Respiratory Diagnostic Pathology

Respiratory Diagnostic Pathology

BOVINE RESPIRATORY DISEASE UPDATE 0749-0720/97 $0.00 + .20 RESPIRA TORY DIAGNOSTIC PATHOLOGY Gordon A. Andrews, DVM, PhD, and George A. Kennedy, DVM...

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BOVINE RESPIRATORY DISEASE UPDATE

0749-0720/97 $0.00 + .20

RESPIRA TORY DIAGNOSTIC PATHOLOGY Gordon A. Andrews, DVM, PhD, and George A. Kennedy, DVM, PhD

Bovine respiratory disease (BRD) remains a significant cause of economic loss to the cattle industryl and source of frustration to the cow / calf sector, the feedlot industry, veterinary practitioners, and laboratory diagnosticians. Death losses in feedyards in the western and midwestern United States due to respiratory disease account for approximately 44 % of all losses on an annual basis, and over 50% of all losses during the late fall and early winter months. l20 Numerous contributing factors are involved, including weaning stress, shipping, commingling, anatomic and physiologic features of the bovine respiratory tract, and multiple infectious agents. The role of many of these agents is currently not fully understood. This has led to the term BRD complex. 57 BRD can be a clinically useful term, but to the laboratory diagnostician and the practitioner trying to design a control program or a treatment regimen, a more specific original diagnosis is generally preferred. Identifying the specific risk factors and agents involved in a particular group of cattle best involves a team approach, and this includes feedlot management and personnel, on-site and consulting veterinarians, and diagnostic laboratory personnel. Good communication between field veterinarian and the diagnostic laboratory are particularly critical, as is an understanding by field veterinarians of the limitations of the various laboratory tests. Early identification and treatment of sick animals is considered to be the key to success in outbreaks of BRD, and early, accurate diagnosis is prerequisite to successful treatment. The inherent time lag in many From the Veterinary Diagnostic Laboratory, Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas

VETERINARY CLINICS OF NORTH AMERICA: FOOD ANIMAL PRACTICE VOLUME 13 • NUMBER 3 • NOVEMBER 1997

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laboratory tests necessitates the practitioner often has to act on their initial clinical impression, but laboratory confirmation and monitoring can be essential to adjusting treatment and preventative protocols. The first step in treatment and control of any condition is an accurate diagnosis, and BRD is no exception. An accurate diagnosis has to start with astute observation and a good clinical history. Nasal swabs can be a useful clinical aid for initiating treatment or monitoring respiratory disease on a premises. If fatalities occur, careful necropsies and appropriate specimens for laboratory examination can be important aids to accurate diagnosis, but laboratory results have to be interpreted prudently and in the context of the overall situation. Communication between practitioner and laboratory personnel can be extremely important in interpretation of laboratory results and help avoid misinterpretation or overinterpretation. NECROPSY EXAMINATION OF THE RESPIRATORY SYSTEM

Necropsy evaluation is a valuable tool for disease diagnosis and monitoring. Ideally, a veterinarian will glean more out of a necropsy than a nonveterinarian; however, trained lay personnel are often used, and can do an adequate job of recognizing important lesions and collecting specimens. The necropsy procedure can often be tailored to the situation, but an orderly and systematic approach is still necessary for maximum value, and at least a cursory look at all tissues and organ systems will pay dividends in the long run. Equipment necessary for necropsy examination of cattle need only include one or more knives, a sharpening stone and steel, axe or pruning shears for cutting ribs, scissors and forceps, protective rubber or latex gloves, and a saw (hacksaw) or cleaver for removing the brain. 6 Sharp instruments take much of the labor out of performing a necropsy. It is recommended to have a set of instruments for necropsy examinations only. When performing a necropsy an often neglected part is the external examination. The animal's body condition and hair coat, state of hydration, wounds, external parasites, discharges from body cavities, and as one proceeds with the dissection, noting whether the tissues are icteric or pale or bruised or hemorrhagic can all be important clues. In food animals, looking for injection-site lesions is also important. When respiratory disease is suspected, emphasis is, of course, on that system, and should start with examination of the nasal cavity, larynx, trachea, lungs, and thoracic cavity. The upper respiratory system should be observed for rhinitis, sinusitis, laryngitis, and tracheitis. 6 These tissues may display important lesions, with diseases such as infectious bovine rhinotracheitis (IBR) and necrotic laryngitis. Occasionally a traumatic laryngitis will be found, indicating poor medication technique. At the same time, the oral cavity and esophagus should always be examined

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for the linear erosions and ulcers suggestive of bovine virus diarrhea (BVD) virus infection. Intense congestion of the trachea, often with whitish or pinkish froth, can be a terminal feature of many diseases, including bloat, and are not necessarily indicative of respiratory disease. Many cases of bronchopneumonia will have some mucus and purulent exudate in the trachea, and this is not necessarily indicative of a primary tracheitis, such as that caused by IBR virus. Cattle dying with IBR will have a necrotizing rhinitis and tracheitis with fibrinopurulent pseudomembranes lining much of the trachea. Careful examination should distinguish between the necrotizing tracheitis and bronchitis of IBR and congestion or coughed-up exudate from a bronchopneumonia. The necrotizing laryngitis of calf diphtheria can look similar, but should be limited to the larynx and proximal trachea. Cattle dying with the socalled honker syndrome will have frank hemorrhage in the tracheal submucosal tissue without necrosis or inflammatory pseudomembrane formation. Examination of the Lungs

Because of the intimate anatomic and physiologic relationship of the cardiovascular and respiratory systems, they should be examined as a unit. After removing the rib cage on the right side, the thoracic cavity should be examined for the presence of fluid or exudate. The visceral and parietal pleura should be examined for the presence of adherent exudate or adhesions. The tongue, larynx, pharynx, trachea, esophagus, lungs, heart, and great vessels (the "pluck") should be removed as a unit and examined. Examine the lungs at this point before making any incisions into them. Palpate all lung lobes for degree of firmness and note the distribution of firmness. Palpable firmness is the single most important gross criterion of pneumonia. 40 Open (incise) the myocardium of the right atrium and ventricle and the pre- and postcava. Examine the epicardial and endocardial surfaces and cut surfaces of the myocardium. Examine the valves for evidence of valvular endocarditis. Continue to incise the right ventricle following the pulmonary outflow, examining the pulmonary valve, and continue to trace the pulmonary arterial system into all lung lobes, looking for evidence of pulmonary thromboembolism. After examining the pulmonary arterial system, examine the left side of the heart in a similar manner, examining the epicardium, endocardium, cut surface of the myocardium, valves, chordae tendonae, and papillary muscles. Finish the examination of the heart by opening the aortic outflow and examining the aortic valve. Open the trachea and mainstem bronchi. Continue to open bronchioles until terminal bronchioles are reached. If lungworms are present, they may only be found in the terminal bronchioles, and are visible with the unaided eye. Note the presence of exudate in the trachea, bronchi, and bronchioles. While opening the arterial system and airways, examine the cut surfaces of the lung parenchyma, noting color,

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texture, and presence of exudate. Several articles detailing necropsy procedures in food animals in general, 6 suckling calves,66 feeder and stocker calves,123 and adult cattle106 are recommended for more detailed description and illustration. GROSS AND HISTOPATHOLOGIC LESIONS OF DISEASES OF THE RESPIRATORY SYSTEM Nasal Cavity and Sinuses, Pharynx, Larynx, and Trachea

