequate housing. The percentage of producers who use calf hutches continues to increase, as the benefits of their use are documented and published.

Veal calves are at greatest risk because they are reared in rooms that are filled to high stocking density with calves from multiple dairies that put minimal effort into ensuring that the calves are fed adequate amounts of high-quality colostrum. Similar problems occur on “calf ranches,” where hundreds to thousands of very young dairy calves are raised to the point at which they are old enough to be returned to dairies or sent on to feedlots. A high proportion of calves that enter calf ranches have FPT. Also, the accumulation of a large number of calves with a variety of histories and from a variety of sources causes problems similar to those encountered with older animals in feedlots. The respiratory defenses of the calf lung include aerodynamic filtration, particle removal, adhesion resistance, secretory defenses, and cellular defenses. The physical respiratory defenses (filtration, removal, adhesion resistance) can be compromised by inhaled noxious gases, temperature extremes, dehydration, and viral infections causing impairment through damage to the mucosal lining of the upper respiratory tract, or by increased viscosity of respiratory secretions. Noxious gases, such as ammonia, methane, hydrogen sulfide, and carbon dioxide, which become increased from inadequate manure handling or poor ventilation, can also impair secretory defenses via damage to the mucosal lining and impair cellular defenses by direct effect on alveolar macrophages. Viral infection may also damage the mucosal lining and impair production of secretory defenses, such as lysozymes, lactoferrin, complement, or secretory immunoglobulin. Viral infections can also have a direct effect on cellular defenses, including alveolar macrophages, and for some viruses, the neutrophils. Stress caused by overcrowding, temperature extremes, commingling, surgical procedures, or vaccination may impair cellular defenses and immunoglobulin production and enhance bacterial adherence.

Calves that have neonatal diarrhea are at greater risk of pneumonia.⁴³⁵ Thus risk factors that are unique to neonatal diarrhea, such as poor sanitation in the calving area, must be added to those outlined in Fig. 31-64 as possible risk factors for dairy calf bronchopneumonia. Calves born in loose housing have a higher risk of illness than those born in individual maternity pens. Treatments at birth can affect subsequent calf health. All dairy calves should have the navel treated. Injections of vitamin A and iron at birth may increase the disease resistance of dairy calves, which can be deficient in these nutrients at birth.

Other risk factors associated with ECP include large herd size, weather extremes (hot and cold), birth to a heifer, and low antibody titers to certain respiratory pathogens.^430,435 Pneumonia of beef calves on the farm has the greatest incidence after weaning. The occasional outbreaks of pneumonia in suckling beef calves may be associated with adverse weather, parasitism, or nutritional deficiencies.

SHIPPING FEVER PNEUMONIA

Risk factors of feedlot calf bronchopneumonia are active in three areas: (1) at the farm of origin, (2) during transit, and (3) in the feedlot^305,442,443 (Fig. 31-65).

Fig. 31-65 Path model for risk factors of feedlot cattle pneumonia. Note: Risk factors in bold-faced rectangles indicate those that may be altered by management.

Several on-farm management practices have a large impact on feedlot cattle pneumonia. Weaning, creep feeding, and performance of routine surgeries at least 3 weeks before shipment have been shown to reduce morbidity rate 20% to 25%.⁴⁴³ Vaccination on the farm against respiratory pathogens would be expected to reduce the incidence of feedlot cattle pneumonia but has not always been beneficial. Other farm factors are deficiencies of nutrients necessary for normal immune responses. Pneumonia has a higher incidence in young calves, and severe outbreaks sometimes occur in early weaned calves that enter feedlots.

Risk factors that are active during transport from the farm to the feedlot include sale through auctions, feeding of low-energy diets before shipping, and prolonged time in market channels (sales barns, transport vehicles). Excessive dehydration or “shrink” from transport has been shown to account for significant morbidity and mortality in the feedlot. Movement through multiple auctions greatly increases the risk of pneumonia.

Feedlot risk factors that influence morbidity and mortality rates include processing procedures, numbers of calves and number of different origins of calves per pen, diet, on-arrival surgeries (e.g., dehorning), and environmental conditions. Calves that arrive in the feedlot with moderate levels of antibodies against the respiratory viruses have been shown to have a decreased incidence of pneumonia, indicating that natural exposure or vaccination at the ranch, rather than the feedlot, is protective. Mixing of calves from different origins and filling of feedlot pens with calves over a prolonged period increase mortality and morbidity rates because infectious agents spread more readily in large populations. Starting calves on diets containing 75% concentrate or greater or feeding corn silage as a major dietary component during the first month is associated with higher mortality and morbidity rates, probably because of an inhibition of alveolar macrophage function caused by acidosis. Nonprotein nitrogen, such as urea, fed to stocker calves at any time or to feedlot calves on arrival is associated with increased levels of pneumonia. The addition of antibiotics to the drinking water of newly arrived feedlot cattle has been shown to be detrimental to their health, possibly because of decreased water consumption.

As mentioned in the earlier discussion of respiratory defenses of dairy calves, endogenous corticosteroid release caused by physical stressors (overcrowding, mixing of calves, surgical procedures, starvation, dehydration), environmental stressors (weather extremes), and damage to respiratory defenses (vehicle exhaust, environmental dust, noxious fumes, acidosis, dehydration, and viral infections) may also weaken or overwhelm the respiratory defenses of feedlot calves.

BRONCHOPNEUMONIA OF ADULT CATTLE

Studies confirming risk factors for bronchopneumonia of adult cattle in modern North American production systems are lacking, but it is assumed that factors are similar to those described previously for calves and for cattle entering feedlots.

BRONCHOPNEUMONIA OF SHEEP AND GOATS

Many of the risk factors that have been found to predispose to bronchopneumonias of sheep and goats are similar to those affecting cattle.²²⁰ Pneumonia is more common in younger animals, after shipping or storms, and under crowded conditions. In addition, cold stress is an important risk factor for pneumonia in young lambs and recently shorn adult sheep and goats. In contrast, heat stress may predispose to pneumonia in unshorn sheep that do not have access to shade. Pneumonia also is associated with semiconfinement or total confinement of sheep in poorly ventilated barns.

MANAGEMENT PRACTICES TO MINIMIZE ENZOOTIC CALF PNEUMONIA

Bronchopneumonia of dairy and veal calves is prevented by eliminating or altering as many predisposing risk factors as possible. Control is based on healthy, well-vaccinated dams giving birth in maternity facilities that limit pathogen exposure. Good colostral management is needed to ensure adequate passive transfer. The calves must have their navels disinfected and be moved to calf housing that limits pathogen exposure by overcrowding and direct contact, provides good-quality air, and protects the calf from environmental extremes.

Evaluation of the microclimate of housed calves is of critical importance in the control and prevention of pneumonia. Equipment useful for evaluating mechanically ventilated buildings includes a smoke generator to visualize airflow patterns, an anemometer to measure air velocity, a psychrometer to determine air temperature and relative humidity, and a gas detector kit to measure ammonia concentrations in the air. Agricultural engineers from animal science departments at regional universities can be often be contacted for guidance in the use of these tools. Naturally ventilated buildings should also be evaluated for adequate sidewall and ridge openings, adequate segregation of age-groups, and stocking densities. Calf hutches that are managed properly provide most, if not all, housing needs required to minimize calf pneumonia. Hutches should be evaluated for proper placement in relation to other hutches, other buildings, prevailing winds, exposure to sun, bedding and draining, and ventilation of the hutch.

After weaning, calves need to move to housing that allows small groups to be segregated from older age-groups. Sharing air space or having direct contact with older calves or adult cattle is an important risk factor for calf respiratory disease. Super hutches or pens in pole sheds separated by barrier walls can effectively provide this postweaning housing. Calves should be fed proper nutrition for protein, energy, minerals, and vitamins and should be vaccinated appropriately. Vaccination programs are often used in dairy calves beginning at 1 to 2 months of age in situations where housing or mixing of calves results in a high incidence of ECP. More information regarding the use of vaccines for preventing infectious respiratory disease is presented in the following sections.

MANAGEMENT PRACTICES TO MINIMIZE FEEDLOT PNEUMONIA

MANAGEMENT PRACTICES FOR PREVENTING SHEEP AND GOAT PNEUMONIA

Prevention of pneumonia in sheep and goats is also based on altering the risk factors that predispose to pneumonia. Minimizing cold and heat stress, providing properly ventilated housing, avoiding overcrowding, and avoiding long transports in adverse weather aid in prevention. Mass medication can be used to control outbreaks of pneumonia in flocks. Injectable long-acting oxytetracycline is often used subcutaneously at 10 mg/kg. Tilmicosin can also be used for mass medication therapy for sheep, but tilmicosin should never be administered to goats, as it can result in fatal reactions. Feedlot lambs are sometimes administered metaphylactic therapy (long-acting oxytetracycline) on arrival.

