JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

September 2026

P-B12

HISTOPATHOLOGIC DESCRIPTION

Lung: Affecting approximately 85% of the lung are large, multifocal to coalescing areas of consolidation in which alveoli and bronchioles and to a lesser extent bronchi are filled with an exudate composed of macrophages, degenerate neutrophils, fibrin, increased clear space (edema), occasional hemorrhage, and abundant eosinophilic cellular and karyorrhectic debris (necrosis). Neutrophils and macrophages are often degenerate with streaming nuclei (“oat cells”). Within affected areas and to a lesser extent extending into less affected areas, alveolar septa are expanded up to 4x normal width by similar inflammatory components. Bronchiolar epithelium is frequently hypertrophic and hyperplastic, often piling up to 3 layers thick. The interlobular, perivascular, and subpleural interstitium is expanded up to 3x normal thickness by abundant fibrin and edema admixed with few neutrophils, macrophages, lymphocytes, and plasma cells. Interstitial lymphatics are markedly ectatic (edema) and contain similar cellular infiltrates and fibrin, hemorrhage, and edema. Arteries are frequently lined by hypertrophied (reactive) endothelium.

GENERAL DISCUSSION

Shipping fever is the most economically important disease of beef cattle in temperate climates

Classic presentation: Pneumonia and/or acute fatal endotoxemia in young cattle following transport from farm of origin to a feedlot (hence, “shipping fever”)

“Enzootic pneumonia”: bacterial pneumonia of young calves; 1-4 month old dairy and veal calves; less common in beef calves

Pasteurellaceae are gram-negative, non-motile coccobacillus and include Mannheimia haemolytica, Histophilus somni, and Pasteurella multocida

Mannheimia haemolytica was previously Pasteurella haemolytica biotype A

Bibersteinia trehalose was previously Pasteurella haemolytica biotype T

Serotypes are differentiated based on soluble capsular polysaccharide antigens

• Serotypes 2: sporadic isolate from the nasopharynx of healthy calves
• Serotypes 1 and 6: common isolates from pneumonic lung

Genotypes

• Genotype 1 is associated with serotype 2
• Genotype 2 is associated with serotypes 1 and 6

15-45% morbidity, 1-5% mortality, and 5-10% case fatality

PATHOGENESIS

Failure of lung defenses > M. haemolytica gains access to the lower respiratory tract > macrophages phagocytose M. haemolytica but are ineffective at killing the bacteria > these macrophages secrete an array of neutrophil chemoattractants > neutrophils that arrive at the site of infection are then killed by leukotoxin > and the cycle repeats

Risk factors for shipping fever:

• Exposure of naïve calves to animals shedding viral pathogens
• Stress: weaning, transport, crowding, deprivation of feed and water, disruption of social groups, handling, vaccination, dehorning
• Metabolic acidosis
• Calf exposure to adverse environmental conditions: changes to temperature and humidity, exposure to rain and snow, and dusty environoments

In healthy cattle, relatively non-pathogenic M. haemolytica serotypes S2 and S4 predominate, and pathogenic serotype S1 is present in low numbers

Although the exact mechanisms are unknown, some studies suggest that stress and/or concurrent viral infections result in a microenvironmental change which favors increased multiplication and colonization of pathogenic serotype S1 in the upper respiratory tract

Reduction in host respiratory immune response (e.g. concurrent viral infection; stressors such as crowding, transport, weaning, etc.; drastic environmental changes) predisposes cattle to pneumonic mannheimiosis

Neutrophil mediated inflammation in cattle with BRDC contributes to development of severe disease

Virulence factors:

