Signalment:  

27-year-old, male, cynomolgus macaque (Macaca fascicularis), nonhuman primate This animal arrived at Wake Forest University from Indonesia about 9 years before death. It was diagnosed with type 2 diabetes on 3/6/2008 (glucose 328 g/dL), and on the following day, became lethargic and dehydrated. Insulin treatment and supportive fluid therapy were attempted, but the animal died on 3/9/2008.

Gross Description:  

The major gross lesion was in the lung. The entire left lung was four times larger than normal, firm, and tan to yellowish-brown, with adherence to the body wall in some areas (Fig. 3-1, 3-2). Similar changes were present in the middle right lung lobe. Cut surfaces revealed suppurative exudate (Fig. 3-3), and 10-20% of the parenchyma was replaced by dense fibrous connective tissue. 

In addition to the pulmonary lesion, the coronary arteries were segmentally thickened by yellow plaques on the intimal surfaces (atherosclerosis).

Histopathologic Description:

Lung: The pulmonary architecture is extensively distorted (Fig. 3-4) by a necrotizing inflammatory reaction composed of abundant neutrophils and protein-rich edema fluid, which fills alveoli and bronchioles. Alveolar walls are often effaced (Fig. 3-5) and bronchiolar epithelium is often absent. Pale perivascular spaces measuring up to 500um in width contain fibrin and edema fluid. Vessels are variably infiltrated by neutrophils and mononuclear phagocytes, contain thrombi, and are surrounded by myriads of short bacterial rods. Similar bacterial colonies are also scattered throughout the pulmonary parenchyma and subpleural space (Fig. 3-6). The pleura is thickened up to 1.5mm owing to the presence of variably mature fibrous connective tissue and suppurative inflammation. Gram staining demonstrates mats of pleomorphic Gram positive bacilli throughout the lung.

Morphologic Diagnosis:  

Pneumonia, diffuse, chronic, severe, fibrinosuppurative with intralesional bacteria (Etiology: Corynebacterium ulcerans)

Lab Results:  

Serum chemistry:
Glucose, 348 mg/dL
BUN 29 mg/dL
K⁺ 6.2 mEq/L
Alkaline phosphatase 588 μ/L
Cholesterol 1099 mg/dL

Hematology:
CBC:
RBC, 6.77 x 10⁵/μL
Hematocrit, 42.3 %
Hemoglobin, 12 mg/dL
MCV, 62fl
MCHC 28.4 g/dL
Platelets 181 x 10³/μL
WBC 15.9 x 10³/μL
Neutrophils, 77% (12243)
Bands, 0
Lymphocytes 17% (2703)
Monocytes, 5% (795)
Eosinophils, 1% (159)
Basophils, 0

Microbiology:
Pleural fluid and a lung swab were submitted for bacterial culture. A heavy pure growth (4+) of Corynebacterium ulcerans was recovered. 

Condition:  

Pleuropneumonia; abundant coccobacilli

Contributor Comment:  

Corynebacteria are Gram positive, non-motile, pleomorphic bacilli.(2) Corynebacterium ulcerans was first isolated in 1926 from a human throat lesion(4), and has since been considered a common cause of laryngitis and cutaneous granulomas in humans.(2) It has also been isolated from abscesses and causes pneumonia and mastitis in nonhuman primates.(3) It is considered a commensal of horses and cattle, although it can cause mastitis and cutaneous infections in cattle (5), and is widely distributed in soil and water. It is often isolated from non-pasteurized milk, the drinking of which has been linked to human infections.(6) Fatal pneumonia caused by C. ulcerans has been reported in humans and macaques.(2) A retrospective study of respiratory disease in 272 nonhuman primates (75 cynomolgus macaques, 97 rhesus macaques, 100 vervets) indicated that C. ulcerans and Streptococcus pneumoniae were major causes of winter respiratory infections in cynomolgus macaques.(3)

The pathogenicity of C. ulcerans is facilitated by potent exotoxins, including diphtheria toxin which inhibits protein synthesis, as well as necrotizing toxin which increases vascular permeability resulting in edema. After inhalation, C. ulcerans proliferates in the respiratory tract epithelium. Subsequent release of the exotoxins causes epithelial necrosis, which in turn initiates marked interstitial edema, neutrophil infiltration, and fibrinosuppurative exudation.(1)

The differential diagnosis for fibrinosuppurative bronchopneumonia in cynomolgus macaques should include Streptococcus pneumoniae, Pasteurella spp., Nocardia spp., Actinobacillus spp., Klebsiella spp., and Legionella pneumophila as well as Corynebacterium sp. 

JPC Diagnosis:  

Lung: Pleuropneumonia, fibrinonecrotic, diffuse, severe, with abundant coccobacilli.

Conference Comment:  

Genetic analysis has revealed that Corynebacaterium ulcerans is a unique organism that is very closely related to Corynebacterium diptheriae and Corynebacterium pseudotuberculosis.(1)

Corynebacterium ulcerans can produce diphtheria toxin similar to that of C. diphtheriae. C. diphtheriae produces a phage-encoded A-B toxin that blocks protein synthesis. Even after vaccination with diphtheroid toxin, C. diphtheriae can still colonize the epithelium, and the vaccine does protect people from the harmful effects of the toxin. Release of the exotoxin in unvaccinated individuals causes necrosis of the epithelium and subsequent profuse fibrionsuppurative exudation. The settling of this exudate on the already ulcerated epithelial surface results in formation of the firm diphtheritic membrane characteristic of the disease. If the fulminant infection is stopped, the membrane may be sloughed via coughing or enzymatic digestion, and the patient can recover.(4)

References:

1 AFIP Wednesday slide conference 23 case # 3, 1999
2. Dessau RB, Brandtchristensen M, Jensen OJ, Tonnesen P: pulmonary nodules due to Corynebacterium ulcerans. European Respiratory Journal 8: 651-653, 1995
3. Panaitescu M, Maximescu P, Michel J, Potorac E: Respiratory pathogens in non-human primates with special reference to Corynebacterium ulcerans. Lab Animal 11:155-157, 1977
4. McAdam AJ, Sharpe AH: Infectious Diseases. In Robins and Cotran Pathologic Basis of Disease, ed. Kumar V, Abbas AK, Fausto N, 7^th ed., pp. 374, Elsevier Saunders, Philadelphia, PA 2005
5. Sing A, Hogardt M, Bierschenk S, Heesemann E: Detection of differences in the nucleotide and amino acid sequences of diphtheria toxin from Corynebacterium diphtheriae and Corynebacterium ulcerans causing extrapharyngeal infections. Journal of Clinical Microbiology 41: 4848-4851, 2003
6. Wagner J, Ignatius R, Voss S, Hopfner V, Ehlers S, Funke G, Weber U, Hahn H: Infection of the skin caused by Corynebacterium ulcerans and mimicking classical cutaneous diphtheria. Clinical Infectious Diseases 33: 1598-1600

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3-1 Lung

3-2 Lung

3-3 Lung

3-4 Lung

3-5 Lung

3-6 Lung

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