JPC SYSTEMIC PATHOLOGY

HEMOLYMPHATIC SYSTEM

April 2024

H-V03

 

Signalment (JPC #1780888): Blue-gold macaw

 

HISTORY: Tissue from a macaw that died suddenly

 

HISTOPATHOLOGIC DESCRIPTION: Thymus: Primarily within the medulla there is diffuse depletion of lymphocytes and multifocal to coalescing areas of lytic necrosis. Areas of lytic necrosis are characterized by moderate amounts of eosinophilic cellular and karyorrhectic debris admixed with fibrin, low numbers of remaining lymphocytes, thymic epithelial cells, macrophages, and moderate numbers of viral syncytial cells up to 70 µm in diameter that contain up to 20 nuclei. Often nuclei of syncytial cells and thymic epithelial cells contain 10 µm brightly eosinophilic viral inclusion bodies that fill the nucleus and marginate the chromatin.

 

Spleen: There is diffuse depletion of white pulp characterized by a paucity of lymphocytes. Multifocally, there are small areas of lytic necrosis within both the red and white pulp. Histiocytes often contain phagocytosed nuclear or cellular debris or erythrocytes (erythrophagocytosis).

 

Liver: There is diffuse, massive loss of hepatic cord architecture, with dissociation and individualization of hepatocytes that are often swollen with vacuolated cytoplasm (degeneration) or shrunken with hypereosinophilic cytoplasm with a pyknotic or karyorrhectic nucleus (necrosis). Degenerate hepatocytes adjacent to areas of necrosis frequently contain a 10 µm, intranuclear, eosinophilic to amphophilic viral inclusion which fills the nucleus and marginates the chromatin. There are increased numbers of lymphocytes and Kupffer cells throughout the hepatic parenchyma. 

 

MORPHOLOGIC DIAGNOSIS: 1. Thymus: Lymphoid depletion and necrosis, acute, multifocal to coalescing, marked, with viral syncytia and eosinophilic intranuclear viral inclusions, blue-gold macaw, avian.

2. Spleen: White pulp depletion, acute, diffuse, marked, with multifocal necrosis.

3. Liver: Hepatocellular degeneration and necrosis, massive, acute, diffuse, severe, with eosinophilic intranuclear viral inclusions.

 

ETIOLOGIC DIAGNOSIS: Herpesviral thymic, splenic, and hepatic necrosis.

 

CAUSE: Psittacid herpesvirus-1 

 

CONDITION: Pacheco’s disease 

 

SYNONYMS: Herpesvirus of psittacine birds; Amazon parrot herpesvirus; Pacheco's parrot disease

 

GENERAL DISCUSSION: 

• Pacheco’s disease is cause of acute, fatal hepatitis in individuals and collections of psittacines 
• Family Herpesviridae: Enveloped, dsDNA viruses that replicate within the nucleus, resulting in intranuclear inclusion bodies; belongs to the Iltovirus genus that is among the causative agents of respiratory disease in birds 
  • Viral envelope acquired via budding through the nuclear membrane
  • Typically have a narrowly restricted host range and are known for the ability to establish latent infections
• Herpesviruses are divided into three broad subfamilies:
  • Alphaherpesvirinae: Lyse host cells and produce necrosis; grow rapidly, producing Cowdry type-A intranuclear inclusion bodies and viral syncytial cells
    • Establish lifelong latent infections in both the lymphoreticular system and the trigeminal ganglion
  • Gammaherpesvirinae: Replicate in lymphoblastic cells and induce lymphoproliferative response; may induce neoplastic transformation of lymphocytes; narrow host range
    • Includes genus Lymphocryptovirus and genus Rhadinovirus
  • Betaherpesvirnae: Cytomegaloviruses (CMV); replicate slowly, have a highly restricted host range and often produce greatly enlarged (cytomegalic) cells
    • Normally found in most species; usually only cause disease in immunosuppressed
• Psittacid herpesvirus-1 (PsHV-1; Pacheco’s disease, see also D-V13):  Alphaherpesvirus that causes acute, systemic disease with high mortality in psittacine birds; outbreaks occur in new birds and in resident flocks after a new bird is introduced; stressors (transport, exposure to cold, onset of breeding) can trigger clinical disease
  • Four genotypes based on UL16 gene sequencing; all four genotypes have been found and there is high species variation; all genotypes are potentially fatal in parrots; much genotype/species variation is seen: 
    • Amazon parrots: All four genotypes
    • Pacific region cockatiels and cockatoos: All four genotypes; however these species are more refractory to disease
    • African gray parrots: Genotypes 2-4
    • Macaws and conures: Genotype 4 is most common, 3 rarely, 1 never 
    • Mucosal papilloma: Genotypes 1, 2, 3
    • Biliary and pancreatic duct carcinomas: Genotype 3
  • There are three to five serotypes; direct correlation between genotype and serotype 
    • Pronounced species variation in mortality rate; Cockatoos and Amazon parrots are highly susceptible and often die suddenly
    • Conures, specifically Nanday and Patagonian, are often implicated as carriers; however, any bird that recovers should be considered a carrier

