Treatment of Severe Adverse Cutaneous Drug Reactions With Human Intravenous Immunoglobulin in Two Dogs
Severe adverse cutaneous reactions were documented in two dogs with acute skin lesions and systemic signs after exposure to several oral and injectable drugs. Because of the high morbidity and mortality rates of many severe cutaneous drug reactions and a poor response to supportive care, wound management, and conventional immunosuppressive therapy, human intravenous immunoglobulin (IVIG) was infused on 2 consecutive days (1 g/kg per day) after informed consent was received. Human IVIG, with supportive care, resulted in rapid resolution of dermatological and systemic signs in both dogs; this treatment may be considered in other cases of severe cutaneous drug reactions.
Introduction
Severe, adverse cutaneous drug reactions are uncommon events in dogs and may include erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and the Stevens-Johnson–toxic epidermal necrolysis-overlap syndrome.1 In veterinary dermatology, differentiation of these diseases has been confusing and difficult. A classification scheme has been created for dogs based on the human scheme for these diseases.1,2 Histopathology is used to support a diagnosis of these disorders, and clinical signs, historical information, and histopathology together are combined to more specifically define the dermatological disease present.1 Diseases in the erythema multiforme–toxic epidermal necrolysis complex are characterized by variable but extensive detachment of the epidermis (i.e., full-thickness), systemic clinical signs, and high mortality rates.3,4 Erythema multiforme involves detachment of <10% of the body surface area and usually affects localized areas. Stevens-Johnson syndrome involves detachment of <10% of the body surface area, with widespread erythematous or purpuric macules. The Stevens-Johnson–toxic epidermal necrolysis-overlap syndrome involves detachment of 10% to 30% of the body surface, with widespread macules. Toxic epidermal necrolysis involves detachment of >30% of the body surface, with widespread macules.2
Although treatment of these diseases, especially toxic epidermal necrolysis and Stevens-Johnson syndrome, has been relatively unrewarding in all species, removal of the triggering agent (i.e., offending drugs) has been combined with aggressive supportive care (e.g., intravenous [IV] fluids and local skin management), with some success.3,4 In addition, immunosuppression has been attempted; however, standard immunosuppressive agents (e.g., glucocorticoids, azathioprine) have not been documented as beneficial.3–5
Recently, human IV immunoglobulin (IVIG) has been reported to be effective and safe in the treatment of a few people with toxic epidermal necrolysis.6–8 Human IVIG is a sterile, purified, immunoglobulin preparation consisting of >90% immunoglobulin G (IgG), with negligible amounts of IgM and IgA.a Human IVIG is approved for use in people and is used to supplement immunoglobulins during immunodeficiencies and to treat various immune-mediated disorders, but its immunosuppressive mechanism of action has not yet been completely elucidated.a
Human IVIG is not yet approved for the treatment of cutaneous drug reactions in humans, and although it is not approved for use in animals, it has been used to treat a few dogs with immune-mediated hemolytic anemia.9 Recently, a cat with life-threatening erythema multiforme and a dog with Stevens-Johnson syndrome have also been successfully treated with human IVIG.10,11 The purpose of this report is to describe two cases of serious adverse cutaneous and systemic drug reactions in dogs that rapidly and completely responded after the administration of human IVIG.
Case Reports
Case No. 1
A 5-year-old, 5-kg, castrated male Yorkshire terrier was presented to the Emergency Service at the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania (MJR-VHUP) with progressive, unresponsive anorexia, vomiting, hematochezia, and lethargy of 1 week’s duration. The dog had a 1-year history of intermittent diarrhea of unknown etiology, which was controlled with intermittent metronidazole. Six days prior to presentation, the diarrhea recurred and the dog was treated with oral metronidazole, subcutaneous injections of metoclopramideb (0.2 mg/kg q 12 hours), enrofloxacin, gentamicinc (2 mg/kg q 12 hours), and fluids (0.9% sodium chloride). The diet was changed (to Hill’s I/D),d and cimetidinee (10 mg/kg q 12 hours) and prednisonef (0.5 mg/kg q 12 hours) were also administered orally.
