Pathology in Practice

Ryan M. Schafbuch Indiana Animal Disease Diagnostic Laboratory, Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Jesús A. Hermida Casas Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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G. Kenitra Hammac Indiana Animal Disease Diagnostic Laboratory, Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Janice E. Kritchevsky Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Margaret A. Miller Indiana Animal Disease Diagnostic Laboratory, Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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History and Clinical Findings

A 7-month-old 110-kg (242-lb) Angus bull calf was evaluated after being found recumbent earlier that same day. On examination, the calf was unresponsive and lying down with all 4 limbs extended. It had respiratory distress, muscle fasciculations, tremors, nystagmus, delayed menace response, and severely depressed mentation. Hematologic and serum biochemical findings included leukopenia and high creatine kinase activity; Hct was 34%, and total protein concentration was 4.8 g/dL with hypoalbuminemia. Despite supportive care, the calf died the following morning and was submitted for necropsy.

Gross Findings

On gross examination, the brain was wet and soft with mildly dilated ventricles and excessive watery transparent CSF. A 1 × 1.5-cm red, soft, cavitated focus was adjacent to the left caudate nucleus in the striatum rostral to the optic chiasm (Figure 1). Multiple, less distinct foci of hemorrhage and malacia were present in the meninges and parenchyma of the brain and spinal cord. Petechiae and ecchymoses were scattered throughout many skeletal muscles, the esophageal adventitia, pulmonic trunk adventitia, visceral and parietal pleurae, small intestinal serosa, and urinary bladder. The lungs were reddened. One liter of transparent yellow watery fluid was in the peritoneal cavity. Multifocal mucosal hemorrhages were evident in the small and large intestine, with blood-tinged mucus in the lumen of the descending colon.

Figure 1—
Figure 1—

Photograph of the brain from a 7-month-old Angus calf that was evaluated after being found recumbent. When examined, the calf was unresponsive and lying down with all 4 limbs extended. It had respiratory distress, muscle fasciculations, tremors, nystagmus, delayed menace response, and severely depressed mentation. Supportive care was ineffective, and the calf later died. Notice the focus of hemorrhage and malacia in the left striatum and basal nucleus (asterisk). Bar = 2 cm.

Citation: Journal of the American Veterinary Medical Association 253, 11; 10.2460/javma.253.11.1417

Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page

Histopathologic Findings

The hemorrhagic and malacic focus in the left frontal lobe and striatum had centralized cavitation with poorly organized thrombi in many surrounding veins and venules (Figure 2). Surrounding neuroparenchyma was rarefied with hemorrhage, necrosis, and infiltration by neutrophils mixed with fewer macrophages and lymphoid cells. Neutrophils were most numerous in the lumen and wall of thrombotic veins (Figure 3). The endothelium in affected vessels was disrupted with extension of fibrinoid material or hemorrhage into the Virchow Robin space and adjacent parenchyma. A few venules had luminal bacteria. Vasculitis, thrombosis, hemorrhage, necrosis, and inflammation were also found in the brainstem, spinal cord, leptomeninges, myocardium, pulmonic trunk, lungs, skeletal muscles, and small intestine.

Figure 2—
Figure 2—

Photomicrograph of a section of the brain from the calf in Figure 1. The malacic focus in the striatum has central cavitation. Surrounding veins contain thrombi. H&E stain; bar = 1 mm. Inset—Neutrophils predominate in a thrombus and extend through the venous wall into adjacent hemorrhagic parenchyma. H&E stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 253, 11; 10.2460/javma.253.11.1417

Figure 3—
Figure 3—

Photomicrograph of another section of brain from the calf in Figure 1. A vein is partially occluded by a poorly organized thrombus. Numerous neutrophils are present in the lumen and infiltrate the vessel wall. H&E stain; bar = 100 μm. Inset—An aggregate of short bacterial rods in the lumen of a venule is visible. H&E stain; bar = 25 μm.