 

PATHOGENESIS: 

• Latently infected parrots (Amazon parrots + few species of conures and macaws) are sources of virus shedding; virus has been identified in oral and cloacal mucosa in up to 92% of some populations
• Additional sources of virus include ingestion, inhalation, and conjunctival exposure; all of which may lead to disease; as expected, parent-fed offspring of infected birds can become infected though they may not develop signs of the disease

• Incubation period and clinical course are shorter (2-6 days) in small species than in larger parrots (5 days to 5 weeks or more)

 

TYPICAL CLINICAL FINDINGS:

• Spontaneous death
• Clinical signs are minimal to absent; rarely depression, anorexia, diarrhea, tremors, and weakness
• Variable clinical disease; some parrots are asymptomatic carriers 

 

TYPICAL GROSS FINDINGS:

• Often in good body condition (well-muscled with adequate body fat) and no gross lesions
• Liver: Hepatomegaly, occasionally; friable, yellow-gray mottling (may be mistaken for hepatic lipidosis) to light red or green tinged; areas of hemorrhage; marked necrosis
• Proventriculus: Lesions similar to Proventricular Dilation Disease; uncommon
• Intestine: Enteritis, mostly mild with occasional severe enteric necrosis and hemorrhage seen grossly on the mucosal and serosal surfaces
• Epidermis: Proliferative lesions of the lower legs and feet seen in psittacine birds, particularly cockatoos and macaws; may be caused by an uncharacterized herpesvirus 

• Cockatoos: Presents as a solitary proliferative nodule or multiple proliferative nodules
• Macaws: Typically a roughening of the skin and/or a flat, raised plaque; depigmentation is common in diseased tissue; very dry and thickened skin is readily scraped away

• Peritoneum and mesenteries: Multifocal serosal and mesenteric petechiation; hemorrhages may be secondary to hepatic necrosis  or viral proliferation in the endothelial cells of blood vessels

• Petechia on serous membranes

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Multifocal, moderate to sub- or massive hepatic (only hepatocytes adjacent to portal triads survive) and splenic necrosis (splenic necrosis less common) +/- syncytia and eosinophilic intranuclear inclusion bodies; minimal inflammation
  1. Other organs: Pancreas, crop, intestine > kidney, endocrine organs, cloaca >> respiratory system
  2. Extrahepatic lesions may occur in the absence of hepatic lesions, uncommon
• Multiorgan necrosis with variable inflammation and INIBs (spleen, pancreas, trachea [rare], crop, intestine)
  1. Spleen: Necrosis of the periarterial mononuclear cells and lymphocytes
  2. Pancreatic necrosis 
  3. Trachea: Severe, necrotizing tracheitis (rare)
  4. Crop: Multifocal ballooning degeneration of the basal cell layer with erosions, ulcers, and rare vesicles 
  5. Intestine: Enteritis in ~30%; mostly mild with occasional severe enteric necrosis and hemorrhage
• Numerous Cowdry type A deeply eosinophilic to lightly basophilic intranuclear viral inclusions (in hepatocytes, splenic reticular cells, biliary epithelium, and other epithelia
• Bursa of Fabricius: Intranuclear inclusion bodies in bursal reticular cells
• Cloaca and mucosa: In New World parrots cloacal papilloma are attributed to PsHV; mucosal papillomas (genotypes 1, 2, 3) have developed in some parrots that survived acute PsHV infection
• Kidney: Uncommonly inclusion bodies in the renal tubular epithelium 
• Epidermis: Epidermal hyperplasia with marked acanthosis, large INIB that fill nucleus +/- clear halo
• Thymus (lymphoid tissue): Atrophy or widespread lymphocytolysis; INIBs in the epithelial cells (reticular cells and Hassall corpuscles); syncytia

