JPC SYSTEMIC PATHOLOGY
Signalment (JPC 1368758): 3-year-old German shepherd dog
HISTORY: Euthanized because of generalized chronic dermatitis
HISTOPATHOLOGIC DESCRIPTION: Haired skin: Multifocally within the dermis there is perifolliculitis composed of moderate numbers of lymphocytes, plasma cells, macrophages, and fewer neutrophils. Inflammatory cells occasionally infiltrate and partially disrupt follicular epithelium (interface mural folliculitis), and there is hydropic degeneration and single-cell necrosis of follicular epithelial cells. Filling and expanding follicles are segments of arthropods, up to 40 um in diameter and 200 um in length, with a thin, eosinophilic, chitinous exoskeleton, short jointed appendages, a hemocoel, striated muscle, and digestive and reproductive tracts. There are few pigment-laden melanomacrophages surrounding follicles (pigmentary incontinence). Diffusely, there is moderate follicular and epidermal hyperplasia with orthokeratotic hyperkeratosis. Apocrine glands are mildly ectatic, occasionally hyperplastic and filled with varying amounts necrotic debris.
Tongue: No significant lesions.
MORPHOLOGIC DIAGNOSIS: Haired skin: Dermatitis, perifolliculitis, and interface mural folliculitis, lymphoplasmacytic and histiocytic, chronic, multifocal, moderate, with epidermal and follicular hyperplasia, hyperkeratosis, and intrafollicular mites, etiology consistent with Demodex canis, German shepherd dog, canine.
ETIOLOGIC DIAGNOSIS: Follicular demodicosis
CAUSE: Demodex canis
CONDITION: Demodectic mange
CONDITION SYNONYMS: Red mange; follicular mange
Signalment (JPC 1051577): A pig
HISTOPATHOLOGIC DESCRIPTION: Haired skin and subcutis: Diffusely, hair follicles are markedly ectatic, up to 2‑3 mm in diameter, and lined by degenerate epithelial cells. These follicles are expanded and filled with numerous elongate mites that are 40 um wide and 150-200 um long, with a thin, eosinophilic, chitinous exoskeleton, short jointed appendages, a hemocoel, striated muscle, and digestive and reproductive tracts. Multifocally surrounding hair follicles, sebaceous glands, and blood vessels are few lymphocytes, plasma cells, macrophages, and eosinophils. Multifocally, apocrine glands are mildly ectatic and filled with numerous neutrophils. Diffusely, the epidermis and hair shafts are absent (due to slaughter scalding and processing).
MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Follicular ectasia, multifocal, marked, with periadnexal and perifollicular lymphoplasmacytic and eosinophilic dermatitis, moderate neutrophilic apocrine adenitis, and numerous intrafollicular mites, etiology consistent with Demodex phylloides, breed not specified, porcine.
ETIOLOGIC DIAGNOSIS: Follicular demodicosis
CAUSE: Demodex phylloides
CONDITION: Demodectic mange
CONDITION SYNONYMS: Red mange; follicular mange
- Common skin parasites of numerous mammalian species; tend to be host specific; more than 140 species have been identified in hair follicles, sebaceous glands, Meibomian glands, and ceruminous glands; Demodex gatoi in cats lives within the stratum corneum rather than in follicles.