• Leukotoxin (Lkt) (Repeats in Toxin [RTX] exotoxin): The most important virulence factor
  • Exclusively affects ruminant leukocytes
  • Produced by M. haemolytica during logarithmic growth phase
  • Composed of 4 genes (lktA, lktB, lktC, and lktD); gene products lktB and lktD required for transport of LKT-A (key virulence gene) from the bacterial cytoplasm to the outer environment
  • Effects are concentration-dependent:
    • Low concentration: (Sublytic affect) Neutrophils undergo respiratory burst and degranulation, stimulate cytokine release from macrophages and histamine release from mast cells, and undergo apoptosis
    • High concentration: (Lytic affect) induces the formation of transmembrane pores with subsequent oncotic cell necrosis
  • Lkt binds to beta 2 integrins, which contain CD18 Lkt receptors, found only on ruminant leukocytes
  • In contrast to most bacterial infections where neutrophils phagocytose the offending bacteria, neutrophils recruited to sites of infection with M.haemolytica are most likely lysed by the effects of leukotoxin, hence, this disease is characterized by massive recruitment of neutrophils that are ineffective in killing bacteria
• Lipopolysaccharide (LPS) (endotoxin):
  • Activates alveolar macrophages (early) and neutrophils (later), inducing them to secrete cytokines (tumor necrosis factor alpha, IL-1 beta), and chemokines (IL-8, ENA, and GRO-alpha), which amplify the inflammatory response
  • Potentiates effect of Lkt; induces increased expression of beta 2 integrins, which contain CD18 Lkt receptor, on leukocytes
• Neuraminidase: Improves adhesion to mucosal epithelium; may reduce mucus viscosity to prevent mucociliary clearance
• Polysaccharide capsule (Gram-negative): Aids in attachment, confers resistance to phagocytosis
• Iron-regulated outer membrane proteins: Tbp1 and Tbp2; involved in iron acquisition and possibly adhesion

TYPICAL CLINICAL FINDINGS

Depression, pyrexia, anorexia, rapid and shallow respiration, and mucopurulent nasal discharge; the basis for profound depression and endotoxemia are poorly understood

Dyspnea, productive cough, thoracic pain, mucopurulent nasal discharge, expiratory “grunt”; cough is more common later in disease

Endotoxemia (fever, tachycardia, tachypnea, dyspnea, pale or dark mucous membranes, prolonged capillary refill time, cold extremities) may cause death even in the absence of significant lung pathology

TYPICAL GROSS FINDINGS

Fibrinopurulent and necrotizing bronchopneumonia with fibrinous pleuritis and pleural effusion; affected and unaffected lung are usually sharply demarcated

Cranioventral distribution; most common in the cranial and middle lung lobes

Interlobular edema: Septa are distended by fibrin and yellow, gelatinous edema fluid

“Marbling” appearance is characteristic: Multifocal coagulative necrosis, interlobular interstitial edema, congestion

Bronchi may contain hemorrhage and/or suppurative material

Laryngeal epithelial necrosis at the point of contact of the focal folds may occur in cattle with severe pneumonia because of traumatic closure of laryngeal folds during dyspnea

Peracute infections

• Red-purple hemorrhagic and infarcted lobules
• Crisp texture on cut section
• Abundant, loosely adherent pleural fibrin

Subacute infections

• Lobular distribution of lesions
• Mottled tan-grey suppurative exudate that oozes from small bronchi
• Purulent or catarrhal exudate on mucosal surface of large airways

Chronic Infections

• Formation of sequestra (necrotic core of firm but friable tissue, enveloped in capsule of fibrous tissue), common as sequelae to coagulation necrosis
• Bronchiectasis
• Abscesses; often unable to express purulent material because inflammatory cells are enmeshed in fibrin
• Fibrous pleural adhesions

TYPICAL LIGHT MICROSCOPIC FINDINGS

Fibrinopurulent bronchopneumonia with necrosis of leukocytes

Massive infiltration of neutrophils and macrophages, which are often lytic and elongated with nuclear streaming (“oat cells” or “swirling macrophages”)

Alveoli filled with edema and fibrin, +/- hemorrhage

Bronchioles filled with leukocytes, +/- epithelial necrosis (if epithelial necrosis is present, consider underlying viral infection), RBCs, fibrin, edema, and possibly bacterial aggregates

