Respiratory Diseases of Cattle: Introduction

Respiratory disease is among the most economically important diseases of cattle in production on a worldwide basis. (See also
CALF DIPHTHERIA,

Necrotic Laryngitis.)

Bovine Respiratory disease Complex

Overview

Enzootic Pneumonia of Calves and Shipping fever Pneumonia

Overview Enzootic Pneumonia of Calves Shipping Fever Pneumonia

Viral Respiratory Tract Infections

Overview Parainfluenza-3 Virus Bovine Respiratory Syncytial Virus Bovine Herpesvirus 1 Bovine Viral Diarrhea Virus Other Bovine Respiratory Viruses

Bacterial Pneumonia
Overview Pneumonic Pasteurellosis Mycoplasmal Pneumonia Chlamydial Pneumonia Contagious Bovine Pleuropneumonia

Interstitial pneumonia
Overview Acute Bovine Pulmonary Emphysema and Edema Anaphylaxis Hypersensitivity Pneumonitis Diffuse Fibrosing Alveolitis Acute Respiratory Distress Syndrome of Feedlot Cattle 4-Ipomeanol Toxicity (Moldy Sweet Potato) and Perilla Ketone Toxicity (Purple Mint Toxicity) Toxic Gases Vena Caval Thrombosis and Metastatic Pneumonia

Bovine Respiratory Disease Complex: Overview

Bovine respiratory disease (BRD) has a multifactorial etiology and develops as a result of complex interactions between environmental factors, host factors, and pathogens. Environmental factors (eg, weaning, transport, commingling, crowding, and inadequate ventilation) serve as stressors that adversely affect the immune and nonimmune defense mechanisms of the host. In addition, certain environmental factors (eg, crowding and inadequate ventilation) can enhance the transmission of infectious agents among animals. Many infectious agents have been associated with BRD. An initial pathogen (eg, a virus) may alter the animals defense mechanisms, allowing colonization of the lower respiratory tract by bacteria.

Enzootic Pneumonia of Calves and Shipping Fever Pneumonia: Overview

Enzootic pneumonia and shipping fever pneumonia share many similarities in their respective etiologies and pathogeneses and general measures for control and prevention.

Enzootic Pneumonia of Calves

Enzootic pneumonia of calves refers to infectious respiratory disease in calves. The term viral pneumonia of calves is sometimes used but is not preferred based on the current understanding of etiology and pathogenesis. Enzootic pneumonia is primarily a problem in calves <6 mo old with peak occurrence from 2-10 wk, but may be seen in calves up to 1 yr of age. It is more common in dairy than in beef calves and is a common problem in veal calves. It is also more common in housed calves than those raised outside. Peak incidence of disease may coincide with decline of passively acquired immunity. Morbidity rates may approach 100%; case fatality rates vary but can reach 20%.

Etiology:
The etiology is similar to that for BRD complex in general ( see Bovine Respiratory Disease Complex: Overview). The pathogenesis involves stress and possibly an initial respiratory viral infection followed by a secondary bacterial infection of the lower respiratory tract. Stress results from environmental and management factors, including inadequate ventilation, continually adding calves to an established group, crowding, and nutritional factors such as poor-quality milk replacers. Partial or complete failure of passive transfer of maternal antibodies is an important host factor related to development of disease. Any of several viruses may be involved, and a variety of bacteria may be recovered from affected calves. Mycoplasmal and bacterial agents including Pasteurella multocida , Mannheimia haemolytica , and Mycoplasma bovis represent the

most frequently isolated pathogenic organisms. The individual viral and bacterial etiologies, clinical signs, lesions, and treatment are discussed under Respiratory Tract Infections: Overview) and
VIRAL RESPIRATORY TRACT INFECTIONS

( Viral

BACTERIAL PNEUMONIA

( Bacterial Pneumonia: Overview).

Control and Prevention:

When calves of varying ages are placed in communal pens, control of enzootic pneumonia is difficult. The severity of the pneumonia may be decreased by improved husbandry, proper housing, adequate ventilation, and good nursing care. Prevention begins with vaccinating the cows against specific respiratory viruses and bacteria 3-4 wk prepartum to improve the quality of colostral antibodies. Calves should receive good quality colostrum at 8-10% of body wt in the first 12 hr after birth. Newborn dairy calves should be housed individually in hutches or stalls and fed whole milk or a high-quality milk replacer with a fiber content of <0.25% until 8-12 wk old. Calves should be vaccinated against respiratory viruses 3-4 wk before the first grouping, although in some situations, the presence of passive immunity may interfere with an active immune response. Calves should be of similar age when assembled into groups and the group should be limited to 10. As calves mature, groups can become larger as the size of the herd , facilities, and available labor dictate. An all in/all out management style should be practiced when establishing and terminating a group. At minimum, newly purchased calves should be isolated before introduction to an existing group. Newborn beef calves and their dams should be moved from concentrated calving areas as soon as the calf is nursing well and is strong enough to travel.

Shipping Fever Pneumonia

Shipping fever pneumonia is a respiratory disease of cattle of multifactorial etiology with Mannheimia haemolytica and, less commonly, Pasteurella multocida or Histophilus somni (Histophilosis : Introduction), being the important infectious agents involved. Shipping fever pneumonia is associated with the assembly into feedlots of large groups of calves from diverse geographic, nutritional, and genetic backgrounds. Disease is typically seen in feeder calves 7-10 days after assembly in a feedlot. Morbidity can approach 35%; mortality is 5-10%.

Etiology:
The pathogenesis of shipping fever pneumonia involves stress factors, with or without viral infection, interacting to suppress host defense mechanisms, which allows the proliferation of commensal bacteria in the upper respiratory tract. Subsequently, these bacteria colonize the lower respiratory tract and cause a bronchopneumonia with a cranioventral distribution in the lung. Multiple stress factors are believed to contribute to the suppression of host defense mechanisms. Transportation over long distances serves as a stressor; it may be associated with exhaustion, starvation, dehydration, chilling and overheating depending on weather conditions, and exposure to vehicle exhaust fumes. Additional stressors include passage through auction

markets; commingling, processing, and surgical procedures on arrival at the feedlot; dusty environmental conditions; and nutritional stress associated with a change to high-energy rations in the feedlot. The individual viral and bacterial etiologies, clinical signs, lesions, and treatment are discussed under Overview) and
VIRAL RESPIRATORY TRACT INFECTIONS

( Viral Respiratory Tract Infections:

BACTERIAL PNEUMONIA

( Bacterial Pneumonia: Overview).

Control and Prevention:

Prevention of shipping fever pneumonia should focus on reduction of the stressors that contribute to development of the disease. Cattle should be assembled rapidly into groups, and new animals should not be introduced to established groups. Auction markets and mixing of cattle from different sources should be avoided if possible. Transport time should be minimized, and rest periods, with access to feed and water, should be provided during prolonged transport. Calves should be weaned 2-3 wk before shipment, and surgical procedures should be performed in advance of transport. Cattle should be processed within 48 hr after arrival at the feedlot. A rest period of 6-12 hr after transport may allow for rehydration and return of cortisol to levels that will have less impact on the immune response to vaccination. Adaptation to high-energy rations should be gradual as acidosis, indigestion, and anorexia may inhibit the immune response. Vitamin and mineral deficiencies should be corrected. Dust control measures should be used. Metaphylaxis with long-acting antibiotics given on arrival for cattle at high risk for developing shipping fever pneumonia has been shown to significantly reduce morbidity and improve rate of gain. The administration of viral respiratory vaccines on entry to the feedlot has been historically controversial, especially with modified live vaccines. These vaccines have been reported to increase the mortality associated with shipping fever pneumonia. Continuous improvements in modified live vaccine production, and the fact that these vaccines do not require a booster, have made them preferred over killed vaccines for on-arrival processing. When possible, vaccinations for the viral and bacterial components of shipping fever pneumonia should be given 2-3 wk before transport and can be repeated on entry to the feedlot.

Viral Respiratory Tract Infections: Overview

Parainfluenza-3 Virus Bovine Respiratory Syncytial Virus Bovine Herpesvirus 1 Bovine Viral Diarrhea Virus Other Bovine Respiratory Viruses

Parainfluenza-3 Virus
Etiology:
Parainfluenza-3 virus (PI-3) is an RNA virus classified in the paramyxovirus family. Infections caused by PI-3 are common in cattle. Although PI-3 is capable of causing disease, it is usually associated with mild to subclinical infections. The most important role of PI-3 is to serve as an initiator that can lead to the development of secondary bacterial pneumonia.

Clinical Findings and Lesions:

Clinical signs include pyrexia, cough, serous nasal and lacrimal discharge, increased respiratory rate, and increased breath sounds. The severity of signs worsens with the onset of bacterial pneumonia. Fatalities from uncomplicated PI-3 pneumonia are rare. Lesions include cranioventral lung consolidation, bronchiolitis, and alveolitis with marked congestion and hemorrhage. Inclusion bodies may be identified. Most fatal cases have a concurrent bacterial bronchopneumonia.

