Is black skin disease in dogs fatal
Congenital and Inherited Skin Disorders in Dogs
There are syndromes in which skin cells grow abnormally, resulting in scaling and thickening of the top layer of skin. Some of these syndromes are associated with various other inherited conditions and may be sex linked. Some involve only localized portions of the skin while others produce generalized signs.
Canine ichthyosiform dermatoses occur sporadically in a number of breeds, including Doberman Pinschers, Rottweilers, Irish Setters, Collies, English Springer Spaniels, Cavalier King Charles Spaniels, Golden Retrievers, Labrador Retrievers, American Bulldogs, and terriers (including Jack Russell Terriers). There is good evidence of a familial inheritance pattern for this condition in Jack Russell Terriers and Golden Retrievers. In dogs with ichthyosiform dermatosis, the body is covered with large scales that may flake off in large sheets. The nose and paws may be noticeably thickened with apparent discomfort. Treatment is difficult, but signs may be lessened with special shampoos or solutions. Some experimental treatments have been useful. Control of secondary infection is frequently required. Your veterinarian will prescribe the most appropriate treatment for your pet.
Familial footpad hyperkeratosis is a syndrome reported in Irish Terriers and Dogues de Bordeaux. Hyperkeratosis is increased thickness of the hard, outer layer of the skin. All footpads are involved starting at an early age. The disease is not usually present at birth (congenital). When the hyperkeratosis is severe, horns, cracks (fissures). and secondary infections cause pain and lameness. No other skin abnormalities are present. Treatment concentrates on relief of signs and often includes soaking footpads, applying softening lotions, and treatment of any bacterial infections.
Granulomatous sebaceous adenitis destroys the oil glands and, in some breeds of dogs, is associated with a severe oil discharge and hair loss. It is hereditary in Standard Poodles and possibly in Akitas. It first appears when the dog is a young adult. Noticeable skin thickening precedes the loss of normal hair kinkiness and progresses to patchy hair loss. Akitas tend to have more oiliness and less hair loss than Poodles. Response to treatment is inconsistent and incomplete. Mildly affected dogs are treated with medicated shampoos. Secondary infections are treated as needed. A medication called modified cyclosporine A may also be effective. Sudden resolution of signs has also been seen in some dogs.
Hereditary congenital follicular parakeratosis is a newly recognized syndrome affecting female Rottweilers and female Siberian Huskies. This is a severe defect of the process that forms the keratins that are a major component of skin. This syndrome is associated with various abnormalities in other areas of the body. Little is presently known about this syndrome.
Psoriasiform-lichenoid dermatosis affects young English Springer Spaniels. It is presumed that this syndrome is inherited (genetic in origin). The most obvious signs are red symmetric abnormalities consisting of small lumps on the skin and solid elevated areas near the ears or groin. The abnormalities are covered with scale and become increasingly thick and hard (hyperkeratotic) if left untreated. In some dogs, the abnormalities may eventually spread. Spontaneous improvement occurs in some dogs while in others, the signs come and go. In some dogs, antibiotic treatment or other medications provide relief. In most cases, however, psoriasiform-lichenoid dermatosis does not respond to treatment.
Cushings Disease in Dogs
If your older dog is drinking and urinating more than usual, it could be caused by a variety of reasons. One cause your veterinarian may test for is Cushings disease (CD), also known as hyperadrenocorticism. This condition, usually caused by a tumor in the pituitary gland, is far more common than we realize, but because of the complex diagnostic testing required, its underdiagnosed. Treatment is expensive and ongoing, and it requires consistent monitoring.
You may have heard of the stress hormone cortisol and the associated fight or flight response. Cortisol is controlled by the adrenal cortex, located on the outer layer of adrenal glands. These two peanut-sized glands, situated in front of the kidneys, produce hormones to help the body perform essential functions.
The pituitary gland, a tiny gland found at the base of the brain, releases adrenocorticotrophic hormone (ACTH), which in turn tells the adrenal glands to release cortisol, also called glucocorticoids. In a pet with CD, a tumor in the pituitary gland or, less commonly, in one of the adrenal glands, causes the cortex to release an excess amount of cortisol.
Symptoms of Cushings Disease
Often owners report that their first clue that something might have been wrong was their dog wanting to go out at night to urinate. The disease causes extreme thirst, so a dog with CD tends to drink tremendous amounts of water and urinate frequently. As the disease progresses, dogs lose muscle and become weak. Owners might notice a thinning of the skin, lesions on the skin, and hair loss on the flanks, neck, and perineum. Obesity and lack of energy are also symptoms.
