Unusual Systemic Signs in a Dog with Sterile Neutrophilic-Macrophagic Lymphadenitis and Nodular Panniculitis

Introduction

Panniculitis refers to a group of diseases of multifactorial etiology characterized by the localization of the major focus of inflammation to the subcutaneous fat.¹ Concurrent systemic signs are also described. Caution has to be observed to distinguish cases with an infectious origin from cases classified as idiopathic requiring immune suppressive treatment.

This report describes a dog that presented first with pyrexia, lymphadenopathy, and gastrointestinal signs, followed by the development of nodular panniculitis. After exclusion of an infectious etiology, treatment was successfully started with prednisolone; however, relapse and marked side effects from the corticosteroid therapy required the addition of cyclosporine to achieve complete remission.

To the authors’ knowledge, this is the first description of a canine case of nodular panniculitis and vasculitis with systemic involvement requiring a combination of prednisolone and cyclosporine to adequately control the symptoms.

Case Report

A 7 mo old, 18 kg, intact female English springer spaniel was referred to the authors’ Companion Animal Hospital of the University of Bern for evaluation of a 1 wk history of diarrhea, vomiting, decreased appetite, apathy, and hyperthermia. The dog was born in Switzerland and had not been abroad, was vaccinated (the dog had last been vaccinated 4 mo previously, but rabies was not included), and had been regularly dewormed with milbemycin and praziquantel^a by the breeder up to the age of 10 wk. The dog had also been dewormed 2 days before presentation by the referring veterinarian. Additional treatments instituted by the referring veterinarian were lactated Ringer's solution (400 mL subcutaneously [SC]), metronidazole^b, and prifinium bromide^c. No improvement was noted and the dog was referred to the authors’ institution the following day.

On presentation, the physical examination revealed lethargy, pyrexia (40.7°C), dehydration, and bilateral mandibular lymphadenomegaly. Abdominal palpation was unremarkable, and no neurologic or orthopedic abnormalities such as neck pain or joint effusion were noted. A complete blood count (CBC) and serum biochemistry panel revealed a mild mature neutrophilia (14.2 × 10⁹/L; reference range, 3.0–11.5 × 10⁹/L), mild hypoalbuminemia (28.9 g/L; reference range, 29.7–40.0 g/L), and a mildly elevated alkaline phosphatase (305 IU; reference range, 10–128 IU). Urinalysis revealed a specific gravity of 1.043, a pH of 7.9 with 10–12 leukocytes/high-power field (hpf), 12–14 erythrocytes/hpf, and many struvite crystals.

An abdominal ultrasound revealed generalized lymphadenomegaly. The mesenteric lymph nodes were mildly enlarged with hypoechoic and homogenous echogenicity surrounded by hyperechoic intra-abdominal fat. A minimal amount of anechoic free abdominal fluid was noted. The other abdominal organs were sonographically within normal limits. Thoracic radiographs revealed a moderate interstitial to alveolar lung pattern. The fine needle aspiration cytology from the mandibular lymph nodes was interpreted as marked plasma cell hyperplasia and mild to moderate neutrophilic-macrophagic inflammation (Figures 1A and B). Infectious organisms were not identified.

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The dog was treated with IV fluids, amoxicillin/clavulanic acid^d (15 mg/kg IV q 12 hr), and doxycycline^e (5 mg/kg per os [PO] q 12 hr). The following day, multiple subcutaneous nodules were observed on both sides of the trunk. The nodules were firm, well circumscribed, and not painful on palpation. The overlying skin was unaffected. The nodules had not been noted on the previous day and the owners had not noticed any skin abnormalities before presentation.

