7-month-old male Angus ox (Bos taurus)A previously healthy bull calf was presented to the Veterinary Teaching Hospital the day it was found down and unresponsive.

Gross Description:  

The brain is wet and soft with mildly dilated ventricles and excessive transparent watery cerebrospinal fluid. A 1 cm x 1.5 cm dark pink, softened and cavitated focus is in the left cerebral hemisphere, adjacent to the caudate nucleus and rostral to the optic chiasm. Less distinct foci of reddening and softening are found elsewhere in the meninges and parenchyma of the brain and spinal cord.

Mandibular, parotid, and cervical lymph nodes are enlarged to 2 cm in diameter. Petechiae and ecchymoses are scattered through many skeletal muscles, esophageal adventitia, pulmonic trunk adventitia, visceral and parietal pleura, small intestinal serosa, and urinary bladder. The lungs are reddened. One liter of transparent yellow watery fluid is in the abdominal cavity.  The small intestine, spiral colon, and descending colon have multifocal mucosal red foci. Several cestodes, up to 70 cm long, are in the jejunal lumen.  Blood-tinged mucus is in the lumen of the descending colon. Gross lesions are not observed in the pituitary gland, trigeminal nerves and ganglia, oral cavity, larynx, trachea, heart, thyroid gland, aorta, stomach, spleen, liver, gallbladder, pancreas, common bile duct, forestomachs, abomasum, adrenal glands, kidneys, testes, joints, or bone marrow.

Histopathologic Description:

In sections of cerebrum (submitted slide), brain stem, and spinal cord, many vessels (mainly veins and venules) have poorly organized thrombi rich in neutrophils.  A few venules contain bacteria.  The endothelium in affected vessels is disrupted with transmural extension of neutrophils and fibrinoid material or frank hemorrhage into Virchow-Robin space and beyond.  Thrombi and hemorrhage are also in the leptomeninges. Surrounding neuroparenchyma is rarefied with hemorrhage, necrosis, and infiltration by neutrophils with fewer lymphocytes or macrophages. Thrombi are also in inflamed vessels of the ventricular myocardium and skeletal muscles.  Neutrophils with fewer lymphocytes and macrophages infiltrate adjacent musculature. Myocytes are necrotic with hypereosinophilic sarcoplasm and pyknosis or karyorrhexis. Multifocal hemorrhage, necrosis, and aggregates of neutrophils are in the tunica media of the pulmonic trunk.

Transmural hemorrhages in the small intestine are associated with submucosal fibrin thrombi, pleocellular leukocytic infiltration, and segmental necrosis of intestinal mucosa. The lung is congested with edematous interlobular septa.  Alveolar spaces contain increased number of macrophages. A few poorly organized thrombi are in small pulmonary vessels. Evaluated sections of lymph node, spleen, liver, kidney, adrenal gland, rumen (several ciliated protozoa), colon, trigeminal nerve and pituitary gland are within normal limits.

Morphologic Diagnosis:  

Thrombotic meningoencephalitis with neutrophilic vasculitis.

Lab Results:  

Aerobic culture of brain:  Histophilus somni
Bovine herpesvirus fluorescent antibody test:  Negative
Negative virus isolation
Fluorescent antibody test for rabies (Indiana State Department of Health): Negative
Fecal flotation:  Numerous trichostrongyle-type eggs as well as eggs/ova of Moniezia benedeni, Nematodirus spp., Eimeria spp.


Histophilus somni

Contributor Comment:  

Rabies had been included in the clinical differential diagnosis, but the differential diagnosis at autopsy, based on the presence of multiple malacic hemorrhages in the brain and spinal cord, included thrombotic meningo-encephalitis and herpesviral encephalomyelitis.  Histologically, the prominent and neutrophilic phlebitis with bacteria in the lumen of venules, plus the absence of trigeminal ganglionitis (and a negative FA test for rabies virus), prompted submission of brain for culture for Histophilus somni, which was isolated.  Lesions of vasculitis, thrombosis, and inflammation were also detected histologically in the myocardium, pulmonic trunk, and skeletal muscles, but lung lesions were minimal in this case. Histophilus somni is the cause of bovine thrombotic meningoencephalitis (TME), formerly known as thromboembolic meningoencephalitis (TEME).  Currently, vasculitis (mainly phlebitis) is considered a primary lesion with thrombosis secondary to the local vasculitis, rather than the result of embolization from a distant site.2  In fact, the tendency to induce thrombosis is a key feature of H. somni, and entails interactions of the bacterium with endothelial cells, leukocytes, and platelets.1  The disease is reportedly more common in older calves and yearlings, and in late fall and early winter;6 this 7-month-old calf died on the 23rd of November.

