Signalment: (JPC ML 21474-30 & 21474-31): Dog, breed and age unspecified.
HISTORY: This tissue is from the footpad and nose of a dog that had anorexia, diarrhea, and pneumonia. Central nervous signs were seen agonally.
HISTOPATHOLOGIC DESCRIPTION: Slide 1: Junction of haired skin and footpad: Diffusely affecting the footpad epidermis and extending to adjacent haired skin, there is marked parakeratotic hyperkeratosis (up to 1.5 mm thick). Within the epidermis there is irregular acanthosis with hyperplasia of the basal layer and frequent mitoses (1/HPF). Numerous keratinocytes contain multiple, round to irregular‑shaped, 4‑15um, homogeneous, eosinophilic, intracytoplasmic and rarely similar intranuclear viral inclusions. Multifocally, primarily within the stratum spinosum, there are swollen keratinocytes that have vacuolated cytoplasm (intracellular edema) and there are rare scattered multinucleated epithelial cells with up to 6 nuclei (syncytial cells). Within the underlying dermal papillae and superficial dermis, there is occasional pigmentary incontinence.
MORPHOLOGIC DIAGNOSIS: Skin, footpad: Hyperkeratosis, parakeratotic, diffuse, moderate, with multifocal intracellular edema, epithelial viral syncytia, and intracytoplasmic and intranuclear eosinophilic viral inclusions, breed unspecified, canine.
HISTOPATHOLOGIC DESCRIPTION: Slide 2: Mucocutaneous junction, nasal planum: Epidermal changes are similar to those in the footpad. There are rare intracorneal pustules containing few degenerate neutrophils and eosinophilic homogeneous material (serum). There are few superficial cocci.
MORPHOLOGIC DIAGNOSIS: Mucocutaneous junction, nasal planum, epidermis: Hyperkeratosis, parakeratotic, diffuse, moderate, with multifocal intracellular edema, epithelial viral syncytia, intracytoplasmic and intranuclear eosinophilic viral inclusions, and intra-corneal pustules, breed unspecified, canine.
ETIOLOGIC DIAGNOSIS: Morbilliviral footpad hyperkeratosis
CAUSE: Canine morbillivirus (canine distemper virus (CDV))
CONDITION: Canine distemper
SYNONYMS: Hard pad disease, Carre's Disease
- Canine distemper is an important, ubiquitous infectious disease of dogs, other canids, wild felids, mustelids, and pinnipeds worldwide
- Systemic disease often with respiratory, gastrointestinal, and central nervous system (CNS) involvement
- CDV is a pantropic, negative-sense, single-stranded, enveloped RNA virus, 150-300 nm diameter, genus Morbillivirus, family Paramyxoviridae
- One recognized serotype; variable strain pathogenicity and tissue tropism
- Over half (55%) of healthy raccoons and grey foxes in eastern Tennessee tested positive for novel genotype CDV via RT-PCR
- Virulence factors: Attachment protein (viral H protein) on viral envelope mediate attachment to host cells; fusion protein (viral F protein) allow penetration of host cells and fusion of infected cells with uninfected cells
- Signaling lymphocyte activation molecule (SLAM, CD150): Leukocyte-restricted, mediates entry into cells
- CD46: Widespread
- Inhalation > virus infects macrophages in upper respiratory tract or lungs > viral replication in tonsils and lymph nodes in first 24 hours > cell-associated viremia by 2 days PI > spread to all lymphoid tissues and blood lymphocytes by 2-5 days PI > lymphocytolysis and leukopenia > immunosuppression > animals with:
- Adequate humoral / cellular immunity: Neutralize virus by 14 days PI; may not shed virus
- Delayed / intermediate humoral / cellular immunity: Viral infection / persistence in mucosal epithelium and brain > may develop neurologic disease +/- disease associated with epithelial infection
- Failure to develop neutralizing antibody by 8 or 9 days PI: Virus disseminates to respiratory, GI, urogenital, and central nervous systems; integumentary, exocrine and endocrine systems also affected > virus shed in all excretions during the systemic phase of infection > secondary infections common
- Common secondary infections: Adenovirus, Bordetella, Clostridium piliforme, Cryptosporidium sp., E. coli, Encephalitozoon sp., Pneumocystis sp., Sarcocystis sp., and Toxoplasma sp.
