History
A 2-year-old castrated male Dachshund was evaluated at a veterinary medical teaching hospital because of progressive lethargy, anorexia, severe generalized erythema, urticaria, and angioedema of 8 days’ duration. There had been no response to prior treatment with anti-inflammatory doses of corticosteroids, broad-spectrum antimicrobials, IV fluid therapy, antihistamines, and antacids. Two days prior to the referral evaluation, skin biopsy specimens were obtained for histologic examination, the results of which were pending at the time of the referral examination. Immediately prior to the referral evaluation, the dog developed marked non-weight-bearing lameness of the left pelvic limb and became acutely hypothermic with a rectal temperature of 33°C (91.4°F).
Clinical Findings
At the referral evaluation, the dog had signs of depression but was alert and responsive. The dog's rectal temperature was 34.8°C (94.6°F), and it was tachypneic (respiratory rate, 54 breaths/min) with increased inspiratory and expiratory effort. There was marked, diffuse erythema and angioedema on the caudoventral aspect of the abdomen, the ventral region of the thorax, axillae, limbs, and prepuce. Numerous circular to coalescing vesicles and bullae were distributed throughout these areas (Figure 1). Coalescing epidermal ulcers created by sloughing of the epidermis were present on all 4 extremities with the caudal, medial, and lateral aspects of the elbow regions and tarsi most severely affected. Femoral pulses were not palpable in the left pelvic limb, and the left pelvic limb, tail, and prepuce were cold to the touch. Blood samples were collected for a CBC, serum biochemical panel, and venous blood gas analysis. The CBC revealed marked nonregenerative anemia with few spherocytes, schistocytes, and nucleated RBCs; marked thrombocytopenia with rare platelet clumps; and severe leukopenia characterized by moderate lymphopenia and severe neutropenia with a left shift and moderate to marked toxic changes. Serum biochemical findings included marked hyperbilirubinemia, hyperphosphatemia, hypermagnesemia, hypoproteinemia, and hypoalbuminemia; markedly high aspartate aminotransferase and creatine kinase activities; moderate hyperglycemia; moderately high BUN concentration; moderately high alanine aminotransferase and alkaline phosphatase activities; and mild hypocalcemia. The venous blood gas analysis revealed marked acidemia, markedly low serum bicarbonate concentration, markedly high partial pressure of CO2, and moderate hyperlactatemia.
Photographs of the caudal ventral aspect of the abdomen (A) and medial aspect of the right elbow, axilla, and ventral thoracic region (B) of a 2-year-old Dachshund that was evaluated because of progressive lethargy, anorexia, severe generalized erythema, urticaria, and angioedema of 8 days’ duration. Marked erythema is associated with numerous circular to coalescing vesicles and bullae, which are primarily distributed on the ventral aspect of the abdomen, inguinal region, axillae, and ventral thoracic region. Coalescing epidermal ulcers created by sloughing of the epidermis were present on all 4 extremities with the caudal, medial, and lateral aspects of the elbows and tarsi being most severely affected.
Citation: Journal of the American Veterinary Medical Association 255, 4; 10.2460/javma.255.4.427
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page →
Additional Clinical Findings
The dog underwent thoracic radiography, which revealed a patchy alveolar pattern within the right caudal lung lobe and ventral regions of the right cranial and middle lung lobes, a diffuse nodular and bronchocentric interstitial pattern with partial effacement of the pulmonary vasculature, and mild left atrial enlargement. Mild hepatomegaly was an incidental finding. Echocardiographic findings included mild mitral valve regurgitation with mild left atrial enlargement but no evidence of mitral or aortic valve endocarditis. Abdominal ultrasonography revealed bilateral renal enlargement with mild right-sided pyelectasia as well as mild to moderate lymphadenomegaly of the medial iliac, colic, and mesenteric lymph nodes. The spleen was diffusely hypoechoic with an irregular, nodular surface. By use of Doppler color flow imaging, splenic circulation was found to be appropriate but there was loss of blood flow within the left pelvic limb. No intra-abdominal thrombi were noted.
Despite administration of IV fluid therapy and supplemental oxygen, the dog became progressively unresponsive and hypotensive (systolic arterial blood pressure as assessed by Doppler ultrasonography, 50 mm Hg) over a period of 6 hours. On the basis of this rapid deterioration in condition, the dog was euthanized by IV administration of a barbiturate solution.