Diagnosis:
Diagnostic procedures for PI-3 are similar to those for Respiratory Syncytial Virus).
BOVINE RESPIRATORY SYNCYTIAL VIRUS

( Bovine

Treatment and Prevention:

Treatment focuses on the antimicrobial therapy directed toward bacterial pneumonia ( Bacterial Pneumonia: Overview). NSAID are also a therapeutic consideration. PI-3 vaccines are available and are almost always combined with bovine herpesvirus 1 (infectious bovine rhinotracheitis). Modified live and inactivated vaccines are available for IM administration. Vaccines containing temperature-sensitive mutants for intranasal administration are also available.

Bovine Respiratory Syncytial Virus

Etiology:
Bovine respiratory syncytial virus (BRSV) is an RNA virus classified as a pneumovirus in the paramyxovirus family. This virus was named for its characteristic cytopathic effect the formation of syncytial cells. In additional to cattle, sheep and goats can also be infected by respiratory syncytial viruses. Human respiratory syncytial virus (HRSV) is an important respiratory pathogen in infants and young children. Antigenic subtypes are known to exist for HRSV, and preliminary evidence suggests that there may be antigenic subtypes of BRSV. BRSV is distributed worldwide, and the virus is indigenous in the cattle population. BRSV infections associated with respiratory disease occur predominantly in young beef and dairy cattle. Passively derived immunity does not appear to prevent BRSV infections but will reduce the

severity of disease. Initial exposures to the virus are associated with severe respiratory disease; subsequent exposures result in mild to subclinical disease. BRSV is an important virus in the bovine respiratory disease complex because of its frequency of occurrence, predilection for the lower respiratory tract, and ability to predispose the respiratory tract to secondary bacterial infection. In outbreaks, morbidity tends to be high, and the case fatality rate can be 0-20%.

Clinical Findings and Lesions:

Fever (104-108F [40-42C]), depression, decreased feed intake, increased respiratory rate, cough, and nasal and lacrimal discharge are common. Dyspnea, possibly with open-mouthed breathing, may become pronounced in the later stages of the disease. Subcutaneous emphysema may occur. Secondary bacterial pneumonia is a frequent occurrence. A biphasic disease pattern has been described but is not consistent. Gross lesions include a diffuse interstitial pneumonia with subpleural and interstitial emphysema along with interstitial edema. These lesions are similar to and must be differentiated from other causes of interstitial pneumonia. See also
INTERSTITIAL PNEUMONIA,

Bovine Viral Diarrhea Virus.

Bronchopneumonia of bacterial origin is usually present. Histologic examination reveals syncytial cells in bronchiolar epithelium and lung parenchyma, intracytoplasmic inclusion bodies, proliferation and/or degeneration of bronchiolar epithelium, alveolar epithelialization, edema, and hyaline membrane formation.

Diagnosis:
A diagnosis of BRSV requires laboratory confirmation. BRSV is a difficult virus to detect, although chances of isolation may improve when sampling animals that are in the incubation or acute phases of infection. An antigen detection enzyme immunoassay is useful in detecting BRSV antigen and establishing a diagnosis. Other procedures that have proved useful in detection of BRSV antigen are fluorescent antibody and immunoperoxidase staining. Paired serum samples can be used to establish a diagnosis. However, the antibody titer of animals with well-developed clinical disease may be higher in the acute sample than in the sample taken 2-3 wk later because the antibody response often develops rapidly, and clinical signs follow virus infection by up to 7-10 days. Single serum samples with high antibody titers from a number of animals in a respiratory outbreak may be useful in making a diagnosis if coupled with clinical signs. Calves that become infected with BRSV in the presence of passively derived antibody may not seroconvert.

Treatment and Prevention:

Treatment focuses on antimicrobial therapy to control secondary bacterial pneumonia ( Bacterial Pneumonia: Overview). There is no specific treatment for the viral interstitial pneumonia. Supportive therapy and correction of dehydration may be necessary. There are anecdotal reports of treatment with antihistamines and/or corticosteroids being of benefit. Most cases will recover in several days without treatment.

General control and prevention are discussed under

FEVER PNEUMONIA

ENZOOTIC PNEUMONIA OF CALVES AND SHIPPING

( Shipping Fever Pneumonia). Inactivated and modified live vaccines are

available and may serve to reduce losses associated with BRSV.

Bovine Herpesvirus 1
(Infectious bovine rhinotracheitis virus, Infectious pustular vulvovaginitis, and associated diseases)

Etiology and Epidemiology:

Bovine herpesvirus 1 (BHV-1) is associated with several diseases in cattle: infectious bovine rhinotracheitis (IBR), infectious pustular vulvovaginitis (IPV), balanoposthitis, conjunctivitis, abortion, encephalomyelitis, and mastitis. Only a single serotype of BHV-1 is recognized; however, three subtypes of BHV-1 have been described on the basis of endonuclease cleavage patterns of viral DNABHV-1.1 (respiratory subtype), BHV-1.2 (genital subtype), and BHV-1.3 (encephalitic subtype). BHV-1.3 has been reclassified as a distinct herpesvirus designated BHV-5. BHV-1 infections are widespread in the cattle population. In feedlot cattle, the respiratory form is most common. The viral infection alone is not life-threatening but predisposes to secondary bacterial pneumonia, which may result in death. In breeding cattle, abortion or genital infections are more common. Genital infections can occur in bulls (infectious pustular balanoposthitis) and cows (IPV) within 1-3 days of mating or close contact with an infected animal. Transmission can occur in the absence of visible lesions and through artificial insemination with semen from subclinically infected bulls. Cattle with latent BHV-1 infections generally show no clinical signs when the virus is reactivated, but they serve as a source of infection for other susceptible animals.

Clinical Findings:
The incubation period for the respiratory and genital forms is 2-6 days. In the respiratory form, clinical signs range from mild to severe, depending on the presence of secondary bacterial pneumonia. Clinical signs include high fever, anorexia, coughing, excessive salivation, nasal discharge that progresses from serous to mucopurulent, conjunctivitis with lacrimal discharge, inflamed nares (hence the common name red nose), and dyspnea if the larynx becomes occluded with purulent material. Nasal lesions consist of numerous clusters of grayish necrotic foci on the mucous membrane of the septal mucosa, just visible inside the external nares. They may later be accompanied by pseudodiphtheritic yellowish plaques. Conjunctivitis with corneal opacity may occur as the only manifestation of BHV-1 infection. In the absence of bacterial pneumonia, recovery generally occurs 4-5 days after the onset of signs. Abortions may occur concurrently with respiratory disease but may be seen up to 100 days after infection. They can occur regardless of the severity of disease in the dam. Abortions generally

occur during the second half of pregnancy, but early embryonic death is possible. In genital infections, the first signs are frequent urination, elevation of the tailhead, and a mild vaginal discharge. The vulva is swollen, and small papules, then erosions and ulcers, are present on the mucosal surface. If secondary bacterial infections do not occur, animals recover in 10-14 days. With bacterial infection, there may be inflammation of the uterus and transient infertility, with purulent vaginal discharge for several weeks. In bulls, similar lesions occur on the penis and prepuce. (See also Vulvitis and Vaginitis in Large Animals: Introduction.) BHV-1 infection can be severe in young calves and cause a generalized disease. Pyrexia, ocular and nasal discharges, respiratory distress, diarrhea, incoordination, and eventually convulsions and death may occur in a short period after generalized viral infection. Lesions: In uncomplicated IBR infections, most lesions are restricted to the upper respiratory tract and trachea. Petechial to ecchymotic hemorrhages may be found in the mucous membranes of the nasal cavity and the paranasal sinuses. Focal areas of necrosis develop in the nose, pharynx, larynx, and trachea. The lesions may coalesce to form plaques. The sinuses are often filled with a serous or serofibrinous exudate. As the disease progresses, the pharynx becomes covered with a serofibrinous exudate, and blood-tinged fluid may be found in the trachea. The pharyngeal and pulmonary lymph nodes may be acutely swollen and hemorrhagic. The tracheitis may extend into the bronchi and bronchioles; when this occurs, epithelium is sloughed in the airways. The viral lesions are often masked by secondary bacterial infections. In young animals with generalized BHV-1 infection, erosions and ulcers overlaid with debris may be found in the nose, esophagus, and forestomachs. In addition, white foci may be found in the liver, kidney, spleen, and lymph nodes. Aborted fetuses may have pale, focal, necrotic lesions in all tissues, which are especially visible in the liver.