- Demodex spp. are normal inhabitants of canine and human hair follicles and sebaceous glands of humans and dogs and probably most mammals
- Significance of infestations is variable and depends on individual host‑parasite relationships
- Canine demodicosis (two forms):
- Localized demodicosis (one to several small lesions, usually resolves spontaneously) and generalized demodicosis (usual unset between 3 and 18 months of age; often severe and linked to immunosuppression; defined by the presence of either many localized lesions, involvement of an entire body region (e.g. face), or with complete involvement of two or more feet)
- Adult-onset generalized demodicosis, defined as onset at 4 years of age or older, is associated with underlying disease including hypothyroidism, hyperglucocorticism, leishmaniasis, malignant neoplasia, and immunosuppressive therapy; often no underlying disease is diagnosed at the time of demodicosis diagnosis but may be diagnosed weeks to months later
- Two species of demodex mites: Demodex canis is the most common, and injai. (D. cornei, the short-tailed mite, has been determined to be a morphologic variant of D. canis)
- injai breed predilection: West Highland white terrier, shih tzu, and wirehaired fox terrier; typically middle aged and older, generalized demodicosis, and prior history of allergic dermatitis, immunosuppression, or immunomodulatory therapy; one case report of otitis externa
- Life cycle (approximately 20-35 days) is similar for all Demodex species
- Mites are obligate parasites with entire life cycle spent on the host, usually in hair follicles or rarely in sebaceous glands
- Females lay fusiform eggs that hatch into six-legged larvae; there are three instar/nymph stages (eight legs) before adulthood (eight legs)
- Transmission is by direct contact from mother to offspring during nursing
- Normal immune response hypothesis: Toll-like receptor 2 (TLR2) membrane proteins of keratinocytes recognize mite chitin, eliciting innate immune response inhibiting mite proliferation without inducing an inflammatory response
- Diseased state is multifactorial and not completely understood; associated with diverse pathologic conditions (neoplasia, endocrine, and metabolic disorders); factors predisposing dogs to generalized demodicosis include immune status, breed and lineage, age, length of hair coat, nutritional status, stage in estrus cycle, parturition, stress, endoparasitism, and debilitating disease
- Demodicosis is thought to be partially genetically mediated, because 1) it shows breed predilection (American Staffordshire terrier, Staffordshire bull terrier, and shar pei), and 2) one study showed association between generalized juvenile demodicosis and certain DNA microsatellite markers; there are likely multiple genes involved
- Associated with several immunological abnormalities, including decreased T-cell function (termed T-cell exhaustion) but NOT decreased numbers; the T-cell exhausted phenotype is usually characterized by low production of supportive/stimulatory cytokines (e.g. IL-2 and IL-21), high levels of suppressive cytokines (IL-10 and TGF-β), and low numbers of circulating CD4+ lymphocytes (his also helps explain the lack of relapse after treatment)
- Disease is due to Type IV hypersensitivity: Perifollicular and peri-mite aggregates of T-helper cells, and perifolicular and mural cytotoxic T-lymphocytes (CD3+/CD8+) in generalized demodicosis
- There is no appreciable humoral immune response
- Recurring demodicosis is associated with increased IL-10, whichinhibits cytokine secretion by Th1 cells including IL-1, IFN-g, and TNF-β; has anti-inflammatory and suppressive effects on most hematopoietic cells, and inhibits antigen presentation by APCs.
- More severe immune suppression is associated with secondary bacterial pyoderma, leading to suppurative folliculitis and furunculosis
TYPICAL CLINICAL FINDINGS:
- Localized lesions appear as focally extensive, scaly, alopecic, erythematous or pustular rashes
- Generalized lesions are more common in juveniles (3-18 months)
- In demodectic pododermatitis, disease is confined to the paws and may be complicated by secondary bacterial infection; there may be a history of generalized demodicosis that healed except for foot lesions
TYPICAL GROSS FINDINGS:
- Alopecia and erythema; may be covered with fine silvery scales
- Periocular; oral commissures; forelegs; more rarely, trunk or rear leg lesions
- Bilateral pruritic ceruminous otitis externa
- Lesions may wax and wane over several months
- Numerous lesions on the head, legs, and trunk; progressively worsening into deep folliculitis and furunculosis with thick exudative crusts, especially with secondary Staphyloccus intermedius infection (also Pseudomonas aeruginosa and Proteus mirabilis)
- Marked peripheral lymphadenopathy
- May progress to chronic pyogenic demodectic pododermatitis
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Adult arthropods that are elongate, 40 x 250-300 um (shorter and longer forms exist), possess a thin chitinous exoskeleton, short jointed appendages, striated muscle, a body cavity (hemocoel), and intestinal and reproductive tracts
- Adults and nymphs have 4 pairs of legs, larvae have 3 pairs of legs