Because it takes time at least one year for these symptoms to develop, and because the symptoms are often mistaken for common signs of aging, many dogs have the advanced form of CD before the owner even recognizes a problem exists.
Causes of Cushings Disease
Cushings disease is a naturally occurring syndrome, but it can also be caused by administering excessive amounts of prednisone or dexamethasone for prolonged periods. Chronic application of steroid-containing ear drops can also cause the condition because the medication is absorbed through the skin. Affected dogs develop symptoms that are identical to those of the tumor-based disease. This form resolves once the steroids are stopped.
Certain breeds are at a higher risk of developing CD. The Poodle, Dachshund, Boston Terrier, Boxer, and Beagle are some breeds to watch. Almost all patients are older than eight years when CD develops.
Diagnosis of Cushings Disease
Diagnosing CD is not easy and can be quite expensive. When a veterinarian suspects this disease, blood, and urine tests are needed to make the diagnosis. Dilute urine and an elevation of the liver enzyme alkaline phosphatase in the blood indicate that testing for CD may be necessary.
Cushings disease can be verified with an adrenocorticotropic hormone (ACTH) stimulation test. For this test, a blood sample is drawn from the patient, then he is given an injection of ACTH, and a second blood test is taken a few hours later. If the dogs cortisol level goes up a little, his adrenal response is normal. If it starts high and climbs even higher, a diagnosis of CD is confirmed.
The veterinarian may also use a second method, the dexamethasone suppression test, in which the dog receives an injection of the steroid dexamethasone. In a healthy dog, the cortisol level goes down over the following few hours because the steroid suppresses adrenal production. If the cortisol level fails to drop, it suggests there is a tumor not responding to the medication.
Ultrasound examinations also allow the veterinarian to determine whether or not a tumor is present, and if its located in the pituitary gland or the adrenal glands.
Treatment of Cushings Disease
The location of the tumor dictates which treatment to use. More than 90 percent of dogs with CD have a pituitary-gland tumor. This type of tumor is only millimeters in size and is often benign, but its problematic because it manufactures and releases uncontrolled quantities of ACTH, which, as explained above, stimulates the adrenal cortex to release excessive amounts of cortisol.
Though pituitary tumors are routinely removed in people, this surgical technique is still in its infancy in dogs. We treat most dogs with pituitary-based CD with medication. Mitotane (Lysodren) and trilostane (Vetoryl) are oral medications that selectively destroy part of the adrenal cortex so that although the pituitary gland tumor continues to release ACTH, cortisol levels remain normal. Careful monitoring is required to ensure that the drugs dont destroy all of the cortex and that the cortisol stays at a defined level.
Adrenal-based CD, which thankfully is the rare form of the disease, is more concerning and best treated with surgery. About one-half of these tumors are malignant, growing aggressively and metastasizing quickly. Surgical excision of a malignant adrenal tumor is unlikely to be curative. If it is a benign growth, surgery may cure it, but the surgery is a complicated procedure.
Once treatment has been initiated, the symptoms of CD should begin to dissipate, starting with a decrease in drinking in one week or so. It takes a little longer (several months) for the skin lesions to resolve.
Prognosis for Dogs With Cushings Disease
The average survival time for a dog with CD is about two years, with only 10 percent of patients living beyond the four-year mark. This statistic, however, does not mean that this disease causes death. Because CD is most often diagnosed in geriatric dogs, most die of unrelated causes brought on by aging.
Dr. Jeff Grognet is a veterinarian with a practice in British Columbia, Canada, who also teaches online veterinary assistant courses.
Case report: Uncommon immune-mediated skin disease involving systemic disorders in dogs
Front Vet Sci. 2022; 9: 915775.
Case report: Uncommon immune-mediated skin disease involving systemic disorders in dogs
,
1,2,
1,2and
1,2,*Soomin Kim
1Department of Veterinary Internal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
2BK21 Project Team, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
Yoonji Kim
1Department of Veterinary Internal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
2BK21 Project Team, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
Ha-Jung Kim
1Department of Veterinary Internal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
2BK21 Project Team, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
1Department of Veterinary Internal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
2BK21 Project Team, College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
Corresponding author.