Diagnosis:
Uncomplicated BHV-1 infections can be diagnosed based on the characteristic signs and lesions. However, because the severity of disease can vary, it is best to differentiate BHV-1 from other viral infections by viral isolation. Samples should be taken early in the disease, and a diagnosis should be possible in 2-3 days. A rise in serum antibody titer also can be used to confirm a diagnosis. It is not possible to detect a rising antibody titer in abortions, because infection generally occurs a considerable length of time before the abortion, and titers are already maximal. BHV-1 abortion can be diagnosed by identifying characteristic lesions and

demonstrating the virus in fetal tissues by virus isolation, immunoperoxidase, or fluorescent antibody staining. Gross and microscopic lesions detected shortly after death may help to establish a diagnosis.

Treatment and Control:

Antimicrobial therapy is indicated to prevent or treat secondary bacterial pneumonia. General

recommendations for control are discussed under

SHIPPING FEVER PNEUMONIA

( Shipping Fever

Pneumonia). Immunization with modified live or inactivated virus vaccines generally provides adequate protection against clinical disease. Both IM and intranasal modified live vaccines are available, but the IM types may cause abortion in pregnant cattle. The intranasal vaccines can be used in pregnant cattle. The IM vaccines are easier to use and often are the vaccines of choice in feedlots. Breeding and replacement heifers and bulls should be immunized when 6-8 mo old, before breeding, and yearly thereafter. Some recommend that young bulls not be vaccinated because they may be discriminated against when sold for breeding if they have antibody titers. Feeder calves should be immunized 2-3 wk before entry into the feedlot. Eradication of the virus is possible by serologic testing and either culling reactors or running a strict 2-herd system. To aid in eradication, deletion mutant vaccines have been developed that permit discrimination between antibody produced in response to the vaccine and antibody produced in response to natural exposure.

Bovine Viral Diarrhea Virus

Bovine viral diarrhea virus (BVDV) is an RNA virus classified as a Pestivirus in the family Flaviviridae ( Bovine Viral Diarrhea and Mucosal Disease Complex). The role of BVDV in BRD has been controversial, but appears to be that of a virus capable of inducing immunosuppression, which allows for the development of secondary bacterial pneumonia. Seroconversion to BVDV has been reported to be predictive of the occurrence of respiratory disease in feedlot calves, and BVDV has been reported to be the virus most frequently associated with multiple viral infections of the respiratory tract of calves. Treatment for BVDV infection is supportive and includes antimicrobials to prevent or treat bacterial pneumonia. General principles of control are discussed under
SHIPPING FEVER PNEUMONIA ENZOOTIC PNEUMONIA OF CALVES AND

( Shipping Fever Pneumonia). Inactivated and modified live vaccines are

available for IM administration. Recently, vaccines containing both the type I and type II genotypes have become available. Modified live vaccines can induce immunosuppression and should be used with caution in highly stressed cattle. Modified live BVDV vaccines are not approved for use in pregnant cattle.

Bovine Viral Diarrhea and Mucosal Disease Complex

Bovine viral diarrhea (BVD) is most common in young cattle (6-24 mo old) and generally is accompanied by typical mucosal lesions; it must be distinguished from other viral diseases that produce diarrhea and mucosal lesions. These include malignant catarrhal fever ( Malignant Catarrhal Fever: Introduction), which usually is a sporadic disease in more mature cattle, and

rinderpest ( Rinderpest: Introduction), which can be seen in outbreak form but is exotic in most countries. Bovine viral diarrhea virus (BVDV), the causal agent of BVD and mucosal disease complex, is classified in the genus Pestivirus in the family Flaviviridae. Although cattle are the primary host for BVDV, several reports suggest most even-toed ungulates are also susceptible. Isolates of BVDV are separated into noncytopathic and cytopathic biotypes based on cytopathic effects observed in infected cell cultures. Noncytopathic BVDV are the predominant viral biotype in nature. Cytopathic BVDV are relatively rare and arise in cattle that are persistently infected with noncytopathic BVDV. The switch in viral biotype is triggered by mutations that often involve recombination of noncytopathic viral RNA with itself, with heterologous viral RNA, or with host cell RNA. Based on viral RNA sequence, there are at least 2 viral genotypes of BVDV that can be further divided into subgenotypes. The viral genotypes are termed BVDV type 1 and BVDV type 2, and both cytopathic and noncytopathic BVDV are represented in each viral genotype. Although the viral genotypes are antigenically related, serologic assays can separate BVDV type 1 from BVDV type 2.

Etiology and Epidemiology:

Serologic surveys indicate that BVDV is distributed worldwide. The prevalence of antiviral antibody in cattle varies among countries and may vary between geographic regions within a country. Prevalence of antiviral antibody may be >90% if vaccination is practiced commonly in a geographic region. Although cattle of all ages are susceptible, most cases of overt clinical disease are seen in cattle that are between 6 mo and 2 yr of age. Cattle that are persistently infected with noncytopathic BVDV serve as a natural reservoir for virus. Persistent infection develops when noncytopathic BVDV is transmitted transplacentally during the first 4 mo of fetal development. The calf is born infected with virus, remains infected for life, and usually is immunotolerant to the resident noncytopathic virus. Transplacental infection that occurs later in gestation results in abortion, congenital malformations, or birth of normal calves that have antibody against BVDV. The prevalence of persistent infection varies among countries and between regions within a country. In some areas, the prevalence of persistent infection in calves may be as high as 1-2% of cattle <1 yr of age. On a given farm, persistently infected cattle are often found in cohorts of animals that are approximately the same age. Persistently infected cattle can shed large amounts of BVDV in their secretions and excretions and readily transmit virus to susceptible herdmates. Clinical disease and reproductive failure often are seen after healthy cattle come in contact with a persistently infected animal. Biting insects, fomites, semen, biologic products, and possibly wild ruminants also can spread BVDV.

Clinical Findings and Lesions:

Disease induced by BVDV varies in severity, duration, and organ systems involved. Acute disease results from infection of susceptible cattle with either noncytopathic or cytopathic BVDV. Acute

BVD, also termed transient BVD, often is an inapparent to mild disease of high morbidity and low mortality. Biphasic fever (~104F [40C]), depression, decreased milk production, transient inappetence, rapid respiration, excessive nasal secretion, excessive lacrimation, and diarrhea are typical signs of acute BVD. Clinical signs of disease usually are seen 6-12 days after infection and last 1-3 days. Transient leukopenia may be seen with onset of signs of disease. Recovery is rapid and coincides with production of viral neutralizing antibody. Gross lesions seldom are seen in cases of mild disease. Lymphoid tissue is a primary target for replication of BVDV, which may lead to immunosuppression and enhanced severity of intercurrent infections. Some isolates of BVDV induce clinically severe disease that manifests as high fever (~107F [4142C]), oral ulcerations, eruptive lesions of the coronary band and interdigital cleft, diarrhea, dehydration, leukopenia, and thrombocytopenia. In thrombocytopenic cattle, petechial

hemorrhages may be seen in the conjunctiva, sclera, nictitating membrane of the eyes; and on mucosal surfaces of the mouth and vulva. Prolonged bleeding from injection sites also occurs. Swollen lymph nodes, erosions and ulcerations of the GI tract, petechial and ecchymotic hemorrhages on the serosal surfaces of the viscera, and extensive lymphoid depletion are associated with severe forms of acute BVD. The duration of overt disease may be 3-7 days. High morbidity with moderate mortality is common. Severity of acute BVD is related to the virulence of the viral strain infecting the animal and does not depend on viral biotype or genotype. In pregnant cattle, BVDV may cross the placental barrier and infect the fetus. The consequences of fetal infection usually are seen several weeks to months after infection of the dam and depend on the stage of fetal development and on the strain of BVDV. Infection of the dam near the time of fertilization may result in reduced conception rates. Infection during the first 4 mo of fetal development may lead to embryonic resorption, abortion, growth retardation, or persistent infection. Congenital malformations of the eye and CNS result from fetal infections that occur between months 4-6 of development. Fetal mummification, premature birth, stillbirth, and birth of weak calves also are seen after fetal infection. Persistent infection is an important sequela of fetal infection with noncytopathic BVDV. Persistently infected calves may appear healthy and normal in size, or they may show stunted growth and be prone to respiratory or enteric ailments. They often have a short lifespan, and death before 2 yr of age is common. Persistently infected cows give birth to persistently infected calves, but most calves sired by a persistently infected bull will not be infected with virus in utero. Lesions attributable to BVDV often are not seen in persistently infected cattle at necropsy. Antibody against BVD seldom is detected in persistently infected cattle in the absence of vaccination or superinfection with an antigenically heterologous BVDV. Persistently infected cattle exposed to BVDV that is antigenically different from their resident noncytopathic virus can produce antiviral antibody. Therefore, screening for persistent infection using the viral neutralization test to identify animals that lack antiviral antibody may not detect some

