2-month-old male crossbreed calf (Bos taurus).Respiratory issues in multiple 2-month old calves.

Gross Description:  

Cranioventral lung lobes were consolidated and covered in areas with fibrin.

Histopathologic Description:

Lung: There are marked multifocal and extensive areas of necrosis demarcated by dense zones of neutrophils which form a subgross mosaic pattern.  The necrotic regions contain large amounts of seroproteinaceous fluid, red blood cells, neutrophils and cell debris; some cells are degenerate with elongate nuclei (streaming leukocytes/oat cells).  In remaining tissue, multifocal bronchi and bronchioles are dilated and contain large numbers of neutrophils and cell debris.  There is diffuse thickening of the inter-lobular septa by edema and infiltrates of neutrophils.  In one lobular area there is moderate thickening of alveolar septa by mild to moderate type II cell hyperplasia and occasional infiltrates of lymphocytes and macrophages.  The pleura is thickened by edema and covered in some areas by a thick mat of fibrin and cell debris.

Lab Results:  

Lung: Mannheimia haemolytica

Immunohistochemistry: Bovine viral diarrhea virus (BVD)


Bovine Respiratory Disease Complex/Mannheimia haemolytica

Contributor Comment:  

Bovine respiratory disease (BRD) complex is multifactorial and susceptibility is related to stress, environmental and housing conditions, management, hydration and immune status, and exposure/levels of microbial pathogens.5  Feedlot density has increased progressively in the United States and global demand for beef is trending upward; therefore, the incidence of BRD may continue to  increase over time.5  Viral infections with agents such as bovine respiratory syncytial virus (BRSV), bovine parainfluenza virus 3 (BPIV-3), bovine viral diarrhea virus (BVDV), bovine coronavirus (BCV), and bovine herpesvirus (BHV-1) can damage mucosal epithelia, decrease mucin production, as well as hinder innate and adaptive immune responses. This predisposes calves to secondary infections with bacteria, such as Mannheimia haemolytica and Histophilus somni, as in this case, as well as Pasteurella multocida, and Mycoplasma bovis.1

In a 2005 study, the prevalence of BVDV was determined in 2000 cattle arriving to a feedlot.  The prevalence of persistently infected (PI) cattle was only 0.3%, but 2.6% of chronically ill cattle, and 2.5% of dead cattle were BPIV-3 positive.  Cattle exposed to a PI animal had an increased risk for treatment of BRD by 43%.  In total, 15.9% of initial respiratory tract disease conditions were associated with exposure to a PI animal. Thus, very few cattle arrive to feedlot PI; however, those cattle are much more likely to require treatment and at place other cattle at-risk for incidence of respiratory disease.4,6  Of the subtypes of BVDV, BVDV1b subtype is more commonly identified than BVDV1a and BVDV2a based on a survey of BVD isolates of cattle entering feedlots.3  Experimentally, it has also been shown that exposure of steers to steers PI with BVDV enhances M. haemolytica disease severity.1

In this case, the animal had significant BVDV antigen detected by immunohistochemistry, which could alter lung and mucosal (e.g. tonsil) immunity, thus pre-disposing to enhanced bacterial rep-lication/colonization.  Other factors such as stress and other viruses (e.g., BRSV, BPIV-3, coronavirus, BHV-1), could have contributed to this predisposition along with the BVD, although lesions of RSV, BPIV-3, and BHV-1 were not seen and BHV (IBR), BCV, BRSV, and BPIV-3 were not detected by PCR.

JPC Diagnosis:  

Lung: Bronchopneumonia, fibrinosuppurative and necrotizing, diffuse, severe, with numerous necrotic leukocytes (oat cells)

Conference Comment:  

This case is an excellent example of a classic presentation of the bovine respiratory disease complex (BRD). Mannheimia haemolytica is a gram-negative coccobacillus of the Pasteurellaceae family. It is typically is a commensal bacterium in the nasopharynx and tonsillar crypts of immunocompetent ruminants.2 Many members of this family of bacteria can produce respiratory disease and septicemia in naïve and immunosuppressed domestic animals.2,4,5 Other common pathogenic members of this family include: Pasteurella multocida of rabbits, swine, ruminants, and cats; Bibersteinia trehalosi and Histophilus somni in ruminants; Actinobacillus pleuropneumoniae, A. suis, and Haemophilus parasuis in swine; and A. equuli in horses.2 