Further diagnostic tests included fine needle aspiration cytology of the abdominal lymph nodes and subcutaneous nodules, bronchoscopy, and biopsies of the subcutaneous nodules. Cytologic interpretation of the abdominal lymph nodes was plasma cell hyperplasia and marked neutrophilic-macrophagic lymphadenitis. Cytology of the skin nodules revealed clusters of adipocytes interspersed with vacuolated macrophages, nondegenerate neutrophils, and occasional plump spindle cells. These findings were interpreted as panniculitis. Bronchoscopy revealed mild hyperemia and edema of the tracheal and bronchial mucous membranes with mucous secretions present in the bronchi. A bronchoalveolar lavage (BAL) revealed mixed inflammation consisting of activated macrophages and low numbers of neutrophils.

Urine, BAL fluid, and peripheral lymph node aspirates were submitted for aerobic and anaerobic cultures. Skin biopsies were submitted for histologic examination as well as aerobic, anaerobic, fungal, and mycobacterial cultures. Titers for Ehrlichia canis, Anaplasma phagocytophilum, Leishmania spp., Toxoplasma gondii, and Neospora caninum were submitted. Peripheral lymph node material was also submitted for PCR directed against Leishmania spp.

Pending results, antimicrobial treatment was extended to include clindamycin^f (8 mg/kg PO q 12 hr) to cover potential infection with either T. gondii or N. caninum, but the dog's temperature remained elevated (39.0–40.5°C). Four days after presentation, the preliminary results from the cultures were negative and the submitted titers all returned negative. The dog was then treated with prednisolone^g (1 mg/kg PO q 12 hr) for a suspected immune-mediated disease. This resulted in a rapid improvement, return of appetite, and resolution of the fever.

Histopathology of the skin biopsies revealed a moderate inflammation of the panniculus extending into the deep dermis. In one biopsy, the cutaneous muscle and the underlying adipose tissue were also inflamed. The inflammatory infiltrate was mainly composed of neutrophils infiltrating the interlobular connective tissue and the fat lobules multifocally (Figure 2A). Some fat lobules were necrotic and were replaced by lipid-laden macrophages. Endothelial swelling and a neutrophilic infiltrate in the wall of small capillaries was present in the interlobular connective tissue. Multifocal fibrinoid necrosis of small and medium sized blood vessels with fibrin exudation and occasional fibrin thrombi was observed (Figure 2B). Mild multifocal fibrin exudatation and septal fibrosis were present. Special stains for bacteria (Gram), mycobacteria (Ziehl-Neelsen, Fite-Faraco), and fungi (Grocott, periodic acid-Schiff) were all negative. Based on these findings, a morphologic diagnosis of acute moderate neutrophilic panniculitis and multifocal neutrophilic and fibrinoid vasculitis was made. All pending cultures were negative.

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The dog was discharged with amoxicillin/clavulanic acid^h (15 mg/kg PO q 12 hr) for 14 days, doxycycline (5 mg/kg PO q 12 hr) for 5 days, and prednisolone (1 mg/kg PO q 12 hr, to be tapered with an improvement of clinical signs). On a follow-up examination performed 10 days later, the nodules appeared markedly smaller, no fever was present, and no other abnormalities were noted on physical examination. A CBC, biochemical profile, and urinalysis revealed a mature neutrophilia and mildly elevated liver enzymes consistent with corticosteroid treatment.

Six weeks later, all clinical signs had resolved. The interstitial to alveolar lung pattern initially observed on the thoracic radiographs had markedly improved. Only a mild interstitial pattern was still noted. An abdominal ultrasound revealed only a mild mesenteric lymphadenopathy. At this point, the prednisolone was being administered at a dose of 0.5 mg/kg PO q 24 hr.