Necropsy Findings
In addition to the severe skin lesions, postmortem evaluation of the dog revealed multifocal subcutaneous hemorrhage, 5 mL of serosanguineous thoracic effusion, and lung lobes that were wet, rubbery, and diffusely mottled pink to dark red with multifocal to coalescing pale tan foci. All lung lobes floated in formalin; on cut surfaces, the lungs exuded foamy pale pink fluid, which was interpreted as edema. The liver had a mildly enhanced reticular pattern. Numerous irregularly shaped, dark purple nodules were scattered throughout the splenic parenchyma. Several dark red, flat foci within the renal cortices were suggestive of acute hemorrhage. Mild mitral valve endocardiosis was an incidental finding.
Histopathologic Findings
Histologically, sections of the initial skin biopsy specimens had moderate diffuse acanthosis, moderate exocytosis of degenerate neutrophils and occasional eosinophils that formed small clusters adjacent to individual apoptotic keratinocytes, and a marked perivascular to diffuse dermatitis with associated moderate dermal edema (Figure 2). Neutrophils and occasional eosinophils predominated within the dermal infiltrate. Most neutrophils had hypersegmented nuclei, and many had degenerate changes. Compared with histopathologic findings for the skin biopsy specimens, sections of skin lesions obtained at necropsy had much more severe changes. Numerous hypersegmented and degenerate neutrophils infiltrated the epidermis, which had innumerable and frequently coalescing clusters of apoptotic keratinocytes. Lesions involved the epidermis but also extended into the superficial follicular epithelium. Apoptotic keratinocytes were characterized by bright red cytoplasm and pyknotic nuclei (Figure 3). There was multifocal dermo-epidermal clefting secondary to severe basal cell damage. The perivascular to interstitial dermatitis was predominated by hypersegmented and degenerate neutrophils.
Photomicrographs of sections of skin biopsy specimens obtained from the dog in Figure 1 two days prior to the referral evaluation. A—Numerous neutrophils surround dermal vessels (arrowheads) and are spread throughout the dermal collagen. There are clusters of neutrophils infiltrating the epidermis (arrows). H&E stain; bar = 100 μm. B—Numerous degenerate neutrophils have infiltrated the epidermis (small arrows) and are accompanied by occasional eosinophils (arrowhead). Individual apoptotic keratinocytes (large arrow) are closely associated with the intraepidermal neutrophils. H&E stain; bar = 25 μm.
Citation: Journal of the American Veterinary Medical Association 255, 4; 10.2460/javma.255.4.427
Photomicrographs of sections of skin specimens obtained from the dog in Figure 1 during necropsy. A—The epidermis is detached from the underlying dermis forming a subepidermal cleft (arrowhead). Dispersed individual apoptotic keratinocytes are associated with numerous infiltrating cells (arrows). H&E stain; bar = 100 μm. B—Numerous degenerate neutrophils (arrows) have infiltrated and partially effaced the entire epidermis. Individual apoptotic keratinocytes are present in direct association with intraepidermal neutrophils (arrowheads). H&E stain; bar = 25 μm.
Citation: Journal of the American Veterinary Medical Association 255, 4; 10.2460/javma.255.4.427
Additional pertinent histopathologic findings included multifocal thrombosis in the lungs, liver, kidneys, spleen, peripancreatic adipose tissue, mesenteric lymph node, heart, and left femoral artery and vein. The parenchyma of each of those organs and tissues was regionally necrotic, secondary to infarction, and infiltrated with neutrophils. There was mild, acute, multifocal neutrophilic myocarditis; acute centrolobular hepatic necrosis with lymphoplasmacytic, histiocytic hepatitis; multifocal lymphoplasmacytic interstitial pneumonia with intra-alveolar hemorrhage, edema, and histiocytosis; and myeloid hyperplasia of the bone marrow.
Morphologic Diagnosis and Case Summary
Morphologic diagnosis: severe, acute, generalized, multifocal to coalescing, neutrophilic dermatitis with marked neutrophilic exocytosis associated with coalescing clusters of keratinocyte apoptosis in the epidermis and follicular epithelia, and dermo-epidermal clefting.