IBR virus causes inflammatory and necrotizing lesIons in the upper respiratory tract, trachea, and conjunctiva. Mild uncomplicated lesions consist of seromucinous rhinotracheitis and conjunctivitis. More severe cases will have mucopurulent exudate, acute inflammation, focal hemorrhages, erosions, and ulcerations progressing to fibrinopurulent or fibrinonecrotic (diphtheritic) membranes on the nasopharyngeal, laryngea, and tracheal mucosa. Fulminating infections can also result in severe necrotizing bronchitis and bronchiolitis with serofibrinous flooding of alveoli and exudative interstitial pneumonia with or without interstitial emphysema. 3 Secondary bacterial complications of these lesions are common. Histopathologic lesions vary from serous to mucopurulent inflammation in mild cases to epithelial necrosis and formation of a surface layer of fibrin and necrotic debris in severe cases. The submucosa will be infiltrated with mixed inflammatory cells. Eosinophilic intranuclear viral inclusion bodies may be observed in infected epithelial cells within the first 2 to 3 days of infection, but are rarely found in necropsy cases. 33 Systemic viral infection in neonatal and young calves results in acute rhinitis, pharyngitis, and epiglottitis with multifocal necrosis, ulceration and fibrinonecrotic membranes on the mucosa of the esophagus and forestomachs. Foci of necrosis may also be observed grossly and histologically in the lymph nodes, kidney, liver, and spleen. 7 A seasonal allergic rhinitis, sometimes referred to as atopic rhinitis, occurs in cattle, and is believed to be due to a hypersensitivity reaction to pollen or fungal antigens. 91 A familial predisposition has been reported. 70, 92 Grossly, the nasal mucosa is thickened by edema fluid, and mucosal erosions may be visible in the anterior nares. The nasal discharge varies from serous to mucopurulent, with eosinophils in the exudate. Histologic lesions in mild cases consist of nasal epithelial hyperplasia or erosion with eosinophil infiltration or glandular epithelial hyperplasia with excess mucus production. Nasal granuloma of cattle is considered to be a chronic form of allergic rhinitis. 1 Lesions occur initially in the posterior portion of the nasal vestibule and anterior nasal septum and ventral meatus, and may progress to involve the posterior nasal cavity, larynx, and proximal trachea. 24 Grossly, the mucosal surface has a granular or multinodular appearance. Histologically, the nodules consist of hyperplastic and meta-

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plastic epithelium covering edematous lamina propria with a central core of inflammatory granulation tissue. Submucosal glands exhibit goblet cell hyperplasia. Active lesions are infiltrated by eosinophils and mast cells. Chronic lesions are characterized by vascular proliferation, fibroplasia, and infiltrates of lymphocytes and plasma cells in the cores of the lesions. 1, 25 Nasal granuloma in cattle may also be caused by fungal infection. The gross lesions most often occur in the anterior portion of the nasal cavity, and range from multinodular to large polypoid masses (Fig. 1). Histologically, the lesions are similar to those of chronic allergic nasal granulomas, but also contain hyphae and chlamydospores of fungi surrounded by macrophages, giant cells, and eosinophils.1 7, 77, 103 A variety of saprophytic fungi have been isolated. Acute or chronic frontal sinusitis in cattle may be caused by dehorning in which the sinus is entered, formation of bone sequestra subsequent to dehorning, fracture or avulsion of horns, fracture of the frontal bones or may be associated with respiratory tract disease (Fig. 2). Actinomyces pyogenes and Pasteurella multocida are the most common bacterial isolates in chronic cases in dairy cattle. 121 Necrotic laryngitis can occur in calves in conjunction with oral necrobacillosis (calf diphtheria) caused by Fusobacterium necrophorum or may occur without oral lesions. Grossly, the lesions are well-demarcated, yellow-grayish dry areas of necrosis surrounded by a zone of hyperemia. The necrotic tissue projects slightly above the normal surface, and is friable and adherent. The necrotic tissue may slough to leave deep ulcers (Fig. 3). Histologically, the lesion consists of a focal zone of necrosis first surrounded by a vascular reaction, then a thin but dense rim of infiltrating leukocytes, and finally by a zone of granulation tissue. Bacteria are arranged in filaments at the leading edge of the lesion. Laryngitis and tracheitis can also be caused by Haemophilus somnus. 37 Laryngeal contact ulcers or scars of the mucus membranes over the

Figure 1. Nasal polyps (arrowheads) in the cranial portion of the nasal cavity.

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Figure 2. Chronic frontal sinusitis. The frontal sinuses are filled with caseated material, resulting in deformation of the frontal bones.

vocal processes and medial angles of the arytenoid cartilages are reported in 13.10/0 of fattened feedlot cattle. 60 The proposed pathogenesis is that mucositis develops from mixed viral and bacterial (including Pasturella Haemophilus 32 and Mycoplasma) infections. Reflex coughing and swallowing accelerate the rate of closure of the larynx leading to erosion and ulceration of the swollen mucus membranes (Fig. 4). These lesions

Figure 3. Necrotic laryngitis. The laryngeal mucosa is bilaterally covered by friable, adherent necrotic tissue.

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Figure 4. Laryngeal contact ulcer (arrowhead) of the mucosa on the medial aspect of the arytenoid cartilage. (Courtesy of International Veterinary Pathology Slide Bank, University of Georgia. Slide #5690 contributed by R. Panciera and D. Mosier, Oklahoma State University)

are benign and lack clinical signs; however, it is believed that some ulcers may develop into chronic laryngeal diphtheria caused by invasion of the ulcers by Fusobacterium necrophorum or develop into papillomas caused by invasion of the ulcers by papovavirus. 61 Tracheal edema and hemorrhage occur in the clinical syndrome referred to as honker syndrome (Fig. 5). The disease occurs most fre-

Figure 5. Trachea from a case of bovine "honker syndrome." There is diffuse submucosal edema and hemorrhage compromising the lumen. (Courtesy of International Veterinary Pathology Slide Bank, University of Georgia. Slide #5696 contributed by R. Panciera and D. Mosier, Oklahoma State University)

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quently in the summer in heavy feedlot cattle during the latter stages of the feeding period. The lesion consists of edema and hemorrhage of the submucosa and mucosa of the dorsal trachea. 87 The thickening may be as much as 5 cm thick, 20 to 30 cm long, and extend from the midcervical region to the thoracic inlet or as far as the tracheal bifurcation. Tracheal obstruction caused by the lesion leads to dyspnea and death by asphyxiation. The precise cause is unknown. Neoplasia of the upper respiratory system in cattle is rare. 112 Tumors reported include squamous cell carcinoma, adenocarcinoma, undifferentiated carcinoma, sarcomas, and miscellaneous and unclassified tumors. Occasional reports of tumors of the ethmoid region occurring in clusters has led to the use of the term endemic ethmoidal carcinomas. 99 ,100 A viral cause has been proposed, but is unproven. There are no reports of ,a similar syndrome from the United States. CLASSIFICATIONS OF PNEUMONIA IN CATTLE

Numerous classification schemes exist for bovine pneumonias, and are based on different criteria, including anatomy (lobar), exudate (fibrinous), cause (viral, Pasteurella pneumonia), histopathology (interstitial), and clinical description (shipping fever, BRD complex, acute respiratory distress syndrome, enzootic pneumonia).13, 40, 94, 114, 115, 124 This article emphasizes an approach to diagnosis of BRD by anatomic-pathologic findings. The gross lesions of respiratory disease are emphasized and differential diseases are considered based on lesions observed at necropsy examination. The clinical history and knowledge of the herd or individual husbandry, in combination with gross lesions, will allow the clinician to further refine the differential list and guide the clinician to take appropriate samples for further diagnostic testing to arrive at a causal diagnosis whenever possible. Essential to this approach is the postmortem examination of cattle with respiratory disease. Clinical-descriptive terms, such as shipping fever and BRD complex, will be introduced as appropriate for each anatomic-pathologic section. BRONCHOPNEUMONIA

Bronchopneumonia is inflammation of the lung that originates at the bronchiolalveolar junction as an extension of inflammation of the bronchi. 40 The pathogenesis of bronchopneumonia is aerogenous, and the causes are primarily bacterial. The development of bronchopneumonia in cattle is a multifactorial syndrome involving the interplay of infectious agents, including viruses,104 bacteria,43 mycoplasma,26, 55,110,113 and chlamydia; stressors, including transportation, mishandling, poor ventilation, starvation, and dehydration; and host susceptibility, including the state of immunity, respiratory defenses, and level of host stress. 105