Edited by: Tanmoy Rana, West Bengal University of Animal and Fishery Sciences, India
Reviewed by: Tara Piech, Zoetis Reference Laboratories, United States; Byeongteck Kang, Chungbuk National University, South Korea
This article was submitted to Veterinary Emergency and Critical Care Medicine, a section of the journal Frontiers in Veterinary Science
Received 2022 Apr 8; Accepted 2022 Jul 8.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Abstract
Case 1, a 6-year-old, spayed female Pug, presented with severe systemic urticaria, edema, and erythema. The dog had received a famotidine injection as a treatment for repeated vomiting in another hospital. On physical examination, hyperthermia was observed. Moderate pancytopenia, hypoalbuminemia, and increased CRP and D-dimer were also observed in blood tests. Hyposthenuric proteinuria, pulmonary interstitial infiltration, and hepatomegaly were found in other tests. In the histology of the skin, dermal edema and infiltration of inflammatory cells were observed. Therefore, she was diagnosed with acute systemic hypersensitivity. Case 2, a 13-month-old, neutered male Pembroke welsh corgi, presented with severe and patchy systemic ulcerative skin lesions. The dog had a history of soft feces and pain around the anus 2 days before. Thrombocytopenia, and increased CRP and D-dimer were observed in blood tests. In histology, epidermal necrolysis, separation of the epidermis and dermis, and infiltration of inflammatory cells were observed. Therefore, he was diagnosed with an immune-mediated disease with necrolysis dermatitis. Case 3, a 12-year-old, spayed female Pomeranian, presented with severe systemic alopecia, pustule, and crust on the skin. The dog had received an infection treatment from a local hospital. Severe regenerative anemia (hematocrit 15.3%, negative saline agglutination test, negative slide agglutination test, negative Coomb's test, prominent spherocytes) elevated liver enzymes, and increased CRP and D-dimer were observed in blood tests. On histopathology of the skin, pustules, acantholytic cells, and inflammatory cells were observed in the keratin layer of the epithelium. Therefore, she was diagnosed with Pemphigus foliaceus concurrent with immune-mediated hemolytic anemia. The 3 cases were diagnosed with fatal immune-mediated skin disease concurrently with hematological and systemic abnormalities. All the cases were treated with immune-suppressive drugs, prednisolone, and cyclosporine. In cases 2 and 3, the dogs also received human intravenous immunoglobulin as an immune modulator. The treatment was successful with significant improvements in all the 3 cases.
Keywords: immune mediated skin diseases, adverse drug reaction, Pemphigus foliaceus, dog, immune suppressive agents
Introduction
Immune-mediated skin diseases are rare but challenging diseases in small animals (1). They are reported to comprise 1.4% of all canine skin diseases and 1.3% of all feline skin diseases (2). Sometimes the condition spreads and targets multiple organs including systemic vessels in dogs. Such cases are life-threatening and their management could be challenging.
Adverse drug reaction (ADR) is an unintended and harmful response to a drug (3, 4). In humans, clinical signs vary from skin changes to cardiovascular changes or bronchospasm (5). In dogs, ADRs have been reported to present with skin changes and thrombocytopenia (68). Cutaneous ADR is an adverse drug reaction that appears on the skin first (2), and the lesions imitate any other skin disease (2, 9, 10). Immune-mediated hypersensitivity can be classified as an ADR and its phenotype such as anaphylaxis, urticaria, edema, and vasculitis can occur in both humans and dogs (9, 11). Skin lesions such as papules, pustules, and angioedema are also included (12).
Famotidine and antibiotics like quinolones and sulfonamide can cause hypersensitivity and anaphylaxis in humans (1214). Foods such as beef, dairy products, eggs, wheat, and nuts are also known causes of anaphylactic reactions in humans and dogs (15, 16).
Pemphigus foliaceus (PF) is the most common autoimmune disease in dogs, that occurs in the subcorneal region of the epidermis (17, 18) and presents as skin lesions including pustules, crusts, and alopecia (19). With Pemphigus, systemic symptoms like lymphadenomegaly, limb edema, fever, anorexia, and depression can also occur (20). Further, Pemphigus can be accompanied by immune-mediated hemolytic anemia (IMHA) in humans and immune-mediated thrombocytopenia in very rare cases, in dogs (21, 22). The present case series describe the successful management of rare immune-mediated skin diseases that occurred concurrently with fatal systemic abnormalities using immune-suppressive drugs in dogs.
Case presentations
Case 1) A 6-year-old, spayed female Pug presented with urticaria, severe systemic epidermal edema, erythema, and dehydration. The dog had received a famotidine (1 mg/kg, once) injection due to gastrointestinal symptoms, vomiting. After that, erythema and petechiae were observed on the whole body. A few days later, the dog had received the additional dose (0.5 mg/kg, bid) of famotidine injection. Then, anorexia and weakness were observed along with severe generalized skin lesions.