Case summary: toxic shock syndrome (TSS) in a 2-year-old dog.
Comments
In dogs, TSS is a very rare, life-threatening cutaneous and multisystemic disease process that is thought to be mediated by superantigen toxin-producing Staphylococcus spp.1–3 Typically, TSS in dogs is clinically characterized by regional to generalized macular erythema that primarily affects the face, pinnae, trunk, and limbs and is often associated with severe edema.1,4,5 Affected dogs can also have variable degrees of crusting, petechiation, vesicle and pustule formation, ulceration, cutaneous hyperesthesia, and signs of pain, in addition to signs of systemic illness that may include pyrexia, severe lethargy, anorexia, and vomiting.1,4,5 Differential diagnoses for TSS in dogs include generalized vasculitis, canine sterile neutrophilic dermatoses (similar to Sweet syndrome), canine eosinophilic dermatitis and edema (similar to Wells syndrome), severe forms of erythema multiforme, Steven-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).1 The most common hematologic and serum biochemical abnormalities associated with TSS in dogs include anemia, hypoalbuminemia, and neutrophilia with or without leukocytosis or a left shift.1,3 As observed in the dog of the present report, disseminated intravascular coagulation may be clinically suspected and is a consistent postmortem finding in animals with poor clinical outcomes.1,3,4 Signalment predispositions for TSS in dogs have not been reported owing to the infrequency with which the syndrome is clinically encountered.1
Results of histologic examination of affected tissue are required for definitive diagnosis of TSS in dogs.1 Given the rapid progression and frequent fatal outcome of TSS, it is crucial that early histopathologic lesions are identified to initiate immediate appropriate treatment.1,3 Early lesions can be very subtle as illustrated by the case described in the present report. A classic feature of TSS is clusters of intraepithelial degenerate neutrophils and occasional eosinophils in close association with individual apoptotic keratinocytes that are dispersed throughout the epidermis and superficial follicular epithelium. This is referred to as neutrophilic satellitosis.1 The clustered rather than diffuse distribution of the infiltrate is described as a scattershot pattern. Small epidermal pustules and variable superficial crusting may also develop.1 Early histopathologic lesions of TSS in dogs may resemble sterile neutrophilic dermatosis because of the variable degrees of superficial interstitial to diffuse neutrophilic dermatitis associated with both syndromes. Keratinocyte apoptosis and neutrophilic satellitosis are not features of sterile neutrophilic dermatosis and, when present, help differentiate these 2 disease processes.3 At a later stage, TSS may be mistaken for SJS, TEN, or SJS-TEN overlap syndrome because areas of epidermal and follicular epithelial necrosis are more prominent and associated with subepidermal clefting.6,7 However, whereas SJS, TEN, and SJS-TEN overlap syndrome are associated with lymphocytic satellitosis, TSS is characterized by a lack of lymphoid infiltrate, prominent neutrophilic inflammation, and neutrophilic satellitosis.1,6,7
The histologic characteristics of TSS in dogs are identical to those of staphylococcal TSS in humans, and the presumed pathogenesis of TSS in dogs has largely been extrapolated from what is known about human staphylococcal TSS.1,3 Human staphylococcal TSS is a superantigen-mediated, life-threatening systemic inflammatory response to toxins produced by Staphylococcus aureus and is clinically characterized by sudden-onset macular erythroderma of the trunk, extremities, palms, and soles, which typically desquamates within 1 to 2 weeks, along with concomitant hypotension, pyrexia, and multi-organ dysfunction.1,8–11 The main toxins involved in TSS in humans are TSS toxin-1 and staphylococcal enterotoxins B and C.1,8 However, primary sites of infection and concurrent production of staphylococcal exotoxins have yet to be identified in dogs with TSS that has been confirmed histologically.1,12–14
Treatment of humans with staphylococcal TSS generally involves intensive supportive care, aggressive administration of antimicrobials, and adjunctive immunomodulatory therapy. Vancomycin is often prescribed empirically in combination with clindamycin for humans with staphylococcal TSS while results of bacterial culture and antimicrobial susceptibility testing are pending.8,11 Adjunct human IV immunoglobulin (hIVIG) treatment has also been advocated to neutralize various bacterial exotoxins as well as modulate host immune responses in severe or refractory cases.8,9,10,11
Given that a mortality rate of 55% has been reported for a group of 11 dogs with TSS,3 it is prudent that skin biopsies are performed early when TSS is a suspected differential diagnosis. Biopsy specimens need to be processed and examined promptly to facilitate immediate appropriate treatment. Efforts should be made to identify a source of infection as well as confirm production of staphylococcal exotoxins in dogs with clinicopathologic and histologic findings consistent with TSS. In confirmed cases, dogs should be hospitalized and closely monitored for development of disseminated intravascular coagulation. Because the use of vancomycin in veterinary medicine remains controversial,15 administration of a first-generation cephalosporin in combination with clindamycin may be considered while awaiting the results of bacterial culture and antimicrobial susceptibility testing. Successful use of hIVIG treatment in veterinary patients with a variety of immune-mediated conditions including immune-mediated thrombocytopenia, pemphigus foliaceus, and cutaneous adverse drug reactions has been reported.16 To our knowledge, the possible benefit of hIVIG treatment in dogs with TSS has not been reported; however, hIVIG administration in such cases remains an interesting consideration.