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The multiple causation of bovine bronchopneumonia has led to use of the term BRD complex. 41 Although numerous infectious agents have been reported to be involved in the BRD complex, only a handful appear to be of major causal significance (Table 1). The clinical term shipping fever pneumonia relates to the association of transportation stress with the development of bronchopneumonia. 58 Although numerous bacteria have been isolated from pneumonic bovine lungs,43 only three appear to be of major importance: P. haemolytica, P. multocida, and H. somnus. All three species involved in feedlot pneumonias can cause overlapping morphologic lesions, making a causal diagnosis based on gross or histologic criteria unreliable. 40 Complicating matters even more is the fact that these three pathogens may coexist in the same set of pneumonic lungs and the isolate recovered on culture may not represent the primary agent responsible for causing the pneumonia. Prior viral infections may not always be necessary for these bacteria to cause clinical pneumonia, but some form of stress to the respiratory defense mechanisms usually has occurred. Uncomplicated viral pneumonias, with the possible exception of bovine respiratory syncytial virus infection, tend to be mild, and seldom come to necropsy. Current concepts are that the various viral, mycoplasmal, and chlamydial agents compromise pulmonary defenses resulting in secondary bacterial pneumonia, which then can result in severe clinical disease. Bronchopneumonia is characterized grossly by irregular consolidation (palpable firmness) of cranioventral lung lobes. A reddened or purple lung may be nothing more than congestion or postmortem change if not accompanied by palpably firm lungs. Bronchopneumonia may be classified (or modified) by duration (acute, subacute, chronic) or

Table 1. INFECTIOUS AGENTS INVOLVED IN BRD COMPLEX IN FEEDLOT CATTLE Major Importance

Minor or Unknown Importance

Viruses Bovine Herpes 1 (IBR) Bovine Virus Diarrhea Bacteria Pasteurella hemolytica Pasteurella multocida Hemophilus somnus

Viruses Bovine Respiratory Syncytial Virus (BRSV) Parainfluenza-3 virus (PI-3) Coronavirus Adenoviruses Other herpes viruses Bacteria Actinomyces pyogenes Streptococcus sp. E. coli Salmonella sp. Staphylococcus sp. Mycoplasma sp. Chlamydia

From Kennedy, GA: Diagnostic considerations for bovine respiratory disease. Proc Am Assoc Bov Prac Annual Meeting 1996, p 142; with permission.

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Figure 6. Acute bovine bronchopneumonia. The cranial ventral aspect of the lung is reddened and consolidated.

by the type of exudate (catarrhal, fibrinous, suppurative, hemorrhagic, or necrotizing). Typically the shipping fever pneumonia of weanling and feedlot calves will be cranioventral in distribution and usually bilateral. 64 There generally is a rather sharp demarcation between affected and nonaffected lung (Fig. 6). With time there is a progression of lesions caudally and dorsally so that the cranial (apical), intermediate (cardiac), and caudal (diaphragmatic) lobes are involved in advanced cases. The intermediate lobes are the most severely affected. The affected lung is enlarged, firm, and heavy. The pleura may be covered by variable amounts of fibrin (Fig. 7), which can adhese adjacent affected lobes to one another, or to the pericardial sac. The thoracic cavity can contain variable

Figure 7. Fibrinous pleuritis. The pleural surface of the middle (cardiac) lobe is covered by a thick sheet of fibrin.

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amounts of fibrinous effusion. The lung parenchyma will have an accentuated lobular pattern visible on the pleural and cut surfaces imparting a marbled appearance (Fig. 8). Individual lobules are firm and vary in color from pink to gray to tan to red or red-black. The red-black lobules represent areas of acute hemorrhagic infarction. Foci of necrosis are tan to gray-brown and surrounded early by a gray line, and later are clearly circumscribed. Necrotic tissue may progress to abscessation, or become sequestered and firm. Actinomyces pyogenes is frequently recovered from these "abscesses," and generally considered to be a secondary invader. Antibiotic sensitivities on these isolates will be of little value. Progressive fibroplasia develops around these abscesses within intralobular septa, and the early fibrinous pleural adhesions become organized into firm fibrous adhesions. Subpleural and interlobular septae are widened by edema and fibrinous fluid. Lymphatics are dilated and may contain fibrin clots. Variable amounts of mucus and purulent exudate are present in airways. An interstitial emphysema is often present in the more caudodorsal regions secondary to forced respirations. In the pneumonia caused by P. haemolytica, histologically the alveoli are filled with an exudate composed of variable proportions of edema fluid, fibrin, neutrophils, alveolar macrophages, and red blood cells, and contain bacteria. A characteristic feature is the presence of masses of elongated or streaming degenerate leukocytes, sometimes referred to as oat cells within alveoli. Necrotic areas seen grossly histologically correspond to areas of coagulative necrosis in previously pneumonic tissue. The periphery of these areas is composed of densely compacted inflammatory cells with a streaming appearance, necrotic debris, and bacteria, which corresponds to the white or gray circumferential zone

Figure 8. Cut surface of a bovine lung with bronchopneumonia. The affected lung is well demarcated from adjacent, more normal appearing lung. Individual lobules are firm and vary in color from dark red to gray to tan. The interlobular septae are distended by fibrinous fluid which will become fibrous connective tissue in chronic cases. (Courtesy of International Veterinary Pathology Slide Bank, University of Georgia. Slide #8305 contributed by R. Farrell, University of Georgia)

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observed grossly. Alveolar capillaries are hyperemic and frequently thrombosed, resulting in hemorrhage into alveoli. Interlobular septa and perivascular, peribronchiolar, and subpleural connective tissues are distended with serofibrinous or fibrinous fluid. The lymphatics are also distended with similar fluid, and often contain fibrin clots. The pleura may be covered with a sheet of fibrin. Arterioles and veins coursing through severely affected regions may exhibit vasculitis by local extension, and may be thrombosed. Bronchioles supplying affected areas frequently contain fibrinous or fibrinosuppurative exudate. Pneumonia caused by P. multocida is generally less fulminating than that caused by P. haemolytica40; however, particularly virulent strains can cause lesions that are very similar.48 The severity of the pneumonia is a result of the interplay of bacterial virulence, dose of bacteria, and host immune responsiveness. In general, histologic examination is of limited value in differentiating the common "shipping fever-type" feedlot pneumonias, but it can be helpful in giving a rough estimate of the age of lesions and in differentiating these bronchopneumonias from interstitial pneumonia and other respiratory conditions, such as lungworms and metastatic pneumonia. Fatal lesions of fibrinous or lobar pneumonia can develop surprisingly fast, within 2 to 3 days.56 Grossly, the cut surface of the lung is diffusely reddish-black. Discrete tan areas of necrosis appear within 3 days. 2, 45 Histologically, fibrosis can be recognized within 5 to 7 days, but gross fibrosis may be difficult to recognize in less than about 3 weeks. 35 The best areas to sample for histologic examination to establish the approximate age of the lesions are areas of tan discoloration surrounded by white or yellow borders.35 These are areas of necrosis and fibroplasia, the lesions used to age the pneumonia. H. somnus causes a pneumonia that has been described or classified as a fibrinous pleuritis and pleuropneumonia. 56, 124 The respiratory form of the H. somnus disease complex53 is sporadic and may occur in a group of cattle in conjunction with septicemic forms, including thromboembolic meningoencephalitis, myocarditis, or arthritis.56 Gross lesions of the fibrinous pleuritis consist of exudation of fibrin and straw-colored fluid in the thoracic cavity, with thick sheets of fibrin on the pleura. More commonly, there is a pleuropneumonia (inflammation of the pleura and lung parenchyma) characterized by consolidation of cranioventrallung lobes, widened interlobular septae, which contain fibrin, and fibrin on the pleural surfaces of affected lung lobes. The gross and histologic lesions of both naturally occurring5,86 and experimentally induced disease31 , 47, 59,101 are strikingly similar to pneumonia caused by P. haemolytica. Pulmonary edema and congestion caused by acute heart failure due to H. somnus myocarditis may be grossly mistaken for interstitial pneumonia. 53 Careful examination of the heart and bacterial cultures are necessary to establish the diagnosis. Lobar pneumonia is a term applied to pneumonia in which entire lobes or major portions of lobes are uniformly consolidated. 40 Lobar pneumonias are rapidly confluent, aggressive fulminating bronchopneu-

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monias in which the bronchiolar orientation may not be grossly evident. Pasteurellae and Haemophilus are the major causes in cattle. Incomplete resolution of acute bronchopneumonia can lead to chronic bronchopneumonia117 or chronic suppurative bronchopneumonia. lOB Multiple lung abscesses, tubular or saccular bronchiectasis, and localized pleurisy may be seen with chronic suppurative bronchopneumonia.13 Bronchiectasis

Bronchiectasis is defined as a permanent, abnormal dilation of bronchi that occurs most frequently as an acquired lesion secondary to some form of bronchitis. 40 Bronchiectasis occurs in two forms: saccular and cylindrical. Saccular bronchiectasis consists of thin-walled outpouchings of bronchial or bronchiolar walls, and can result from focal necrotizing bronchitis and bronchiolitis. Cylindrical bronchiectasis either affects a portion of bronchi or may affect the entire length. The lesion is considered to develop from chronic suppurative bronchitis, which may follow bronchopneumonia. Bronchiectasis in cattle is usually bilateral and found in the intermediate (cardiac) and cranial (apical) lobes. The lobes grossly are firm, heavy, lumpy, and do not collapse. 62 On cut surface of the lung, saccular or cylindrical dilatations are observed (Fig. 9). The mucosa lining the affected bronchi and bronchioles may be either hypertrophic or atrophic. The lumens contain malodorous and tenacious exudate that may be inspissated or hemorrhagic. The intervening parenchyma can be atelectic or pneumonic. Bacteria isolated from these lungs are the same mixture of species associated with shipping fever pneumonia.