Examinations results showed systemic hypotension (78 mmHg), hyperthermia (about 40 C), delayed skin turgor, and labored breathing were found. Severe and generalized erythema, edema, and urticaria were also presented (). Complete blood cell count showed severe pancytopenia (non-regenerative anemia, neutropenia, and thrombocytopenia). Auto-agglutination, spherocytes, and infectious agents were not found in the blood smear. Coombs test was negative. Decreased total protein and albumin, increased C-reactive protein (CRP), hypertriglyceridemia in serum chemistry, prolonged activated partial thromboplastin time (aPTT), and elevated D-dimer were found in the coagulation test (Supplementary Table 1). Pancreatitis was ruled out by the measurement of serum canine specific lipase concentration (Eurolyser Lipase Test Kit, Eurolyser Diagnostica GmbH, Salzburg, Austria). An X-ray showed right side cardiomegaly, pulmonary infiltration, moderate hepatomegaly () and moderated dilation of the caudal vena cava and hepatic veins were noted on ultrasonography. Although urea nitrogen and creatine were in normal range, hyposthenuria and proteinuria were noted in urinalysis, therefore, kidney function failure was suspected. As the hepatic congestion was suspected on ultrasonography, bile acid test was performed. In the result, pre-prandial and post-prandial bile acid were over 25 mol/L and therefore liver function failure was confirmed.
Photographs of the skin condition of Case 1. (A,B) Severe systemic erythema, edema, and urticaria at presentation. (C,D) One week after treatment initiation, erythema and edema disappeared. (E) Pulmonary interstitial infiltration and right-side cardiomegaly at the presentation on X-ray. (F) One week later, after treatment initiation, the infiltration of the lung disappeared.
In histopathology of the abdominal skin, dermal edema, and infiltration of inflammatory cells such as neutrophils, mast cells, and macrophages in the dermis with edema were found (Figures 4A,B). Therefore, the skin lesions were histopathologically diagnosed as acute hypersensitivity allergy. Based on all the examination results the dog was finally diagnosed with drug hypersensitivity reaction (DHR) with multiple organ function failure and famotidine was suspected as the causative drug. Furosemide (Lasix, Handok, Seoul, Korea; 1 mg/kg, PO, bid) for pulmonary and systemic edema and congestion, rivaroxaban (Xarelto, Bayel Korea, Seoul, Korea; 0.5 mg/kg, PO, sid) for hypercoagulation, and immunosuppressive dose of prednisolone (Solondo, Yuhan, Seoul, Korea; 2 mg/kg, PO, bid) and cyclosporine (Cipol-N, Chongkundang, Seoul, Korea; 7 mg/kg, PO, bid) were prescribed.
After 1 week, the edema, erythema, and urticaria disappeared (). Laboratory examinations showed that the abnormalities were significantly improved (Supplementary Table 1). Proteinuria and pulmonary infiltration also disappeared (). The dog went back to the local hospital.
Case 2) A 13-month-old, neutered male Pembroke Welsh Corgi presented with severe systemic ulcerative skin lesions. The dog had shown soft feces after having a new snack 2 days ago, and the owner had also seen patchy ulcerative skin lesions around the hip. The lesions were spreading to the neck and flank. The dog showed systemic weakness and anorexia.
Physical examinations showed hyperthermia (about 40 C), generalized patchy ulcerative lesions, and erythema around the skin lesions (). Complete blood cell count showed thrombocytopenia. Elevated alkaline phosphatase (ALKP) and CRP were found in serum chemistry. Prolonged aPTT and elevated D-dimer were identified in the coagulation test (Supplementary Table 1). Cytology of skin lesion impressions showed numerous sterile inflammatory cells (neutrophils and macrophages). The x-ray did not show specific findings except for mild splenomegaly. In histopathology of the dorsal skin lesions, dermis and epidermis were separated and infiltrations of inflammatory cells such as neutrophils, macrophages, and lymphocytes were found on the interface sites (Figures 4C,D). Based on these results, the skin lesions were diagnosed with immune-mediated skin disease induced by an unknown cause (new snack suspected). The patient received an immunosuppressive dose of prednisolone (Solondo, Yuhan, Seoul, Korea; 2 mg/kg PO bid), cyclosporine (Cipol-N, Chongkundang, Seoul, Korea; 7 mg/kg PO bid), and human intravenous immunoglobulin (hIVIG) (Liv -Gamma, SK Plasma, Seongnam, Korea; 0.5 g/kg, IV, 2 days in a row).