Three days prior to referral, an open, ulcerative sore was noted on the right front leg, which was managed with warm compresses. Laboratory tests performed by the referring veterinarian revealed an elevated serum alkaline phosphatase (1241 U/L, reference range 23 to 212 U/L), hyperbilirubinemia (3.6 mg/dL, reference range 0.0 to 0.9 mg/dL), hypoalbuminemia (2.2 g/dL, reference range 2.7 to 3.8 g/dL), hyponatremia (139 mmol/L, reference range 144 to 160 mmol/L), and hypochloremia (105 mmol/L, reference range 109 to 122 mmol/L). Results of an adrenocorticotropic hormone-stimulation test were normal, so the serum electrolyte abnormalities were thought to be related to losses associated with the diarrhea.
Because of a lack of response and progression of local and systemic signs, the dog was referred 1 week after the onset of illness. The dog was depressed, and the mucous membranes were icteric and dry. Petechiations and ecchymoses were found on the ventral trunk. A small area of skin on the right forelimb was denuded. A complete blood count [see Table] revealed a moderate neutropenia with marked toxic changes in the granulocytes, thrombocytopenia, and a few circulating mast cells. Previous serum biochemical abnormalities were confirmed, except for normalization of the serum sodium concentration, a marked increase in total bilirubin, and severe hypokalemia [see Table]. A urinalysis showed dilute urine (specific gravity of 1.002) and bilirubinuria. Differential diagnoses that were initially considered included hepatopathy (e.g., hepatocutaneous syndrome), posthepatic biliary tract disease (e.g., pancreatitis), sepsis, immune-mediated disorders, and other systemic illnesses. The dog was rehydrated with a crystalloid solutiong at 10 mL/kg per hour. A colloid solutionh (1 mL/kg per hour) and 120 mL of dog erythrocyte antigen (DEA) 1.1- negative fresh-frozen plasma were administered for their oncotic effects. All previous medications were discontinued, and IV metronidazolei (10 mg/kg q 8 hours), famotidinej (0.5 mg/kg q 12 hours), and ampicillink (22 mg/kg q 8 hours) were instituted instead. Sucralfatel (0.25 g per os [PO] q 6 hours) was also started.
The next day, a large lesion (12 to 15 × 7 to 8 cm) of necrotized skin was detected on the ventral chest. It was covered by an eschar and extended cranially to include the ventral neck [Figures 1A, 1B]. A similar lesion on the proximal right front leg (2 × 1 cm) was also noted. An abdominal ultrasound showed mild peritoneal effusion. The liver was isoechoic to the spleen but had normal margins. Bacterial cultures of blood (aerobic and anaerobic) and urine (aerobic) were negative, as were serum titers for Ehrlichia canis, Rickettsia rickettsi, Borrelia burgdorferi, and Leptospira spp. Based upon the negative laboratory findings, the progressive skin lesions, and recent exposure to multiple medications, a severe drug eruption was considered likely.
Because of the possibility of a drug reaction, the ampicillin was withdrawn. Systemic antibiotics were changed to amikacinm (15 mg/kg IV q 24 hours) and clindamycinn (10 mg/kg IV q 8 hours) because of concerns about sepsis. Progressive hypoalbuminemia occurred [see Table], so fresh-frozen plasma transfusions (12 mL/kg IV q 8 to 12 hours) and hetastarch (1 mL/kg IV per hour) were continued. Butorphanolo (0.2 to 0.5 mg/kg IV or intramuscularly [IM] q 4 hours) was given for pain. Daily wet-to-dry bandages were applied to the skin lesions. At each bandage change, necrotic tissue was débrided.
On day 3 of hospitalization, a moderate, nonregenerative anemia was noted [see Table]. Immune-mediated red cell destruction was considered, but the direct Coombs’ test and an antinuclear antibody serum titer were both negative. The anemia was thought to be caused by gradual blood loss into the skin and gastrointestinal tract, and acute loss and inflammation may have explained the lack of a regenerative response. Cholestasis associated with sepsis was thought to be the cause of the hyperbilirubinemia, but prehepatic causes of both the anemia and hyperbilirubinemia could not be ruled out.
Histopathology of skin biopsies [Figure 2] collected on day 3 from the ventral abdomen and the proximal right fore-limb revealed severe, multifocal, necrotizing epidermitis and mild, focal, suppurative dermatitis under areas of full-thickness ulceration. A few degenerating granulocytes and pyknotic cells were seen within areas of parakeratin. Although toxic epidermal necrolysis is typically associated with minimal to no inflammation and is generally peracute, the histopathological findings in this dog, together with the clinical and laboratory findings, were most consistent with toxic epidermal necrolysis.2 Another consideration was that the skin reaction was a toxic epidermal necrolysis-like drug reaction and not toxic epidermal necrolysis specifically.