Figure 9. Bronchiectasis in a bovine lung secondary to chronic bronchitis. (Courtesy of International Veterinary Pathology Slide Bank, University of Georgia. Slide #2709 contributed by J. Wright and D. Duncan, North Carolina State University)

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INTERSTITIAL PNEUMONIA

Interstitial pneumonia is defined by diffuse or patchy damage to alveolar septa. 40 These are inflammatory conditions in which there is acute diffuse damage to alveolar walls followed by an intra-alveolar exudative phase, which is then followed by a proliferative and fibrotic response. Agents that may initiate the alveolar damage include viruses, chemicals, acute pancreatitis, shock (especially endotoxic shock), and septicemia. High concentrations of oxygen used therapeutically can exacerbate the initial injury. Grossly, interstitial pneumonia is characterized by lesions distributed throughout the lungs, often with greater involvement of the dorsocaudal regions. Pulmonary edema and emphysema are lesions often observed with many of the interstitial pneumonias. It is important to be cautious in interpreting the gross finding of pulmonary edema and emphysema when found at necropsy examination. 16, 127 Pulmonary emphysema occurs secondary to labored respiration of any cause, and is observed as an agonal change in animals without respiratory disease. Pulmonary edema and emphysema may also be seen in animals with left heart failure. In interstitial pneumonias there may be some cranioventral consolidation in which case, differentiating interstitial pneumonia from bronchopneumonia with secondary dorsocaudal agonal emphysema can be difficult. Interstitial pneumonia should have a diffuse distribution, a subtle "meaty" texture on palpation, and often a dull grayish overall appearance. Histologic examination may be necessary to distinguish between the two. The best histologic sample in these cases is a slice of tissue from the junction of the consolidated or "hepatized" tissue and the emphysematous tissue. Atypical Interstitial Pneumonia, Acute Respiratory Distress Syndrome, Acute Bovine Pulmonary Edema and Emphysema, Pulmonary Adenomatosis

The term atypical interstitial pneumonia (AlP) was introduced by Blood10 in 1962 to describe BRD in which some or all of the following pulmonary lesions were found: congestion, edema, hyaline membranes lining alveoli, interstitial emphysema, alveolar epithelial hyperplasia (type II cell hyperplasia), fibrosis, and cellular infiltration of interalveolar septa.lO Grossly the lungs nearly fill the thoracic cavity and do not collapse, are pale with diffuse emphysema consisting of distended air and/ or edema-filled interlobular septa, and frequently air-filled bullae (Figs. 10 and 11). There may be some cranioventral consolidation. At the time, the pathogenesis of the condition was unknown, but it was recognized that there were probably multiple causes. The justification for choosing the word atypical was that the reaction of the pulmonary tissue was unlike that of any of the standard forms of pneumonia (presumably

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Figure 10. Lung from a case of bovine atypical interstitial pneumonia. The lung is hyperinflated and fails to collapse. Interlobular emphysema is present.

infectious), and there was no response to standard treatments for pneumonia.lO It is now known that there are multiple causes of pulmonary disease exhibiting these gross and histologic lesions. Breeze13 suggested the term acute respiratory distress syndrome to describe the clinical presentation of an acute onset of dyspnea resulting from any combination of pulmonary congestion and edema, hyaline membrane formation, alveolar epithelial hyperplasia, and interstitial emphysema, having ruled out other specific causes of respiratory distress, such as parasitic bronchitis. 13 These animals present in respiratory distress with open-mouth breathing, extended head, and protruding tongue. 94 Respirations are rapid and

Figure 11. Cut surface of a bovine lung with atypical interstitial pneumonia. The lung is heavy and wet due to edema fluid in the interlobular septa, bronchi, and bronchioles.

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labored with an expiratory grunt. The temperature may be normal or slightly elevated. The term pulmonary adenomatosis has sometimes been applied to this group of diseases as a histologic term characterizing the histopathologic lesion of type II cell hyperplasia. 83, 119 Acute bovine pulmonary edema and emphysema or acute bovine pulmonary emphysema is an anatomic-pathologic diagnosis used in the United States and Canada13: 28, 88,125 that describes the gross and histologic lesions of this group of diseases. Breeze considers that the diagnosis of acute bovine pulmonary edema and emphysema should be reserved for the specific disease associated with the movement of cattle from dry sparse grazing to lush green pastures, historically referred to as fog fever in Great Britain.13, 14 It must be accepted that the clinical, gross, or histopathologic diagnosis of acute respiratory distress syndrome, acute pulmonary edema and emphysema, atypical interstitial pneumonia, or pulmonary adenomatosis are nonspecific diagnostically for a disease occurring in an individual or group of animals that has a specific cause, and that cause must be sought by further investigation into the history, husbandry, management practices, and possible toxicities and viral, bacterial, or parasitic infections that may be responsible. The diagnosis then can become atypical interstitial pneumonia caused by 4-ipomeanol, for example. The pneumonia caused by bovine respiratory syncytial virus (BRSV), hypersensitivities, and lungworms may have some gross and histologic similarities to the atypical interstitial pneumonias, but there are enough discriminating features that they will be discussed separately. L-tryptophan

Pulmonary disease associated with movement of adult cattle to lush green pasture has been well known in Europe and Great Britain for over 200 years, and has historically been referred to as fog fever from the term fog pastures or foggage (i.e., aftermath, the regrowth after a hay or silage cut).109 The disease occurs in Canada and the United States, where it is referred to as acute bovine pulmonary edema and emphysema (ABPEE), when cattle are moved from dry summer range onto lush pastures in the fall, or in the spring, when cattle are moved from dry winter ranges to lush, irrigated valley pastures. 9, 10, 76 The lush pasture may be any of a variety of grasses, alfalfa, rape, kale, and turnip topS.102, 108, 126 The pathogenesis of the disease involves conversion Ltryptophan present in the forage to 3-methylindole (3MI) by ruminal microflora. The 3MI is activated to a pneumotoxic agent by the cytochrome P-450 mixed function oxidase system in bronchiolar Clara cells and alveolar type 1 pneumocytes to produce the pulmonary damage. l l, 13,14 Nonciliated bronchiolar epithelial cells, type I alveolar epithelial cells, and pulmonary endothelial cells are most susceptible to injury.27 The composition of the ruminal microflora is important in the develop-

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ment of ABPEE, and the low plane of nutrition is believed to alter the ruminal microflora to one which readily converts tryptophan to 3MI.125 The tryptophan content of pastures associated with disease outbreaks has not been found to be higher than control pastures. 75 All breeds of cattle are susceptible13; however, one study demonstrated that hereford cattle were more susceptible to experimental induction of respiratory disease by oral administration of tryptophan. 84 The gross and histologic lesions have been described. 95