There are twelve serotypes of M. haemolytica based on their capsular polysaccharide antigens.2,5 Serotypes 1 and 2 are typically isolated from the upper respiratory tract of cattle as part of the normal commensal flora;2 however, in a naïve or stressed animal, serotype 1 is often isolated from pneumonic lungs. As mentioned by the contributor, stress and cold weather causes the proliferation of commensal bacteria in the upper respiratory tract, overwhelming pulmonary defenses. In addition, co-infection with the respiratory viruses mentioned above can reduce mucociliary escalator clearance and impair the function of alveolar macrophages.2

Conference participants briefly discussed the various virulence factors for M. haemolytica and how they contribute to the classic histopathologic appearance of this case. Virulence factors include: leukotoxin, lipopolysaccharide, capsular polysaccharide, transferring-binding proteins A and B, O-sialogylcoprotease, neuraminidase, IgG1-specific protease, outer membrane proteins, adhesins and fimbriae.2 These virulence factors allow M. haemolytica to resist host clearance, avoid host defenses, and impair leukocyte function. The result is massive recruitment of neutrophils into alveoli, as seen in this case.2,5 Neutrophils are ineffective at killing bacteria and cause damage to capillary endothelial cells, resulting in hemorrhage, fibrin and edema in alveolar, interstitial, and interlobular spaces.2

Leukotoxin, a type of repeats in toxin (RTX), is an important exotoxin produced by M. haemolytica. It induces leukocyte recruitment at low concentrations and lysis of leukocytes and platelets in high concentrations.2 Leukotoxin binds to CD18 on the leukocyte surface, forming a pore in the cell membrane. Interestingly, BoHV-1 causes the up-regulation of CD18 on the surface of neutrophils which makes these cells more susceptible to leukotoxin.2 Lytic and necrotic leukocytes exhibit a streaming pattern of basophilic chromatin and are commonly referred to as “oat cells.” 1,2,5,6

Most conference participants noted multi-focal fibrin thrombi present throughout pulmonary parenchyma. Additionally, in many slides, there was a sharply demarcated area of tinctorial change with loss of differential staining surrounded by a band of degenerate neutrophils- interpreted as an infarct. Focal areas of coagulation necrosis and infarction are characteristic for M. haemolytica.2 These are secondary to thrombosis as well as direct damage to the lung by leukocyte secretion of pro-inflammatory IL-8, oxygen radicals, and nitric oxide synthetase. Activated alveolar macrophages also express tissue factor, which promotes the formation of fibrin thrombi.2


1. Burciaga-Robles L, Step D, Krehbiel C, et al.  Effects of exposure to calves persistently infected with bovine viral diarrhea virus type 1b and subsequent infection with Mannheima haemolytica on clinical signs and immune variables: Model for bovine respiratory disease via viral and bacterial interaction.  J An Sci. 2010; 88:2166-2178.

2. Caswell J, Williams K. Respiratory system, In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016: 537-546.

3. Fulton W, Ridpath J, Ore S, et al.  Bovine viral diarrhea virus (BVDV) subgenotypes in diagnostic laboratory accessions:  Distribution of BVDV 1a, 1b and 2a subgenotypes.  Vet Microbiol. 2005;  111:35-40.

4. Loneragan G, Thomson D, Montgomery D, et al.  Prevalence, outcome, and health consequences associated with persistent infection with bovine viral diarrhea virus in feedlot cattle.  J Am Vet Med Assoc. 2005; 226:595-601.

5. Mosier D.  Review of BRD pathogenesis:  The old and the new.  Anim Health Res Rev. 2014; 15:166-168.

6. O’Conner A, Sorden S, Apley M.  Association between the existence of calves persistently infected with bovine virus diarrhea virus and commingling on pen morbidity in feedlot cattle.  Am J Vet Res. 2005; 66:2130-2134.

Click the slide to view.

4-1. Lung, calf.

4-2. Lung, calf.

4-3. Lung, calf.

4-4. Lung, calf.

4-5. Lung, calf.

Back | VP Home | Contact Us |