Because of the severity and progression of the skin lesions and lack of response to initial therapy, human IVIG was considered. After receiving informed consent from the owner, human IVIGa was administered as a 6% solution in 0.9% saline, at a dose of 1 g/kg IV over 4 hours on days 3 and 4. During the two administrations, food, IV fluids, and all medications were withheld to diminish the likelihood of an adverse reaction, and the human IVIG infusions were well tolerated.
Three days after initiating human IVIG, the dog was brighter and began to eat and drink. The anemia became regenerative, but the dog remained thrombocytopenic [see Table]. The denuded skin appeared drier, and areas of healthy granulation tissue became evident. The edges of the wound appeared viable, as evidenced by pink tissue and blood vessels. This was the first time the wound showed any evidence of healing. Clindamycin, famotidine (0.5 mg/kg IV q 24 hours), and sucralfate (0.25 g PO q 6 hours) were continued. On day 11, the dog was discharged from the hospital on clindamycin, sucralfate (for 10 days), and every-other-day bandage changes.
On reexamination at the hospital on day 29, the dog was doing well. The large, open wounds were contracting, with healthy beds of granulation tissue [Figures 3A, 3B]. All laboratory test results had returned to normal. On day 43, the site of the original skin damage was only a large scar, and the clindamycin was discontinued. The dog remained healthy throughout the following 3-year observation period.
Case No. 2
An 11-year-old, 27-kg, spayed female, mixed-breed dog was referred to the MJR-VHUP with a history of progressive, ulcerative skin lesions of the head, neck, and fore-limbs. Sixteen days prior to presentation, the dog was anesthetized with ketamine, diazepam, and thiopental by the referring veterinarian for dental care and an excisional biopsy of a benign interdigital mass of the right forelimb. The dog recovered from anesthesia uneventfully and was given a subcutaneous injection of a sustained-release formulation of moxidectin as a heartworm preventive.p
Ten days later, the referring veterinarian noted a few erythematous macular lesions on the head and neck. Because of the rapid progression of the skin lesions, treatment with parenteral triamcinolone acetate and an oral antihistamine and prednisone combination (i.e., Temaril P) was initiated. The macular lesions became ulcerative, and the dog developed peripheral edema of the limbs. Cefazolinq (22 mg/kg IV) was also begun prior to referral.
At the time of referral, multifocal, intensely erythematous, ulcerative lesions were present on the skin of the face, ventral abdomen, and forelimbs [Figure 4]. Lesions were also present on the inner surface of the pinnae [Figure 5] and over the dorsal neck. Lesions were estimated to affect >50% of the body surface area, with extensive epidermal detachment over 10% to 30% of the body surface.
Routine laboratory test results were normal, except for mild hyperkalemia (potassium 6.0 mmol/L, reference range 3.9 to 4.9 mmol/L) and elevated serum alanine aminotransferase (122 U/L, reference range 16 to 91 U/L) and alkaline phosphatase (1325 U/L, reference range 24 to 174 U/L). Skin scrapings for ectoparasites were negative. Cytology of ear canal exudates and direct impression smears of perioral skin revealed pyogranulomatous inflammation with intracellular and extracellular cocci. Bacterial cultures were positive for Staphylococcus intermedius and nonhemolytic Streptococcus spp. Multiple, 6-mm, punch skin biopsies were obtained from the margins of affected areas.
Given the dog’s recent history of several drug exposures and the type of dermatological lesions present, an adverse cutaneous drug reaction was suspected. The skin lesions were most consistent with toxic epidermal necrolysis or Stevens-Johnson syndrome. Other differential diagnoses included pyoderma, pemphigus foliaceous or vulgaris, systemic lupus erythematosus, cutaneous vasculitis, and eosinophilic dermatitis with edema (canine Wells’-like syndrome).5
Histopathological evaluation of the skin biopsies revealed single-cell necrosis of keratinocytes within all layers of the epidermis and the outer root sheath of the hair follicles [Figure 6]. Multifocal, marked lymphocytic exocytosis in close association with apoptotic keratinocytes (i.e., satellitosis) was seen, and the epidermis contained areas of necrosis and ulceration. A mild infiltrate of mononuclear cells was noted in the superficial dermis, and the blood vessels in this layer were dilated. The histological findings were diagnostic for one of the erythema multiforme or toxic epidermal necrolysis-type diseases. These findings, along with the extensive epidermal detachment that involved between 10% and 30% of the body surface, were consistent with the Stevens-Johnson–toxic epidermal necrolysis-overlap syndrome.1,12
The dog was started on IV crystalloid fluids,g cephalexinr (22 mg/kg PO q 12 hours), and pentoxifyllines (12 mg/kg PO q 8 hours). Topical silver sulfadiazine (0.1% spray) was applied to affected areas. Hydromorphonet (0.1 mg/kg IV) was administered every 6 hours for pain. The dog became increasingly anorexic and lethargic and developed severe erythematous and exudative ulceration of the ventral abdominal skin on the 3rd day of hospitalization [Figure 7]. Laboratory results were unchanged except for corrected hyperkalemia.