4-lpomeanol

A respiratory distress syndrome of high morbidity and mortality has been reported in the south and southeastern United States associated with the feeding of moldy sweet potatoes: Ipomoea batatas. The histologic lesion of alveolar epithelial cell hyperplasia led to the use of the diagnosis of pulmonary adenomatosis. 46, 50, 83,119 The disease was reproduced by feeding sweet potatoes experimentally infected with Fusarium solani (F. javanicum) originally isolated from moldy sweet potatoes fed to a herd which experienced the respiratory disease. 9o The toxic compound is 4ipomeanol, produced by the sweet potato in response to infection by the fungus. The 4-ipomeanol is activated by the cytochrome P-450 mixed function oxidase system to a pneumotoxic compound. The disease has been experimentally reproduced by intraruminal administration of synthetic 4-ipomeano1. 38 Ultrastructural studies showed that type I alveolar epithelial cells and nonciliated bronchiolar epithelial cells are most susceptib Ie to injury. 71

Perilla Ketone (Purple Mint) Toxicity

The first association of an acute respiratory distress syndrome in cattle associated with ingestion of the leaves and seeds of Perilla frutescens (purple mint) was made by Peterson in Oklahoma. 93 The toxic principle perilla ketone was subsequently isolated, and experimentally produced an acute interstitial pneumonia and pleural effusion by intravenous injection into cattle and sheep.128

Brassica and Other Plant Toxicity

Acute respiratory distress is reported in cattle feeding on kale, rape, and turnip topS.16, 102, 126 Specific toxic compounds are unknown in these plants. Atypical interstitial pneumonia associated with these plants may be due to tryptophan or some as yet unidentified toxin.13

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Atypical Pneumonia Associated with Ryegrass Staggers in Calves

An atypical interstitial pneumonia was recently described in a group of calves in the pacific northwest associated with ingestion of turf-quality perennial ryegrass (Lolium perenne) straw infected with an endophyte (Acremonium lolii).89 A. lolii-infected ryegrass contains the toxic compound lolitrem-B, and is the cause of ryegrass staggers. The affected calves exhibited both nervous signs typical of ryegrass staggers and respiratory distress. Calves examined at postmortem had lungs that were diffusely white-gray, failed to collapse, and had bullous emphysema and edema. Early histologic lesions in the lungs included necrosis and sloughing of alveolar lining cells and mild, diffuse type II cell hyperplasia. Small foci of fibrin and neutrophils were observed in alveoli, and were considered secondary to aspiration. More chronic lesions were diffuse type II cell hyperplasia, hyaline membranes, and increased fibrous connective tissue in alveolar septae. Feeding of the straw to experimental calves reproduced the neurologic disease, but not the pulmonary disease. Poison Gasses and Fumes

Acute respiratory distress and deaths have sporadically been reported in cattle exposed to nitrogen dioxide released from silos,18 smog, zinc oxide fumes produced by oxyacetylene cutting and arc welding of galvanized pipe, and gases released from bulk storage tanks for liquid manure. Experimental evidence in all cases, however, is lacking. 13 Milk Allergy

Milk allergy is the name applied to a rapid-onset urticarial condition sometimes accompanied by respiratory distress seen in milking cattle that have been put on once-daily milking near the end of lactation, or in animals that have had a sudden change in milking routine. Pulmonary lesions consist of pulmonary edema and hyaline membranes, congestion, intra-alveolar hemorrhage, and interstitial emphysema. The disease is an auto-allergy to alpha-casein in the milk. 23 Atypical Interstitial Pneumonia of Feedlot Cattle

An interstitial pneumonia with gross and histopathologic lesions indistinguishable from the atypical interstitial pneumonia of pastured animals occurs sporadically in feedlot calves, and is referred to as either atypical interstitial pneumonia or pulmonary edema and emphysema of feeder calves. 54, 63 Although sporadic, the disease is a significant cause of

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death in feedlots. 56 The cause of this form of pneumonia in feedlot cattle is still unclear, and is probably multifactorial. The historical and epidemiologic features are not compatible with the disease, as it occurs in adult pastured cattle moved from poor to lush pasture associated with ruminal production of 3-MI from ingestion of high levels of Ltryptophan present in the lush forage. Lungworms, hypersensitivity reactions to moldy feed, and plant toxins have also been implicated, but do not explain most feedlot cases. Some authors have reported an association between atypical interstitial pneumonia of feedlot cattle with preexisting bacterial bronchopneumonia. 56 A similar association has been made in intensively managed dairy calves with a history of enzootic pneumonia. 34 BRSV has been incriminated as a cause of interstitial pneumonia in weanling and feedlot cattle, but is not proven; however, several studies have associated BRSV infection with atypical interstitial pneumonia, particularly as it relates to the disease in feedlot cattle,44,54 and immunohistochemical procedures have demonstrated BRSV in cases previously diagnosed as atypical interstitial pneumonia of unknown cause. 30 Hypersensitivity Diseases

Hypersensitivity pneumonitis or extrinsic allergic alveolitis is a diagnosis applied to conditions in which the inhalation of organic dusts results in a hypersensitivity reaction in nonatopic patients. In cattle, the only described hypersensitivity pneumonitis is that caused by inhalation of the spores and metabolic products of thermophilic actinomycetes, including Micropolyspora faeni and Thermoactinomyces vulgaris found in the dust of moldy hay, grain, or other vegetable produce. 13 The same disease occurs in humans, and is referred to as farmers lung. The clinical disease occurs more commonly in housed dairy cattle, and may occur in acute or chronic forms. Precipitating antibodies to M. faeni are found in the serum in most cases; however, the disease cannot be diagnosed only on the presence of positive serology, as the presence of antibody only indicates exposure to the antigen. 36,96 Gross lesions in the lungs of acute cases consist of small gray spots on the pleural surface of many lobules. 97, 129 The peripheral acini of some lobules are overinflated, resulting in a pale pink, raised edge around a darker red central portion. Histologically, the alveolar septae are infiltrated with lymphocytes, plasma cells, interstitial cells, and lymphocytic aggregates without germinal centers that correspond to the gray spots observed grossly. If there has been recent exposure to antigen, there may also be epitheloid granulomas with multinucleated giant cells and foci where alveoli contain edema fluid, red cells, neutrophils, and alveolar macrophages. Neutrophils may also be found within alveolar septae with lymphocytes and plasma cells. There may also be bronchiolitis and bronchiolitis obliterans. An acute outbreak in a herd of dairy cattle is described to be associated with feeding of moldy hay in which the gross and histologic lesions

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were edema and emphysema with neutrophilic and eosinophilic inflammation. 127 In chronic cases, affected lobules are pale white to yellow and firm. The distribution tends to be multifocal rather than diffuse. Histologic lesions, in acute cases, may include the addition of focal fibrosis of alveolar septae and alveolar epithelial cell hyperplasia possibly including replacement of alveolar epithelium by columnar ciliated or mucus secreting cells. Diffuse Fibrosing Alveolitis

Diffuse fibrosing alveolitis is a respiratory disease of cattle clinically characterized by insidious onset and chronic progressive course of weeks to 2 years. The disease is well documented in Great Britain,1s,108 but occurs sporadically in the United States. 81 Clinical signs include nonproductive cough, tachypnea, hyperpnea, and exercise intolerance. Cor pulmonale and congestive heart failure may result. Lesions are diffuse and involve all lobes. The lungs grossly are pale, almost white, fleshy, firm, and heavy. Some lobes may contain gray-red, slightly collapsed lobules that contain edema fluid. The trachea and bronchi contain thick mucus. Histologically, the acini are filled with alveolar macrophages and desquamated type II pneumocytes, and may contain mucus. The acini are lined by cuboidal type II pneumocytes or columnar ciliated cells and mucus-secreting cells. Alveolar septae are thickened by fibrous connective tissue and infiltrates of a mixture of plasma cells, lymphocytes, mast cells, and fibroblasts. The cause of this type of pneumonia in cattle is unknown. The disease has been experimentally reproduced by repeated oral dosing with 3-MI.73 It is likely that the end stage of the disease represents repeated pulmonary damage caused by a variety of endogenous or exogenous pulmonary toxins. Interstitial Pneumonia Caused by BRSV

BRSV can cause fatal infection in calves98 and in adult cattle. 42 Grossly, the lungs are heavy, voluminous, and fail to collapse. Lung lesions are present in the cranioventral and caudodorsal aspects, and there is usually a well-defined demarcation between the two portions. 21 ,68 Cranioventrallung lobes are firm, consolidated, edematous, and vary from grayish-white to red to plum colored. 68 The caudodorsal lung lobes are distended by severe interstitial emphysema and edema. Interlobular septa are widened by emphysema, and edema and may contain large, air-filled bullae. Nonspecific lesions related to dyspnea include congested, cyanotic mucosae and petchiae in the subcutis, endocardium, pericardium, lungs, and mucosae of the airways. Histologic lesions in cranioventral lobes in the acute stage consist of degeneration and necrosis of ciliated and nonciliated bronchiolar respiratory epithelial cells, and type I and type II alveolar epithelial cells,