Vaccination To Prevent Respiratory Disease

Factors That Affect Success of Vaccination

Many factors can affect the success of vaccination. For a vaccine to successfully prevent disease, the vaccine must induce a protective immune response against a pathogen to which the host will be exposed. Apparent vaccine failure is often blamed on the product or the manufacturer, but in many cases other factors may have led to vaccine failure. Possible causes of apparent vaccine failure that must be also be considered when vaccinated animals contract disease are related to the administration of the vaccine, the ability of the host to respond to vaccination, and to the nature of pathogen exposure. Examples are listed in Box 31-6. Although the points listed may be obvious, it is important to carefully consider and rule out these problems when a vaccine has failed to prevent respiratory disease before making a quick switch to another brand or type of vaccine.

Box 31-6 Reasons for Apparent Vaccine Failure

FACTORS RELATED TO ADMINISTRATION OF THE VACCINE

Improper storage of live vaccines

Residual chemical disinfectant in reusable syringes

Using live vaccine reconstituted days or weeks previously

Administration into wrong anatomic location

Administration of antibiotics with live bacterial vaccines

Incorrect timing of vaccine administration

Animals already incubating disease

Failure to allow time for immune response to occur

Administering booster too early, too late, or not at all

FACTORS RELATED TO ABILITY OF HOST TO RESPOND TO VACCINATION

Age (very young or very old animals)

High levels of maternal antibody

Immunocompromise resulting from concurrent disease or stress

Genetic factors

Poor air quality or other environmental insults

FACTORS RELATED TO PATHOGEN EXPOSURE

Disease caused by pathogens not included in vaccines

Antigenic variation (strain variation) of naturally occurring pathogens

Overwhelming pathogen exposure

In addition to the factors just discussed, vaccine characteristics can also affect the success of a vaccination program. Once the decision has been made regarding choice of pathogens to be included in the vaccine, the use of a live versus killed vaccine must be considered. Much research has evaluated the immune response of animals to modified live versus killed (inactivated) vaccines, and the subject has been the focus of much discussion. To summarize:

Modified live virus (MLV) vaccines in general stimulate cell-mediated immunity, important for an effective immune response to most viral pathogens, as well as effective humoral immunity.

Live vaccines can sometimes elicit protective immunity with only a single dose of vaccine.

Live vaccines contain a smaller dose of organisms, because the organisms in the vaccine are expected to replicate at least minimally.

Live vaccines generally do not require adjuvants, which are often a major cause of adverse reactions after vaccination (however, some MLV vaccines do contain adjuvants to improve the immune response).

Live vaccines are generally cheaper.

Disadvantages of live vaccines include the possibility of causing abortion in pregnant animals, transmission to nonvaccinated animals, exacerbation of morbidity in sick or immunocompromised animals, and reversion to a more virulent form with disease possibly occurring.

Another disadvantage of live vaccines is that they can be inactivated in a short time by exposure to heat or light.

In contrast, inactivated vaccines do not generally stimulate effective cell-mediated immunity, although certain adjuvants can overcome this.

Inactivated vaccines often stimulate high levels of antibody.

Inactivated viral vaccines require at least two doses at a 14–28 day interval to induce an effective anamnestic response to subsequent challenge.

Adjuvants in killed vaccines can cause adverse reactions.

Inactivated vaccines are safe in pregnant or immunocompromised animals, and storage requirements are not as rigorous for inactivated vaccines as for MLV vaccines.

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Much of the above has been determined using viral vaccines; the situation with bacterial vaccines is less well characterized. Modified live bacterial vaccines may stimulate both humoral and cell-mediated arms of the immune response better than inactivated products (bacterins). However, for extracellular bacterial pathogens such as M. haemolytica, humoral immunity is the most critical component of an effective immune response. Past evidence has suggested that live M. haemolytica vaccines are superior to inactivated products; however, recent comparisons have shown some nonliving products to provide superior resistance to experimental challenge. Live bacterial vaccines can be inactivated if animals are given antibiotics at or near vaccination.

It is important to note that all vaccines for a given disease are not necessarily equal. If a vaccine is inactivated, the means by which it is inactivated can influence antigenicity. Moreover, a wide variety of adjuvants exist, and the adjuvant included in a vaccine can greatly influence the type and duration of immune response elicited. Adjuvants are included in inactivated and some modified live products. The choice of adjuvant to include in a vaccine is the subject of much creative thinking and research effort by manufacturers; this is emphasized by the fact that it is often very difficult to obtain detailed information about the adjuvant contained in a vaccine.

Impact of Maternal Antibody on the Response to Vaccination

For many decades veterinarians have been taught that young animals cannot be effectively vaccinated when they have moderate levels of maternal antibodies obtained through passive transfer after birth. This was based on numerous research studies that showed that vaccination of young animals with maternal antibodies did not lead to the expected increase in serum antibodies to the agent in the vaccine. However, an important finding is that some vaccines appear to prime calves for an improved response to subsequent challenge, even when vaccination occurs in the presence of maternal antibodies. In such cases vaccination does not induce an increase in serum antibody titer within 2 weeks of vaccination, but when calves are vaccinated or challenged at a later date, they respond with what appears to be an anamnestic response as measured by increased serum antibodies, or protection against disease resulting from experimental or natural challenge, as compared with unvaccinated calves.^{351,352,452,453} In general, a response was induced most reliably when modified live vaccines were administered and when the calves received at least two doses of vaccine at an appropriate (2- to 4-week) interval. Similarly, calves exposed to live pathogens in the face of maternal antibody can develop a protective immune response, even though they do not seroconvert after exposure.^454,455 It has been shown that a cell-mediated immune response can be measured even when there is no evidence of humoral response in calves infected in the face of maternal antibodies.⁴⁵⁵ Although multiple studies show that calves can be primed for an anamnestic immune response in the face of maternal antibodies, if very high titers of maternal antibody are present, priming by the vaccine can be blocked, as traditionally understood.⁴⁵³

This information suggests that at least in some cases a protective immune response can be initiated in calves when the first dose of vaccine is given in the face of maternal antibodies; a cell-mediated response may occur even if calves do not have an increase in serum antibody titer after vaccination. This is particularly useful in the context of pneumonia in nursing dairy or beef calves, as it supports the concept that vaccination can improve the immune response to challenge even if calves have some level of maternal antibodies at the time of vaccination. More research is needed to confirm which vaccines have this effect and to determine how this information should be used to guide vaccination recommendations for calves. It is also not known if this information can be extrapolated to sheep and goats.

Efficacy of Vaccines for Preventing Ruminant Respiratory Disease

Information regarding the use of vaccines for individual agents that cause ruminant respiratory disease was presented earlier in the section describing the individual infectious agents. There has been considerable debate over the years regarding whether vaccines have any impact on ruminant respiratory disease.⁴⁵⁶ The literature on the subject is extensive, and interpretation of the data is complicated by the fact that there is much variation among research studies in the type and number of animals studied, the nature of animal management, and the outcomes measured as evidence of efficacy. There are three major types of research studies by which vaccine efficacy can be measured: studies that measure production of antibodies or in vitro cell-mediated immune responses in vaccinated animals; studies that measure the resistance of vaccinated animals to experimental challenge with viral or bacterial pathogens; and studies that measure the impact of vaccination on health and productivity of animals in a conventional field setting (field trials). Of the three methods, field trials are the most meaningful, but they are also the most expensive and difficult to undertake. When they are undertaken, it is often in small numbers of animals under management practices that may not be representative of practices in other regions. Moreover, they rely on the natural occurrence of the disease in question in the animals under study. A well-designed field trial can be very expensive and time-consuming, and the results can be useless if no animals in the study contract the disease naturally.

In spite of these limitations the results of some field trials testing the efficacy of respiratory disease vaccines have been published. For some important pathogens (e.g., BVDV), there are still no large-scale field trials published that show evidence of efficacy in preventing respiratory disease. One trial showed an economic advantage to administering a modified live vaccine containing BHV-1, BVDV, PI3, and BRSV over the use of a modified live vaccine containing only BHV-1 in feedlot cattle,⁴⁵⁷ but it was not possible to determine which component of the multivalent vaccine was responsible for efficacy. Multiple field trials have been published that tested currently available vaccines against M. haemolytica^311-314 and BRSV^193-196; these are discussed further in the earlier sections on these specific pathogens. In general, some of these studies found that vaccination could prevent disease and sometimes improve productivity, and some of these studies could not find a beneficial effect of vaccination. It is important to remember that in nearly all of these field trials, the effect of vaccination to decrease all respiratory disease was measured. That is, in most cases, no effort was made to determine whether disease specifically caused by the agent included in the vaccine was affected by vaccination. Therefore the apparent lack of efficacy of vaccines in some studies may have been because animals developed disease caused by other respiratory pathogens.