persistently infected cattle. Mucosal disease is a highly fatal form of BVD that may be acute or chronic and is seen infrequently in persistently infected cattle. Mucosal disease is induced when persistently infected cattle become superinfected with cytopathic BVDV. The origin of the cytopathic BVDV is usually internal, resulting from a mutation of the resident persistent, noncytopathic BVDV. In those cases, the cytopathic virus is antigenically similar to the resident noncytopathic virus. External origins for cytopathic BVDV include other cattle and modified live virus vaccines. Cattle that develop mucosal disease due to exposure to a cytopathic virus of external origin often produce antiviral antibody. Prevalence of persistent infection usually is low, and many persistently infected cattle do not develop mucosal disease, regardless of exposure. Acute mucosal disease is characterized by fever, leukopenia, dysenteric diarrhea, inappetence, dehydration, erosive lesions of the nares and mouth, and death within a few days of onset. At necropsy, erosions and ulcerations may be found throughout the GI tract. The mucosa over Peyers patches may be hemorrhagic and necrotic. Extensive necrosis of lymphoid tissues, especially gut-associated lymphoid tissue, is seen on microscopic examination. Clinical signs of chronic mucosal disease may last several weeks to months and are less severe than those of acute mucosal disease. Intermittent diarrhea and gradual wasting are common. Coronitis and eruptive lesions on the skin of the interdigital cleft cause lameness in some cattle. Lesions found at necropsy are less pronounced than, but similar to, those seen in acute mucosal disease. Often, the only gross lesions seen are focal ulcerations in the mucosa of the cecum, proximal colon, or rectum, and the mucosa over, Peyers patches of the small intestine may appear sunken.

Diagnosis:
BVD is diagnosed tentatively from disease history, clinical signs, and gross and microscopic lesions. Diagnostic laboratory support is required when clinical signs and gross lesions are minimal. Laboratory support also is required in some outbreaks of mucosal disease or clinically severe acute BVD because either disease may appear similar to rinderpest ( Rinderpest: Introduction) or malignant catarrhal fever ( Malignant Catarrhal Fever: Introduction). Laboratory tests for BVDV include virus isolation and assays that detect antibody in serum or detect viral RNA or viral antigen in clinical specimens and tissues. Because antibody against BVDV is prevalent in most cattle populations, a single serologic test is seldom sufficient for diagnosis. A >4-fold increase in antibody titer in paired serum samples obtained 2 more weeks apart is necessary to verify recent infection. Isolation of BVDV from blood, nasal swab specimens, or tissues confirms active infection. Identification of persistent infection requires detection of virus in clinical specimens obtained at least 3 wk apart. At necropsy, tissues of choice for viral isolation include spleen, lymph node, and ulcerated segments of the GI tract. Alternatives to viral isolation include antigen-capture ELISA from blood or serum,

immunohistochemistry to detect viral protein in frozen or fixed tissues, PCR to detect viral RNA in clinical specimens, and PCR or in situ hybridization to detect viral RNA in fresh or fixed tissues. Differentiation of viral genotypes usually is done by PCR or PCR followed by nucleic acid sequencing. Monoclonal antibody binding assays and nucleic acid hybridization assays also differentiate viral genotypes.

Treatment and Control:

Treatment of BVD is limited primarily to supportive therapy. Control is based on sound management practices that include use of biosecurity measures, elimination of persistently infected cattle, and vaccination. Replacement cattle should be tested for persistent infection before entry into the herd. Quarantine or physical separation of replacement cattle from the resident herd for 2-4 wk should be considered, and vaccination of replacement cattle for BVD should be done before commingling with the resident herd. Embryo donors and recipients also should be tested for persistent infection. If vaccination of embryo donors or recipients is warranted, it should be done at least 1 estrous cycle before embryo transfer is performed. Because BVDV is shed into semen, breeding bulls should be tested for persistent infection before use. Artificial insemination should be done only with semen obtained from bulls free of persistent infection. Screening cattle herds for persistent infection is done by virus isolation from serum or buffy coat cells, antigen-capture ELISA from serum or buffy coat, or antigen detection in skin biopsies. Several strategies, based on herd size, type of herd being screened, financial limitations of the herd owner, and testing ability of the diagnostic laboratory being used, are available to screen herds for persistent infection. When identified, persistently infected cattle should be sold for slaughter as soon as possible. Inactivated and modified live virus vaccines are available. They contain a variety of strains of BVDV representing both viral biotypes and viral genotypes 1 and 2. Antigenic diversity among BVDV may affect the efficacy of a given vaccine if the vaccine virus or viruses differ significantly from the challenge virus. Proper and safe immunization of cattle with either inactivated or modified live virus vaccines requires adherence to the manufacturers instructions. Because BVDV is fetotropic and may be immunosuppressive, use of modified live virus vaccines is not recommended in cattle that are pregnant or showing signs of disease. Inactivated viral vaccines may be used in pregnant cattle. Protection conferred by inactivated vaccines may be of short duration, and frequent vaccination may be necessary to prevent disease or reproductive failure. Colostral antibody confers partial to complete protection against disease in most calves for 3-6 mo after birth. Vaccination of neonatal cattle that have acquired colostral antibody may not stimulate a protective immune response, and revaccination at 5-9 mo of age may be necessary.

Other Bovine Respiratory Viruses

Several other viruses may potentially be involved in BRD. Bovine herpesvirus-4 has been implicated in several diseases, including BRD. Bovine adenovirus has been associated with a wide spectrum of diseases, with bovine adenovirus type 3 being the serotype most often associated with BRD. Two serotypes of bovine rhinovirus have been recognized to cause respiratory tract infections in cattle. Other viruses reported to be associated with BRD include bovine reovirus, enterovirus, and coronavirus. There is growing evidence that bovine coronavirus may have a more important role in BRD than previously recognized. These viruses have a role similar to the other viruses previously discussed in that, in combination with other stressors, they can serve as initiators of bacterial pneumonia. Vaccines are not available for prevention of these viral respiratory diseases.

Bacterial Pneumonia: Overview

Pneumonic Pasteurellosis Mycoplasmal Pneumonia Chlamydial Pneumonia Contagious Bovine Pleuropneumonia

Pneumonic Pasteurellosis
Etiology:
Mannheimia haemolytica , serotype 1 is the bacterium most frequently isolated from the lungs of cattle with BRD. Although less frequently cultured, Pasteurella multocida is also an important cuase of bacterial pneumonia. Histophilus somni is being increasingly recognized as an important pathogen in BRD; these bacteria are normal inhabitants of the nasopharynx of cattle (Histophilosis : Introduction). When pulmonary abscessation occurs, generally in association with chronic pneumonia, Arcanobacterium pyogenes is frequently isolated. Under normal conditions, M haemolytica remains confined to the upper respiratory tract, in particular the tonsillar crypts, and is difficult to culture from healthy cattle. After stress or viral infection, the replication rate of M haemolytica in the upper respiratory tract increases rapidly, as does the likelihood of culturing the bacterium. The increased bacterial growth rate in the upper respiratory tract followed by inhalation and colonization of the lungs may occur due to suppression of the hosts defense mechanism related to environmental stressors or viral infections. It is during this log phase of growth of the organism in the lungs that virulence factors are elaborated by M haemolytica , such as an exotoxin that has been referred to as leukotoxin.

The interaction between the virulence factors of the bacteria and host defenses results in tissue damage with characteristic necrosis, thrombosis, and exudation and the development of pneumonia. The pathogenesis of pneumonia caused by P multocida is poorly understood. This organism may opportunistically colonize lungs with chronically damaged respiratory defenses, such as occurs with enzootic calf pneumonia or existing lung lesions of feedlot cattle, and cause a purulent bronchopneumonia. H somni may invade the lung and cause pneumonia following damage to the respiratory defenses. This organism is capable of systemic spread from the lung to the brain, myocardium, synovium, and pleural and pericardial surfaces; often death can occur later in the feeding period from involvement of these additional organ systems.

Clinical Findings:
Clinical signs of bacterial pneumonia are often preceded by signs of viral infection of the respiratory tract. With the onset of bacterial pneumonia, clinical signs increase in severity and are characterized by depression and toxemia. Fever (104-106F [40-41C]); serous to mucopurulent nasal discharge; moist cough; and a rapid, shallow respiratory rate may be noted. Auscultation of the cranioventral lung field reveals increased bronchial sounds, crackles, and wheezes. In severe cases, pleurisy may develop, characterized by an irregular breathing pattern and grunting on expiration. The animal will become unthrifty in appearance if the pneumonia becomes chronic, which is usually associated with the formation of pulmonary abscesses. Lesions: M haemolytica causes a severe, acute, hemorrhagic fibrinonecrotic pneumonia. The pneumonia has a bronchopneumonic pattern. Grossly, there are extensive reddish black to grayish brown cranioventral regions of consolidation with gelatinous thickening of interlobular septa and fibrinous pleuritis. There are extensive thromboses, foci of lung necrosis, and limited evidence of bronchitis and bronchiolitis. P multocida is associated with a less fulminating fibrinous to fibrinopurulent bronchopneumonia. In contrast to M haemolytica , P multocida is associated with only small amounts of fibrin exudation, some thromboses, limited lung necrosis, and suppurative bronchitis and bronchiolitis. H somnus infection of the lungs results in purulent bronchopneumonia that may be followed by septicemia and infection of multiple organs. Occasionally, H somni is associated with extensive pleuritis. Pulmonary abscessation can occur as the pneumonia becomes chronic. Abscesses develop in ~3 wk but do not become encapsulated until 4 wk. Arcanobacterium pyogenes is frequently cultured from these abscesses.