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formation of syncytial cells, and eosinophilic cytoplasmic inclusions in both mononuclear and syncytial epithelial cells. 2o,22 Neutrophils are infiltrated between respiratory epithelial cells and within bronchiolar and alveolar lumina. More chronic changes include bronchiolar respiratory epithelial cell hypertrophy and hyperplasia, muscular hypertrophy, increased fibrous connective tissue in bronchiolar walls, formation of fibroblastic polyps in the lumen leading to bronchiolitis obliterans, and peribronchial and peribronchiolar mononuclear cell infiltrates. Alveolar septa are thickened by congestion, edema, and cellular infiltration. Alveoli contain blood, edema fluid, alveolar macrophages, and hyaline membranes. Occasional syncytial cells may be present, lining alveoli or free in the alveolar lumen. Lesions in the caudodorsallobes consist of emphysema with rupture of alveolar walls, atelectasis of surrounding parenchyma, edema fluid and alveolar macrophages within alveolar lumens, hyaline membranes, necrosis of alveolar and bronchiolar epithelium, and type II cell proliferation. Eosinophils may be present in interlobular and peribronchiolar connective tissues 68; bronchiolitis is not a feature in the caudodorsal lung lobes. 68 Gross and histopathologic lesions in the caudodorsallobes are those of atypical interstitial pneumonia. Several studies have associated BRSV infection with atypical interstitial pneumonia, particularly as it relates to the disease in feedlot cattle,44,54 and immunohistochemical procedures have demonstrated BRSV in cases previously diagnosed as atypical interstitial pneumonia of unknown cause. 30 A growing body of evidence implicates a hypersensitivity component in the pathogenesis of the pulmonary lesions. 42, 44, 69,111 Secondary bacterial bronchopneumonia in the cranioventral lobes is common, and may mask the primary lesions. Diagnosis of BRSV infection is based on gross and histopathologic lesions,19 virus isolation, fluorescent antibody testing on fresh tissue, immunohistochemistry on formalin fixed tissue, and virus neutralization testing on serum for antibodies specific for BRSV. Future diagnostic tests may include enzyme immunoassays for antibody or antigen detection and nucleic acid detection tests. 39 ABSCESSES OF THE LUNG AND EMBOLIC PNEUMONIA

Pulmonary abscesses arise from either focal residues of severe suppurative lobar or bronchopneumonia or from septic emboli lodging in the pulmonary vasculature. 4o A cranioventral distribution with associated scarring and bronchiectasis is evidence of abscessation associated with bronchopneumonia. Randomly distributed abscesses are usually associated with hematogenous embolization from a distant site in the body. Less common causes of pulmonary abscesses include aspirated foreign bodies and direct traumatic penetration of the lung. Another condition that may be encountered at necropsy of cattle

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dead with a suspected respiratory condition is so-called metastatic pneumonia. 94 Pulmonary thromboembolism in cattle may be a sequel to phlebitis of the jugular veins, mastitis, metritis, traumatic reticuloperitonitis, hepatic abscessation, infection of the interdigital space, and thrombosis of the posterior vena cava associated with hepatic abscessation. 49 The most common cause in cattle is thrombosis of the posterior vena cava associated with hepatic abscessation. Pulmonary aneurysms and rupture of the aneurysms may occur secondary to embolism of the pulmonary arteries 65 (Fig. 12). Clinical findings in cattle with pulmonary thromboembolism may include acute onset, coughing, expiratory dyspnea, hemoptysis, epistaxis, and abnormal lung sounds on ascultation. Anemia, hepatomegaly, and melena from coughing up and swallowing of blood may be seen in chronic cases. The cases are almost always fatal. Endocarditis may be seen in some cases. The pathogenesis involves rupture of a liver abscess into the posterior vena cava, thrombosis of the vena cava, embolic spread to the lungs, weakening of the arterial wall, formation of an aneurysm, and rupture leading to intrapulmonary hemorrhage. Gross lesions in the lungs include pulmonary edema, emphysema, and intrapulmonary and intrabronchial hemorrhage. The affected lungs may also contain areas of pneumonia and multiple abscesses. Clots of blood may be found surrounding the ruptured vessel, in airways, in the mouth, aspirated into the lung, and swallowed in the rumen. A thrombus should be found in the caudal vena cava and an abscess found in the liver. The liver abscesses are usually secondary to rumenitis associated with acidosis due to high carbohydrate diets. The abscesses often contain F. necrophorus and A. pyogenes, as well as a mixture of gram-positive and gram-negative bacteria. ASPIRATION PNEUMONIA

Aspiration pneumonia is caused by inhalation of foreign material, frequently in liquid form, into the lungs. The response of the lung

Figure 12. Cut surface of a bovine lung contains a massive hematoma secondary to rupture of a pulmonary aneurysm. (Courtesy of International Veterinary Pathology Slide Bank, University of Georgia. Slide #5002 contributed by D.P.N. National, Alberta Animal Health Division)

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depends on the nature of the material, the bacteria carried with it, and the distribution of the materia1. 40 Aspiration of milk can occur in pailor bottle-fed calves, or can occur in calves as a result of improper stomach tube placement. The lungs grossly remain inflated, are hyperemic, and small amounts of exudate can be expressed from airways. Histologic findings include acute bronchiolitis and acute alveolar inflammation. Histologic demonstration of lipids or plant material in the airways is necessary for diagnosis. Recumbent cattle can aspirate ruminal contents, leading to a more severe necrotizing aspiration pneumonia. The aspirated material is usually grossly obvious and is easily observed histologically. It is important to distinguish aspiration pneumonia caused by rumen contents from rumen material that has been aspirated during agonal death. Aspiration pneumonia will have an inflammatory and necrotizing response associated with the rumen contents whereas material agonally aspirated will not. Histologic examination may be necessary to distinguish between the two conditions. Medications improperly administered by balling gun or stomach tube may be deposited in the lung and result in a severe necrotizing pneumonia. An aspiration pneumonia occurs in neonatal calves due to aspiration of meconium and amniotic fluids. 74 The aspiration of meconium and amniotic fluids is believed to be a terminal event associated with severe prolonged intrauterine hypoxia likely associated with dystocia. Grossly, the lungs range from normal to a mild suppurative bronchopneumonia. A few lungs have a well-defined mosaic pattern of dark red pulmonary lobules that represent areas of atelectasis mixed with normal lobules (Fig. 13). Histologic findings include the presence of variable amounts of aspirated meconium, keratin, and squamous cells in the lung. The lungs have a mild diffuse alveolitis characterized by exudation of a few neutrophils, macrophages, and multinucleated giant cells. Occasionally, obstruction of small airways by aspirated material and focal atelectasis is observed. The condition in calves has the same histologic criteria of meconium aspiration syndrome in newborn human beings that frequently results in respiratory distress and occasionally in neonatal death. Clinical disease in human infants results from airway obstruction, impaired gas exchange, atelectasis, pneumonia, and effects on acid-base regulation resulting in severe acidosis. It is hypothesized that calves that aspirate material in utero may be predisposed to other disease problems, such as enteric disease, as it has been demonstrated that calves with neonatal acidosis have impaired colostral absorption and increased neonatal mortality. PARASITIC PNEUMONIA

During certain stages pneumonia due to lungworms (Dictyocaulus viviparus) can be diagnosed by careful dissection and observation of the adult worms in bronchi and bronchioles. It is essential that bronchioles