Occasionally, in addition to evaluating the impact of vaccination on morbidity, mortality, and measures of productivity, investigators calculate the economic advantage or disadvantage of vaccination. When such calculations are made, it is important that the reader assess the assumptions made and determine whether they are appropriate. It has been noted that when the economic advantage of using a given vaccine is calculated, various scenarios should be considered that may prove the vaccine to be economically advantageous in some situations and disadvantageous in others.⁴⁵⁸

The mixed results of clinical trials published to date indicate that vaccines decrease respiratory disease, improve animal productivity, and save money for the producer in some cases, and in some cases they do not. This should not be a surprise when the multitude of factors that can converge to cause an outbreak of respiratory disease is considered. Vaccination should be seen as one component of a multifactorial approach to minimize animal disease; it should not be seen as a guarantee against all disease, all the time. Thus, the value of vaccination will depend on the risk of disease in the population in question, and the risk of disease will depend on the likelihood of pathogen exposure and the likelihood that other host and management factors can be modified to maximize the ability of the host to respond to vaccination and resist disease.

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No single, simple recommendation for vaccination of ruminants for the control of respiratory disease can be made. The veterinarian must individualize each vaccination program to the situation at hand. Many factors need to be considered in formulating recommendations for vaccination, including type of production unit, age of animals, system of management, housing facilities, amount of stress imposed on animals, open or closed herd, type of ration, and level of sanitation. In addition, some infectious agents such as BHV-1, BVDV, and H. somni can cause other disease problems not associated with the respiratory tract. Thus the complete spectrum of disease caused by these agents must be considered in formulation of a vaccination program. Examples of respiratory vaccination protocols that could be used in a cow-calf operation and in a dairy are presented in Boxes 31-7 and 31-8.

BOX 31-7 One Example of a Respiratory Vaccination Protocol for Use in a Cow-Calf Herd

REPLACEMENT HEIFERS

Modified live BHV-1/PI3/BRSV/BVD with boost 2–4 weeks later, prior to breeding

COWS

Modified live BHV-1/PI3/BRSV/BVD prior to breeding

Boost with killed or approved modified live* BHV-1/PI3/BRSV/BVD at pregnancy check

Consider M. haemolytica/P. multocida vaccine at pregnancy check with boost one month prior to calving in herds with history of problems with pneumonia in nursing calves

CALVES

In herds with significant pneumonia in nursing calves, consider killed or approved modified live*(preferable) BHV-1/PI3/BRSV/BVD and M. haemolytica/P. multocida vaccine at 1–4 months of age with boost 2–4 weeks later, timed so that boost occurs 2–4 weeks prior to expected onset of calf pneumonia.

To Minimize Pneumonia in Calves Postweaning;

Killed or approved modified-live*(preferable) BHV-1/PI3/BRSV/BVD one month prior to weaning with boost at weaning

Consider M. haemolytica/P. multocida vaccine preweaning with boost at weaning in herds with a history of post weaning pneumonia, or if required for participants in defined preconditioning programs

^* Certain modified live BHV-1/PI3/BRSV/BVD vaccines are approved for use in pregnant cattle and in calves nursing pregnant cattle when administered in accordance with label directions.

BOX 31-8 One Example of a Respiratory Vaccination Protocol for Use in a Dairy

REPLACEMENT HEIFERS

Modified live BHV-1/PI3/BRSV/BVD with boost 2–4 weeks later, prior to breeding

COWS

Modified live BHV-1/PI3/BRSV/BVD prior to breeding

Consider boost with killed or approved modified live* BHV-1/PI3/BRSV/BVD at dry off

Consider M. haemolytica/P. multocida vaccine at 2 months prior to calving, with boost one month later, in herds with history of problems with pneumonia in nursing calves

CALVES

In herds with significant calf pneumonia prior to weaning, consider modified live† BHV-1/PI3/BRSV/BVD and M. haemolytica/P. multocida vaccine at 1–4 months of age with boost 2–4 weeks later, timed so that boost occurs 2–4 weeks prior to expected onset of calf pneumonia.

To Minimize Pneumonia In Calves Postweaning

Modified live BHV-1/PI3/BRSV/BVD one month prior to weaning with boost at weaning

Consider M. haemolytica/P. multocida vaccine one month prior to weaning with boost at weaning in herds with a history of post weaning pneumonia, or if required for participants in defined preconditioning programs

^* Certain modified live BHV-1/PI3/BRSV/BVD vaccines are approved for use in pregnant cattle when administered in accordance with label directions.

^† Modified live BHV-1 and BVD vaccines can induce disease in very young (<1 month of age) or debilitated calves. In such calves, intranasal MLV BHV-1 vaccines or inactivated vaccines may be safer.

Evaluating Reports of Vaccine Efficacy

Vaccines approved for sale in the United States must be proven by the manufacturer to be safe, potent, stable, and efficacious. Duration of immunity is an additional parameter that manufacturers are beginning to be required to address. Efficacy is usually determined by experimental challenge, using defined methods or methods approved on a case-by-case basis. For many bovine respiratory pathogens (e.g., BHV-1, M. haemolytica), experimental challenge protocols have been developed that can induce disease of reasonable severity. To be approved for sale, vaccines need to prevent to a significant degree clinical signs associated with such experimental challenge. However, whereas protection against experimental challenge is a useful indication of the possible efficacy of a vaccine under field conditions, few experimental challenge protocols closely model the field situation in terms of simultaneous occurrence of other stresses and concurrent infection with other pathogens. Thus, it is ideal to evaluate vaccine efficacy through evaluation of an appropriately designed field trial. The design of field trials has generally improved greatly in recent years, but in the case of many vaccines, no high-quality published field trials evaluating the efficacy of vaccination for prevention of BRD exist.

Veterinarians can arm themselves with useful information by evaluating published studies of vaccine efficacy in a critical manner. In some studies animals are vaccinated but never exposed to the pathogen. Serum and/or mucosal antibody levels may be measured, and markers of cell-mediated activity, such as lymphocyte blastogenesis, cytokine production, or cytotoxic T cell activity, may be assayed. Such studies can indicate the antigenicity of a vaccine, but one must consider whether the parameters measured are known to correlate strongly with protection against disease. More information can be gained when measurements of immune function are evaluated in light of natural or experimental challenge. In experimental challenge studies, relatively small groups of animals are vaccinated and later challenged with the pathogen contained in the vaccine. Although experimental challenge studies are rather artificial compared with the situation animals experience in the field, a high-quality experimental study has certain characteristics. Some questions to ask include the following: Was a nonvaccinated control group, identical to the vaccine group in all ways except vaccination status, included? Were control animals tested at the same time as vaccinated animals? If factors that could affect vaccination were present (e.g., maternal antibody), were affected animals divided equally between control and vaccine groups? Did experimental challenge result in disease in the control group? If not, it is impossible to say if vaccination had an effect on challenge. Were investigators who evaluated clinical or pathologic signs of disease blinded to the treatment status of the animals? This removes an important source of bias that otherwise can make data, particularly subjective data such as “depression” or “dyspnea,” suspect. Were statistical tests used to compare results of vaccine and control groups, and was the P value given to indicate likelihood that differences were due to chance alone? Other questions that can help determine the relevance of the experimental study to the field situation include the following: Was disease resulting from challenge clinically and/or pathologically similar to that seen in field cases? Was the vaccination regimen similar to that used in the field? How soon after vaccination were animals challenged? Did the time between vaccination and exposure mimic the field situation?