- “Old dog encephalitis” may be caused by infection with replication-defective virus
TYPICAL CLINICAL FINDINGS:
- Disease most common in 12-16 week-old puppies (waning passive immunity)
- Early: fever, conjunctivitis -> cough, vomiting, diarrhea, depression, anorexia, serous to mucopurulent oculonasal discharge
- Clinical pathology: Lymphopenia, thrombocytopenia, regenerative anemia, hypoalbuminemia, hypergamma- and alpha-globulinemia
- Later (1-4 weeks): Neurologic disease (seizures, cerebellar or vestibular ataxia, paraparesis, myoclonus); may see minimal or no signs of epithelial infection and only neurologic signs in some dogs
- Late manifestations: Hyperkeratosis of footpads and nose, enamel hypoplasia, “old dog encephalitis” (progressive neurologic disease)
TYPICAL GROSS FINDINGS:
- Integument: Hyperkeratosis of footpads and nose; +/- secondary pyoderma (pustular dermatitis, especially ventral abdomen)
- Lungs: Patchy red-tan, rubbery subpleural and marginal lesions (bronchointerstitial pneumonia); may be edematous and consolidated (secondary bronchopneumonia)
- Eyes/conjunctiva: Conjunctivitis, keratitis
- Lymphoid tissues: Tonsillar enlargement, thymic atrophy
- Teeth: Enamel hypoplasia
- Bone: Impaired osteoclastic resorption of the primary spongiosa (necrotic osteoclast)
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Eosinophilic intracytoplasmic (IC) and/or intranuclear (IN) inclusion bodies:
- Most numerous 10-14 days PI
- Most obvious in brain (often INIBs) and epithelium (usually ICIBs), especially in urinary bladder; less obvious in lymphoid tissues
- Integument: Orthokeratotic and/or parakeratotic hyperkeratosis of footpad, nose, rarely haired skin
- +/- epidermal syncytia
- +/- INIBs / ICIBs in epithelial cells and syncytia
- +/- secondary pustular dermatitis (pyoderma)
- Lungs: Bronchointerstitial pneumonia
- Patchy bronchiolar necrosis/attenuation
- IBs are most obvious in bronchial/bronchiolar epithelium (persist longer than in neural tissues)
- Scant suppurative exudate in airways
- Alveoli: Filled with edema, fibrin, mononuclear cells, necrotic epithelium; type II pneumocyte hyperplasia; septa expanded by mononuclear cells; alveolar epithelial syncytial cells
- Central nervous system:
- White matter: Demyelination of white matter tracts (most severe in cerebellum, rostral medullary velum, optic tracts, spinal cord, surrounding the fourth ventricle)
- Gray matter (lesions less common than white matter lesions): INIBs +/- ICIBs in neurons -> neuronal necrosis -> mononuclear infiltrate surrounding necrotic neurons -> nonsuppurative perivascular encephalitis +/- mild meningitis
- Old-dog encephalitis: INIBs in astrocytes and neurons; nonsuppurative perivascular encephalitis; neuronal necrosis; viral antigen detectable by IHC, but cannot isolate virus from the brain
- Eyes: Early conjunctivitis +/- ulcerative keratitis -> later retinal edema, ganglion cell degeneration, photoreceptor loss, perivacular mononuclear inflammation, INIBs in ganglion cells and glial cells-> neuronal loss, retinal scarring, retinal pigment epithelium proliferation; optic nerve – early papilledema -> later gliosis and demyelinating neuritis
- Lymphoid tissues: Early lymphoid depletion and lymphocytic necrosis -> syncytia +/- IBs -> histiocytic cell hyperplasia
- Teeth: Cystic degeneration of ameloblastic epithelium, syncytia and ICIBs -> enamel defects / hypoplasia
- Other epithelia (urinary bladder; renal pelvis; gastric surface, chief, and parietal cells; cholangiolar epithelium; pancreatic ductular epithelium; epididymis; testis): Degeneration, mononuclear infiltrates, ICIBs +/- INIBs
- Heart: Myocardial necrosis and mineralization
- Bone (experimental): Osteoclast necrosis -> persistent primary spongiosa
- Blood smear: 2-4 um diameter blue-grey inclusion bodies in RBC on modified Wright-stained blood film; eosinophilic inclusion bodies in RBC and leukocytes in Romanowsky-type stain.