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Figure 13. Heart and lungs from a newborn calf with meconium aspiration syndrome. The lungs exhibit a mosaic pattern of red, atalectic lobules interspersed with pink, aerated lobules. (Courtesy of International Veterinary Pathology Slide Bank, University of Georgia. Slide #22199 contributed by A. Lopez, Atlantic Veterinary College)

be examined routinely during postmortem examination, as adult worms may be located only in bronchioles if the worm burden is low. The life cycle, clinical signs, gross and histopathologic lesions, and treatment and prevention have been extensively reviewed. 12 The phases of infection and reinfection are divided into the penetration phase (days 1 to 7), prepatent phase (days 7 to 25), patent phase (days 25 to 55), postpatent phase (days 55 to 90), and the reinfection syndrome, which occurs in adult cattle only. There is no lung pathology during the penetration phase. Lesions during the prepatent phase consist of eosinophilic bronchitis and bronchiolitis. The eosinophilic exudate blocks small bronchi and bronchioles, causing collapse of dependent acini. Grossly, these appear as dark red, wedge-shaped areas of alveolar collapse or atelectasis in the caudoventrallung lobes. During the patent phase there is more extensive tracheitis, bronchitis, and bronchiolitis with occlusion of airways by mucus and eosinophilic exudate surrounding adult worms (Fig. 14), resulting in extensive areas of alveolar collapse that appears grossly as larger areas of atelectasis and consolidation of the ventral caudal lung lobes overlying the diaphragm. Lesions tend to be bilaterally symmetric. There may be secondary bacterial bronchopneumonia in some cases that can confuse the gross picture; however, during this phase the adult worms are found in the airways and confirm the diagnosis of parasitic pneumonia. Lesions during the postpatent phase are reflective of permanent lung injury and gradual resolution of the patent phase. Areas of redden-

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Figure 14. Bovine verminous pneumonia. Adult lungworms (Dictyocaulus viviparus) are present in the bronchi and bronchioles.

ing and consolidation in the ventral caudal lung lobes are similar to those described during the patent phase. There may be bronchiolitis obliterans, bronchiectasis, and chronic bronchopneumonia in some cases. Complicating lesions during the prepatent, patent, and postpatent phases include pulmonary edema, hyaline membrane formation, alveolar epithelial cell hyperplasia (type II pneumocytes), and interstitial emphysema, lesions mimicking atypical interstitial pneumonia. The reinfection syndrome occurs only in adult cattle exposed to a large dose of infective larvae. A few larvae reach the lungs before the immune system can kill or expel the larvae, and lymphoid nodules develop around the dead larvae. Grossly these nodules are subpleural 3 to 4 mm in diameter with a gray-red or greenish-yellow center. The nodules histologically are composed of a central core of eosinophilic parasitic debris surrounded by macrophages, multinucleated giant cells and hyperplastic bronchiolar epithelial cells further surrounded by eosinophils, macrophages, plasma cells, lymphocytes, and giant cells. These eventually are replaced by lymphoid follicles with germinal centers. Eosinophilic inflammation in the bronchial epithelium and interlobular septa can cause the tissue to have a green discoloration. Parasitic pneumonia can also occur in cattle exposed to premises where pigs have previously been housed. The disease clinically presents as an acute respiratory distress characterized by severe dyspnea and expiratory grunt. The lungs grossly are red and firm with a meaty texture, and have edema fluid in the interlobular septae and red froth in the trachea and bronchi. Histologically, the interlobular septae are distended with edema fluid, emphysema, and infiltrates of eosinophils. Septal lymphatics are distended with edema fluid. Alveolar septa are thickened. Alveoli contain an exudate composed of edema fluid, fibrin, and mononuclear cells. Some alveoli are lined by hyaline membranes.

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Bronchioles contain mucus, eosinophils, and mononuclear cells. Parasitic larvae are found in alveoli or bronchioles. 78 PULMONARY NEOPLASIA

Primary pulmonary neoplasms in cattle are uncommon, but are reported in slaughterhouse surveys at an incidence of 19 per 1 million cattle. 4 Histologic diagnoses include pulmonary adenoma,79 pulmonary adenocarcinoma,85 and bronchogenic carcinomas. 4 There are single reports of bronchoalveolar carcinoma107 and pulmonary blastoma. 67 Lymphosarcoma is the most frequent neoplasm metastatic to the lung. It is important to closely examine the reproductive tract to rule out the possibility of uterine or ovarian adenocarcinoma metastatic to the lung when suspected pulmonary neoplasia is observed at gross necropsy examination. 13,82 SAMPLE COLLECTION AND SUBMISSION FOR DIAGNOSTIC TESTING

For collection of specimens, a supply of plastic bags, Whirl-pak (Fisher Scientific, St. Louis, MO) or Zip-Lock bags, wide-mouth plastic containers with 100/0 neutral buffered formalin, sterile cotton swabs and containers for bacterial culture, calcium alginate-free cotton or Dacron swabs for virus isolation, glass slides for smears and blood tubes for serology are all that should be necessary.116 Specimens of lung or trachea for culture should be "fist sized" and from representative lesions. The specimen needs to be large enough that the laboratory can sear the surface and obtain a noncontaminated culture from the interior. Specimens should be submitted chilled and not frozen. Specimens for virus isolation (VI) and fluorescent antibody (FA) examination should be unfixed and selected from representative lesions. Most laboratories prefer FA and VI specimens to be submitted chilled and not frozen. If the specimens for virus isolation will be more than 24 hours in transit, freezing on dry ice will result in greater isolation success. If specimens are submitted on dry ice, the ice should be tightly sealed because the fumes can lower pH in the container, and thereby lower viability of enveloped viral agents, such as IBR. Specimens for histologic examination should be thin slices, not more than 1 cm thick, so that formalin can penetrate, and large enough, at least several centimeters square, for the pathologist to observe the overall architecture. It is important that tissues be fixed in an adequate amount of formalin. A formalin-to-tissue ratio of roughly 10:1 should be used for at least overnight, after which a smaller volume of formalin or gauze sponges heavily soaked in formalin can be used to keep the specimens moist while in transit. Inadequate fixation can seriously compromise the diagnostic value of a specimen and negate a lot of work and expense on

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the part of the veterinarian and feedlot owner or manager. Several specimens from representative lesions in various stages of development are helpful to the pathologist to get the overall picture. A written record of the clinical and necropsy observations is important to identify trends and compare cases over time as an aid to the laboratory pathologist and also to aid one's memory if legal questions later arise. A history form should accompany all diagnostic submissions. 116 Information provided should include owner's name and address, location of the animals, species, breed, age of animal, animal ID numbers if appropriate, morbidity and mortality, vaccination history, treatment and response, clinical symptoms, previous necropsy findings, and list of tentative diagnoses. 116 A good way of shipping specimens is in a large, insulated Styrofoam box with adequate padding and refrigerant to hold specimens in place and keep unfixed tissues chilled until arrival at the laboratory. Specimens with unfixed samples should be shipped so that they arrive within 24 hours. Nasal swabs have been used to monitor potential pathogens in a group of cattle or as diagnostic procedures in early clinical respiratory disease. 29, 80 Collection technique is very important when using nasal swabs, and different types of swabs are necessary for bacterial cultures versus virus isolation. Dry cotton swabs are adequate for bacterial cultures (Culturettes, Becton Dickinson, Cockeysville, MD). Such swabs need to be inserted well into the nasal cavity, taking care not to contaminate the swab with the many nonpathogens in the nostrils. The swab should then be placed in a prepared transport medium or at least saline or lactated Ringer's solution for transport to a laboratory. P. haemolytica and P. multocida inhabit the nasal cavities and upper respiratory tract of normal cattle. 43 The rationale for culturing the upper respiratory tract of incoming or resident cattle or cattle in early stages of respiratory disease is to obtain antibiotic sensitivity data on suspected or potential pathogens. Unfortunately, strains that predominate in the upper respiratory tract may not be the same as those that under appropriate circumstances are capable of colonizing the lower respiratory tract and causing pneumonia. 29 Therefore, the antibiotic sensitivity patterns obtained may not be relevant, and need to be interpreted with care. Lung lavage may provide a more accurate sample, but is more difficult and generally impractical under feedlot conditions. 118 Laryngotracheal cultures using guarded equine swabs is reported to be a compromise in that relevant organisms are more likely to be obtained than from nasal cultures, and although still somewhat difficult, is easier than lung lavage. For identification of viral agents involved in the BRD complex, FA examination of smears from nasal mucosa is preferable to virus isolation. Fluorescent antibody examination is faster, cheaper, and more reliable. Bovine herpesvirus 1 (lBR virus) and respiratory coronavirus are fairly reliably identified with this technique. BRSV and parainfluenza-3 virus (PI-3) can often be found, but false-negative results are more frequent whereas BVD does not lend itself to reliable identification in the nasal