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Field trials are characterized by allocation of animals in a natural “field” situation to either vaccine or control groups. Animals are treated accordingly and then followed for variable periods of time to determine whether disease occurs in vaccinated animals and, if so, whether vaccinated animals have disease less often, have disease that is less severe, or have improved production characteristics (e.g., average daily gain) after vaccination. When evaluating a field trial, consider the following questions to determine the value of the study: Were animals randomly allocated to control or treatment groups? This is critical; if there is no mention of randomization, it is difficult to gain useful information from the study because of the many types of bias that can affect the outcome. Were concurrent controls used, as opposed to historical controls? Historical controls are of much less value in determining vaccine efficacy, as many factors can affect disease outcome in a group of animals from year to year. How many animals were included in the study, and for how long did the study run? In general, trials with larger numbers of animals are more likely to reveal differences between vaccine and control groups. Were evaluators of disease blinded to the treatment groups to remove their bias in interpreting outcomes? Did disease occur in the control animals? One weakness of field trials is that natural disease must occur in the animals under study to determine the effect of vaccination on disease; the investigators have no control over this aspect of the study. If disease did not occur in at least the control animals, the vaccine cannot be evaluated for protection against the disease. Also, ask what outcomes were measured as evidence of protection against disease. In most cases of feedlot trials, fibrinous pneumonia morbidity and mortality are measured. If this was the case, identify how cases were identified, and determine if the definition is accurate. In many trials, total morbidity and mortality is also measured as an outcome. This may be considered a less reasonable outcome; for example, it may not be reasonable to expect BHV-1 vaccination to decrease deaths caused by ruminal acidosis. Production characteristics, such as rate of gain or feed efficiency, are also often evaluated, and net cost of vaccination, including estimated losses due to disease or loss of production, may be calculated. In these cases, evaluate how costs were estimated, and determine if estimates appear to be accurate and reasonable. Finally, veterinarians may want to consider whether the field trial was conducted under conditions similar to that seen in their practice; if so, the results may be more relevant to the needs of their clients (adapted in part from Ribble).⁴⁵⁹

Definition and Etiology

Acute bovine pulmonary edema and emphysema (ABPEE), classically known as fog fever, is an ARDS of adult (over 2 years old) cattle that are changed from dry, sparse forages to lush green pastures. It is caused by the conversion of L-tryptophan ingested in the lush forages to a pneumotoxic compound (3-methylindole [3-MI]), which leads to the development of pulmonary edema, alveolar epithelial hyperplasia, hyaline membranes, and emphysema.⁴⁶⁰

Clinical Signs

Adult brood cows are most commonly affected because this is the type of animal most likely to be subjected to the abrupt pasture change required to produce the condition. No breed is resistant.⁴⁶⁰ The type of pasture appears to be unimportant, as long as it is lush; ABPEE has been reported on a wide variety of grasses, alfalfa, rape, kale, and turnip tops.⁴⁶² Signs usually occur within 2 weeks of the pasture change.⁴⁶⁰ In severe cases there is an acute onset of very severe dyspnea with a loud expiratory grunt, frothing at the mouth, mouth breathing, and tachypnea (35 to 75 breaths/min).⁴⁶² The animals are obviously distressed (as opposed to exhibiting the typical depression that occurs with infectious diseases) and stand with the head and neck extended and elevated and the nostrils dilated.⁴⁶³ Temperature and heart rate may be elevated secondary to the severe dyspnea and hypoxia.⁴⁶³ On auscultation the breath sounds are usually surprisingly soft in view of the gross dyspnea and tachypnea; a few crackles may be heard.⁴⁶² Even mild exercise increases the dyspnea and may precipitate collapse and death. As many as 30% of severely affected patients may die, usually within 2 days.⁴⁶² Those that survive typically show a dramatic improvement after 3 days.⁴⁶² Recovering patients and those that are less severely affected exhibit tachypnea (50 to 80 breaths/min), hyperpnea, harsh breath sounds, and crackles and wheezes, particularly in the caudal lung fields.⁴⁶² SC emphysema may develop. The demeanor of the entire group tends to become more tranquil.⁴⁶² In cattle that have repeated episodes of nonfatal ABPEE, a chronic respiratory condition characterized by diffuse pulmonary fibrosis and alveolitis may develop.⁴⁶⁴ For purposes of differential diagnosis, it is important to note that coughing is not prominent in the individual or the group.⁴⁶² The main differential diagnoses are those diseases that cause ARDS in pastured adult cattle, usually in outbreak form. The association of ABPEE with typical management conditions (e.g., changes of pasture) and the absence of coughing, signs of sepsis, and adventitious lung sounds in early cases are also very important features. Primary considerations should include the other plant toxicities (moldy sweet potatoes, perilla mint, and possibly others) that can be differentiated only by identifying the source. An outbreak of BRSV infection or parasitic bronchitis could cause similar clinical signs and pathology, but these are characterized by more coughing, signs of depression, and more prominent adventitious sounds; fever is common in animals with acute BRSV infection.

Pathophysiology

L-Tryptophan in lush forages is converted by ruminal microorganisms to indole acetic acid and eventually to 3-MI, which is rapidly absorbed from the rumen into the blood. Metabolism of 3-MI by the cytochrome P-450 mixed function oxidase system in the nonciliated bronchiolar epithelial (Clara) cells and type 1 pneumocytes results in one or more highly reactive intermediates that bind to intracellular proteins or other macromolecules. It is thought that these intermediates produce the damage to these cells. These intermediates are detoxified by conjugation with glutathione.⁴⁶⁵ Cellular damage results in degeneration, necrosis, exfoliation of type 1 pneumocytes and Clara cells, and edema. These lesions in turn cause hyaline membrane formation, proliferation of type 2 pneumocytes, and, to a lesser extent, proliferation of Clara cells.⁴⁶⁵ The proliferation of type 2 cells is also known as adenomatosis. Emphysema is probably secondary to the severe dyspnea.⁴⁶⁵

Epidemiology

As indicated, ABPEE is consistently related to management practices in which hungry adult cattle are suddenly moved from sparse, dry grazing to lush green pastures. The British name “fog fever” arose from the association of the disease with “fog” pastures, which are the lush green regrowth pastures after hay or silage has been cut. The problem usually occurs in the fall. In the typical pattern in the western United States, cattle are moved from dry summer range onto irrigated or fertilized aftermath pastures.⁴⁶⁰ The disease usually appears as a herd outbreak, but individuals may be affected to widely varying degrees; morbidity rate commonly approaches 50%, with a case fatality rate as high as 30%.^466,467 Nursing calves are apparently not at risk, and yearlings are less susceptible than adults.⁴⁶⁸

Necropsy Findings

In animals that die of ABPEE, ecchymotic to petechial hemorrhages occur in the larynx, trachea, and bronchi, and frothy fluid is present in the airways. The gross and histopathologic lung lesions are consistent with AIP. Congestion, edema, and hyaline membranes cause deep red-to-purple coloration of the cranial lung lobes and a smooth, glistening appearance to the cut surface. Interstitial emphysema with large bullae and gelatinous yellow interlobular edema is common. Histologically, eosinophilic hyaline membranes line alveoli and alveolar ducts, and there edema and proliferation of type 2 alveolar epithelial cells are present.⁴⁶⁰ In animals that are killed after 3 to 4 days, emphysema and edema are less obvious, and the lungs tend to be light brown, firm, heavy, and rubbery. There is severe diffuse alveolar epithelial hyperplasia (“adenomatosis”), and large mononuclear cells, multinucleated giant cells, and hyaline membranes are present in alveolar spaces. Edema, eosinophils, and inflammatory cells occupy the septa.⁴⁶⁰

Diagnosis

Diagnosis is made based on the history of recent exposure to lush green forage and typical clinical signs and pathology in fatal cases. Thoracic radiographs could be used to identify changes consistent with interstitial pneumonia in valuable individual animals. The results of TTA or BAL cytology have not been reported for cattle with ABPEE, but a nonseptic mixed inflammatory cell response would be expected. There are no unique hematologic or biochemical changes.⁴⁶³ A stress leukogram is often seen.

Treatment and Prevention

The stress of handling cattle can precipitate further losses. Some authors maintain that most cases in an outbreak occur within 4 days, that removing the herd from the pasture does not prevent additional cases, and that leaving the herd on the pasture does not result in additional cases; consequently the recommendation has been to handle severely affected cattle only if necessary to remove them to shade or to slaughter.⁴⁶⁷ Others^460,468 recommend careful removal from the offending pasture. Antihistamines, corticosteroids, epinephrine, atropine, diethylcarbamazine, and diuretics are alleged to be of palliative value,^460,470 but none of these has been properly tested.⁴⁶⁰ Pretreatment with antagonists to postulated mediators of inflammation, including acetylsalicylic acid, mepyramine, sodium meclofenamate, diethylcarbamazine citrate, and betamethasone, did not influence the clinical course or lesions of experimental 3-MI toxicity. Likewise, pretreatment with chloramphenicol or disodium cromoglycate failed to alter signs or lesions.⁴⁶⁹ However, in one small trial, flunixin meglumine at 1.1 mg/kg IV daily given after the onset of 3-MI–induced disease in calves was effective in lessening signs and lesions.⁴⁷⁰ Recovery often occurs without therapy in the less severe cases. In view of the dangers of handling affected cattle, the questionable efficacy of medical treatment, the probable irreversible nature of severe lesions, and the probability of spontaneous recovery in less severe cases, the best treatment may be no treatment. If treatment must be attempted, affected cattle should be handled very cautiously, and furosemide (0.5 to 1 mg/kg IM or IV once or twice daily)⁴⁶³ and flunixin meglumine (1.1 to 2.2 mg/kg IV daily or divided twice daily) or steroids (dexamethasone at 0.05 to 0.2 mg/kg IM or IV once daily) may be given. Most fatalities occur in the first 2 days. Severely affected animals that survive may develop chronic emphysema or heart failure secondary to cor pulmonale.⁴⁶⁷ Moderate to mild cases often show marked improvement after day 3, with recovery over about 10 days; relapses do not occur.