 

ADDITIONAL DIAGNOSTIC TESTS:

• DNA in situ hybridization, immunofluorescent staining, PCR, EM, and virus isolation (lung, liver, kidney, spleen, and brain of birds that were viremic at the time of death)

• PsHV-1 has been found in the livers of some birds that do not have Pacheco’s disease; PCR must be interpreted in conjunction with characteristic lesions of Pacheco’s disease 

• Cytology: Impression smears of the liver may contain hepatocytes with intranuclear viral inclusions

 

DIFFERENTIAL DIAGNOSIS:

• Chlamydia psittaci (D-B12): Hepatomegaly and splenomegaly; intracytoplasmic Gram-negative microcolonies; zoonotic and OIE reportable
• Salmonella typhimurium: Sudden death, hepatomegaly, liquid feces
• Lead poisoning (U-T02): Lethargy, abnormal feces, elevated urates; intranuclear lead inclusions (acid fast and PAS positive)  
• Avian polyomavirus, reovirus, adenovirus: Yellow urates, hepatomegaly, splenomegaly; tend to have more nuclear enlargement and basophilic to deeply basophilic INIB
• Psittacine adenovirus: Sudden death; proventricular and duodenal dilatation; swollen kidneys
• Reovirus: Ubiquitous infection among birds, ~ 85-90% of isolated reoviruses considered nonpathogenic; often involved in other disease syndromes, including respiratory, enteric, and systemic disease

 

COMPARATIVE PATHOLOGY:

• Psittacid herpesvirus-2 (PsHV-2): Identified in cutaneous papillomas in three African gray parrots
• Psittacid herpesvirus-3 (PsHV-3): Causes multiorgan necrosis (especially respiratory) with hemorrhage, syncytia, and intranuclear inclusions in the bronchi, air sacs, trachea, spleen, and kidney of parrots (Bourke’s, eclectus); recent report of PsHV-3 in rose-ringed parakeets with multifocal necrosis of secondary and tertiary bronchial epithelium, eosinophilic intranuclear inclusion bodies in atrial respiratory cells, and multinucleate syncytial cells in the walls of secondary and tertiary bronchi and air capillaries (Murer, J Vet Diagn Invest 2020)

• Can cause hyperplastic lesions of the inner ear 

• Psittacid alphaherpesvirus 5: Indian ringneck parakeets; severe necrotizing bronchitis, parabronchitis, and interstitial pneumonia with syncytia and INIB (Henderson, J Vet Diagn Invest 2023)

 

 

Select alphaherpesviruses

• Pigs: Suid herpesvirus-1 (pseudorabies, Aujeszky’s Disease, E-V01, N-V07)

• Abortions; multifocal inflammation and necrosis in liver, lung, adrenal, and lymphoid tissues; inclusion bodies in chorionic epithelium 
• Adults: Dermatitis, encephalitis

• Goats: Caprine herpesvirus-1 

• Abortions; multifocal inflammation and necrosis in various organs 

• Horses:  

• Equine herpesvirus-1 (P-V10, R-V01)

• Abortions; multifocal inflammation and necrosis in liver, lung, adrenal glands, and lymphoid tissues with intranuclear inclusion bodies
• Adults:  Encephalomyelitis, rhinopneumonitis