Photographs of the skin condition of Case 2. (A,B) Systemic ulcerative patchy lesions at presentation. (C,D) 10 days later, after treatment initiation, the lesions were mostly improved.
After 10 days, the patient's appetite and vitality, and the skin lesions were significantly improved (). The laboratory findings showed that the abnormalities were markedly improved (Supplementary Table 1). The prednisolone was tapered (up to 1 mg/kg PO bid) and the patient came back to the local hospital.
Case 3) A 12-year-old, spayed female Pomeranian presented with severe systemic alopecia, pruritus, pustule, and crust. About 2 months ago, she had discharge from the general skin and mild alopecia. The patient did not respond to antibiotics (amoxicillin, doxycycline, and gentamicin), antifungal agents (clotrimazole), and prednisolone (0.5 mg/kg PO bid) in the local hospital. The lesions were spreading to the whole body.
On the physical examinations, severe generalized alopecia, crusts, and erythema were identified (). Some pustules and epidermal collarettes were also noted on the abdomen (). Complete blood cell counts showed severe normocytic normochromic regenerative anemia (hematocrit 15.3%) and negative on Coombs' test with no direct and indirect agglutinations. Stress leukograms were also observed. Some spherocytes were noted in the blood smear. Moderately elevated liver enzymes (ALKP, GGT) and increased CRP were found in the serum chemistry test (Supplementary Table 1).
Photographs of the skin condition of Case 3. (A,B) Systemic alopecia and crusts at presentation. (C,D) 10 months later, after treatment, alopecia was significantly improved and the crusts disappeared.
Histopathology (H&E staining) and cytology (Diff quick staining) of the [(A,B): Case 1]. (A) Marked edema with diffuse inflammation in the dermis(40x); (B) High magnitude of (A). Inflammatory cells (neutrophils, mast cells, and macrophages) are infiltrated in the edematous dermis (400x); [(C,D): Case 2] (A) Epidermal necrosis and separation of the epidermis and dermis (40x); (D) Infiltration of the inflammatory cells (neutrophils, macrophages) in separated interface sites (200x); [(EH): Case 3] (E) Crusts and intact pustules (dot circle) on the abdomen; (F) Acantholytic cells (black arrows) and numerous neutrophils on the cytology of the pustules (400x); (G) Pustules in the hyperplastic stratum corneum in histopathology (40x); (H) Acantholytic cells (yellow arrows) that are surrounded by inflammatory cells (neutrophils, macrophages) in pustule (200x).
Skin examination including Wood's lamp, skin scraping, and trichogram, did not show remarkable findings. Meanwhile, there were numerous acantholytic cells surrounding inflammatory cells (neutrophils, macrophages) in the pustule on cytology (). Histopathology showed pustules containing numerous acantholytic cells in the stratum corneum similar to those observed in cytology (). Based on the results, the patient was diagnosed with Pemphigus foliaceus concurrent with IMHA which showed no agglutination due to previous steroids administration. The patient received a blood transfusion and then was started with immune suppressants, prednisolone (Solondo, Yuhan, Seoul, Korea; 2 mg/kg PO bid), cyclosporine (Cipol-N, Chongkundang, Seoul, Korea; 7 mg/kg PO bid). Then hIVIG (Liv -Gamma, SK Plasma, Seongnam, Korea; 0.5 g/kg IV, for 2 days in a row) was also used for the treatment of acute immune-suppressive effects.
The prednisolone dose was tapered for over a month. Anemia was resolved (HCT 39.0%) (Supplementary Table 1). Generalized crust and pustules disappeared after a month, and the alopecia gradually improved. The patient showed ocular problems due to the steroid, so prednisolone was replaced by chlorambucil (LeukeranTM, Samil Pharm, Seoul, Korea; 2 mg/kg, PO, sid). The dog was well managed by immunosuppressants for 10 months ().
Discussion
This report describes the successful management of three cases of fatal immune-mediated skin diseases. They were diagnosed as immune-mediated skin diseases relating to CADR, Pemphigus foliaceus, and unknown etiology. The cases showed severe systemic and skin signs. High doses of immunosuppressive drugs and supportive management were successfully applied.