Foci of coagulative necrosis (some areas represent infarcts due to thrombosis of intralobular blood vessels or direct effects of bacterial toxins / and or leukocyte secretions) often bordered by a basophilic rim of oat cells

ADDITIONAL DIAGNOSTIC TESTS

Aerobic and microaerophilic culture of lungs (postmortem) or transtracheal aspiration, bronchoalveloar lavage, or thoracocentesis fluid (antemortem)

Immunohistochemistry to identify M. haemolytica

Serum antibody determination using bacterial agglutination assay, Lkt neutralization assay, or Lkt ELISA

PCR (targeting superoxide dismutase)

DIFFERENTIAL DIAGNOSIS

• Bacterial pneumonias (often secondary): Bronchopneumonia, purulent (less fibrinous), lack characteristic neutrophil necrosis, differentiate using microbiology culture
  • Histophilus somni (formerly Haemophilus somnus): Suppurative and fibrinous bronchopneumonia, coagulative necrosis with streaming necrotic leukocytes
  • Pasteurella multocida (typically presents with less fibrinous bronchopneumonia)
  • Bibersteinia trehalosi
  • Mycoplasma bovis- Caseonecrotic bronchopneumonia with multiple well delineated necrotic foci filled with caseous material.
  • Trueperella pyogenes (formerly Arcanobacterium spp)
• Mycobacterium bovis (P-B10C): Granulomatous pneumonia (not bronchopneumonia)
• Primary viral pneumonias: Interstitial pneumonia, necrotic and attenuated respiratory epithelium +/- inclusion bodies and syncytial cells
  • Bovine respiratory syncytial virus (BRSV, P-V06)
    • Affects cranio-ventral lobes, but lesions are atelectatic, rather than swollen and hard as expected with bacterial pneumonias. Caudal dorsal lobes are voluminous, edematous, heavy, and firm.
    • Bronchointerstitial pneumonia with formation of bronchiolar and alveolar epithelia syncytia
  • Bovine herpesvirus-1 (BHV-1)
  • Bovine parainfluenza-3 (BPIV-3)
  • Bovine coronavirus (BCV)

COMPARATIVE PATHOLOGY

Mannheimia haemolytica in other species:

• Sheep: M. haemolytica causes identical disease in lambs less than 2 months of age, with similar pathogenesis and gross/microscopic lesions; also causes septicemia in lambs; is the most common cause of mastitis in sheep
  • Bibersteinia trehalosi (formerly P. trehalosi or Mannheimia haemolytica biotype T) causes pneumonia and septicemia in lambs 5 months or older
• Goats: Sporadic cases of acute bronchopneumonia and pleuritis in kids
• Deer: Experimentally demonstrated to cause hemorrhage and congestion, necrosis, degeneration, inflammation, edema in all female reproductive organs (except vagina and cervix), and mild to moderate lesions in the testes, epididymis, vas deferens, and prostate; occasional cause of bronchopneumonia and septicemia in deer but less common than Trueperella pyogenes or Fusobacterium necrophorum

Other similar bacterial pneumonia:

• Pigs: Gross and microscopic findings in pneumonia caused by Actinobacillus pleuropneumonia (APP, P-B04) are similar to those in pneumonic mannheimiosis of cattle APP produces 4 cytotoxins that are members of the RTX family and cause cytolysis of neutrophils, alveolar macrophages, erythrocytes, endothelium, and epithelium

REFERENCES

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2. Dao X, Hung CC, Yang Y, Wang J, Yang F. Development and validation of an insulated isothermal PCR assay for the rapid detection of Mannheimia haemolytica. J Vet Diagn Invest. 2022 Mar;34(2):302-305.
3. Jones MEB, Gasper DJ, Mitchell E. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:134-135.
4. Lopez A, Martinson SA. Respiratory System, Thoracic Cavities, Mediastinum, and Pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier; 2022:608-614.
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