Canine perianal fistulas

Canine perianal fistulas (PAF), also known as anal furunculosis, are fistulous tracts, sinuses, and ulcers that develop in the perianal region. They can be painful and negatively impact the dog’s quality of life, as well as that of the owners. German shepherd dogs are a predisposed breed and may have genetic susceptibility to the disease. An immune-mediated pathogenesis is suspected; therefore, long-term medical management with immunomodulatory medications are recommended.

PATHOGENESIS

The pathogenesis of PAF is currently unknown but was once attributed to anatomic conformation (1). Poor conformation of the perianal region and tail, low tail carriage, trauma, foreign body reaction, fecalith impaction resulting in abscessation, and spread of infection from the anal glands are just a few proposed mechanisms of this disease (2). However, occurrence of PAF in breeds without low tail carriage and a lack of response to antimicrobial therapy make these hypotheses less likely. Perianal fistulas are now recognized as an immune-mediated disease.

Previous studies have presented various theories for the immune-mediated pathogenesis of PAF, including abnormal wound healing due to increased expression of matrix metalloproteinase mRNA in lesional skin, lymphocyte response abnormalities such as altered interleukin-2, an innate immunodeficiency due to NOD2 dysfunction, and reduced lymphocyte proliferation in lesional skin (3–6). Staphylococcal folliculitis has also been discussed as another initiating factor in PAF development. Dogs with PAF have been documented to have increased anti-staphylococcal immunoglobulin G levels compared to healthy dogs (7,8). Other recent studies have demonstrated that PAF development may be a sequela of T-cell mediated inflammation in the perianal region; aggregates of CD31 T-lymphocytes can be documented in lesional skin of affected individuals (8). Increased expression of T-cell-associated cytokine mRNA has also been detected in lesional skin of dogs with PAF (9).

A recent study noted that there are changes in the rectal and cutaneous microbiota over time and with immunomodulatory therapy in German shepherd dogs with PAF; microbial diversity was significantly different between healthy and affected individuals (10). Other studies support these findings and highlight that individuals with dysbiosis of their microbiome may have more severe clinical signs compared to non-dysbiotic individuals (11). Based on these findings, gut microbiota is likely involved in the pathogenesis of PAF.

In humans there is a perianal form of Crohn’s disease (CD) similar to PAF in dogs. Crohn’s disease is a chronic immune-mediated inflammatory bowel disease due to an immune response to intestinal triggers in genetically susceptible humans (12). Approximately 75% of patients with large bowel CD develop perianal ulcers, fistulae, abscesses, blind sinus tracts, and strictures (13). Histopathology of intestinal tissue of patients with Crohn’s disease often has evidence of colitis with granulomas and lymphoid aggregations as some of the most specific indicators of CD (13). German shepherd dogs with PAF can have clinical and histological evidence of colitis and inflammatory bowel disease in up to 50% of cases, so there is concern that enteral triggers (food allergies, bacterial antigens) may contribute to development of the disease (14). One study reported a significant association between perianal fistulas and adverse food reaction, but only 4 dogs with perianal fistulas were included and all were German shepherd dogs (15). Other studies report positive clinical response when a novel protein diet was instituted in dogs with perianal fistulas; however, in many of these studies, dogs are concurrently receiving medications or alternative therapies (15,16). It is unclear in the literature whether dogs could maintain disease remission through dietary modification as the sole treatment.

German shepherd dogs are predisposed to fistula development. In some studies, German shepherd dogs are dramatically overrepresented, accounting for up to 84% of the patient population (17). Therefore, a heritable component is suspected. One study provided evidence for an association between an MHC Class II allele and a haplotype in the development of PAF; dogs with the DLA-DRB1*00101 allele have an approximate 5 times higher risk of developing PAF (18). Dogs homozygous for the DLA-DRB1*00101 allele may also develop perianal fistulas earlier in life (< 8 y of age) (18,19). A potential association between the ADAMTS16 and CTNND2 gene regions has been reported (20).

Many breeds have been documented to be affected by PAF, including Irish setters, collies, border collies, Old English sheepdogs, Labrador retrievers, English bulldogs, beagles, Bouvier des Flandres, Australian shepherds, Chesapeake Bay retrievers, and mixed breeds (1,17,21). Kennedy et al (18) reported a male bias in PAF cases (female 36%, male 55% and unknown 9%) compared to controls (female 40%, male 42% and unknown 16%), although this was not statistically significant.

CLINICAL PRESENTATION

Canine PAF is a chronic and progressive disease that can lead to pain and discomfort in affected animals. Individuals with PAF are generally middle-aged, with few reports available of dogs younger than 1 y (22). A definitive sex predisposition has not been demonstrated (1).