ADDITIONAL DIAGNOSTIC TESTS:
- Virus isolation, immunohistochemistry (IHC), fluorescent antibody test
- IHC on skin lesions shows CDV antigen at all levels of the epidermis but most abundant in stratum spinosum, granulosum, and in epithelium of eccrine sweat glands; rare in basal layer
DIFFERENTIAL DIAGNOSIS (for cutaneous lesions):
- Idiopathic nasodigital hyperkeratosis
- Immune mediated diseases (pemphigus vulgaris, bullous pemphigoid, lupus erythematosus, toxic epidermal necrolysis): Lack many systemic signs, more widespread skin lesions
- Parakeratosis in dogs:
- Thallium toxicosis: Swollen paws may resemble hard pad disease, but pattern of cutaneous lesions is distinct (begin at lip commissures or nasal cleft (or ear margins) > expand over face and head > later involve interdigital skin, footpads, axillae, inguinal areas, perineum, lateral extensor surfaces)
- Superficial necrolytic dermatitis (hepatocutaneous syndrome): Histologic lesions virtually pathognomonic [red (parakeratotic hyperkeratosis), white (superficial epidermal edema and acanthosis), and blue (basal cell hyperplasia)]
- Zinc-responsive dermatosis: Two clinical syndromes [syndrome I = inherited (Alaskan malamutes and Siberian huskies); syndrome II = rapidly-growing, large breed dogs with relative dietary Zn deficiency]
- Generic dog food dermatosis: Deficiency of multiple trace minerals, vitamins, and amino acids; rapid onset; systemic illness is common
- Lethal acrodermatitis of bull terriers: Autosomal recessive inheritance; pathogenesis of low plasma Zn disease unknown but copper deficiency may play a role; growth retardation, progressive dermatopathy, paronychia, diarrhea, bronchopneumonia, death by 18 months of age; thymic and lymph node hypoplasia and giant cell bronchopneumonia are important findings
- Vitamin A responsive dermatosis: Lesions primarily in chest and abdomen; histologically there is marked follicular keratosis
- Sarcoptic mange and flea-hypersensitivity dermatitis may also have diffuse parakeratosis, but usually many more lymphocytes, eosinophils, plasma cells, and/or mast cells are present
- Other species affected:
- Canidae – dingo, fox, coyote, jackal, wolf
- Mustelidae – weasel, ferret, mink, skunk, badger, marten, otter
- Ferrets particularly susceptible
- Procyonidae – raccoon, coati
- Ursidae – bears, panda
- Felidae – lions, leopards, cheetahs, tigers, civets
- Large felids: Fatal neurologic disease due to a distinct CDV variant
- African lions contract the virus from hyenas and feral dogs
- Hard pads are rare – CNS signs most common
- Phocids (e.g. Baikal seals) susceptible to CDV and phocine distemper virus
- Marmota: Asian marmots
- Other morbilliviruses:
- RP: Primarily large ruminants – oral mucosal erosions, diarrhea
- PPRV: Small ruminants – respiratory signs, oral mucosal erosions, diarrhea
- Cetacean morbillivirus (dolphin morbillivirus and porpoise morbilliviruses are two strains of the same species): Closely related to RP and PPRV
- Phocine distemper virus (PDV): Closely related to CDV
- Measles virus: Humans and non-human primates
- Cantile C, Youssef S. Cytopathology of nervous tissue. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Saunders Elsevier; 2016: 384-385.
- Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:574-576.
- Craig LE, Dittmer KE, Thompson KG. Structure and function of bone tissue. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Saunders Elsevier; 2016: 104-105.
- Deem SL, Spellman LH, Yates RA, et. al. Canine distemper in terrestrial carnivores: a review. J Zoo Wildl Med. 2000;31(4):441-451.
- Gelberg HB. Alimentary system and the peritoneum, omentum, mesentery, and peritoneal cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby Elsevier; 2016: 545-546.
- Greene CE, Appel MJ. Canine distemper. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis, MO: Saunders Elsevier; 2006:25-41.
- Grone A, Doherr M, Zurbriggen A. Canine distemper virus infection of canine footpad epidermis. Vet Dermatol. 2004;15:159-167.
- Grone A, Doherr M, Zurbriggen A. Up-regulation of cytokeratin expression in canine distemper virus-infected canine footpad epidermis. Vet Dermatol. 2004;15:168-174.
- Grone A, Engelhardt P, Zurbriggen A. Canine distemper virus infection: proliferation of canine footpad keratinocytes. Vet Pathol. 2003;40:574-578.
- Koutinas AF, Baumgarnter D, Tontis Z, et. al. Histopathology and immunohistochemistry of canine distemper virus-induced footpad hyperkeratosis (hard pad disease) in dogs with natural canine distemper. Vet Pathol. 2004;41:2-9.
- Murphy FA, Gibbs EPJ, Horzinek MC, et. al. Veterinary Virology. 3rd ed. San Diego, CA: Academic Press; 1999:167-169.
- Origgi FC, Sattler U, Pilo P, Waldvogel AS. Fatal combined infection with canine distemper virus and orthopoxvirus in a group of Asian marmots (Marmota caudata). Vet Pathol. 2013;50(5):914-920.
- Pope JP, Miller MC, Riley EA, Wilkes RP. Characterization of a novel canine distemper virus causing disease in wildlife. J Vet Diagn Invest. 2016;28(5):505-513.
- Scott DW, Miller Jr. WH, Griffin CE. Muller and Kirk’s Small Animal Dermatology. 6th ed. Philadelphia, PA: W.B. Saunders Co; 2001:523-524.
- Techangamsuwan S, Banlunara W, Radtanakatikanon A, Sommanustweechai A, Siriaroonrat B, Lombardini ED, Rungsipipat A. Pathological and molecular virologic characterization of a canine distemper outbreak in farmed civets. Vet Pathol. 2015;52(4):724-31.
- Townsell MY, Pohlman LM, Harkin KR. Pathology in Practice. J Am Vet Med Assoc. 2015;246(6):613-615.
- Zachary JF. Mechanisms of microbial infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Mosby Elsevier; 2016: 225-226.