Sometimes drug reaction is mainly presented with immune mediated skin problems in dogs. Immune-related drug reactions can be classified as, (1) exanthematous drug eruptions (hypersensitivity reaction type IV-T lymphocyte-cytotoxicmediated): reappears in 1 to 3 days by subsequent exposure; (2) urticaria, angioedema, anaphylaxis (type 1 IgEmediated reactions): emerges within minutes to hours of exposure to the offending agent and may occur in combination or individually; (3) allergic contact dermatitis (type IV- T lymphocyte-macrophagemediated): usually occurs within 48 to 72 h of contact with the allergen including various poison agents; (4) drug hypersensitivity syndrome (type IV- T lymphocyte-eosinophilmediated): a drug-induced maculopapular eruption accompanied by eosinophilia with fever, facial edema, and organ dysfunction (hepatic, renal, or hematologic); fixed drug eruptions; erythema multiforme, and serum sicknesslike reactions (23).
Case 1 may be related to urticaria, angioedema, anaphylaxis and is included in second classification of above reference (23). Angioedema is characterized by a localized, self-limiting, and transient subcutaneous or submucosal swelling, which can present with or without episodes of urticarial (24). The systemic skin swelling may be due to increased vascular permeability of small vessels in dermis. The case also showed systemic signs including edematous with congestive cardio-pulmonary problems which are very rare in that skin disease in dogs. The congestive heart and systemic conditions could be related to increased vascular permeability by hypersensitivity reaction.
There are several causes of angioedema and urticaria such as food, drug, or insect in dogs (25). The dog had no certain etiology relating hypersensitivity and only previous using a drug, famotidine was suspected. It is not reported that adverse drug reactions are induced by famotidine in veterinary medicine. Notably, in humans, there is a previous study reported H2-receptor antagonists' adverse reactions (26). In the report, dermatological reactions, such as urticaria, pruritus, erythema, and alopecia constituted 35% of the H2-receptor antagonists ADRs (27). The majority of ADRs were caused by cimetidine and ranitidine (26). Famotidine ADRs are very rare with only 2 cases of ADRs that affected the skin and a case report of famotidine-induced anaphylaxis in humans reported so far (14). The patient showed dyspnea, seizure-like activities, and became comatose after intravenous injection of cefazedone and famotidine (14). There was no report about famotidine-induced cutaneous ADR accompanied by other organs' abnormalities in humans and dogs.
Food, such as cow milk, egg, shrimp, and wheat, have been reported to induce urticaria and anaphylaxis in children (28). In the dogs, probable walnut-induced anaphylaxis has been reported (15). The dog had showed acute diarrhea, vomiting, respiratory distress, and skin swellings (15). The dog in case 2 had a history of eating a new snack before the symptoms appeared. There was no history of other dietary or environmental changes except. The skin lesions may be associated with food hypersensitivity to the new snack, but unfortunately we could not confirm the information on the snack's ingredients.
On histopathology, the case 2 reveals a lichenoid interface dermatitis which is possibly associated with systemic lupus erythematosus (SLE). For the diagnosis of probable SLE, fulfillment of at least four criteria is needed (29). The criteria include erythema, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorders, neurologic disorders, hematologic disorders, immunologic disorders, and antinuclear antibodies (29). Although we did not perform immunologic tests, only two abnormalities of skin and hematologic finding (thrombocytopenia) are included.
Food hypersensitivity (allergy) is included in the adverse food reactions which also include non-immune mediated reactions (30). IgE-mediated reactions (type I hypersensitivity) is the most common food hypersensitivity in dogs and man and type I, type III, and type IV hypersensitivity are possible immunologic mechanisms in dogs and cats (27). Case 2 showed soft feces and skin problems which are not typical in food hypersensitivity, a few hours after having a snack. The phenotype is very similar to type I hypersensitivity including systemic abnormalities. So far, no report describes ulcerative and split lesions associated with immune-mediated skin diseases with systemic illness induced by foods in dogs.
Pemphigus is associated with autoantibodies against desmoglein 1 and desmoglein 3 in the skin junction (31). In humans, Pemphigus Vulgaris concurrent with IMHA has been reported (21). In this report, cytokines such as interleukin, tumor necrosis factor- (TNF-), and granulocyte-macrophage colony-stimulating factor in blister fluid were measured and TNF- was significantly increased in the blister fluid (21). Case 3 showed IMHA and it was suspected that those antibodies may be related to antibodies on the red blood cells surface. Based on the hypothesis, the antibodies about desmoglein can attack the red blood cell surface and immune-mediated hemolytic anemia will occur. However, there is no related research.
In the present cases, conventional immune-suppressive drugs (prednisolone and cyclosporine), treatment was well tolerated. However, sometimes additional alternative drugs including hIVIG and chlorambucil were also needed. The mechanism of hIVIG is to block Fc receptors, remove pathogenic autoantibodies, modulate cytokine synthesis, and mediate Fas-Fas ligand interactions (32). In humans, hIVIG is used in thrombocytopenia, lymphocytic leukemia, autoimmune hemolytic anemia, and toxic epidermal necrolysis. However, it is not used well in dermatologic disorders because of side effects (33). In dogs, hIVIG is used in various immune-mediated diseases including IMHA, IMT, Pemphigus, and cutaneous drug reactions (3235).