Diagnosis:
Generally, neither serologic testing nor direct bacterial detection are performed, and diagnosis relies on bacterial culture. Because the bacteria involved are normal inhabitants of the upper respiratory tract, the specificity of culture can be increased by collecting antemortem specimens

from the lower respiratory tract by tracheal swab, transtracheal wash, or bronchoalveolar lavage. Lung specimens can be collected for culture at postmortem. If possible, specimens for culture should be collected from animals that have not been treated with antibiotics to permit determination of antimicrobial sensitivity patterns.

Treatment:
Early recognition by trained personnel skilled at detecting the early symptoms of disease and treatment with antibiotics are essential for successful therapy. Antibiotics effective against the 3 gram-negative bacteria most often involved in BRD should be selected. Responses to treatment should be monitored and periodic culture and sensitivity should be performed to aid in the selection of antibiotics. Long-acting antibiotics have been specifically developed for treating bacterial pneumonia in cattle. It is important that antibiotic therapy extend beyond apparent recovery to avoid relapses. Mass medication in feed or water is of limited value because sick animals do not eat or drink enough to achieve inhibitory blood levels of the antibiotic, and many of these oral antibiotics are poorly absorbed in ruminants. NSAID have been shown to be a beneficial ancillary therapy in treating bacterial pneumonia. If pulmonary abscessation has occurred, it is difficult to achieve resolution with antimicrobials and culling of the animal should be considered.

Control:
General principles of control are discussed under
PNEUMONIA ENZOOTIC PNEUMONIA OF CALVES AND SHIPPING FEVER

( Enzootic Pneumonia of Calves and Shipping Fever Pneumonia: Overview ). The value

of M haemolytica and P multocida bacterins is questionable, and some reports indicate they may even exacerbate the disease. Newer vaccines, which include live culture and subunit vaccines ( leukotoxin), show much more promise for disease prevention. Vaccination should be done 3 wk before transport to the feedlot and can be repeated on arrival. In dairy calves, vaccination of the dam may be of benefit by providing passive immunity to the calf. H somni bacterins are available, and there is some evidence that they are effective in control of BRD.

Mycoplasmal Pneumonia

The exact role of mycoplasmas and ureaplasmas in BRD requires better definition. Mycoplasmas can be recovered from the respiratory tract of nonpneumonic calves, but the frequency of isolation is greater in those with respiratory tract disease. Mycoplasmas commonly recovered from the lungs of pneumonic calves include Mycoplasma dispar , M bovis , and Ureaplasma spp . M bovis has been associated with otitis media in young calves and polyarthritis in feedlot cattle. Experimental infections usually result in inapparent to mild signs of respiratory disease. This does not preclude a synergistic role for mycoplasmas in conjunction with viruses and bacteria in BRD. Lesions include focal pulmonary abscessation and necrosis with histologic lesions of peribronchial

and peribronchiolar lymphoid cuffing and alveolitis. Culture of these organisms requires special media and conditions; growth of the organisms may take up to a week. Mycoplasmas are sensitive to several antibiotics, including the tetracyclines and macrolides.

Contagious Bovine Pleuropneumonia

This highly contagious pneumonia is generally accompanied by pleurisy. It is present in Africa, the Iberian peninsula, and parts of India and China; minor outbreaks occur in the Middle East. The USA has been free of the disease since 1892, the UK since 1898, and Australia since 1973.

Etiology:
The causal organism is Mycoplasma mycoides mycoides small colony type. (See also
CAPRINE PLEUROPNEUMONIA, CONTAGIOUS

Contagious Caprine Pleuropneumonia.) Susceptible cattle become

infected by inhaling droplets disseminated by coughing in affected cattle. Goats and sheep are not important in the epidemiology. Septicemia produces lesions in the kidneys and placenta, which can be sources of infection. Transplacental infection of the fetus can occur. Viability of the organism in the environment is poor. The incubation period varies, but most cases occur 38 wk after exposure. In some localities, susceptible herds may show up to 100% morbidity, but much lower infection rates (~10%) associated with clinical signs are more common. Mortality is likely to be ~50%. Of recovered animals, 25% may become carriers with chronic lung lesions in the form of sequestra of variable size. Because carriers may not be detectable clinically or serologically, they constitute a serious problem in control programs. Breed susceptibility, management systems, and general health of the animal are important factors that influence the infection.

Clinical Findings:
In acute cases, signs include fever up to 107F (41.5C), anorexia, and painful, difficult breathing. In hot climates, the animal often stands by itself in the shade, its head lowered and extended, its back slightly arched, and its elbows turned out. Percussion of the chest is painful; respiration is rapid, shallow, and abdominal. If the animal is forced to move quickly, the breathing becomes more distressed and a soft, moist cough may result. The disease progresses rapidly, animals lose condition, and breathing becomes very labored, with a grunt at expiration. The animal becomes recumbent and dies after 1-3 wk. Chronically affected cattle usually exhibit signs of varying intensity for 3-4 wk, after which the lesions gradually resolve and the animals appear to recover. Subclinical cases occur and may be important as carriers. Lesions: The thoracic cavity may contain up to 10 L of clear yellow or turbid fluid mixed with fibrin flakes, and the organs in the thorax are often covered by thick deposits of fibrin. Varying amounts of one or both lungs may be involved, the affected portion being enlarged and solid.

On section of the lung, the typical marbled appearance of pleuropneumonia is evident due to the widened interlobular septa and subpleural tissue that encloses gray, yellow, or red consolidated lung lobules. Microscopically, this is a severe, acute, fibrinous pneumonia with fibrinous pleurisy, thrombosis of pulmonary blood vessels, and areas of necrosis of lung tissue; the interstitial tissue is markedly thickened by edema fluid containing much fibrin. In chronic cases, the lesion has a necrotic center sequestered in a thick, fibrous capsule, and there may be fibrous pleural adhesions. Organisms may survive in these sequestra, and the animals become carriers.

Diagnosis:
Diagnosis is based on clinical signs, complement fixation test, and necropsy. Confirmation is by histopathology, detection of organisms in pleural fluid using darkfield microscopy, isolation of the organism from lung or pleural fluid, or demonstration of specific antigens in lung tissue by immunodiffusion or immunofluorescence and hyperimmune antigalactan serum. Subclinical disease is detected by complement fixation test. As soon as an outbreak is suspected, slaughter and necropsy of presumptively infected cattle is advisable.

Control:
The disease is reportable by law in many countries from which it has been eradicated by slaughter of all infected and exposed animals. In countries where cattle movement can readily be restricted, the disease can be eradicated by quarantine, blood testing, and immunization with attenuated vaccine (eg, T1/44 strain). Where cattle cannot be confined, the spread of infection can be limited by vaccination. Tracing the source of infected cattle detected at abattoirs, blood testing, and imposition of strict rules for cattle movement also can aid in control of the disease in such areas. Treatment is recommended only in endemic areas because the organisms may not be eliminated, and carriers may develop. Tylosin (10 mg/kg, IM, be effective.
BID

for 6 injections) is reported to

Chlamydial Pneumonia: Introduction

Chlamydiae have been identified in various parts of the world as a cause of enzootic pneumonia in cats, calves, mice, sheep, piglets, foals, and goats. In cats, pneumonia may occur as a rare sequela of the more common chlamydial conjunctivitis and rhinitis. The main clinical sign of zoonotic chlamydiosis in humans is pneumonia, generally contracted from pet birds.

Etiology and Epidemiology:

The causative agent is Chlamydophila (Chlamydia) psittaci . Some respiratory isolates from calves have properties of immunotypes 1 and 6 and are similar to strains recovered from intestinal infections ( Intestinal Chlamydial Infections: Introduction) and abortions of cattle and sheep

(Abortion in Large Animals: Introduction). Immunotype 6 has been recovered from pneumonic lungs of calves and pigs. Thus, the GI tract of carrier animals should be considered as an important site in the pathogenesis of chlamydial infections and as a potential source of the organisms. Infection most commonly occurs via inhalation of organisms from fecal carriers or other respiratory cases. Chlamydial pneumonia has affected calves under range conditions as well as on dairy farms. The disease in sheep is most frequently seen in feeder lambs assembled from different sources in feedlots or on irrigated pastures. Stressed lambs under these conditions are frequently subject to various secondary bacterial infections, which can result in higher mortality and morbidity rates than are seen in uncomplicated chlamydial respiratory infections.