Prevention is based on management and prophylactic drugs. Management strategies that prevent the exposure of susceptible cattle to potentially toxic pastures include the following:

Because such management changes are frequently not feasible, prophylactic medication is a promising alternative. Monensin or lasalocid at 200 mg/head/day PO reduces the conversion of tryptophan to 3-MI.⁴⁶² Treatment with monensin should be started at least 1 day before pasture change and should be continued an additional 10 days, whereas lasalocid requires a longer pretreatment period of 6 days.⁴⁷¹ For example, 1 kg/head/day of a protein or energy supplement containing 0.15% Rumensin 60 supplies 200 mg of monensin.⁴⁶⁰ Monensin or lasalocid is not expected to be beneficial after the onset of signs. Future possibilities include blockers of the mixed function oxidase system and enhancers of intracellular glutathione levels.

Definition and Etiology

In feedlot cattle an ARDS occurs that is commonly referred to as feedlot AIP. The exact cause of this syndrome is unknown, and it is probably multifactorial. Feedlot management practices typically do not include exposure of cattle to lush forages similar to those that cause ABPEE, and the feeding of moldy sweet potatoes has not been associated with feedlot AIP.⁴⁷² A variety of causes have been proposed^473,474; unfortunately, the amount of research to confirm or refute the various hypotheses ranges from small to nonexistent. The most commonly suggested possible causes or predisposing factors are (1) feed-associated pneumotoxins such as 3-MI^475-477 or dietary factors related to protein metabolism⁴⁷⁸; (2) chronic bacterial pneumonia^479-481; (3) gender^475,476 and hormonal influences^482,483; (4) chronic small airway injury^480,481,484; (5) BRSV infection^481,485; (6) heat or dust exposure^484,486; and (7) hypersensitivity reactions.^484,487,488 These possible causes could also work together in various combinations to cause feedlot AIP.^477,481

Support for 3-MI as a cause of feedlot AIP comes from research that showed that levels of a stable metabolite of 3-MI, 3-methyleneindolenine (3-MEIN), were significantly higher in the blood of cattle with AIP than in control cattle.^475,476 Increased levels of 3-MEIN may be a result of decreased clearance of the toxin.⁴⁷⁵ Loneragan and colleagues also found that 3-MEIN levels were higher in lung tissue of AIP cases as compared with animals without lung disease, but they were not higher than 3-MEIN levels in the lung tissue of cattle with bronchopneumonia; this suggested that 3-MI may contribute to the pathogenesis of both AIP and bronchopneumonia.⁴⁷⁶ The mechanism by which 3-MI is generated and leads to lung damage was discussed earlier in the section describing ABPEE. If 3-MI does contribute to the pathogenesis of feedlot AIP, it is not clear what about the feedlot diet predisposes cattle to produce high levels of 3-MI. Normal cattle produce some 3-MI through metabolism of dietary proteins. It may be that the protein composition (e.g., the tryptophan concentration) of feedstuffs sometimes added to feedlot rations can lead to spikes in 3-MI production. Cattle with feedlot AIP have been found to have higher ruminal pH values than expected for cattle adapted to a high concentrated diet. Ruminal pH in AIP cases ranged from 5.6 to 7.2 in one study⁴⁸¹ and from 4.9 to 7.4 in another,⁴⁸⁹ whereas the ruminal pH of cattle adapted to a high concentrate diet is typically about 5.5 to 5.6.⁴⁹⁰ Many proteins are relatively basic; therefore the high ruminal pH could be related to abnormal protein metabolism. However, the relatively high ruminal pH could also be caused by anorexia. The concept that abnormal ruminal protein metabolism could contribute to feedlot AIP was also supported by a small study that found increased ammonia levels in the ruminal gas cap of cattle with AIP.⁴⁹¹ An interaction between digestive health and AIP was also suggested by the finding that in feedlot pens in which at least one animal had died from digestive disease, the incidence of AIP was approximately 70% greater than in pens in which digestive disease deaths did not occur.⁴⁷⁸

The hypothesis that bacterial bronchopneumonia contributes to feedlot AIP is supported by the finding by multiple authors that cattle with AIP frequently have superimposed gross and histopathologic lesions consistent with bacterial bronchopneumonia.^479-481 In a study evaluating the bacteria isolated from the lungs of cattle with feedlot AIP that had not received antimicrobial therapy, P. multocida and Mycoplasma species were significantly more likely to be isolated from the lungs of cattle with AIP than from the lungs of normal penmates.⁴⁸¹ An earlier study found that bacterial respiratory pathogens were not more likely to be isolated from cases of AIP as compared with controls, but the samples in this study were collected at necropsy of animals that received antimicrobial treatment before death in at least some cases.⁴⁹² It should be noted that no study has yet been able to confirm whether in cases with both lesions the bacterial bronchopneumonia was present before AIP occurred or the bacterial bronchopneumonia developed after the animals had AIP. If bacterial bronchopneumonia leads to the development of AIP, it is not clear how this happens. In humans with ARDS, bacterial infection is often a predisposing factor that appears to lead to ARDS through the induction of high local or systemic levels of proinflammatory cytokines.^493,494 The role of proinflammatory cytokines in cattle with feedlot AIP has not been investigated.

A role for gender and/or hormonal influences in the pathogenesis of feedlot AIP is related to the frequent (although not inevitable)⁴⁸⁰ finding that the majority of affected animals are heifers.^{475,478,481,495} Feeding of melengestrol acetate (MGA), which is fed to heifers to control estrus, has been suggested to contribute to AIP by some authors,^473,482 but others have not found evidence of any association between MGA and AIP.^478,495 Although one research study indicated that MGA could exacerbate experimentally induced AIP in sheep,⁴⁸² a well-controlled experimental study to determine the effect of MGA on AIP in cattle in the field is needed to clarify the involvement of MGA with AIP. It has also been suggested that growth hormone implants may contribute to development of feedlot AIP, although a survey of feedlot managers did not find data to support this.⁴⁹⁵

Infection with BRSV was linked to feedlot AIP in an early study.⁴⁸⁵ Because BRSV infection can sometimes cause AIP, the possibility that a ruminant with lesions of AIP is simply a case of BRSV infection must always be considered. However, cattle with feedlot AIP do not always have a fever,⁴⁸¹ which is expected in animals with acute BRSV infection. Moreover, feedlot AIP can occur in outbreaks, but cases often occur sporadically, which would be less consistent with BRSV infection. Neither Sorden and colleagues nor Loneragan and colleagues found BRSV significantly more often in animals with feedlot AIP than in controls.^480,492 In another study the difference in frequency of identification of BRSV in feedlot AIP cases as compared with normal penmates approached significance (P = .07).⁴⁸¹ It is interesting to note that in this study BRSV antigen was not found in airway epithelial cells, as is characteristic of acute BRSV infection,⁴⁹⁶ but rather was found in cells, possibly macrophages, that were surrounding airways. The significance of this was not clear; perhaps the BRSV antigen found in these cases was residual antigen in phagocytic cells that was engulfed during BRSV infection in the recent past.

Although AIP is by definition “acute,” it is interesting that several authors have reported histopathologic evidence of chronic airway injury (particularly, bronchiolitis fibrosa obliterans) in the lungs of animals with AIP.^480,481,484 In one study, the presence of bronchiolitis fibrosa obliterans was identified significantly more often in cattle with AIP than in penmates with no history of treatment for respiratory disease; this was in spite of the fact that AIP cases in the study also had no history of previous treatment for respiratory disease.⁴⁸¹ It is not known how past airway injury is related to the development of AIP, although chronic airway injury could be linked to the occurrence of chronic bacterial pneumonia, which has also been associated with feedlot AIP, as described previously. It may be that the chronic airway injury is related to dust exposure, although it is not clear why animals with AIP would be more likely to have airway injury caused by dust exposure than other penmates. Dust exposure has been anecdotally related to AIP,^484,486 and feedlot managers often report that efforts to control dust, such as spraying water lightly onto the surface of pens, decreases AIP occurrence when the disease is a problem. However, repeated exposure to feedlot dust or to fungal organisms from feedlot dust did not induce AIP in sheep or goats in experimental studies.^497,498 One study of the effect of dust on feedlot respiratory disease found only a weak association between airborne dust particles and respiratory disease.⁴⁹⁹