Citation: Journal of the American Veterinary Medical Association 253, 11; 10.2460/javma.253.11.1417

Additional Test Results

Brain tissue submitted to the Indiana State Department of Health was negative for rabies virus as determined by fluorescent antibody testing. The brain was also negative for bovine herpesvirus-4 as determined by fluorescent antibody testing and virus isolation. Histophilus somni was isolated on bacterial culture of brain tissue samples.

Morphologic Diagnosis and Case Summary

Morphologic diagnosis and case summary: thrombotic meningoencephalitis (TME) with neutrophilic vasculitis resulting from infection with H somni in a calf.

Comments

For the calf of the present report, rabies had been included as a clinical differential diagnosis, but the result of testing for rabies virus was negative. Given the presence of hemorrhage and malacia in the brain and spinal cord identified during necropsy, TME and herpesviral encephalomyelitis were considered the most likely diseases. Histologic examination of brain tissue revealed prominent and neutrophilic phlebitis with bacteria in the lumens of venules. These findings, along with the absence of trigeminal ganglionitis (and a negative result of fluorescent antibody testing for rabies virus), prompted submission of brain tissue for culture of H somni, the result of which was positive. 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 a causative agent of enzootic pneumonia in calves during the summer and shipping fever in feedlot cattle during late fall to early winter. It is also the cause of bovine TME, formerly known as thromboembolic meningoencephalitis. Currently, vasculitis (mainly phlebitis) is considered a primary lesion, with thrombosis developing secondary to the local vasculitis rather than as a result of embolization from a distant site.1 In fact, the tendency to induce thrombosis is a key feature of H somni, and induction of thrombosis entails interactions of the bacteria with endothelial cells, leukocytes, and platelets.2 The disease is reportedly more common in older calves and yearlings during late fall and early winter3; the 7-month-old calf of the present report died in late November.

Lipooligosaccharide is considered the major virulence factor of H somni.1,2 Caspase-mediated apoptosis of endothelial cells (and of other host cells)2 triggered by lipooligosaccharide (probably by its lipid A component) is thought to initiate the vasculitis of TME.4 Lipooligosaccharide is also thought to have roles in the development of inflammation (via Toll-like receptor 4) and in the bacteria's antigenic mimicry, resistance to phagocytosis and killing by leukocytes, and evasion of the immune response.5 Macrophages that ingest H somni are soon killed by the bacteria and are unlikely to have a long-term influence on dissemination of infection.

For the calf of the present report, the herd of origin was on a vaccination schedule that included administration of H somni bacterin, according to the manager. However, the calf was not vaccinated because it was deemed too young on the day when herd vaccination was scheduled. The extant vaccination program may explain why only 1 animal in the herd was affected. Vaccination can prevent H somni–induced respiratory tract disease among calves; in an experimental study,3 calves vaccinated against H somni had decreased incidence of respiratory disease and death, compared with findings in unvaccinated controls. Antimicrobials can be administered to prevent or treat respiratory tract disease associated with H somni infection. In herds with a high prevalence of H somni infection, prophylactic treatment with oxytetracycline may prevent clinical disease. However, CNS localization of the infection typically results in acute and severe disease; therefore, antimicrobial treatment is unlikely to be successful in calves with H somni–associated neurologic signs, such as those in the calf of the present report.

References

  • 1. Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's pathology of domestic animals. Vol 1. 6th ed. St Louis: Elsevier, 2016;363364.

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  • 2. Behling-Kelly E, Rivera-Rivas J, Czuprynski CJ. Interactions of Histophilus somni with host cells. Curr Top Microbiol Immunol 2016;396:7187.

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  • 3. O'Toole D, Sondgeroth KS. Histophilosis as a natural disease. Curr Top Microbiol Immunol 2016;396:1548.

  • 4. Inzana TJ. The many facets of lipooligosaccharide as a virulence factor for Histophilus somni. Curr Top Microbiol Immunol 2016;396:131148.

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  • 5. Corbeil LB. Host immune response to Histophilus somni. Curr Top Microbiol Immunol 2016;396:109129.

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