Clinical Findings:
Calves, lambs, and goats with chlamydial pneumonia are usually febrile, lethargic, and dyspneic. They develop a serous and later mucopurulent nasal discharge with a dry hacking cough. Calves of weaning age are affected most frequently, but older cattle may also show signs. Lesions: The acute pulmonary lesion is bronchointerstitial pneumonia. The anteroventral parts of the lungs are affected but, in severe cases, entire lobes can be involved. The dry cough is attributed to tracheitis. Microscopic changes in the lungs include suppurative bronchitis and alveolitis progressing to type II pneumocyte hyperplasia and interstitial thickening due to an ingress of mixed inflammatory cells. Lymphocytic aggregates are frequently seen around airways and pulmonary vessels.

Diagnosis:
Neither clinical signs nor lesions allow a definitive diagnosis of chlamydial pneumonia because they are not sufficiently different from those seen in the bovine or ovine respiratory disease complex. Diagnosis requires isolation of chlamydiae from affected tissues in tissue culture or chick embryo. Chlamydial inclusion bodies may be detected in affected tissues. Diagnosis may be supported by fluorescent antibody tests and serologic assays performed on acute and convalescent samples. Predominantly, IgG2 antibodies are induced by chlamydial infections in cattle. Subclinical chlamydial infections occur as well.

Prevention and Treatment:

Vaccines are not available. Several antimicrobials (eg, penicillin, erythromycin, tylosin, and tetracyclines) can interfere with chlamydial replication, but tetracycline is generally the drug of choice. Treatment must start as early as possible and continue for at least 5-7 days.

Interstitial Pneumonia: Overview

This classification represents a group of respiratory diseases that are characterized by an acute onset of respiratory distress and a combination of lung lesions that include pulmonary edema and congestion, interstitial emphysema, alveolar epithelialization, and hyaline membrane formation. Lungworm infection in cattle can also result in an atypical interstitial pneumonia ( Lungworm Infection: Introduction).

Lungworm Infection: Introduction

(Verminous bronchitis, Verminous pneumonia)

An infection of the lower respiratory tract, usually resulting in bronchitis or pneumonia, can be caused by any of several parasitic nematodes, including Dictyocaulus viviparus in cattle and deer; D arnfieldi in donkeys and horses; D filaria , Protostrongylus rufescens , and Muellerius capillaris in sheep and goats; Metastrongylus apri in pigs; Oslerus (Filaroides) osleri in dogs; and

Aelurostrongylus abstrusus and Capillaria aerophila in cats. Other lungworm infections occur but are less common. The first 3 lungworms listed above belong to the superfamily Trichostrongyloidea and have direct life cycles; the others belong to the Metastrongyloidea and, except for O osleri and C aerophila , have indirect life cycles. Some nematodes that inhabit the right ventricle and pulmonary circulation, eg, Angiostrongylus vasorum and Dirofilaria immitis , both found in dogs in certain areas of the world, may be associated with pulmonary disease. Clinical signs relating to a cardiac or a pulmonary syndrome or to a combination of both may occur. Diseases caused by the 3 Dictyocaulus spp are of most economic importance. The cattle lungworm D viviparus is common in northwest Europe and is the cause of severe outbreaks of husk or hoose in young (and more recently, older) grazing cattle. The lungworm of goats and sheep, D filaria , is comparatively less pathogenic but does cause losses, especially in Mediterranean countries, although it is also recognized as a pathogen in Australia, Europe, and North America. D arnfieldi can cause severe coughing in horses and, because patency is unusual in horses (but not in donkeys), differential diagnosis with disease due to other respiratory diseases can be difficult. M capillaris is prevalent worldwide and, while usually nonpathogenic in sheep, can cause severe signs in goats. Other lungworm infections cause occasional sporadic infections in many animal species in many countries.

Epidemiology:
Dictyocaulus spp Adult females in the bronchi lay larvated eggs that hatch either in the bronchi ( D viviparus ), or in host feces ( D arnfieldi ) after being coughed up and swallowed. The larvae can become infective in feces on pasture after a minimum of 1 wk in warm, moist conditions, but typically in summer in temperate northern climates will require 2-3 wk. Once infective, the larvae can be further dispersed from fecal pats mechanically or by the sporangia of the fungus Pilobolus. A proportion of infective larvae will survive on pasture throughout the winter until the following year but, in very cold conditions, most will become nonviable. The principal source of new infections each year is from infected carrier animals, with overwintered larvae providing a secondary but not unimportant contribution in some countries. In the case of D arnfieldi , donkeys are the prime source of pasture contamination for horses. Because D viviparus infection in cattle is the most economically important, it has been most investigated and many of the observations from it are applicable to the other species. Clinical disease usually develops on first exposure to sufficient infective larvae; the severity of disease and stimulation of an immune response is related to the number of larvae ingested. In cattle and sheep, this usually occurs during their first season at pasture; however, an increase in the number of older cattle affected has been reported and is attributed to the efficiency of some prophylactic anthelmintic regimens, which prevent exposure at an earlier age. Because transmission of infection to horses requires infected donkeys, first infections can occur at any age in that species. Once infected, adults generally become immune to further disease, but a proportion will contract subclinical infections during which they act as a source of further larval contamination. Occasionally, when previously infected adults or groups that have not been exposed to reinfection for >1 yr, and in which immunity may have waned, are exposed to an overwhelming level of infection, clinical disease may recur. In areas in which cattle are housed during winter and first grazing season calves turned out in late April or May, the first infections can be seen between mid June and late July, but most severe infections develop in previously unexposed calves after multiplication of a second generation of infective larvae on pasture between August and early October. Other SpeciesBecause other lungworm species either require an intermediate host or are found in nonherd animals, disease caused by them is more sporadic. Metastrongylus apri in pigs requires an earthworm as intermediate host; thus, infection is confined to pigs with access to pasture and may become more common as a result of organic farming methods. Muellerius capillaris and Protostrongylus rufescens in sheep and goats require slugs or snails as intermediate hosts, which must be eaten for infection to occur. Aelurostrongylus abstrusus is normally transferred to cats after ingestion of a paratenic host such as a bird or rodent that has previously eaten the slug or snail. Adults of Oslerus osleri live in nodules in the trachea of dogs, and larvated eggs laid by adults hatch there. Pups become infected from saliva or feces of an infected dog, in the former case by being licked by their dams. Capillaria aerophila in cats has a direct cycle, with infective eggs being ingested with food or water.

Pathogenesis:
The pathogenic effect of lungworms depends on their location within the respiratory tract, the number of infective larvae ingested, and the animals immune state. During the prepatent phase of Dictyocaulus viviparus infection, the main lesion is blockage of bronchioles by an infiltrate of eosinophils in response to the developing larvae; this results in obstruction of the airways and collapse of alveoli distal to the block. Clinical signs are moderate unless large numbers of larvae are present, in which case the animal may die in the prepatent phase with severe interstitial emphysema. In the patent phase, the adults in the segmental and lobar bronchi cause a bronchitis, with eosinophils, plasma cells, and lymphocytes in the bronchial wall; a cellular exudate, frothy mucus, and adult nematodes are found in the lumen. The bronchial irritation causes marked coughing, and the entire reaction leads to increased airway resistance. A major component of the patent stage is development of a chronic, nonsuppurative, eosinophilic, granulomatous pneumonia in response to eggs and first-stage larvae aspirated into alveoli and bronchioles. This is usually in the caudal lobes of the lungs and is severe when widespread; in combination with the bronchitis, death may result. Interstitial emphysema, pulmonary edema, and secondary bacterial infection are complications that increase the likelihood of death. Survivors may suffer considerable weight loss. If the animal survives until the end of patency (2-3 mo for D viviparus ), most or even all of the adult worms are expelled, and the cellular exudate resolves over the ensuing 4 wk. Most recover unless secondary infection develops in the damaged lungs during the postpatent phase. In a few animals, clinical signs are exacerbated in the postpatent phase due to development of a diffuse, proliferative alveolitis characterized by hyperplasia of the type II alveolar epithelial cells. The cause is unknown, but it is observed much less in cattle treated with anthelmintics with a persistent action against D viviparus such as the macrocyclic lactones ivermectin, doramectin, eprinomectin, and moxidectin. D filaria is similar to D viviparus , but interstitial emphysema is not a common complication. Bronchial lesions predominate in D arnfieldi infections; when an alveolar reaction occurs, as in donkeys or foals, there are lobular areas of overinflation due to intermittent obstruction of small bronchi. The pathogenic effect of the other lungworms has a similar basis, but frequently such severe clinical signs are not produced, perhaps due to a more restricted localization in the lungs and less severe infections. The patent phase and the associated lesions last >4 mo for some lungworms ( M apri and A abstrusus ) but can be >2 yr ( M capillaris ). The lesions in pigs with M apri are a combination of localized bronchitis and bronchiolitis with overinflation of related alveoli, usually at the edges of the caudal lobes. In pigs, hypertrophy and hyperplasia of bronchiolar and alveolar duct smooth muscle with marked mucous cell hyperplasia are striking features. Near the end of the patent period (as adult worms are killed), gray-green lymphoid nodules (2-4 mm) are formed; fragments of dead worms may be found microscopically in these nodules composed of lymphocytes and plasma cells surrounding a central zone of eosinophils.