- Eggs are elongated and ovoid
- Variable histologic appearance depending on the stage of the disease and presence of secondary bacterial infection, and variable numbers of mites are present (few to countless)
- Early uncomplicated lesions: predominantly lymphocytic mural interface folliculitis; lymphocytic infiltration of the isthmus and infundibulum with varying degrees of vacuolar degeneration and apoptosis of keratinocytes of the outer root sheath; follicular melanosis or pigment clumping in the outer rooth sheath; perifollicular pigmentary incontinence; perifolliculitis with infiltrates of plasma cells, macrophages, and lymphocytes with fewer mast cells and eosinophils; mural folliculitis may be present
- Mural infiltrating lymphocytes are CD8+ cytotoxic T-cells whereas perifollicular infiltrates are mixed CD4+ and CD8+ T-lymphocytes
- Follicles may contain numerous mites without folliculitis, indicating possible poor immune response
- Follicles containing large numbers of mites with build-up of mite products and marked follicular hyperkeratosis may cause follicular plugging; follicular plugging with follicular keratosis, mite proliferation, and folliculitis can lead to follicular rupture with release of mites, bacteria, sebum, keratin, and other irritants into the dermis stimulating a pyogranulomatous reaction (furunculosis)
- Bacterial proliferation (Staphylococcus spp.) often induces suppurative luminal folliculitis
- Epidermal changes include hyperplasia, orthokeratotic and parakeratotic hyperkeratosis, variable spongiosis, neutrophilic exocytosis, ulceration, crusting
- Later stages: Mural folliculitis consistently present; perifollicular mid to deep dermal and occasionally subcuticular granulomas that sometimes contain mite remnants; marked dermal fibrosis often with adnexal obliteration; mites or fragments of mites may be seen in subcapsular sinus of regional lymph nodes
- injai: Marked sebaceous gland hyperplasia, lymphoplasmacytic periadnexal dermatitis; very few if any mites seen
- In the absence of mites in sections, pigmentary incontinence around the follicular isthmus and hyperpigmentation of the outer root sheath at the same location strongly suggest demodicosis
For gross lesions:
- Generalized pyoderma may occur as a sequel to generalized demodicosis or as an independent entity
- Dermatophytosis; pustular dermatitis; acne; allergic contact dermatitis; pemphigus; epidermolysis bullosa simplex; incidental abrasions; localized seborrheic dermatitis
For histologic lesions:
- If mites are not present the lesion may be confused with bacterial furunculosis or dermatophytosis; however; if parafollicular granulomas are present, even if the mite is not present, demodicosis should be suspected until proven otherwise
- Dog – canis, D. injai
- Cat – cati (182-291µm, follicular involvement, similar presentation as D. canis, associated with diabetes mellitus, feline immunodeficiency virus, and squamous cell carcinoma), D. gatoi (shorter 91-108µm, stratum corneum involvement, pruritic, contagious), third unnamed species (139 +/- 4.5µm)
- Ox – bovis; D. ghanensis; D. tauri: Nodular demodicosis. Uncommon, worldwide; only D. bovis is known to cause clinical disease, assumed underlying immunocompromise (e.g. concurrent disease, poor nutrition, stress, genetic predisposition); economic consideration due to hide damage
- Gross lesions: Variable numbers of multiple cutaneous papules or nodules
- Goat – caprae: Nodular demodicosis; common; similar to cattle
- Sheep – ovis; D. aries: Nodular demodicosis; relatively rare; D. ovis in medium- to coarse-wooled sheep in Meibomian glands and sebaceous glands; has been associated with matted fleece/”stringy wool;” D. aries infests large sebaceous glands of vulva, prepuce, and nostrils
- Horse – caballi; D. equi: Commonly found in Meibomian glands, but disease is rare; associated with glucocorticoid administration and pituitary pars intermedia disfunction (PPID); D. caballi in pilosebaceous units of eyelid and muzzle, D. equi over body
- Pig – phylloides: Nodular demodicosis; uncommon, relatively unimportant compared to sarcoptic mange; in pilosebaceous units; economic loss (hide); small red macules develop into cutaneous nodules covered by surface scale
- Alpaca, llama – Rare
- Guinea pig – caviae
- Hamster – criceti; D. aurati
- Mouse – flagellurus (preputial/clitoral gland); D. lacrimalis (Meibomian gland); D. musculi: One study demonstrated an overgrowth of D. musculi in SCID mice,CD3E transgenic mice (lack mature T lymphocytes and natural killer cells), and Prad1 transgenic mice (overexpress human cyclin D1, manifest severe thymic hyperplasia)
- Another study demonstrated musculi demodicosis in a double-knockout mice lacking CD28 (a co-stimulatory inflammatory molecule) and STAT6 (involved in humoral immunity), whereas single knockouts of either did not have disease or overgrowth
- A 2016 study showed musculi demodicosis in BALB/c-Tg(DO11.10)II13™ mice (defect in Th2 immunity) although mites were identified in parental and other strains without developing clinical signs
- Reports of demodicosis in wild ruminants, black bears, raccoons, ferrets, and Armenian hamster
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