Sixteen weeks after the first presentation, the dog suffered an acute relapse with pyrexia (41.0°C) and diarrhea. At this time, the prednisolone dose was 0.5 mg/kg PO q 48 hr and was the sole medication being administered to the dog. Physical examination revealed marked muscle wasting and reappearance of skin nodules. Blood work revealed a slight elevation of serum alkaline phosphatase (322 IU). On abdominal ultrasound, the mesenteric lymph nodes were enlarged (up to 2 cm in diameter) with heterogenous, mainly hypoechoic, echogenicity. The intestinal walls and thickness of the small and large bowel loops were sonographically within normal limits. Serum vitamin B₁₂, folic acid, and trypsin-like immunoreactivity were unremarkable. The dog was again dewormed with fenbendazolⁱ (50 mg/kg PO q 24 hr for 3 days) and placed on a novel antigen diet^j to rule out a primary food-responsive diarrhea. A presumptive diagnosis of a relapse of an immune-mediated disorder associated with vasculitis and panniculitis was made. The dose of prednisolone was increased to 0.5 mg/kg PO q 24 hr and treatment with cyclosporine^k (5 mg/kg PO q 24 hr) was initiated. Cyclosporine was added in an attempt to avoid a higher dosage of corticosteroid to control the disease because the dog showed marked side effects from the administration of corticosteroids (i.e., polyphagia, polydipsia, polyuria, and muscle wasting). Addition of the cyclosporine resulted in a rapid improvement of clinical signs and the dog was discharged 2 days later.

By wk 20 after the initial presentation, the dog's general condition was excellent, blood work was normal, and the abdominal lymphadenomegaly was regressing. Cyclosporine was continued (5 mg/kg PO q 24 hr) and prednisolone was reduced (0.5 mg/kg PO q 48 hr). The novel antigen diet was continued. At 26 and 32 wk, the dog was clinically well and the abdominal lymphadenomegaly had regressed further. The medications were tapered at each of these visits (prednisolone was reduced to 0.25 mg/kg PO q 48 hr and cyclosporine was decreased to 5 mg/kg PO q 48 hr). The prednisolone and cyclosporine were discontinued at wk 45 and 65, respectively. At the time of writing, the dog had been challenged with different food without recurrence of the diarrhea thereby excluding a food-responsive diarrhea. By 98 wk after the first presentation, the dog had not experienced a further relapse.

Discussion

Panniculitis refers to a group of diseases of multifactorial etiology characterized by the localization of the major focus of inflammation to the subcutaneous fat.¹ The cutaneous lesions of the dog described in the present report were most consistent with a vasculitis associated with nodular panniculitis. Most dogs with clinical signs of nodular panniculitis are diagnosed with idiopathic sterile nodular panniculitis (ISNP). This term comprises all sterile inflammatory diseases of the panniculus of unknown etiology. A breed predilection for Dachshunds has been reported; however, neither age nor sex predilections have been noted.¹ Clinically, the disease is characterized by the development of multiple firm to fluctuant subcutaneous nodules that may ulcerate. Predilection sites are the trunk, neck, and proximal extremities.^2,3 Systemic signs, consisting of pyrexia, anorexia, and general malaise, are commonly described, as was the case in the dog in the present report. Differential diagnoses include opportunistic mycobacterial infections, systemic and opportunistic fungal infections, aerobic and anaerobic bacterial infections, foreign body reactions, protozoal infections such as toxoplasmosis, leishmaniasis, and neosporosis, as well as neoplasia. Histologic examination of the nodules reveals a lobular to diffuse panniculitis, which contrasts with the more prominent vasculitis found in the dog in the present report.¹ Although in most previously reported cases, the emphasis was given to the clinical description of the lesions and less so to the histopathological pattern, the combination of both lobular and septal panniculitis with prominent vasculitis in this dog is uncommon and atypical of ISNP lesions.^2,4 Indeed, vasculitic septal panniculitis in dogs is a very rarely described disease, possibly caused by systemic infection, drug administration, or of idiopathic origin.¹ In this dog, no medication was given prior to the initial development of clinical signs and a systemic infection was not found. Other differential diagnoses for ISNP include canine juvenile cellulitis (CJC) and pancreatic panniculitis. CJC is typically observed in puppies and generally causes severe facial dermatitis, which may be accompanied by extensive panniculitis of the trunk, fever, lymphadenomegaly, and general malaise. The accompanying panniculitis can be difficult to distinguish from ISNP, but histologically, it is also characterized by periadnexal pyogranulomatous inflammation, which was not present in the dog described in this case report.^1,3 In one report, CJC and ISNP occurred simultaneously in three springer spaniels potentially suggesting a common underlying disease process.⁵