In M capillaris and P rufescens infections, chronic, eosinophilic, granulomatous pneumonia seems to predominate; the reaction is in the bronchioles and alveoli that contain the parasites, their eggs, or larvae. They are surrounded by macrophages, giant cells, eosinophils, and other

immunoinflammatory cells, which produce gray or beige plaques (1-2 cm) subpleurally in the dorsal border of the caudal lung lobes. Small (1-2 mm), greenish, nodular lesions may also develop. The effect of these lesions in sheep is minor, perhaps because of the predominantly subpleural location. This infection represents the lower end of the pathogenic spectrum for lungworms. In cats, A abstrusus produces nodular areas of granulomatous pneumonia in the caudal lobes that, if sufficiently generalized, can be clinically significant and occasionally fatal; a notable feature is the hypertrophy and hyperplasia of the smooth muscle in the media of pulmonary arteries and arterioles. The nodules of O osleri , found in the mucous membrane of the trachea and large bronchi, can produce extreme airway irritation and persistent coughing. Capillaria aerophila infection causes chronic tracheitis and bronchitis. In adult animals not previously exposed to infection, the lesions and pathogenesis are the same as in young animals. However, in adults with some degree of immunity, reexposure to the parasite (eg, husk in adult cattle) can result in different lesions. Despite the immune response, many larvae reach the lungs before they are killed in the terminal bronchioles and alveoli. Larvae that are not killed in the terminal bronchioles may reach the bronchi and cause a bronchitis characterized by marked eosinophilic infiltration of the bronchial walls and greenish yellow exudate in the lumen comprising eosinophils, other inflammatory cells, and parasitic debris. The reaction associated with this process can lead to severe clinical signs if the nodules are numerous and the eosinophilic bronchitis extensive; this is responsible for the reinfection phenomenon.

Clinical Findings:
Signs of lungworm infection range from moderate coughing with slightly increased respiratory rates to severe persistent coughing and respiratory distress and even failure. Reduced weight gains, reduced milk yields, and weight loss accompany many infections in cattle, sheep, and goats. Patent subclinical infections can occur in all species. The most consistent signs in cattle are tachypnea and coughing. Initially, rapid, shallow breathing is accompanied by a cough that is exacerbated by exercise. Respiratory difficulty may ensue, and heavily infected animals stand with their heads stretched forward and mouths open, and drool. The animals become anorectic and rapidly lose condition. Lung sounds are particularly prominent at the bronchial bifurcation. In adult dairy cattle, milk yield drops severely, and abnormal lung sounds are heard over the caudal lobes. The reinfection phenomenon in adult dairy cattle is usually seen in the fall; although less severe than in initial infections, the signs are widespread coughing and tachypnea and a marked drop in milk yield. The signs in sheep and goats infected with D filaria are similar to those in cattle. Pulmonary signs usually are not associated with M capillaris or P rufescens in sheep, but the former can affect goats

similarly to D filaria . D arnfieldi is associated with coughing, tachypnea, and unthriftiness in older horses, but few if any signs in foals or donkeys. The main clinical sign of M apri in pigs is a persistent cough that may become paroxysmal. Coughing and dyspnea occur in cats and dogs with A abstrusus and O osleri infections, respectively. Fatalities are relatively uncommon with these lungworms, although they do occur in kittens.

Diagnosis:
Diagnosis is based on clinical signs, epidemiology, presence of first-stage larvae in feces, and necropsy of animals in the same herd or flock. Bronchoscopy and radiography may be helpful. Larvae are not found in the feces of animals in the prepatent or postpatent phases and usually not in the reinfection phenomenon. ELISA tests are available in some laboratories, but because the antigens used are derived from adult worms, the test is mainly of use in detecting cattle that have not been exposed rather than as a differential diagnosis tool in acute respiratory disease. In the early stages of an outbreak, larvae may be few in number. First-stage larvae or larvated eggs can be recovered using most fecal flotation techniques with the appropriate salt solutions. Bronchial lavage can reveal D arnfieldi infections in horses. A convenient method for recovering larvae is a modification of the Baermann technique in which large fecal samples (25-30 g) are wrapped in tissue paper or cheese cloth and suspended or placed in water contained in a beaker. The water at the bottom of the beaker is examined for larvae after 4 hr; in heavy infections, larvae may be present within 30 min. In domestic pets and horses, because of the relative infrequency of infection, diagnosis may be made only after failure of antibiotic therapy to ameliorate the condition. Adults of Dictyocaulus spp and M apri are readily visible in the bronchi during the patent phases of infection. However, examination of smears from bronchial mucus or histologic sections from lesions may be necessary to confirm the diagnosis during other stages of lungworm infection (and also for other lungworms).

Capillaria aerophila, egg

Dictyocaulus spp, equine lung

Dictyocaulus viviparus

Filaroides osleri larva

Nodules of Filaroides (Oslerus) osleri

Bronchoscopy can be used to detect nodules of O osleri or to collect tracheal washings (dogs and horses) to examine for eggs, larvae, and eosinophils.

Necropsy should include examination of the trachea, particularly at the bifurcation, for O osleri and the lesions they induce.

Treatment:
Several drugs are useful (see Table: Recommended and Treatments and for Lungworms). The

benzimidazoles

(fenbendazole,

oxfendazole,

albendazole),

macrocyclic

lactones

(ivermectin, doramectin, eprinomectin, and moxidectin) are frequently used in cattle and are effective against all stages of D viviparus . These drugs are also effective against lungworms in sheep, horses, and pigs. Levamisole is used in cattle, sheep, and goats but treatment may need to be repeated 2 wk later as it is less effective against larvae during the early stages. Fenbendazole has been used successfully in cats for A abstrusus . O osleri in dogs is a problem, but there is evidence that fenbendazole and albendazole are effective if treatment is prolonged. C aerophila in cats is similarly difficult, but three 5-day cycles of levamisole at 9-day intervals has been reported to be successful. Animals at pasture should be moved inside for treatment, and supportive therapy may be needed for complications that can arise in all species.

Control:
Lungworm infections in herds or flocks are controlled primarily by vaccination or anthelmintics. Oral

vaccines are available in Europe for D viviparus (northeastern areas) and D filaria (southeast). Two doses of irradiated infective larvae are given 4 wk apart at least 2 wk before the start of grazing or exposure to probable infection. Used properly, they prevent clinical disease, but some vaccinated animals may become mildly infected to the extent that larvae are excreted to perpetuate further infection. Anthelmintic prophylaxis has become feasible with the advent of anthelmintics with prolonged activity (eg, ivermectin, doramectin, moxidectin, eprinomectin) and sustained-release intraruminal boluses containing oxfendazole or fenbendazole. With persistent anthelmintics, 2 or 3 treatments during the grazing season, the timing of which depends on local grazing practice and epidemiology, are effective and may, by disrupting developing infections, stimulate immunity to the parasite. Boluses provide continuous anthelmintic protection but, as with the use of multiple treatments, they delay exposure to D viviparus until the animal is adult, when infection (albeit usually less severe) can occur. However, these methods have become popular in that GI parasites are controlled simultaneously. Other more sporadic infections can be controlled more easily by management, eg, avoidance of grazing horses with donkeys, indoor husbandry of pigs, and by not mixing sheep and goats on the same grazing.

Acute Bovine Pulmonary Emphysema and Edema

(Fog fever, Bovine atypical interstitial pneumonia)

Acute bovine pulmonary emphysema and edema (ABPEE) is one of the more common causes of acute respiratory distress in cattle, particularly adult beef cattle, and is characterized by sudden onset, minimal coughing, and a course that ends fatally or improves dramatically within a few days. It is a disease involving groups of cattle; morbidity may be >50%, although usually only a small minority develops severe respiratory distress. Typically, ABPEE occurs in fall, 5-10 days after change to a better, often lush, pasture. A similar condition has been reported on a wide variety of grasses, alfalfa, rape, kale, and turnip tops.

