Toxic Shock Syndrome in Two Dogs
Two young, unrelated, spayed female Labrador retrievers were evaluated for severe, diffuse, generalized erythema and edema of the skin. Both dogs exhibited signs of disseminated intravascular coagulopathy and were euthanized. On postmortem examination, toxic shock syndrome (TSS) was diagnosed based on histopathology and supported by skin cultures. TSS is a rarely reported disease in veterinary medicine and can cause acute and profound clinical signs. Rapid recognition of this disease process and immediate treatment may improve the clinical outcome.
Introduction
Toxic shock syndrome (TSS) is a systemic disease initiated by bacterial infections, usually involving Staphylococcus spp. or Streptococcus spp. Gram-positive bacteria can induce both local and systemic infections. They generate exotoxins that exhibit superantigen activity, which induces endogenous production of excessive amounts of cytokines. TSS is associated with capillary leakage, hypotension, fever, multiorgan dysfunction, and skin desquamation. Dogs afflicted with TSS are acutely and profoundly ill. This syndrome is rarely reported in veterinary medicine. The following manuscript describes TSS in two young, spayed female, unrelated Labrador retrievers.
Case Report
Case 1
A 3 yr old spayed female Labrador retriever weighing 40.4 kg was referred to the Lloyd Veterinary Medical Center at Iowa State University with a 6 day history of diffuse erythema and pitting edema of her skin, vomiting, and anorexia. The dog had previously been treated at the local emergency/primary care veterinary hospital for 4 days prior to referral. At the time of presentation to the primary veterinarian, the dog was hyperthermic (39.6°C) and had diffusely erythematous skin affecting her trunk and limbs. A possible allergic reaction was suspected by the referring doctor. The dog was administered dexamethasonea (2 mg/kg IV q 24 hr) and diphenhydramineb (3.75 mg/kg IV q 24 hr) for 2 consecutive days. Other treatments consisted of IV crystalloid fluids, prednisonec (2 mg/kg per os [PO] q 12 hr), diphenhydramineb (2.5 mg/kg PO q 12 hr), doxycyclinee (2.5 mg/kg PO q 12 hr), pentoxifyllinef (10 mg/kg PO q 8 hr), famotidineg (0.5 mg/kg PO q 12 hr), sucralfateh (25 mg/kg PO q 8 hr), and tramadoli (3.75 mg/kg PO q 8 hr). In addition, the dog testedj negative for Ehrlichia, Borrelia, and Anaplasma antibodies as well as heartworm antigen. Due to the persistent erythema, edema, and pain, skin biopsies were obtained by the referring veterinarian and the dog was subsequently referred.
On presentation to the Lloyd Veterinary Medical Center at Iowa State University, the dog was severely depressed, moderately dehydrated, and normothermic (rectal temperature was 38.9°C). The dog’s mucous membranes were red and injected and she exhibited diffuse muscle atrophy. There was diffuse erythema, edema, and raised vesicles that were seeping serous fluid on the ventral abdomen and inner pinnae. The skin was also painful to the touch. Initial diagnostic testing included a complete blood count (CBC), serum biochemistry, urinalysis, prothrombin time (PT), and partial thromboplastin time (PTT).
The CBC revealed a leukocytosis consisting of a neutrophilia (28.0 × 103/μL; reference range, 3.0–11.4 × 103/μL) with a band neutrophilia (1.9 × 103/μL; reference range, 0.0–0.3 × 103/μL); a normochromic, normocytic anemia (hematocrit was 29.6%; reference range, 37–55%); and thrombocytopenia (41 × 103/μL; reference range, 200–500 × 103/μL). The serum biochemistry revealed azotemia. Blood urea nitrogen was 79 mg/dL (reference range, 10–30 mg/dL) and creatinine was 1.9 mg/dL (reference range, 0.5–1.5 mg/dL). Hyperphosphatemia (7.9 mg/dL; reference range, 3.2–6.0 mg/dL), hypoalbuminemia (1.7 g/dL; reference range, 2.7–4.0 g/dL), hyperglycemia (165 mg/dL; reference range, 68–115 mg/dL), elevated alkaline phosphatase (311 IU/L; reference range, 20–150 IU/L), and hyperbilirubinemia (6.11 mg/dL; reference range, 0.10–0.60 mg/dL) were also noted. Urinalysis revealed a specific gravity of 1.026 with bilirubinuria and a mild proteinuria. The PT and PTT were both increased at 12.8 sec and 28.3 sec, respectively (reference ranges, 5.5–7.9 sec and 10.4–19.3 sec, respectively).