High ambient temperatures are thought to contribute to feedlot AIP because several investigators have found that the majority of cases occur in the summer,^478,484 but no mechanism by which hot weather might exacerbate AIP has been researched. Hypersensitivity reactions are often suggested to cause AIP.^502,503 It is true that anaphylaxis can cause pulmonary edema, hemorrhage, and emphysema, with microscopic evidence of hyaline membrane formation.⁵⁰⁰ However, animals that survive longer than a few hours after an episode of anaphylaxis do not have lung changes consistent with AIP, such as type 2 pneumocytic proliferation and interstitial inflammatory cell infiltrate.⁵⁰¹ Therefore an anaphylactic reaction may cause an occasional case of sudden death with lung changes typical of AIP, but anaphylaxis does not explain the majority of feedlot AIP cases. Other types of hypersensitivity-mediated lung disease have pathology that is unlike that seen in feedlot AIP, also making other types of hypersensitivity an unlikely cause of the majority of feedlot AIP cases.^460,473

In summary, the cause of feedlot AIP is unknown, but the strongest support currently exists for some role for (1) factors related to feed, or ruminal metabolism, including 3-MI; (2) infectious respiratory disease, especially chronic bacterial pneumonia, and possibly BRSV; (3) gender and/or other hormonal influences; and (4) chronic airway injury, which may be related to infectious respiratory disease. It seems likely that multiple factors can contribute to the development of feedlot AIP, and the factors may act in some as-yet unidentified combination in at least some cases. It is also possible that some causes predominate in some feedlots or individual cases, whereas other causes predominate in other feedlots or individual cases. A study evaluating the occurrence of bacterial respiratory pathogens in cattle with feedlot AIP found bacterial respiratory pathogens in the lungs of the majority of cases in one feedlot, and in almost none of the cases in a second feedlot,⁴⁸¹ suggesting that bacterial infection played a role in the development of AIP cases in the first feedlot but not the second.

Clinical Signs

Feedlot cattle with AIP may be found dead in the pen.⁵⁰⁴ Clinical presentation includes rapid onset of expiratory dyspnea and tachypnea, although if the respiratory effort is great, the actual respiratory rate may not be greatly elevated. Cattle typically stand with their heads extended and front legs spread apart, and exhibit open-mouth breathing (see Fig. 31-66). Frothing from the mouth may also be observed. Rectal temperatures are variable, ranging from normal to elevated.⁴⁸¹ Physical examination may reveal cyanosis, tachycardia, and SC emphysema that extends from the cervical to dorsal thoracic area.⁵⁰⁵ Auscultation of lungs reveals dull areas throughout the lungs, along with some crackles. Differential diagnoses of bronchopneumonia, tracheal edema, tracheal obstruction, and hypersensitivity pneumonitis should be considered.

Pathogenesis

Because the cause of feedlot AIP is unknown, the pathogenesis is also uncertain. If feed-related pneumotoxins cause at least a subset of cases with AIP, the pathogenesis will be similar to that described for ABPEE, 4-ipomeanol toxicity, and perilla ketone toxicity. If bacterial infection is a cause of some cases of feedlot AIP, as is true for some human cases of ARDS, then proinflammatory cytokine production and the resultant inflammatory cascades they initiate are likely involved. More research is necessary to determine the cause and the pathogenesis of feedlot AIP.

Epidemiology

In the 1999 NAHMS survey of feedlots, AIP was identified as the second leading cause of feedlot mortality, behind bronchopneumonia (shipping fever).⁵⁰² Mortality rates resulting from AIP of 0.03% to 0.15% have been reported.^{478,479,484,495} An important feature of AIP is the tendency of the disease to occur most often in cattle on feed more than 60 days,^{475,481,484,492,495} as opposed to shipping fever, in which mortality peaks by 45 days after feedlot entry.⁵⁰⁶ This means that losses due to AIP deaths are amplified by the fact that relatively more resources in feed and labor have been invested in cattle that die of AIP, as compared with cattle that die of shipping fever. Most cases of feedlot AIP occur in the summer,^478,484,495 but the disease can occur in any season of the year; and most studies report that heifers are disproportionately affected.^475,476,495 One survey found the odds of an animal with AIP being a heifer were 3.1 times greater than the odds of the animal being a steer.⁴⁷⁶ In feedlot pens in which an animal died from a digestive disorder, the relative risk of AIP occurring was about 1.7, indicating that pens with a digestive disorder death were about 70% more likely to also have an AIP death, as compared with pens with no digestive disorder deaths.⁴⁷⁸

A survey of feedlot managers was undertaken to determine risk factors for feedlot AIP.^495,503 Although the response rate was relatively poor (12%), the responding managers oversaw just under 2.5 million cattle, which represented about 10% of the U.S. feedlot inventory the year the survey was undertaken.⁵⁰³ Feedlots in northern states were significantly less likely to recognize AIP as a cause of morbidity or mortality as compared with feedlots elsewhere, whereas larger feedlots and feedlots placing a higher proportion of yearlings were more likely to recognize AIP as a cause of morbidity or mortality. Feedlots that vaccinated less than 95% of placements for M. haemolytica ± P. multocida were more likely to recognize AIP as a cause of disease, and these feedlots recognized AIP as a cause of a larger proportion of deaths, as compared with feedlots that vaccinated more than 95% of cattle for these pathogens.⁴⁹⁵ If the data reported by the feedlot managers are representative of a true association between Mannheimia and Pasteurella vaccination and AIP, the reason for the link is not clear. It may simply be related to the association between placement of a high proportion of yearling cattle and AIP, as yearlings are less likely to be vaccinated for Mannheimia and Pasteurella than younger cattle. It may also be related to the finding that AIP cases have increased likelihood of having concurrent bacterial pneumonia in some feedlots, but more research is necessary before any definite conclusions can be made.

Necropsy Findings

The gross pathology of feedlot AIP is essentially the same as that described for ABPEE. If there is concurrent bacterial bronchopneumonia, there may be cranioventral consolidation, with fibrin deposition on the pleura, but in cases with no concurrent bacterial pneumonia, the pleura is free of fibrin. Grossly it is common to see a “patchwork” appearance of dark and light colored lobules interspersed, and the lobules are freely movable^473,481 (see Fig. 31-67). Histologically, the most acute cases will have only hyaline membrane formation and alveolar edema, possibly with hemorrhage in the alveoli or interstitium; cases that have been going on longer will have proliferation of type 2 alveolar epithelial cells and inflammatory cell infiltrate into the interstitial space (septa). It is not unusual to find evidence of chronic airway injury, such as peribronchiolar lymphoid cuffing, peribronchiolar vascular fibrosis, and bronchiolitis fibrosa obliterans.^480,481 Whether the chronic airway injury is related to the pathogenesis of AIP or whether it is an incidental finding is unknown, but in one study bronchiolitis fibrosa obliterans was significantly more common in AIP cases than in penmates with no history of lung disease.⁴⁸¹

Diagnosis

Diagnosis of feedlot AIP can be confirmed only by histopathologic evaluation of lung from animals that die or are euthanized because of the disease. Clinical signs and even gross pathology are not definitive; only 65% to 80% of cases identified based on clinical signs were confirmed by histopathologic evaluation to have AIP in two studies.^475,481

Treatment and Prevention

Treatments recommended are similar to those recommended for ABPEE. However, feeding monensin does not preclude development of feedlot AIP, as cattle that die of AIP are often consuming feed including monensin when they contract AIP.⁴⁸¹ Treatment is supportive and typically includes administration of antiinflammatory drugs such as steroids (dexamethasone at 0.05 to 0.2 mg/kg once or twice) or flunixin meglumine (1.1 to 2.2 mg/kg IV q24h), and diuretics such as furosemide (1 mg/kg IM or IV q12-24h). Antimicrobial drugs are appropriate given the fact that cases often have superimposed bacterial pneumonia (see Table 31-10). There are no studies evaluating the response of cattle with AIP to any treatment, and such studies would be difficult because there is no perfect method of making an antemortem diagnosis of the disease. However, anecdotal reports indicate that the prognosis is guarded even with treatment. It is important to note that simply moving cattle out of the pen could lead to death from severe respiratory compromise. Because of the risks and uncertainties of treatment and the expected high case fatality rate, immediate salvage slaughter may be the most economic course to take⁵⁰⁷; if salvage slaughter is attempted, remember to observe proper drug withdrawal times.

Because the cause of feedlot AIP is unknown, it is difficult to recommend control measures. Administration of aspirin and of vitamin E have been suggested as rational preventative strategies to counteract inflammatory pathways suspected to be involved in feedlot AIP; however, two trials showed no clear effect of these therapies on levels of 3-MI in treated cattle.^508,509 No cattle in these trials developed AIP, so an effect on disease could not be identified. The risk factors identified suggest that management strategies to minimize abrupt dietary changes and to control infectious respiratory disease may be helpful; anecdotal reports also suggest that efforts to control feedlot dust may be helpful.