Lipooligosaccharide (LOS) is considered the major virulence factor of H. somni.1,2 Its diverse activities contribute to the pathogenicity of H. somni.  Caspase-mediated apoptosis of endothelial cells (and of other host cells)1 triggered by LOS (probably by its lipid A component), is thought to initiate the vasculitis of TME.4 LOS is also thought to play a role in antigenic mimicry, inflammation (via Toll-like Receptor-4), resistance to phagocytosis and killing by leukocytes, and evasion of the immune response.3

Although most vaccine studies have been focused on the bovine respiratory disease complex, results suggest a role for humoral immunity.  Macrophages that ingest H. somni are soon killed by the bacteria, so are unlikely to play a long-term role in dissemination of infection.  This may also suggest that Th1 immunity is less important in disease control than humoral immunity.3

JPC Diagnosis:  

Brain: Vasculitis, fibrinous and necrotizing, multifocal, severe, with thrombosis, infarction, and numerous colonies of coccobacilli, Angus, Bos taurus.

Conference Comment:  

The contributor provides an outstanding example of the hallmark lesions of Histophilus somni in the brain of a feedlot calf. Conference participants localized the examined tissue section to the corpus striatum of the cerebrum due to the heterogeneous mix of white and grey matter tracts. H. somni is a facultative anaerobic gram-negative coccobacillus that is a normal commensal bacterium of the bovine genital tract and nasal cavity.2 In 6 to 12-month-old calves, infection usually occurs following a stressor, such as transportation, inclement weather, crowding, or changes in diet.2,3,6 Virulent strains of H. somni often cause septicemia resulting in a wide variety of lesions secondary to vasculitis and thrombosis caused by virulence factor, lipooligo-saccharide (LOS), discussed by the contributor above. Typical lesions associated with H. somni include thrombotic meningoencephalitis, myocarditis, mastitis, metritis, orchitis, conjunctivitis, necrotizing laryngotracheitis, and polyarthritis H. somni fibrinopurulent broncho-pneumonia as part of the bovine respiratory disease complex.2,3,6 Readers are encouraged to read for a review of the bovine respiratory disease complex. Small ruminants, bighorn sheep (Ovis canadensis), and North American bison (Bison bison) can also be affected; although the clinical manifestations are often not as severe likely due to less intensive management practices in these species.6

While the histologic lesions of H.somi are widespread, the bacteria has a tropism for the small venules of the cerebral vascular tissue and the most severe changes often occur within the brain, as in this case.2 Affected calves often acutely die without treatment. In this case, there is severe fibrino-necrotic vasculitis and thrombi containing numerous coccobacilli resulting in a focally extensive infarct of the neuroparenchyma. Numerous colonies of bacteria are also present in the neuropil. Most conference participants agreed that the hemorrhage and infarction of the brain is a result of fibrinonecrotic vasculitis rather than a primary necrosuppurative meningoencephalitis.

As mentioned by the contributor, H. somi secretes an endotoxin (LOS) causing caspase 3-mediated apoptosis of endothelial cells leading to vasculitis and thrombus formation.2 Recent studies indicate that H. somni can also stimulate endothelial cell tissue-factor (factor 3) activity and disrupt intercellular junctions enhancing pro-coagulant activity on the endothelial surface.1 H. somni and LOS also activate bovine platelets, which further enhances tissue factor activity on the endothelial surface, upregulates leukocyte adhesion molecules (P-selectin, E-selectin, and ICAM-1), and initiates endothelial cell apoptosis via the FasL (caspases 8 and 9).2,5 They also induce endothelial cell cytokine and reactive oxygen species production.3,4,5 The mechanisms of H. somni induced vasculitis and thrombus formation are complex and research is ongoing to fully elucidate the pathogenesis.


1. Behling-Kelly E, Rivera-Rivas J, Czuprynski CJ. Interactions of Histophilus somni with host cells. Curr Top Microbiol Immunol. 2016; 396:71-87.
2. Cantile C, Youssef S.  Nervous system.  Maxie MG ed. In: Jubb Kennedy and Palmer's Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA:  Elsevier Saunders; 2016:364-365.
3. Corbeil LB. Host immune response to Histophilus somni. Curr Top Microbiol Immunol. 2016; 396:109-129.
4. Inzana TJ. The many facets of lipooligosaccharide as a virulence factor for Histophilus somni. Curr Top Microbiol Immunol. 2016; 396:131-148.
5. Kuckleburg CJ, McClenahan DJ, Czuprynski CJ. Platelet activation by Histophilus somni and its LOS induces endothelial cell pro-inflammatory responses and platelet internalization. Shock. 2008; 29:189-196
6. O’Toole D, Sondgeroth KS. Histophilosis as a natural disease. Curr Top Microbiol Immunol. 2016;396:15-48.

Click the slide to view.

4-1. Cerebrum, ox.

4-2. Cerebrum, ox.

4-3. Cerebrum, ox.

4-4. Cerebrum, ox.

4-5. Cerebrum, ox.

4-6. Cerebrum, ox.

4-7. Cerebrum, ox.

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