Given the severity of the skin lesions and the concern about sepsis secondary to bacterial colonization of the skin, glucocorticoids were not administered. Azathioprine was not thought to have a rapid enough onset of action for use in this case.12,13 Informed client consent was obtained, and the dog was administered two 4-hour infusions of human IVIG (1 g/kg) on 2 consecutive days, without any untoward effects.
Three days after initiating IVIG therapy, an overall clinical improvement was noted. The erythema was less intense on the pinnae, the muzzle, the periorbital skin, and the ventral inguinal areas. The skin lesions were no longer exudative, and the areas of ulceration were covered by a layer of thick, dry crust [Figure 8]. Within 7 days of the IVIG infusions, the skin lesions improved with less exudation, ulceration, and erythema. The dried crusts were shedding to reveal a reepithelialized epidermis [Figures 9A, 9B]. At this time, the dog developed pruritus. Prednisonef (0.9 mg/kg PO q 12 hours) and azathioprineu (2.2 mg/kg PO q 48 hours) were started. The plan was to taper the prednisone, leaving the azathioprine as an immunomodulating agent to prevent relapse after the IVIG had been completely metabolized.
Three weeks after the IVIG infusions, dermatological evaluation revealed several new, small, erythematous lesions over the caudal dorsal trunk and some small, multifocal, firm, white papules over the ventral inguinal area. Cytological evaluation of skin scrapings of these intact papules revealed crystalline amorphous debris, with no microorganisms or white blood cells. Calcinosis cutis secondary to the administration of prednisone was suspected, although recurrence of the overlap syndrome could not be ruled out. The prednisone was quickly tapered over the next 2 weeks, and the new lesions resolved within 10 days. The azathioprine therapy was discontinued after 6 months, and the dog has been clinically normal over the following 3-year observation period.
Discussion
Despite supportive care, wound management, and immunosuppression, toxic epidermal necrolysis and the overlap syndrome in humans have been associated with a high degree of morbidity and mortality.14 The same appears to be true in dogs, although no formal studies have been published. Based upon the recent success of IVIG therapy in humans with toxic epidermal necrolysis, the two dogs of this report were treated with human IVIG, and the treatment was successful.
The mechanism of action of toxic epidermal necrolysis and the overlap syndrome is thought to be secondary to Fas and its ligand (FasL) interaction causing keratinocyte apoptosis.15,16 Fas is a transmembrane protein cell surface receptor, which upon recognition of its ligand, rapidly triggers cell destruction via apoptosis.16 Fas is expressed by keratinocytes, and in humans with Stevens-Johnson syndrome and toxic epidermal necrolysis, the peripheral blood mononuclear cells secrete high levels of FasL.15 Delivery of FasL to keratinocytes via peripheral blood circulation provides high concentrations of the ligand, thus inducing the death signal.15 Human IVIG has been shown to have numerous immunomodulating properties, including blockade of Fc receptors on phagocytes (leading to reduction of the clearance of autoantibody-coated targets), modulation of cytokine synthesis, complement inhibition, and interference with T and B cell functions.17,18 In addition, at least some preparations contain anti-Fas antibodies that are able to block Fas-FasL binding in vitro and thereby inhibit the death signal of apoptosis.16,19,20 This anticell death effect of human IVIG may be one mechanism by which it halts toxic epidermal necrolysis and related allergic skin and systemic reactions. Recently, some investigators have suggested that Fas-FasL binding may not be the primary mechanism of toxic epidermal necrolysis, and thus human IVIG may have other mechanisms for its therapeutic effects in these people. A recent study in humans suggests that the pathogenesis of toxic epidermal necrolysis is directly related to drug-specific, major histocompatibility complex class I-restricted, perforin/granzyme-mediated cytotoxicity.21 This would suggest that in addition to inhibition of Fas-FasL interaction, an alternate mechanism of action of IVIG for treatment of these adverse cutaneous drug reactions is possible. In the two dogs described here, both proposed mechanisms could explain the dramatic beneficial responses seen.