• Equine herpesvirus-3: Coital exanthema
• Equine herpesvirus-4: Rhinopneumonitis

• Cattle:  

• Bovine herpesvirus-1 (infectious bovine rhinotracheitis, infectious pustular vulvovaginitis, infectious balanoposthitis [R-V02]): Pneumonia, rhinotracheitis, and vulvovaginitis
• Bovine herpesvirus-2: Bovine mammillitis, pseudo-lumpy skin disease
• Bovine herpesvirus-5: Encephalitis

•  Cats: Feline herpesvirus-1 (P-V09)

• Rhinitis, sinusitis, and conjunctivitis with intranuclear viral inclusions, may have eosinophilic necroulcerative facial dermatitis
• Cheetahs: Eosinophilic facial dermatitis 

• Non-human primates: Macacine herpesvirus-1 (B virus)  

• Characteristic vesicular and ulcerative lesions on oral and genital mucosae with multinucleated, syncytial cells, and intranuclear viral inclusions 

• Avian

• Gallid herpesvirus-1 (infectious laryngotracheitis virus; ILTV): Severe respiratory disease in poultry (chickens, pheasants); pheasant-chicken crosses, peafowl, and turkeys also susceptible
• Gallid herpesvirus-2 (Marek’s disease, I-V13, N-V08): Chickens; quails, pheasants, and commercial turkeys also susceptible; bursal and thymic atrophy; unilateral or bilateral enlargement of sciatic, brachial, and vagus nerves and spinal root ganglia
• Anatid herpesvirus type-1 (duck plague, duck viral enteritis, D-V10): Ducks, geese and swans, with Muscovy ducks considered most susceptible; sudden death with high mortality; petechial and ecchymotic hemorrhages in heart and mesentery; multifocal necrosis in gastrointestinal system, lymphoid tissue, and liver; hepatomegaly

• Columbid herpesvirus-1: Necrotizing disease in raptors, including owls; conjunctivitis, fibrinonecrotic exudate in pharynx, esophagus, and crop; hepatomegaly with multifocal necrosis
• Passerid herpesvirus I (PaHV-1): Tracheitis in Gouldian finches (Erythrura gouldiae)
• Amazon tracheitis virus: closely related to ILTV; isolated from Amazon parrots (Amazona spp.) with tracheitis

 

REFERENCES: 

1. Abdul-Aziz T, Fletcher OJ. Hepatobiliary system. In: Abdul-Aziz T, Fletcher OJ, Barnes HJ, eds. Avian Histopathology. 4^th ed. Jacksonville, FL: AAAP; 2016:389-390, 608. 
2. Crespo R, Franca MS, Fenton H, Shivaprasad HL. Galliformes and columbiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:747, 752-754. 
3. Fenton K, McManamon R, Howerth EW. Anseriforms, ciconiiformes, charadriiformes, fruiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:707-708.
4. Henderson EE, Streitenberger N, Asin J, Armien A, Crossley BM, Childress AL, Wellehan JFX Jr, Uzal FA. Psittacid alphaherpesvirus 5 infection in Indian ringneck parakeets in southern California. J Vet Diagn Invest. 2023;35(1):67-71.
5. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:627.
6. Murer L, et al. Psittacid herpesvirus 3 infection in rose-ringed parakeets in southern Brazil. J Vet Diagn Invest. 2020;32(3):409-412.
7. Reavill DR, Dorrestein G. Psittacines, coliiformes, musophagiformes,cuculiforme. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:787.
8. Schmidt RE, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2nd ed. Philadelphia, PA: John Wiley & Sons, Inc.; 2015:29-30, 70, 78, 87, 96-98, 130, 181, 183, 247, 277, 283.
9. Yin JH, Oster S, McHale B, Neto R. Naturally occurring psittacid alphaherpesvirus 3 and probable adenovirus coinfection in an Indian ringneck parakeet in the United States. J Vet Diagn Invest. 2023;35(6):772-776.

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