The dog was hospitalized for further diagnostics and treatment. As there was concern for disseminated intravascular coagulation (DIC), a fresh frozen plasma transfusion was administered and the dog was administered a combination of hetastarchk (20 mL/kg/day) and fluid therapyl (50 mL/kg/day). The systolic blood pressure was 180 mm Hg (by Doppler). There was a suspicion of an immune-mediated dermatologic condition in addition to pain, a possible infection, and a history of vomiting. The patient received dexamethasonea (0.4 mg/kg IV q 24 hr), ampicillinm (22.5 mg/kg IV q 8 hr), dolasetronn (0.6 mg/kg IV q 24 hr), famotidineo (0.5 mg/kg IV q 12 hr), and hydromorphonep (0.05 mg/kg IV q 6 hr).
The biopsy results obtained by the referring veterinarian were available 24 hr after presentation. There was a diffuse, suppurative, and eosinophilic dermatitis with perivasculitis, subepithelial clefts, and epithelial pustules. Differential diagnoses included vasculitis induced by a bacterial agent, canine sterile neutrophilic dermatosis (Sweet’s syndrome), or a hypersensitivity reaction. A CBC and serum biochemistry were repeated the following day. The CBC had not changed significantly. The azotemia was slightly improved, but additional increases in alkaline phosphatase and total bilirubin were noted. Further diagnostic and treatment options were discussed with the owners, but given the lack of improvement, euthanasia was elected and a necropsy was performed.
At the time of necropsy, skin biopsies were obtained for culture. Moderate mixed growth (2 + growth in the primary and secondary areas on the plate) of S. pseudintermedius, Pseudomonas aeruginosa, Klebsiella pneumonia, and multidrug-resistant Enterococcus was obtained. Gross pathologic lesions of the skin revealed diffusely reddened areas with vesicles. The neck, limbs, and abdomen were edematous. The pinnae of both ears had vesicles, and small ulcerations were present on the left hind limb.
The histopathologic lesions included acute and severe pustular and necrotizing dermatitis with cleft formation and vascular thrombosis. There was also pancreatic and lymph node hemorrhage, bile stasis, and nephrosis with glomerular fibrin. The pathologic diagnosis was consistent with TSS as the neutrophils were most abundant in the epidermis with necrosis and separation of the epidermis and the dermis.
Case 2
A 5 year old spayed female Labrador retriever weighing 36.4 kg presented to the Lloyd Veterinary Medical Center at Iowa State University for lethargy, skin erythema, and generalized edema. One week prior to referral, the patient was treated by the primary veterinarian for acral lick dermatitis on the lateral distal right hind limb with cephalexinq (13.8 mg/kg PO q 12 hr). Four days later, intermittent vomiting and swelling around the eyes and ears were noted, and the cephalexin was discontinued. An injection of dexamethasonea (0.22 mg/kg) was administered subcutaneously as a drug or allergic reaction was suspected. The following day, the dog’s condition worsened and she received another injection of dexamethasonea (0.22 mg/kg IV). Prednisoner (0.83 mg/kg PO q 12 hr) and doxycyclinee (5.5 mg/kg PO q 12 hr) were initiated. The patient was hospitalized overnight for observation. The patient had no improvement and became reluctant to walk. The dog was then referred for further evaluation.