In dogs, drugs that have been associated with toxic epidermal necrolysis include cephaloridine, levamisole hydrochloride, and 5-fluorocytosine.4 As with both cases of this report, the precise cause of the cutaneous drug reaction may not always be identified; hence, management is aimed at removal of all possible offending drugs. The first dog had repeatedly received metronidazole; thus, the cutaneous reaction may have occurred rapidly following reexposure. This dog also received multiple other drugs over a brief period of time (i.e., 6 days)—none of which have been previously associated with toxic epidermal necrolysis. In case no. 2, the administration of injectable moxidectin 10 days prior to the onset of the skin lesions suggested it may have been the trigger. However, this animal was also exposed to anesthetic agents at the same time, so without a challenge study (which was considered unethical), it was not possible to determine the specific inciting cause. Based upon consultation with the manufacturer of moxidectin, this is the first report of any severe adverse cutaneous drug reaction temporally related to administration of that drug.v
General recommendations for the management of adverse cutaneous drug reactions in dogs and people consist of immediate drug withdrawal and supportive measures, such as fluid therapy, antibiotics, local wound treatment, and immunosuppressive drugs.3,4,25,26 Drug withdrawal as the first line of treatment can be difficult in many cases, because the offending drug may not be known or may have long-lasting effects. In case no. 1, the definitive cause was uncertain; therefore, most drugs were immediately withdrawn when the suspicion of a drug reaction arose, and drugs with different mechanisms of action were chosen for supportive management. In case no. 2, the long-acting effects of moxidectin made immediate withdrawal impossible. However, case no. 2 responded completely to human IVIG, and the animal remained in remission throughout the following months while moxidectin was being metabolized.
The aggressive supportive care provided to the dogs in this report was similar to that given to severe burn cases. Fluid, electrolyte, and colloid replacements were administered in large quantities to restore those lost through the skin.3,4,25,26 Although not used in the cases reported here, enteral or parenteral feedings may be utilized to provide nutritional support. Intravenous, broad-spectrum antibiotics may be indicated if sepsis is highly suspected; these should be directed initially at Staphylococcus organisms and then at gram-negative rods, which colonize the skin secondarily.3 Antibiotics should be chosen carefully to prevent further skin reactions, and they should be from a different class of drugs than the suspected triggering agent. The skin wounds are best treated conservatively, and aggressive surgical debridement is not generally recommended.3,25 As with case no. 1, wounds may require some repeated debridement with multiple dressing changes.
Very little information exists in the veterinary literature regarding immunosuppression in the treatment of adverse cutaneous drug reactions. There is controversy over its use in humans with these diseases.25,26 It is important to differentiate toxic epidermal necrolysis from the other immune-mediated dermatological disorders of dogs that greatly benefit from glucocorticoids, such as the pemphigus complex and systemic lupus erythematosus.5 In case no. 2, because of the long-lasting effects of the inciting drug and reports of success in people with immunosuppression, azathioprine and prednisone were added for potential long-term control.3
Recently, high-dose human IVIG has been described as a promising therapy for suspected immune-mediated skin diseases in dogs and people.17–19,27–29 Recent case studies of IVIG use in humans with toxic epidermal necrolysis and Stevens-Johnson syndrome indicated rapid success, although no controlled, randomized trials have been performed.27,28 Cessation of epidermal detachment an average of 4.8 days after IVIG therapy was also seen in eight of nine humans with toxic epidermal necrolysis.27 In another study, treatment with IVIG resulted in rapid resolution of skin and mucosal detachment in 43 of 48 human patients, with 42 patients surviving the incident.28 That study reported an improved survival time for patients that received IVIG earlier in the course of their disease.28 In the two cases reported here, dermatological and overall clinical improvement was also noted within 3 days. Administration of the human IVIG was well tolerated, and the response was dramatic and almost immediate, with eventual complete resolution of all signs.
Despite success with the use of human IVIG in the dogs reported here, its widespread use in companion animals for adverse cutaneous drug reactions cannot yet be recommended. Larger prospective clinical trials are needed to determine the efficacy of IVIG for treatment of severe erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and related adverse cutaneous drug reactions in dogs.
Conclusion
Two dogs with suspected severe, adverse cutaneous drug reactions were treated with human IVIG as part of their acute therapy, with a successful outcome. Based on the cases reported here and elsewhere, clinical trials to further assess the efficacy and safety of human IVIG are warranted in dogs.