Definition and Etiology

Moldy sweet potato toxicity is caused by the ingestion of a furanoterpenoid toxin produced by sweet potatoes (Ipomoea batatas) in response to infestation with the fungus Fusarium solani (javanicum). It should be emphasized that this disease is an intoxication and not an allergic response to the fungus.⁴⁶⁰

Clinical Signs

There is an acute onset of tachypnea, tachycardia, hyperpnea, and dyspnea, with loud expiratory grunting, frothing at the mouth, extension of the head and neck, flaring of the nostrils, and frequent deep coughing. Crackles and harsh bronchial sounds are heard on auscultation.⁵¹⁰ Signs usually occur within 1 day of exposure, and deaths may occur 2 to 5 days later.⁴⁶⁰ Differential diagnoses are as for ABPEE (see earlier discussion), which this condition closely resembles, except for the history of exposure and the more prominent cough and adventitious lung sounds.

Pathogenesis

When F. solani (or closely related species) grows on sweet potatoes, the potato produces several 3-substituted furans, including 4-hydroxymyoporone, which is hepatotoxic. This is converted by the fungus to a series of pneumotoxins, the most abundant of which is 4-ipomeanol. When ingested by cattle in sufficient amounts, this toxin is absorbed, carried to the lungs in the blood, and converted to a highly reactive metabolite by a cytochrome P-450–dependent mixed function oxidase system.⁴⁶⁰ From this point the pathogenesis is similar to that of ABPEE—that is, the toxin binds to intracellular macromolecules in the cell, causing cellular damage, particularly in Clara cells, type I pneumocytes, and endothelium; edema, hemorrhage, cellular necrosis, hyaline membrane formation, and proliferation of cuboidal epithelium result, with secondary emphysema.

Epidemiology

The disease usually occurs in outbreak form when groups of cattle are fed damaged sweet potatoes. Morbidity and case fatality rates are high. Calves nursing affected cows are unaffected.⁵¹¹

Necropsy Findings

The lungs are wet, firm, and large and fail to collapse. Hemorrhages, yellow gelatinous edema fluid, and emphysema with bullae occur throughout. Lobules are dark red and firm.^510,511 Microscopic lesions include edema, emphysema, hyaline membranes, hemorrhage, mixed interstitial infiltrates, alveolar epithelial hyperplasia, peribronchiolar fibrosis, and bronchiolitis obliterans.⁵¹¹

Diagnosis

Diagnosis is made based on history of feeding sweet potatoes and identification of clinical signs and pathology consistent with AIP. Other diagnostic tests as described for ABPEE could also be attempted in valuable individual animals.

Treatment and Prevention

Treatment has not been investigated. Because the pathophysiologic mechanisms are similar to those of ABPEE, similar recommendations are offered here: handle affected animals with extreme care; if treatment is attempted, furosemide (0.5 to 1 mg/kg IM or IV q12-24h) and flunixin meglumine (1.1 to 2.2 mg/kg IV daily or divided twice daily) or dexamethasone (0.05 to 0.2 mg/kg IV or IM q24h) may be given. The prognosis for moderate to severe cases is grave, regardless of management. Because toxicity is difficult to predict and is usually severe and irreversible when it occurs, the feeding of mold-damaged sweet potatoes should be strictly prevented.

Definition and Etiology

Perilla ketone toxicity is an ARDS caused by ingestion of a pneumotoxin found in the leaves and seeds of Perilla frutescens, a common weed in the southeastern United States. This plant is also known as purple mint, perilla mint, wild coleus, and beefsteak plant.⁵¹² It is an erect herbaceous annual about 2 m high, with characteristic square stems, an aromatic odor, and opposite, coarsely serrated ovate leaves 5 to 10 cm long and 4 to 8 cm wide, with a purplish tint at maturity. The seed and flower stage, which occurs in August to October, appears to be most toxic.⁵¹² The flowers are small, white to purple blooms on a long raceme.⁵¹² The plant prefers semishade, such as damp, open wooded areas.

Clinical Signs

Animals are often found dead.⁵¹² Signs observed include a sudden onset of moderate to severe dyspnea, wheezing, frothing at the mouth, and an expiratory heave or grunt.^512,513 In less severe cases the cow may pant.⁵¹³ Exertion worsens the signs and may precipitate death. Mature cows are most often affected, but deaths have been reported in yearlings and calves.⁵¹² Death occurs in 3 to 7 days in experimental toxicity.⁵¹² Differential diagnoses are as for ABPEE (see earlier discussion), which this condition closely resembles and from which it can be differentiated only by history of exposure.

Pathogenesis

The volatile oils of P. frutescens contain a number of 3-substituted furans that are chemically similar to 4-ipomeanol, the moldy sweet potato toxin. One of these, perilla ketone, predominates in the later growing season (when most toxicities occur) and has been shown to be pneumotoxic when given parenterally to mice, hamsters, goats, calves, and sheep.⁵¹² The toxin is absorbed from the rumen, carried to the lungs through the blood, and probably metabolized to the toxic form by the mixed function oxidase system, as for 4-ipomeanol and 3-MI (see earlier). The pathogenesis from this point parallels that of ABPEE or moldy sweet potato toxicity.

Epidemiology

P. frutescens seems to thrive in late summer, when pastures in the southeastern United States are frequently dry and dormant.⁵¹³ This also corresponds with the more toxic stage of the plant.⁵¹² Cattle normally avoid the plant when other pasture is available but may be forced to consume it during this critical period.⁵¹³ However, under experimental conditions calves were noted to prefer the mint.⁵¹² The preseed stage appears to be of relatively low toxicity; the green seed-stage plant is most toxic, especially the seed parts; dried hay from seed-stage plants is less toxic than green plants but is still potentially lethal; and frosted plants appear to have relatively low toxicity.⁵¹² The exact toxic dose is unknown, but 2.3 kg of green seed-stage plant and 11.2 kg of hay were lethal for cattle in one trial.⁵¹²

Necropsy Findings

The lungs are distended (often bearing the impressions of the ribs), fail to collapse, and are moist, heavy, edematous, and emphysematous. There are often bullae, pleural effusions, and froth in the airways. Histologic characteristics are edema, extensive alveolar epithelial hyperplasia, emphysema, and congestion.

Diagnosis

Diagnosis is based on history of exposure to perilla mint and characteristic clinical signs and lung pathology. Other diagnostic tests as described for ABPEE could also be attempted in valuable individual animals.

Treatment and Control

Treatment has not been investigated. On the basis of the similar pathophysiologic mechanisms, the recommendations for ABPEE should be followed (see earlier discussion). The prognosis for severe cases is grave, regardless of management. Cattle should be provided sufficient forage that they do not seek out perilla mint; once they have begun to eat it, they should be fenced away from stands of the plant, and other forage should be provided.

NITROGEN DIOXIDE

Nitrogen dioxide (NO₂) is a yellow-orange to brown gas with an acrid odor that is produced by anaerobic fermentation of green plant material. It is a major component of “silo gas.” Acute exposure of farm workers to high concentrations of NO₂ causes a respiratory condition known as “silo-filler’s disease,” characterized by severe acute edema and congestion and followed by bronchiolitis obliterans and progressive interstitial pulmonary fibrosis. A similar condition has been induced experimentally in cattle,⁵¹⁷ and apparent (although unproved) spontaneous field cases have been reported.^518,519 Clinical signs in experimental and apparent field cases include cough, tachycardia, tachypnea, respiratory grunting, depression, anorexia, hypogalactia, extension of the head, open-mouth breathing, fever, salivation, lacrimation, and SC emphysema. Auscultation reveals decreased breath sounds and crackles.^518,519 The primary differential diagnoses should include other ARDSs of housed cattle that occur in outbreak form, especially exposure to other toxic gases (manure pit gases, zinc oxide, chlorine, carbon monoxide), and hypersensitivity pneumonitis from moldy hay. Nitrate toxicity should also be considered. Clinical pathologic evaluation is of limited benefit. Leukocyte counts remained normal in experimental cases; methemoglobin levels increased to a peak at 30 minutes after exposure and returned to normal in 12 to 24 hours.⁵¹⁷ The pathophysiologic mechanism probably involves the dissolution of the NO₂ in the water of the respiratory tract to form nitric acid. Nitrates and nitrites are also formed; these are irritating, and the nitrites cause methemoglobinemia.⁵¹⁹ Nitrogen dioxide is also an oxidant itself and may contribute directly to the injury. The disease occurs as an outbreak, usually in housed cattle in proximity to a silo chute in a tight or poorly ventilated barn.^518,519 Nitrogen dioxide is heavier than air and layers on the top of silage or spills out around the bottom of the silo. Corn silage produces more gas than hay, and a high nitrate content increases the danger. The levels are highest in the first 48 hours after filling the silo but may remain dangerous for 2 to 3 weeks.