On presentation to the Lloyd Veterinary Medical Center at Iowa State University, the patient was extremely lethargic and reluctant to walk. She exhibited severely erythematous skin and had generalized edema, especially on the limbs and chest. She was extremely hyperesthetic and painful on skin and abdominal palpation (Figure 1). Her temperature was mildly elevated at 39.1°C. She had a pulse of 154 beats/min and a grade 2/6 right apex systolic murmur was auscultated. Her sclerae were injected, and the systolic blood pressure was 125 mm Hg (by Doppler). Hydromorphonep (0.05 mg/kg IV) was administered for analgesia. The patient was started on IV fluid therapys at a rate of 50 mL/kg/hr. Initial diagnostic testing included a CBC, serum biochemistry, urinalysis, Snap 4Dx Test, PT, and PTT. The CBC revealed that the WBCs were within the reference range, but there were marked toxic neutrophils and a band neutrophilia (0.472 × 103/μL; reference range, 0.0–0.3 × 103/μL). Thrombocytopenia (136 × 103/μL; reference range, 200–500 × 103/μL) was also noted. The serum biochemistry revealed hypoproteinemia (4.9 g/dL; reference range, 5.2–7.1 g/dL), hypoalbuminemia (2.3 g/dL; reference range, 2.7–4.0 g/dL), hyperglycemia (125 mg/dL; reference range, 68–115 mg/dL), hypocalcemia (8.7 mg/dL; reference range, 9.7–11.3 mg/dL), increased alkaline phosphatase (178 IU/L; reference range, 20–150 IU/L), and hyperbilirubinemia (0.78 mg/dL; reference range, 0.10–0.60 mg/dL). The urinalysis revealed mild proteinuria with a urine specific gravity of 1.040. The Snap 4Dx Test was negative. There was a prolonged PT of 13.7 sec (reference range, 5.5–7.9 sec) and a PTT of 65.7 sec (reference range, 10.4–19.3 sec). The differentials at this point included an unknown coagulopathy, vasculitis of unknown origin, hypersensitivity reaction, Sweet’s syndrome, or TSS. As DIC was suspected and the patient’s edema of the neck and abdomen worsened, euthanasia with necropsy was elected.
Citation: Journal of the American Animal Hospital Association 48, 6; 10.5326/JAAHA-MS-5815
Immediately postmortem, skin biopsy samples were obtained for histopathology and aerobic bacterial culture. The original acral lick granuloma of the left hind tarsal area was biopsied in addition to the skin of the right inguinal region and left ventral abdomen.
The bacterial culture of the acral lick granuloma revealed a heavy mixed growth of S. pseudintermedius and P. aeruginosa. Bacterial culture of the unaffected skin from the inguinal area revealed a low to moderate (2 + growth in the primary and secondary areas on the plate) pure growth of S. pseudintermedius. Grossly, there was diffuse erythema on the body and pitting edema on the distal extremities and the head. The major veins were markedly dilated. There were congested serosal vessels of the stomach, duodenum, small intestine, cecum, colon, and rectum. The kidneys were congested bilaterally. Histopathologic analysis of the haired skin revealed necrosis with moderate pustule formation. There was evidence of dermal edema and congestion as well as degenerate and necrotic keratinocytes. The superficial to middermis contained low to large numbers of perivascular to interstitial neutrophils and eosinophils that were admixed with fewer macrophages, plasma cells, and lymphocytes (Figure 2). The epidermal and dermal lesions were compatible with TSS.
Citation: Journal of the American Animal Hospital Association 48, 6; 10.5326/JAAHA-MS-5815
Discussion
TSS is a devastating disease often caused by either staphylococci or streptococci exotoxins that exhibit superantigen activity.1,2 Superantigens are virulent polypeptides that can cause T-cell activation by circumventing normal antigen processing.3 This activity results in the production of excessive amounts of cytokines, which are integral in the generation of cutaneous lesions.4 Superantigens and their role in TSS have been extensively studied in humans and mice but little is known about their prevalence and roles in dogs.