Etiology:
Metabolites of the naturally occurring amino acid L-tryptophan probably are responsible for many outbreaks. In the rumen, L-tryptophan is degraded to indoleacetic acid, which can be converted to 3-methylindole by some ruminal microorganisms. 3-methylindole is absorbed into the bloodstream and is the source of the pneumotoxicity after metabolism by the mixed function oxidase system, which is very active in the lungs. Apparently, the level of L-tryptophan in crops is most likely to be high in lush, rapidly growing pastures, particularly (but not exclusively) in the fall.

Clinical Findings:
ABPEE is most common in heavy beef cows but may occur in either sex and in dairy or beef cattle under similar management conditions. Nursing calves are unaffected. Outbreaks usually develop within 5-10 days of a change to better grazing and rarely occur in animals that have been on a field >3 wk. Mild cases may go unnoticed. Cattle are subdued but still alert; there is tachypnea and hyperpnea, but auscultation is usually unrewarding. Such cattle usually recover spontaneously within days. Severely affected cattle show extensive respiratory distress with mouth breathing, extension of the tongue, and drooling. A loud expiratory grunt is common, but coughing is unusual. In the early stages, auscultation reveals surprisingly soft respiratory sounds. Mild exercise increases dyspnea and may precipitate death. If death does not occur, the animals improve dramatically and resume eating by the third day. At this stage, auscultation reveals harsh respiratory sounds and, in some animals, dorsal (emphysematous) crackles. Some cattle have subcutaneous emphysema extending along the back from the withers. Full clinical recovery may require 3 wk. Lesions: In affected cattle that have died or been slaughtered in extremis, the lungs are heavy and do not collapse normally. They are widely affected with various degrees of firmness; there is extensive edema and emphysema, often with the formation of large air-filled bullae in interlobular and subpleural regions. Submucosal hemorrhages are often present on the larynx and in the trachea and larger bronchi. Histologically, the lesion is characterized by congestion, alveolar edema, hyaline membrane formation, and areas of early alveolar epithelial hyperplasia of type II pneumocytes; occasionally, areas of bronchiolar necrosis may be found. The emphysema is often dramatic and is limited to interstitial fascia where it is accompanied by edema. In animals that are slaughtered after 3 days of illness, the lungs are still heavy and do not collapse normally. They are pinkish gray and of increased firmness; edema and emphysema are inconspicuous or absent. Histologically, widespread alveolar epithelial hyperplasia characteristic of a diffuse, acute, proliferative alveolitis is seen.

Diagnosis:
Diagnosis is based on history, signs, and lesions. Because the syndrome is not specific with regard to cause, evidence must be obtained from management factors such as change in pasture.

Treatment:
Severely affected animals have so little pulmonary reserve that any driving or handling must be done with caution to prevent immediate deaths. Removal of cattle from the offending pastures may not prevent the development of new cases for the next 4-7 days. No treatment has been identified that will reverse the fully developed lesions of ABPEE.

Control:

One approach to control is dietary management, including the following options: 1) avoiding pastures likely to induce ABPEE, 2) feeding hay before turn out on pasture and limiting exposure time on suspect pastures, 3) limiting grazing time and gradually increasing exposure to the pasture over time, 4) using pastures before they become lush, 5) delaying use of lush pastures until after a hard frost, 6) initially grazing pastures with less susceptible stock (cattle <15 mo of age or sheep), or 7) using strip grazing. A medical approach to control involves feeding monensin or lasalocid, which inhibit the bacteria that convert L-tryptophan to 3-methylindole. Treatment with monensin can be started 1 day before introduction to pasture, whereas lasalocid requires a 6-day pretreatment period. These drugs are of no benefit after onset of clinical signs.

Anaphylaxis

Anaphylaxis or Type I hypersensitivity reactions in cattle can result in an atypical interstitial pneumonia. The lung is a major target organ in cattle for Type I hypersensitivity. Clinical signs are those of acute respiratory distress. Cattle that die of anaphylaxis may have lesions consistent with those described for atypical interstitial pneumonia. Treatment is the administration of epinephrine; supportive treatment includes anti-inflammatory therapy with corticosteroids or NSAID. If pharyngeal or laryngeal edema is present, a tracheostomy may be indicated.

Hypersensitivity Pneumonitis
(Extrinsic allergic alveolitis, Farmers lung disease)

A condition that appears to be similar to farmers lung disease in humans occurs in both acute and chronic forms in adult cattle. The human and bovine forms of the disease may coexist on problem farms due to common exposure to dust from moldy hay.

Etiology:
The disease occurs when sensitized individuals inhale antigens from thermophilic actinomycetes, commonly the spores of Micropolyspora faeni . The actinomycetes proliferate in vast numbers in hay, grain, or other vegetable material that has overheated to ~150F (65C) after damp storage (30-40% moisture content). Dust that contains large numbers of spores is released when this moldy hay is shaken. The small size (1 m) of the spores allows them to reach the smallest airways and alveoli to provoke a reaction that has been termed a hypersensitivity pneumonitis; this is considered to be predominantly a Type III hypersensitivity reaction, although a Type IV hypersensitivity component is suspected (see Diseases: Introduction et seq).
IMMUNOPATHOLOGIC DISEASES,

Immunopathologic

Affected herds exist in areas where significant rainfall usually occurs during the haymaking season, suggesting that a clinical problem may arise only after repeated sensitization and challenge from the spores. Clinical disease tends to arise during the latter half of the winter feeding period and usually only when moldy hay is fed indoors. Under such circumstances, serum antibodies (usually detected by immunodiffusion) to M faeni are widespread among adult cattle by the end of each winter feeding period, and many apparently normal cattle are seropositive. By contrast, few adult cattle are seropositive on other farms on which good hay or grass silage is fed.

Clinical Findings:
Cattle may succumb to the acute form of the disease over a period of weeks. Usually, only severe acute cases are noticed. There is respiratory distress, anorexia, and agalactia in animals 5 yr old; coughing and pyrexia also occur, and adventitious sounds are occasionally heard on auscultation. Death is rare. The chronic disease usually has a higher morbidity; in most instances, the signs are weight loss, poor production, and persistent coughing. Affected cattle are fairly bright and eat reasonably well, but tachypnea, hyperpnea, and coughing are widespread. Auscultation may reveal cranioventral crackles and sometimes, in more severe cases, scattered rhonchi. Exercise intolerance may be seen, and congestive cardiac failure can develop if pulmonary fibrosis is widespread. Lesions: The macroscopic lesions are often unremarkable; usually, there is mild peripheral lobular overinflation with diffusely scattered, small, gray, subpleural spots. Although transient pulmonary edema may be a feature of severe acute cases, the histologic lesions that are consistently found are interalveolar cellular infiltration, epithelioid granulomata, and bronchiolitis obliterans. In some chronic cases, small foci of alveolar epithelial hyperplasia and metaplasia with interstitial fibrosis are found. These areas may extend to include most, if not all, of the lung substance to produce cases clinically indistinguishable from diffuse fibrosing alveolitis ( see Diffuse Fibrosing Alveolitis). Circumstantial evidence suggests that some cases of diffuse fibrosing alveolitis are the end stage of hypersensitivity pneumonitis.

Treatment and Control:

Because it is often impossible to completely shield cattle from further challenge, most recover only partially after dexamethasone treatment (1 mg/5-10 kg body wt). However, improvement is usually marked when cattle are turned out in the spring. Prevention is difficult in areas where hay is likely to be wet during the curing process and it is not possible to alter the feeding regimen.

Acute Respiratory Distress Syndrome of Feedlot Cattle

An acute respiratory distress syndrome has been described in feedlot cattle with clinical signs and pathologic findings of an atypical interstitial pneumonia. The syndrome occurs sporadically and the etiology remains undefined. Bovine respiratory syncytial virus, abnormal production of 3methylindole in the rumen, dusty conditions, and pre-existing lesions of chronic cranioventral bacterial pneumonia have been suggested as causes or contributing factors. Clinical signs include respiratory distress characterized by tachypnea and dyspnea, and affected cattle may be found dead if clinical signs are unobserved. Lesions are those of atypical interstitial pneumonia with prominent emphysema and edema in the lungs. Treatment protocols have not been defined, and thus would be symptomatic and supportive. Management strategies suggested include vaccinating for bovine respiratory syncytial virus, controlling dust in the feedlot, and avoiding abrupt dietary changes.

Toxic Gases

Nitrogen dioxide is a major component of silo gas; in humans, the disease associated with exposure to NO2 is termed silo fillers disease. Exposure of cattle results in respiratory distress and necropsy findings of atypical interstitial pneumonia. Treatment is empirical and includes diuretics, corticosteroids, and antibiotics to prevent pneumonia. Zinc oxide is produced during oxyacetylene cutting or arc welding of galvanized pipes. These activities in closed facilities in which cattle are housed may result in toxicity characterized by respiratory distress. Lesions are similar to those described for atypical interstitial pneumonia. Treatment is as described for nitrogen dioxide toxicity.