Necropsy findings in experimental disease include hyperemia of the upper airways; hemorrhages, fibrinous membranes, and froth in the trachea; distended, noncollapsing lungs with rib imprints; a mottled appearance caused by consolidated lobules alternating with emphysematous lobules; and bullae. Microscopic lesions include alveolar epithelial hyperplasia, large foamy alveolar macrophages, hyaline membranes, hyperemia, hemorrhage, and edema.

Treatment involves the establishment of adequate ventilation; cows should be completely removed from closed buildings if necessary. Corticosteroids have apparently been beneficial in field cases,^518,519 but no controlled studies have been performed. Because of the obvious differences in pathophysiologic characteristics, it would be unwise to extrapolate treatment regimens from those of ABPEE. Suggested empiric therapy might include corticosteroids (dexamethasone at 0.05 to 0.2 mg/kg IM or IV daily), furosemide (0.5 to 1.1 mg/kg IM or IV daily or twice daily), and appropriate antibiotics to prevent secondary bacterial infections.

ZINC OXIDE

Zinc oxide (ZnO) fumes have been associated with an ARDS in cattle.⁵²⁰ Oxyacetylene cutting or arc welding of galvanized pipe results in production of white fumes of zinc oxide containing colloidal particles 0.3 to 0.4 mm in diameter, which can reach the terminal alveoli when inhaled.⁵²⁰ Construction activities in closed barns containing animals may result in toxicity in animals in close proximity or in the path of ventilation. All ages may be affected.

Clinical signs in severe cases include acute onset of anorexia, frothing at the mouth, anxiety, extension of the head and neck, mouth breathing, expiratory grunting, tachypnea, tachycardia, mild fever, SC emphysema, and crackles on auscultation of the lungs. Death may occur within 12 hours. Less severely affected animals exhibit depression, mild fever, and tachypnea.⁵²⁰ Differential diagnoses include other ARDS of housed cattle that occur in outbreak form such as exposure to other toxic gases (nitrogen dioxide, manure pit gases) or hypersensitivity pneumonitis. The pathophysiologic process presumably involves direct damage to cells by the ZnO and its products dissolved in the fluid lining the respiratory tract. Necropsy findings include purulent conjunctivitis; SC emphysema; congestion of the airways; tracheal hemorrhages; stiff, noncollapsing lungs; and pulmonary congestion, edema, and emphysema with bullae.⁵²⁰ Histologic lesions include pulmonary congestion, emphysema, edema, and mixed cellular infiltrates with a prominent eosinophil component. Treatment of severe cases with epinephrine, antihistamine, atropine, and corticosteroids had no effect in one outbreak,⁵²⁰ whereas mild cases recover spontaneously. Suggested empiric therapy could include ventilation of the area, dexamethasone (0.05 to 0.2 mg/kg IM or IV daily), furosemide (0.5 to 1.1 mg/kg IM or IV daily or twice), and appropriate antibiotics to control secondary bacterial invaders.

CHLORINE

Chlorine is a greenish yellow gas widely used in manufacturing. Animal exposure is usually the result of industrial accidents. Exposed animals may be found dead. Signs include depression, profuse nasal discharge, lacrimation, and dyspnea; crackles may be heard on auscultation.⁵²¹ The toxic effects are the result of the formation of hydrochloric and hypochlorous acids; the latter breaks down to hydrochloric acid and oxygen, both of which are toxic to tissues. Necropsy findings include congestion of the nasal mucosa, tracheitis, and pulmonary edema, hemorrhage, and emphysema. Histologic lung lesions include edema, emphysema, hemorrhage, atelectasis, hyaline membrane formation, and lymphocytic bronchitis.⁵²¹ Treatment is empiric; suggestions include corticosteroids (dexamethasone at 0.05 to 0.2 mg/kg IM or IV daily), furosemide (0.5 to 1.1 mg/kg IM or IV daily to twice daily), and appropriate antibiotics to prevent secondary bacterial infection.

MANURE GASES

Manure gases include mixtures of hydrogen sulfide, ammonia, carbon dioxide, methane, and carbon monoxide.⁴⁶⁰ Accumulation of these gases can result in asphyxiation of animals in enclosed barns over manure pits.

SMOKE INHALATION

Smoke inhalation injury may occur in animals that survive barn fires. Many clinical changes may not become evident for 24 to 48 hours after the fire. It is important to assess the degree of damage as early as possible and to attempt to anticipate sequelae so that early aggressive therapy can be instituted.⁵²² Common problems for which to check include oral burns, conjunctivitis, and laryngospasm. Hoarseness, expiratory wheezes, and carbonaceous sputum indicate potentially serious sequelae. Crackles and wheezes on auscultation may occur very early or may be delayed for hours. Cough, stridor, and tachypnea may also occur. Bright red mucous membranes may indicate CO poisoning or burns and may mask cyanosis.⁵²² Carboxyhemoglobin determinations on iced venous blood (often available at human hospitals), serial arterial blood gas determinations, transtracheal wash, and bronchoscopy are useful in delineating the extent of damage and prognosis.⁵²²

The pathophysiology of smoke inhalation is complex and involves two main mechanisms: CO toxicity and smoke toxicity. CO toxicity results in tissue hypoxia in all organs, especially the brain; O₂ consumption in the fire and the pulmonary effects of smoke may aggravate this hypoxia. Heat damage in animals is usually limited to the upper airways. Smoke toxicity is related to the inhalation of soot, superheated particles, and a variety of noxious gases (e.g., aldehydes, oxides of sulfur and nitrogen, benzene from plastics), which results in the formation of dissolved acids, alkaloids, and other direct irritants in pulmonary fluids. These mechanisms eventually (usually 2 to 24 hours after inhalation) result in alveolar damage, interstitial edema, hypoxia, and secondary bronchopneumonia.⁵²²

Treatment involves establishing a patent airway with intubation or tracheostomy if necessary. Oxygen, up to 100% for short periods, is indicated⁵²²; care must be exercised because 100% oxygen can also cause pulmonary damage. IV fluids should be given, with careful monitoring for pulmonary edema. The use of corticosteroids is controversial.⁵²² Antibiotics are indicated to prevent secondary bronchopneumonia. Bronchodilators such as aminophylline at 6 to 10 mg/kg IV or PO three times daily may help relieve soot-induced bronchospasm.

Anaphylaxis

In ruminants the lung is the major target organ in immediate (type I) hypersensitivity reactions. Precipitating antigens include vaccines, drugs, blood, Hypoderma bovis or Hypoderma lineatum larvae, insect bites, and bee stings. Signs of anaphylaxis usually develop in 10 to 20 minutes and include severe acute dyspnea, with flaring of the nostrils, extension of the head and neck, open-mouth breathing, frothing of the mouth, hyperpnea, and abduction of the elbows. Pharyngeal and laryngeal edema cause stertor and inspiratory dyspnea. Urticaria may occur in some cases, such as milk allergy in Jersey cows. Shivering, salivation, lacrimation, pruritus, diarrhea, fever, edema (eyes, muzzle, anus, and vulva), collapse, nystagmus, cyanosis, and discharge of froth from the nostrils also may occur. On auscultation there are harsh breath sounds, large airway sounds, and crackles. The primary differential diagnosis is peracute interstitial pneumonia. The pathogenesis involves an initial exposure to the antigen, which results in a genetically determined production of homocytotropic antibodies. In humans and dogs, this is immunoglobulin E (IgE); in ruminants various classes may be involved.⁵²⁶ This antibody attaches to receptors on mast cells and basophils. On subsequent exposure to the antigen, bridging of the Fab parts of the antibody on these cells results in degranulation, with release of a variety of mediators such as histamine, bradykinin, 5-hydroxytryptamine, serotonin, slow-reacting substance-anaphylaxis (SRS-A), eosinophil chemotactic factor A, platelet activating factor, kinins, and prostaglandins.^526-528 These mediators result in a cascade of vascular events, notably increased vascular permeability, which in turn results in acute severe edema. Pulmonary venous constriction, pulmonary artery hypertension, splanchnic pooling, increased mucus secretion, and bronchospasm also occur. Ruminants that die of anaphylaxis have severe pulmonary congestion and edema, laryngeal edema, and froth in the airways. Lung lesions of ARDS may be present.

The treatment of choice is epinephrine, 4 to 8 mg (4 to 8 mL of 1:1000 solution) IV or SC or 1 to 5 mg IV for an average 500-kg cow and 1 to 3 mg IV or SC for an average adult sheep or goat. Epinephrine has a short half-life, and animals should be observed closely for relapse. Ancillary therapy includes corticosteroids (dexamethasone, 0.1 mg/kg IM or IV; prednisolone, 2.2 mg/kg IM or IV daily). Other supportive therapies include shock doses of IV fluids (40 mL/kg/hr); aminophylline; diuretics such as furosemide; oxygen therapy; and tracheostomy if necessary.