Lesions may vary from pinpoint ulcers to sinuses and fistulas in the skin of the perianal, anal and perirectal tissues. True sinus tracts have either blind ends, communicate with the anal sacs, anorectal lumen, or maybe interconnected. True sinus tracts are rare and do not often communicate with the rectal lumen or anal sacs (1). Hemorrhage may also be noted if the tracts are well-developed and tunneling deep into perianal tissue. Discharge, if present, is usually serosanguinous to purulent, pending the presence of secondary infection.

Often when dogs are brought in for examination, owners may not be aware of specific lesions in perianal tissue. Dogs may present due to licking of the anal region, tenesmus, hematochezia, mucopurulent discharge, vocalization upon defecation, constipation, ribbon-like stool, self-mutilation, bleeding from the region, scooting, odor, weight loss, anorexia, and low tail carriage (1,2). Based on the association between perianal fistulas and colitis, owners may report diarrhea, soft/mucoid stool, and increased frequency of defecation (1).

DIAGNOSIS

As with any dermatological disease, diagnosis of PAF is based on a thorough history, physical examination findings, and ruling out other differential diagnoses. Differentials for this disease would include neoplasia (perianal adenoma, anal sac adenocarcinoma), anal sac disease (abscess, rupture), atypical bacterial infection, mucocutaneous lupus erythematosus, and certain fungal diseases (1). Obtaining a minimum database of complete blood (cell) count, serum biochemistry, and urinalysis is useful prior to any immunomodulatory therapy. Cytology may reveal pyogranulomatous inflammation and can rule in/out the presence of a secondary bacterial pyoderma. If a pyoderma is documented and systemic therapy is to be started, bacterial culture and susceptibility should be performed to guide selection of an oral antibiotic.

When interpreting culture results, it is imperative that the clinician does not overinterpret potential contaminants. Controlling secondary infections in this anatomic region may take weeks to months. A rectal examination should be undertaken but this may require heavy sedation or general anesthesia, based on the patient’s pain and tolerance of the procedure. The rectal region should be palpated for any masses that may indicate presence of a neoplastic process. The rectal mucosa is commonly thickened, and the anal sacs can be within the fibrosis. The anal sacs should also be palpated and expressed to determine if the sinuses or fistulous tracts communicate with these glandular structures. Anal sac ducts can be flushed with sterile saline to reveal unobserved tracts if necessary. Anal sac impaction, difficult expression, or rupture may occur in patients with PAF secondary to inflammation and fibrosis in the region of the anal sac ducts (23).

Tracts/sinuses may be probed with a blunt instrument to determine severity and involvement with other structures. Fine-needle aspiration or biopsy of affected disease will rule out neoplasia if necessary. Histopathology is rarely performed unless presentation is unusual, or signs are noted in a breed uncommonly affected by PAF. Histopathologic features of canine perianal fistulas include periadnexal inflammation and fibrosis, with or without furunculosis, hidradenitis, ulceration, and formation of epithelial-lined sinus tracts within the dermis (24). Within these tracts will often be inflammatory infiltrates, composed of neutrophils, lymphocytes, plasma cells, and macrophages (24). Other potential diagnostics include pelvic radiography, colonoscopy with biopsy and fungal culture. If intestinal biopsies are undertaken, histologic signs of colitis can be present in ~50% of dogs with PAF (14).

TREATMENT

It is imperative to begin treatment quickly, as up to 36.6% of dogs can be euthanized due to complications from fistulas (25).

Systemic antibiotics are recommended if secondary infection is confirmed on cytology. Selection of the most appropriate antibiotic must be based on culture and susceptibility (2). Enemas are also beneficial for patients suffering from constipation or obstipation (2). A restrictive diet trial should also be considered to rule out an adverse food reaction, based on suspicion that in some cases, a cutaneous adverse food reaction may trigger fistula development. Harkin et al (14) evaluated response to immunosuppressive treatment with prednisone as well as a novel protein diet; fistulas resolved in 1/3 of cases and improved in another 1/3 of cases following this protocol.

Multiple studies report a positive response to therapy with oral cyclosporine, so it is the preferred first-line treatment in a recent literature review with author consensus and recommendations (26). In a study by Matthews and Sukhiani (21), all patients treated with cyclosporine improved after 4 wk. Cyclosporine is an immunomodulatory and immunosuppressive agent inhibiting T-cell activation and promoting early death of activated T-cells (27). This therapy should be started at a dose of 5 mg/kg BW, q24h. Treatment should be continued until a cure is achieved, with resolution of all sinuses and fistulous tracts. The average time to complete remission is 15 wk (range: 8 to 20 wk) (17,21). The efficacy of cyclosporine is dose-dependent so the dose can be increased if response is inadequate (17,21). Cyclosporine in combination with ketoconazole has also been used in many treatment protocols to reduce cyclosporine dose (due to ketoconazole inhibiting cytochrome P-450 pathways and decreasing cyclosporine clearance). However, antifungal resistance and long-term use should be considered with addition of ketoconazole, as it has its own potential side effects and may be contraindicated (28,29).