Pancreatitic panniculitis is a very rare disease and is most often related to pancreatic adenocarcinoma/carcinoma, bile duct carcinoma, or pancreatitis.¹ Serum alpha 1-antitrypsin deficiency has been identified as an underlying cause for pancreatic panniculitis in humans, but neither deficiency nor polymorphism of the responsible gene was found to predispose dogs to pancreatic panniculitis.⁶ In the dog described herein, no pain on abdominal palpation was noted and no ultrasonographic evidence of pancreatitis was found. Canine specific pancreatic lipase was not measured as this test was not readily available in Europe at the time and the results would not haven been available for many weeks if the test had been performed. Previously described cases of pancreatic neoplasia or pancreatitis and panniculitis always presented marked changes on abdominal ultrasound, which were not present in the present case and therefore such a disease process was considered very unlikely.^7–9 Moreover, severe skin fat necrosis with saponification, which is described in pancreatitic panniculitis, was not found in this dog.¹ Therefore, pancreatic disease as a cause of the clinical signs of this dog was unlikely.

The striking feature in this case was the systemic extension of the disease. Not only was peripheral and intra-abdominal neutrophilic-macrophagic lymphadenitis found, but also a mixed pulmonary inflammation. The cases of ISNP described so far did not present with such extensive changes. In contrast, mandibular and prescapular lymphadenopathy with a pyogranulomatous inflammation is considered a hallmark for CJC.³ Springer spaniels might be prone to a specific type of sterile skin disease with systemic involvement. Indeed, a number of springer spaniels presenting with generalized lymphadenopathy and pyrexia with or without concurrent pyogranulomatous dermatitis resembling lesions of sterile nodular granuloma or pyogranuloma syndrome were reported in a journal letter published in 2002. Although infectious agents could not be demonstrated, two of the dogs responded to antibiotics alone and one dog responded to corticosteroids.¹⁰

Another interesting finding in the case presented herein was the diarrhea described both at initial presentation and when the clinical signs recurred. Gastrointestinal parasites were considered unlikely as the dog had been dewormed prior to the first presentation and was again dewormed at the time of the relapse. No significant gastrointestinal tract changes were found on ultrasound. A food-responsive diarrhea was excluded by a change in diet followed by a dietary challenging without recurrence of the problem. Inflammatory bowel disease (IBD) could not be ruled out as IBD may respond to corticosteroid treatment. The authors therefore could not exclude that the skin nodules were secondary to IBD, although this has not been previously described in dogs. Panniculitis (in the form of erythema nodosum) does, however, occur in a considerable percentage of people affected with Crohn's disease and can even precede internal systemic disease.^11,12 In some patients, vasculitis can also be found in the skin.¹³

The rapid and sustained improvement of the dog's condition with corticosteroid treatment supports the authors’ presumptive diagnosis of a noninfectious disease. Indeed, worsening of signs was expected to follow corticosteroid treatment if an infection had been present, as described in a dog treated for presumptive sterile pyogranulomatous disease, which developed generalized cutaneous sporotrichosis.¹⁴

Treatment of ISNP may be discontinued after 3–8 wk with subsequent long-term or permanent remission, especially in young dogs.³ Given the relapse after 16 wk of corticosteroid treatment in the dog described here, combination therapy with prednisolone and cyclosporine was considered warranted to continue long-term treatment without excessive steroid side effects. Whether permanent remission will be achieved remains to be seen. The dog had not relapsed until 2 yr after stopping all treatment.

Conclusion

The authors present an unusual case of systemic sterile neutrophilic-macrophagic lymphadenitis with nodular panniculitis and vasculitis associated with pulmonary and gastrointestinal signs that responded to immunosuppressive treatment. To the authors’ knowledge, this is the first description of a canine case of nodular panniculitis and vasculitis with systemic involvement requiring a combination of prednisolone and cyclosporine to control the symptoms.