Sandoglobulin; Sandoz Pharmaceuticals, East Hanover, NJ 07936
Metoclopramide; Baxter Healthcare Corp., Deerfield, IL 60015
Gentamicin; The Butler Company, Dublin, OH 43017
Hill’s I/D; Hill’s Pet Nutrition, Inc., Topeka, KS 66601
Cimetidine; Abbott Laboratories, North Chicago, IL 60064
Prednisone; West-ward Pharmaceutical Corp., Eatontown, NJ 07724
Normosol-R; Abbott Laboratories, North Chicago, IL 60064
Hetastarch; Abbott Laboratories, North Chicago, IL 60064
Metronidazole; Abbott Laboratories, North Chicago, IL 60064
Famotidine; Baxter Healthcare Corp., Deerfield, IL 60015
Ampicillin; Bristol-Myers Squibb Company, Princeton, NJ 08543
Sucralfate; Aventis Pharmaceuticals, Inc., Kansas City, MO 64137
Amikacin; The Butler Company, Columbus, OH 43228
Clindamycin; Abbott Laboratories, North Chicago, IL 60064
Torbugesic; Fort Dodge Animal Health, Fort Dodge, IA 50501
Proheart; Fort Dodge, Overland Park, KS 66210
Cefazolin; GC Hanford Mfg. Co., Syracuse, NY 13201
Cephalexin; Ceph International Corp., Carolina, Puerto Rico 00985
Pentoxifylline; Mylan Pharmaceuticals, Inc., Morgantown, WV 26505
Hydromorphone; Baxter Healthcare Corp., Deerfield, IL 60015
Azathioprine; Roxanne Laboratories, Columbus, OH 43216
Written communication from Steven F. Sundlof, DVM, PhD, Director, Center for Veterinary Medicine, Food and Drug Administration, Rockville, MD 20855
Acknowledgments
The authors thank Dr. Michael Goldschmidt and Dr. Elizabeth Mauldin, Department of Pathobiology, Veterinary Hospital of the University of Pennsylvania, for histological evaluation of skin biopsy specimens, as well as for their help in obtaining histopathological photomicrographs. The authors also thank Dr. Kevin Byrne for his help in the management of case no. 1, and Dr. Sharon Johnson for her contributions in the management of case no. 2.
Citation: Journal of the American Animal Hospital Association 42, 4; 10.5326/0420312
Citation: Journal of the American Animal Hospital Association 42, 4; 10.5326/0420312
Citation: Journal of the American Animal Hospital Association 42, 4; 10.5326/0420312
Citation: Journal of the American Animal Hospital Association 42, 4; 10.5326/0420312
Citation: Journal of the American Animal Hospital Association 42, 4; 10.5326/0420312
Citation: Journal of the American Animal Hospital Association 42, 4; 10.5326/0420312
Citation: Journal of the American Animal Hospital Association 42, 4; 10.5326/0420312
Citation: Journal of the American Animal Hospital Association 42, 4; 10.5326/0420312
Citation: Journal of the American Animal Hospital Association 42, 4; 10.5326/0420312
Photographs showing a severe, necrotizing skin lesion covering the proximal third of the ventral surface of the body and an area on the medial aspect of the right front limb of a 5-year-old Yorkshire terrier (case no. 1) with toxic epidermal necrolysis. The head is to the left in both photos. Figure 1B is a close-up of the ventrum.
Histopathological section of the skin biopsied from the ventrum of the dog in Figures 1A, 1B, revealing coagulation necrosis of the epidermis (above double arrowhead) resulting in a brightly eosinophilic, acellular layer. Reepithelialization is occurring (below double arrowhead) in areas of healing. Dermal inflammation is sparse. (Hematoxylin and eosin stain; bar=50 μm)
Ulcerative dermatitis of the face and pinnae of an 11-year-old, mixed-breed dog (case no. 2).
Histopathological section of a skin biopsy from the dog in Figure 4. Brightly eosinophilic cells (right upper arrow), which represent apoptosis of individual keratinocytes, are present throughout all levels of the epidermis. Lymphocytic exocytosis is occurring throughout the epidermis in close association with some of the apoptotic keratinocytes (lower left arrow). Vacuolar degeneration of the basal cell layer and a perivascular to interface mononuclear dermatitis are also present. (Hematoxylin and eosin stain; bar=50 μm)
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