TSS in humans is caused by the effects of exotoxin and cytokine induction coupled with host factors.4 It has been associated with S. aureus and group C streptococci infections.3,5,6 TSS has been associated with menstruating women using super absorbent tampons as well as infections following surgery, childbirth, blunt trauma, or burns. The clinical manifestations in humans include fever, rash, desquamation, and multisystem involvement.3 The superantigens, caused by staphylococci and streptococci toxins in TSS, lead to massive T-cell activation that releases proinflammatory cytokines such as interlukin-2, interferon γ, and tumor necrosis factor.2–4 The superantigens’ ability to activate massive amounts of cytokines causes capillary leakage, hypotension, and, in turn, multiorgan dysfunction, which may include myocardial necrosis and renal tubular cell death.3 In humans, there is an acute onset of the disease process, usually within 48 hr of hospitalization.3 Prognosis in humans improves with immediate antibiotic therapy, supportive care, and surgery such as wound debridement, abscess drainage, or foreign body removal if indicated.3 TSS in humans results in a moderately edematous dermis with prominent inflammation, including neutrophils and eosinophils surrounding the apoptotic epithelial cells, leading to massive devitalization of the epidermis.4
TSS is rarely reported in veterinary medicine. This may be a result of its tendency for rapid onset and progression in as little as 48 hr from the onset of clinical signs.5 The most common clinical presentation of TSS in dogs is generalized cutaneous erythema and edema, especially of the head and extremities. Hypoalbuminemia, mild anemia, and neutrophilia are commonly observed. On histopathology, TSS exhibits superficial dermatitis with neutrophilic exocytosis and necrotic keratinocytes.4,7 There are three main diagnostic criteria described for TSS in dogs, which are dermatopathy, characteristic histologic features, and systemic clinical signs.1,4 TSS has been described in the veterinary literature since the early 1980s in research dogs and racing greyhounds.8 In the 1990s, one report described dogs in Ontario, Manitoba, and British Columbia with severe, systemic disease and shock associated with β-hemolytic S. canis infection.5 The origin of the systemic bacteria is often not known.1,8 Reports indicate that the skin, cervix, and respiratory systems have provided sites of entry for the bacteria.2,5,7 At this time, there is no known cause for the individual affected animal to have a superantigen response.1,4 The intensity of the inflammatory response produced by the superantigens varies from individual to individual, possibly due to the variability of T-cell receptors determined by genetic make-up.2,3,9 Higher numbers of T cells, with elements complementary to superantigens, lead to a greater degree of T-cell activation, which has been correlated with severity of clinical disease.3,9 In a recent study regarding the prevalence of genes for enterotoxins among clinical isolates from canine origin, 24.3% of the isolates carried the gene for canine type C staphylococcal enterotoxin and S. intermedius exfoliative toxin genes.10 The canine type C staphylococcal enterotoxin has superantigenic activity. At this time, it is not known what the biologic significance is of the possession of both toxins in dogs with either pyoderma or otitis.10
Conclusion
In both of the cases described here, S. pseudintermedius and P. aeruginosa were isolated. S. pseudintermedius is a bacterium frequently associated with canine dermatitis and other skin conditions and has been implicated in cases of canine TSS.1,3 The treatment protocol and the response to therapy for canine TSS are variable. As this disease progresses rapidly, patients suspected of having TSS should be hospitalized and systemic treatment with antimicrobials effective against Staphylococcus spp. and Streptococcus spp. should be initiated.1,7 Supportive measures including IV fluids, pain medications, and cleaning of visibly infected wounds may also be beneficial.7 Despite appropriate treatment, many dogs develop DIC, as was the case for the two dogs in this report.8 There are too few cases of TSS documented to assess signalment predilections; however, in one report, 3 of 10 dogs were pugs, and all dogs were < 6 yr of age except one dog.4 It is important to consider TSS as a differential diagnosis when presented with patients with acute cutaneous erythema, edema, and pain. Further research regarding potential sites of entry, species of bacteria cultured, and response to therapy is warranted.
Photograph of the dog in case 2 with hyperemic skin with pustules on the pinna.
Pustular dermatitis with cleft formation, vascular thrombosis, and neutrophilic infiltration was noted on histology. Figure 2 was sampled from ventral abdomen of case 2. Hematoxylin and eosin stain, original magnification ×100.
Contributor Notes