The present cases were diagnosed as immune-mediated skin diseases concurrent with fatal abnormalities of other organs. The dogs had severe thrombocytopenia, decreased liver function, or secondary IMHA. To the best of the author's knowledge, so far, there are no reports on immune-mediated skin diseases with fatal clinical signs.
Conclusion
The present case series showed very rare immune-mediated skin diseases concurrent with fatal other organs' abnormalities. A combination of appropriate immune-suppressive drugs with supportive management for the emergency status of systemic dysfunctions yielded successful clinical outcomes in the dogs.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
SK: clinical management of the first and second cases, writing of the first manuscript draft, and review and editing of the manuscript. YK: clinical management of the third case and writing of the first manuscript draft. H-JK: clinical management of all three cases, review and editing of the manuscript, and study supervision. All authors contributed to write and edit this manuscript.
Funding
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2020R1A2C2005364).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
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References
1.
Day MJ, Hanlon L, Powell LM. Immune-mediated skin disease in the dog and cat. J Comp Pathol. (1993) 109:395407. 10.1016/S0021-9975(08)80302-7 [PubMed] [CrossRef] [Google Scholar]2.
Miller WH, Griffin CE, Campbell KL. Small Animal Dermatology. 7th ed. Missouri: Elsevier Mosby; (2013). p. 432. [Google Scholar]3.
Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. (2000) 356:12559. 10.1016/S0140-6736(00)02799-9 [PubMed] [CrossRef] [Google Scholar]6.
Royaux E, Bhatti S, De Cock H, Van Ham L, Kitshoff A, Vandenabeele S. Cutaneous adverse drug reaction in a dog associated with imepitoin. Vet Dermatol. (2016) 27:11821e32. 10.1111/vde.12289 [PubMed] [CrossRef] [Google Scholar]9.
Dykewicz MS, Lam JK. Drug hypersensitivity reactions. Med Clin North Am. (2020) 104:10928. 10.1016/j.mcna.2019.09.003 [PubMed] [CrossRef] [Google Scholar]10.
Macy E. Immune-Related adverse drug reactions and immunologically mediated drug hypersensitivity. Immunol Allergy Clin North Am. (2020) 40:63547. 10.1016/j.iac.2020.06.003 [PubMed] [CrossRef] [Google Scholar]11.
Voie KL, Campbell KL, Lavergne SN. Drug hypersensitivity reactions targeting the skin in dogs and cats. J Vet Intern Med. (2012) 26:86374. 10.1111/j.1939-1676.2012.00927.x [PubMed] [CrossRef] [Google Scholar]12.
Neuman MG, Cohen LB, Nanau RM. Quinolones-Induced hypersensitivity reactions. Clin Biochem. (2015) 48:71639. 10.1016/j.clinbiochem.2015.04.006 [PubMed] [CrossRef] [Google Scholar]13.
Khan DA, Knowles SR, Shear NH. Sulfonamide hypersensitivity: fact and fiction. J Allergy Clin Immunol Pract. (2019) 7:211623. 10.1016/j.jaip.2019.05.034 [PubMed] [CrossRef] [Google Scholar]14.
Kim YI, Park CK, Park DJ, Wi JO, Han ER, Koh YI. A case of famotidine-induced anaphylaxis. J Investig Allergol Clin Immunol. (2010) 20:166. [PubMed] [Google Scholar]15.
Rostaher A, Fischer NM, Kmmerle-Fraune C, Couturier N, Jacquenet S, Favrot C. Probable walnut-induced anaphylactic reaction in a dog. Vet Dermatol. (2017) 28:251e66. 10.1111/vde.12406 [PubMed] [CrossRef] [Google Scholar]17.
Bizikova P, Olivry T. Oral glucocorticoid pulse therapy for induction of treatment of canine pemphigus foliaceus a comparative study. Vet Dermatol. (2015) 26:3548. 10.1111/vde.12241 [PubMed] [CrossRef] [Google Scholar]18.
Melchionda V, Harman KE. Pemphigus vulgaris and pemphigus foliaceus: an overview of the clinical presentation, investigations and management. Clin Exp Dermatol. (2019) 44:7406. 10.1111/ced.14041 [PubMed] [CrossRef] [Google Scholar]19.