Topical tacrolimus, used for treatment of other immunemediated skin disease in dogs (e.g., discoid lupus erythematosus and pemphigus erythematosus), healed sinus tracts in ~50% of individuals with PAF after 4 mo of therapy and improved lesions in 90% of dogs (30,31). Tacrolimus can cause local irritation or burning but otherwise appeared well-tolerated. Tacrolimus should be applied twice daily during the initial stages of treatment. Owners must be advised to wear gloves during application. Once resolution of clinical signs is noted, application should be reduced to the lowest frequency that controls inflammation long term, without recurrence of clinical signs (often q24h to q72h can be achieved). Tacrolimus can also be used in conjunction with other systemic therapies to decrease induction doses of systemic medication.

Systemic glucocorticoids such as prednisone can resolve clinical signs in anywhere from 0 to 50% of cases, based on a recent literature review (26). In a greater number of cases, these glucocorticoids will lead to improvement, but not full resolution. In most studies, glucocorticoids are used in combination with other therapies, so it is challenging to determine their effect if used solely as treatment. Doses used range from 1 mg/kg BW, q12h to 2 mg/kg BW, q24h for 2 wk and then tapered to 1 mg/kg BW, q24h and 1 mg/kg BW, q48h (14,30,32).

Once remission has been achieved or lesions are mild and do not affect the quality of life, medical therapy should be tapered to a maintenance dose that the patient tolerates and provides an adequate response.

In refractory cases azathioprine has been used to resolve clinical signs. Generally, this therapy is only utilized if other, safer, alternatives have been trialed and failed. It can be used as monotherapy or in combination with other systemic treatments (33). One study used a combination of azathioprine and metronidazole prior to surgical en bloc excision and anal sacculectomy in a small number of dogs. Fistulas did not fully resolve prior to surgery but lesions became smaller/shallower with less inflammation. Treatment continued for 2 to 6 wk following surgery. After surgery, all lesions resolved and investigators felt medical therapy facilitated success (34).

Surgery for PAF used to be a first choice for disease management. Surgical procedures can involve en bloc excision, laser excision, tail amputation to prevent contamination of the area, cauterization, and cryotherapy (2,35,36). Surgical complications such as anal stenosis or fecal incontinence should be discussed with owners prior to surgery. These complications can be frequently noted following surgery. Vasseur (25) documented development of clinically evident fistulas in 56.1%, some form of incontinence in 26.8%, tenesmus in 19.5%, flatulence in 17.1%, and anal stricture in 14.6%. The recurrence rate was as high as 70%; therefore, surgery is no longer recommended as a first-line therapy and is instead reserved for cases in which medical management fails, or the dog’s quality of life is too severely affected (26).

In a study where surgical en bloc excision with anal sacculectomy was followed by metronidazole, 94% of cases had an improved quality of life and an acceptable level of fecal incontinence (23). Lombardi and Marino (16) followed dogs treated with en bloc excision, anal sacculectomy and then an exclusive white fish and potato diet; fecal incontinence was not reported but 87.9% had complete or near-complete resolution (16).

Fluorescent light energy (FLE) and photobiomodulation have also been studied for treatment of PAF. In one study, 4 dogs were treated with weekly FLE and all had significant reductions in licking, vocalization, and straining within 2 wk. No adverse effects were noted and after 5 wk, lesions had significantly decreased in most of the dogs; therefore, FLE may be another treatment option for dogs with PAF (37).

Other treatments that have been reported, with variable responses, include use of oclacitinib, mycophenolate mofetil, cryotherapy, restricted diet trials, platelet rich plasma, and adipose derived mesenchymal stem cells (26,38–40).

PROGNOSIS

Dogs with PAF should be scheduled for recheck examination according to the therapy selected for management. Rechecks should involve examination of the affected region, along with rectal examinations. If immunosuppressive medications are used, dogs should have recheck bloodwork performed every 2 to 4 wk (depending on the dose used). Improvements in clinical signs can be documented at each recheck and whether any signs of discomfort are still present, e.g., constipation, vocalization, etc. If a secondary infection is being treated, repeat cytology is a must prior to discontinuation of antibiotic therapy. Once resolution of signs has been observed, therapy can be slowly tapered to find an appropriate maintenance dose.