References
1. Gross TL, Ihrke PJ, Walder EJ, et al. Necrotizing diseases of the epidermis. In: Skin diseases of the dog and cat: clinical and histopathologic diagnosis. 2nd ed. Oxford, England: Blackwell, 2005;84–86.
2. Miller WH, Griffin CE, Campbell KL. Bacterial skin diseases. In: Muller and Kirk's small animal dermatology. 7th ed. St Louis: Elsevier Mosby, 2013;214–215.
3. Ramiro-Ibanez F, Walder EJ, Gross TL. Retrospective histological and clinical characterisation of a dermatopathy associated with toxic shock-like syndrome in dogs. In: Hillier A, Foster AP, Kwochka KW, eds. Advances in veterinary dermatology. Vol. 5. Oxford, England: Blackwell, 2005;277–285.
4. Slovak JE, Parker VJ, Deitz KL. Toxic shock syndrome in two dogs. J Am Anim Hosp Assoc 2012;48:434–438.
5. Declercq J. Suspected toxic shock-like syndrome in a dog with closed-cervix pyometra. Vet Dermatol 2007;18:41–44.
6. Yager JA. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis: a comparative review. Vet Dermatol 2014;25:410–426.
7. Banovic F, Olivry T, Bazzle L, et al. Clinical and microscopic characteristics of canine toxic epidermal necrolysis. Vet Pathol 2015;52:321–330.
8. Travers JB, Mousdicas N. Gram-positive infections associated with toxin production. In: Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick's dermatology in general medicine. 8th ed. New York McGraw-Hill, 2012;2152–2156.
9. Lin YC, Peterson ML. New insights into the prevention of staphylococcal infections and toxic shock syndrome. Expert Rev Clin Pharmacol 2010;3:753–767.
10. Silversides JA, Lappin E, Ferguson AJ. Staphylococcal toxic shock syndrome: mechanisms and management. Curr Infect Dis Rep 2010;12:392–400.
11. DeVries AS, Lesher L, Schlievert PM, et al. Staphylococcal toxic shock syndrome 2000–2006: epidemiology, clinical features and molecular characteristics. PLoS One 2011;6:e22997.
12. Burkett G, Frank LA. Comparison of production of Staphylococcus intermedius exotoxin among clinically normal dogs, atopic dogs with recurrent pyoderma, and dogs with a single episode of pyoderma. J Am Vet Med Assoc 1998;213:232–234.
13. Hendricks A, Schuberth HJ, Schueler K, et al. Frequency of superantigen-producing Staphylococcus intermedius isolates from canine pyoderma and proliferation-inducing potential of superantigens in dogs. Res Vet Sci 2002;73:273–277.
14. Yoon JW, Lee GJ, Lee SY, et al. Prevalence of genes for enterotoxins, toxic shock syndrome toxin 1 and exfoliative toxin among clinical isolates of Staphylococcus pseudintermedius from canine origin. Vet Dermatol 2010;21:484–489.
15. Weese JS. Issues regarding the use of vancomycin in companion animals. J Am Vet Med Assoc 2008;233:565–567.
16. 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;21:471–483.