Rosenkrantz WS. Pemphigus: current therapy. Vet Dermatol. (2004) 15:908. 10.1111/j.1365-3164.2004.00360.x [PubMed] [CrossRef] [Google Scholar]20.
Hnilica KA, Patterson AP. Small Animal Dermatology, A Color Atlas and Therapeutic Guide. 4th ed. Missouri: Elsevier Mosby; (2017). p. 245 [Google Scholar]21.
Ujihara M, Hamanaka S, Matsuda S, Numa F, Kato H. Pemphigus vulgaris associated with autoimmune hemolytic anemia and elevated TNF. J Dermatol. (1994) 21:568. 10.1111/j.1346-8138.1994.tb01412.x [PubMed] [CrossRef] [Google Scholar]22.
Kawarai S, Hisasue M, Matsuura S, Ito T, Inoue Y, Neo S, et al.. Canine pemphigus foliaceus with concurrent immune-mediated thrombocytopenia. J Am Anim Hosp Assoc. (2015) 51:5663. 10.5326/JAAHA-MS-6044 [PubMed] [CrossRef] [Google Scholar]23.
Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. (2003) 68:178190 [PubMed] [Google Scholar]24.
Santacroce R, D'Andrea G, Maffione AB, Margaglione M, d'Apolito M. The genetics of hereditary angioedema: a review. J Clin Med. (2021) 10:2023. 10.3390/jcm10092023 [PMC free article] [PubMed] [CrossRef] [Google Scholar]25.
Rostaher A, Hofer-Inteeworn N, Kmmerle-Fraune C, Fischer NM, Favrot C. Triggers, risk factors and clinico-pathological features of urticaria in dogs - a prospective observational study of 24 cases. Vet Dermatol. (2017) 28:38e9. 10.1111/vde.12342 [PubMed] [CrossRef] [Google Scholar]26.
Andersen M, Schou JS. Adverse reactions to H2-receptor antagonists in Denmark before and after transfer of cimetidine and ranitidine to over-the-counter status. Pharmacol Toxicol. (1991) 69:2538. 10.1111/bcpt.1991.69.4.253 [PubMed] [CrossRef] [Google Scholar]27.
Muller GH, Kirk RW, Scott DW. Food hypersensitivity. In: Dyson J, editor. Small Animal Dermatology. Philadelphia: WB Saunders Company; (1989). p. 47074. [Google Scholar]28.
Wananukul S, Chatchatee P, Chatproedprai S. Food induced urticaria in children. Asian Pac J Allergy Immunol. (2005) 23:1759. [PubMed] [Google Scholar]29.
Muller GH, Kirk RW, Scott DW. Systemic Lupus Erythematosus in the dog. In: Dyson J, editor. Small Animal Dermatology. Philadelphia: WB. Saunders Company; (1989). p. 453459. [Google Scholar]30.
Roudebush P, Guilford WG, Shanley KJ. Adverse reactions to food. In: Hand MS, Thatcher CD, Remillard RL, Roudebush P, editors. Small Animal Clinical Nutrition. Missouri: Mark Morris Institute; (2000). p. 431453 [Google Scholar]31.
Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet. (2019) 394:88294. 10.1016/S0140-6736(19)31778-7 [PubMed] [CrossRef] [Google Scholar]32.
Spurlock NK, Prittie JE A. review of current indications, adverse effects, and administration recommendations for intravenous immunoglobulin. J Vet Emerg Crit Care (San Antonio). (2011) 21:47183. 10.1111/j.1476-4431.2011.00676.x [PubMed] [CrossRef] [Google Scholar]33.
Nuttall TJ, Malham T. Successful intravenous human immunoglobulin treatment of drug-induced Stevens-Johnson syndrome in a dog. J Small Anim Pract. (2004) 45:35761. 10.1111/j.1748-5827.2004.tb00248.x [PubMed] [CrossRef] [Google Scholar]34.
Rahilly LJ, Keating JH, O'Toole TE. The use of intravenous human immunoglobulin in treatment of severe pemphigus foliaceus in a dog. J Vet Intern Med. (2006) 20:14836. 10.1111/j.1939-1676.2006.tb00770.x [PubMed] [CrossRef] [Google Scholar]35.
Ramos SJ, Beale VM, Langohr IM, Woodward MC. Erythema multiforme major in a dog treated with intravenous human immunoglobulin and immunosuppressive therapy. J Am Anim Hosp Assoc. (2020) 56:1338. 10.5326/JAAHA-MS-6896 [PubMed] [CrossRef] [Google Scholar]