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cavity. If one chooses to attempt VI on swabs of the upper or lower respiratory tract, the swabs need to be calcium alginate-free cotton or Dacron (Baxter Diagnostics, Inc., Scientific Products Division, McGaw Park, IL). Regular cotton swabs used for bacterial cultures can be inhibitory to many viruses. The swabs should then be shipped, chilled but not frozen, in a viral transport media (Hanks Balanced Salt Solution, Gibco Laboratories, Grand Island, NY). Some viruses, such as BRSV, cannot be recovered from mail-in samples. An ELISA test on swabs or lung tissue has been reported to be effective for BRSV diagnosis. 8o An emerging technique in disease diagnosis is the use of immunohistochemistry or immunoperoxidase techniques to demonstrate either viral or bacterial antigen, or bacterial products, such as endotoxin or leukotoxin in formalin-fixed, paraffin-embedded tissues. The technique has a high sensitivity, and is useful in cases where only formalin-fixed tissue is received by the laboratory for examination, or in cases where there is a discrepancy between the histopathologic lesions and results of viral or bacteriologic studies. In BRD research and diagnosis, immunohistochemical techniques are reported for P. multocida,52 H. somnus,47 P. haemolytica,51, 122 BRSV,3° BVD virus,8 and PI-3 virus,72 to name a few. References 1. Allan EM, Gibbs HA, Wiseman A: Pathological features of bovine nasal granuloma (atopic rhinitis). Vet Rec 112:222, 1983 2. Allan EM, Gibbs HA, Wiseman A, et al: Sequential lesions of experimental bovine pneumonic pasteurellosis. Vet Rec 117:438, 1985 3. Allan EM, Pirie HM, Msolla PM, et al: The pathological features of severe cases of infectious bovine rhinotracheitis. Vet Rec 107:441, 1980 4. Anderson LJ, Sandison AT: Pulmonary tumours found in a British abattoir survey: Primary carcinomas in cattle and secondary neoplasms in cattle, sheep and pigs. Br J Cancer 22:247, 1968 5. Andrews H, Anderson TD, Slife LN, et al: Microscopic lesions associated with the isolation of Haemophilus somnus from pneumonic bovine lungs. Vet PathoI22:131, 1985 6. Andrews H, Van Alstine WG, Schwartz KL: A basic approach to food animal necropsy. Vet Clin North Am Food Anim Pract 2:1, 1986 7. Baker JA, McEntee K, Gillespie JH: Effects of infectious bovine rhinotracheitis-infectious pustular vulvovaginitis (lBR-IPV) virus on newborn calves. Cornell Vet 50:156, 1960 8. Baszler TV, Evermann JF, Kaylor PS, et al: Diagnosis of naturally occurring bovine viral diarrhea virus infections in ruminants using monoclonal antibody-based immunohistochemistry. Vet Pathol 32:609, 1995 9. Blake JT, Thomas DW: Acute bovine pulmonary emphysema in Utah. J Am Vet Med Assoc 158:2047, 1971 10. Blood DC: Atypical interstitial pneumonia in cattle. Can Vet J 3:40, 1962 11. Bray TM, Carlson JR: Role of mixed-function oxidase in 3-methylindole-induced acute pulmonary edema in goats. Am J Vet Res 40:1268, 1979 12. Breeze R: Respiratory disease in adult cattle. Vet Clin North Am Food Anim Pract 1:311, 1985 13. Breeze R: Parasitic bronchitis and pneumonia. Vet Clin North Am Food Anim Pract 1:277, 1985 14. Breeze RG, Carlson JR: Chemical-induced lung injury in domestic animals. Adv Vet Sci Comp Med 26:201, 1982

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15. Breeze RG, Pirie HM, Dawson CO, et al: The pathology of respiratory diseases of adult cattle in Britain. Folia Vet Lat 5:95, 1975 16. Breeze RG, Selman IE, Pirie HM, et al: A reappraisal of atypical interstitial pneumonia in cattle. Bovine Practitioner 13:75, 1978 17. Bridges CH: Maduromycosis of bovine nasal mucosa (nasal granuloma of cattle). Cornell Vet 50:468, 1960 18. Brightwell AH: "Silo gas" poisoning in cattle. Can Vet J 13:224, 1972 19. Bryson DG: Necropsy findings associated with BRSV pneumonia. Vet Med 88:894, 1993 20. Bryson DG, McConnell S, McAliskey M, et al: Ultrastructural features of alveolar lesions in induced respiratory syncytial virus pneumonia of calves. Vet Pathol 28:286, 1991 21. Bryson DG, McNulty MS, Logan EF, et al: Respiratory syncytial virus pneumonia in young calves: Clinical and pathologic findings. Am J Vet Res 44:1648, 1983 22. Bryson DG, Platten MF, McConnell S, et al: Ultrastructural features of lesions in bronchiolar epithelium in induced respiratory syncytial virus pneumonia of calves. Vet Pathol 28:293, 1991 23. Campbell SG: Milk allergy: An autoallergic disease of cattle. Cornell Vet 60:684, 1970 24. Carbonell PL: Bovine nasal granuloma: A review. Aust Vet J 52:158, 1976 25. Carbonell PL: Bovine nasal granuloma: Gross and microscopic lesions. Vet Pathol 16:60, 1979 26. Carter GR: Pleuropneumonia-like organisms isolated from bronchopneumonia of cattle. Science 120:113, 1954 27. Castleman WL, Lacy S, Slauson DO, et al: Pulmonary lesions induced by 3-methylindole and bovine respiratory syncytial virus-in calves. Am J Vet Res 51:1806, 1990 28. Ciszewski DK, Slocombe RF: Acute bovine pulmonary emphysema and edema. Compendium on Continuing Education for the Practicing Veterinarian 10:766, 1988 29. Clarke CR: Live animal sampling for antibacterial susceptibility testing. Proceedings of the American Association of Bovine Practitioners 27:150, 1994 30. Collins JK, Jensen R, Smith GH, et al: Association of bovine respiratory syncytial virus with atypical interstitial pneumonia in feedlot cattle. Am J Vet Res 49:1045, 1988 31. Corbeil LB, Widders PR, Gogolewski R, et al: Haemophilus somnus: Bovine reproductive and respiratory disease. Can Vet J 27:90, 1986 32. Corstvet RE, Panciera RJ, Rinker HB, et al: Survey of tracheas of feedlot cattle for Haemophilus sonmus and other selected bacteria. J Am Vet Med Assoc 163:870, 1973 33. Crandell RA, Cheatham WJ, Maurer FD: Infectious bovine rhinotracheitis: The occurrence of intranuclear inclusions in experimentally infected animals. Am J Vet Res 20:505, 1959 34. Curtis RA, Thomson RG, Sandals WCD: Atypical interstitial pneumonia in cattle. Can Vet J 20:141, 1979 35. Daoust PY: Morphological study of bacterial pneumonia of feedlot cattle: Determination of age of lesions. Can Vet J 30:155, 1989 36. Dawson CO, Wiseman A, Pirie HM, et al: Studies of the incidence and titres of precipitating antibody to Micropolyspora faeni in sera from adult cattle. J Comp Pathol 87:287, 1977 37. Dillman RC: Laryngitis in feedlot calves and its association with the Haemophilus somnus (Somnifer) complex. Proceedings of the US Animal Health Association 76:498, 1972 38. Doster AR, Mitchell FE, Farrell RL, et al: Effects of 4-ipomeanol, a product from mold-damaged sweet potatoes, on the bovine lung. Vet Patho115:367, 1978 39. Dubovi EJ: Diagnosing BRSV infection: A laboratory perspective. Vet Med 88:888, 1993 40. Dungworth DL: The respiratory system. In Jubb KVF, Kennedy PC, Palmer N (eds): Pathology of Domestic Animals, vol. 2, ed. 4. New York, Academic Press, 1993 41. Dyer RM: The bovine respiratory disease complex: Infectious agents. Comp Cont Educ 3:S374, 1981 42. Ellis JA, Philibert H, West K, et al: Fatal pneumonia in adult dairy cattle associated with active infection with bovine respiratory syncytial virus. Can Vet J 37:103, 1996

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