The anal fistula, as a chronic inflammatory process, does not heal spontaneously. Although the conservative management, which consists of antibiotic therapy against the Gram-negative organisms and anaerobic bacteria, may be effective in the acute and early phase of the anal disease, surgery remains the elective treatment. Since 400 BC, when Hippocrates described a fistulotomy and the employment of a cutting seton made of horsehair, the surgical rationale has always been the same. Nowadays the main surgical options are fistulotomy, fistulectomy and loose or cutting seton insertion. Seton insertion is often performed only to prevent further abscess formation, and the laying-open remains the efficacious surgical treatment of the fistula-in-ano. On the other hand the best choice depends on the anatomical characteristics of the fistula, and particularly if the fistulous tract crosses the external sphincter. In this case the surgical dissection could lead to severe sphincter damage with sequent fecal incontinence if the sphincter injury is too extensive. From this point of view, in order to prevent such a sphincter damage causing fecal incontinence, the most fundamental issue is to quantify the remaining functional sphincter. Only when at least 1-2 cm of functional sphincter are saved from surgical dissection the laying-open can be performed without affecting fecal continence. Otherwise the seton drainage with secondary fistulotomy, staged fistulotomy or sliding flap advancement has to be considered in order to reduce the risk of postoperative incontinence. Anyway there are still many patients suffering from postoperative permanent disturbance in anal continence, which is mostly represented by loss of flatus control and soiling, and only seldom by severe fecal incontinence. Nevertheless, a temporary early postoperative incontinence, which improves within 2-3 weeks, is a frequent complication after surgery of any fistulous tract dissecting the sphincter 1234567891011 (Table 1). Another postoperative complication after surgical treatment of an anal fistula is the recurrence (0-9%) 1234567891011 (Table 1). Basically it depends on an ineffective surgical treatment but also on the fistula etiology. For these reasons newer sphincter-saving approaches have been applied in the treatment of perianal fistula in order to avoid the risk of fecal incontinence, particularly in patients with high risk. Among these approaches the fibrin glue application is standing out because it is a simple and repeatable technique, whose success rate is improved by repeated injections, and does not interfere or compromise subsequent surgical options. Moreover the prolonged discomfort associated with wound dressing after surgery may be avoided. The first series studies about the fibrin glue treatment of anal fistulas were published by Abel and Hjortrup in the early 90' years 1213. Respectively they reported 60% (in 10 patients) and 52% (in 15 patients) healing rates and they both stressed out the importance of thorough curettage to remove all granulation tissue and debris, as well as a wide antibiotic administration. More recent studies do not report the same successful use of this technique, showing low healing rates 14151617. The aim of this review is to assess the cure and complication rate of fibrin glue application compared to surgery alone for the treatment of perianal fistula.

We performed two subgroup analyses assessing other sphincter saving approaches for the treatment of fistulas-in-ano in patients with high risk of postoperative disturbance in anal continence:

- Fibrin glue in combination with intra-adhesive antibiotics vs. fibrin glue alone.

- Anal fistula plug vs. fibrin glue.

Fibrin glue treatment of anal fistulas is simple, safe, and painless and the injections can be repeated to increase the healing rate without preventing from other eventual following surgical procedures. For these reasons in the past decade this technique became increasingly popular, but today many doubts about fibrin glue procedure still remain because of its poor long-term results 232425.

Our statistical analysis confirms the poor long-term results in the patients who underwent fibrin glue treatment rather than surgery, considering both healing and not-healing after an adequate 6-month follow-up, regardless of the fact that the not-healing rate would be a recurrence or not. We did not calculate any recurrence rate after fibrin glue treatment, as we could not find satisfactory data in literature about accurate recurrence rate in the two included studies. Another important point to consider about fistula healing is that the closure of the external skin wound does not always mean complete healing. Buchanan et al. reported a prospective clinical trial with 22 patients presenting the possibility to establish a complete healing of idiopathic complex anorectal fistulas after fibrin glue treatment. The Authors evaluated the fistula tract healing on the basis of the clinical examination and magnetic resonance imaging (STIR sequence MRI long-term can detect deep persistence). Despite of the skin healing in 77% of the patients at 14 days after treatment, 3 cases (14%) were clinically healed at 16 months and only 2 cases (9%) were radiologically healed at 16 months 25. In Table 3 we analyzed the different fistulas etiologies in order to estimate the prognostic value of the etiology in the fibrin glue treatment of the perianal fistula 1215161920262728. Even though most of the studies in literature include fistulas of mixed etiologies, cryptoglandular fistulas are the major group, whereas no-cryptoglandular fistulas represent only a small amount. The fistula healing rate varies widely (0-100%) in Crohn disease patients. In HIV-associated and rectovaginal fistulas the healing rate appears to be poor, although the number of patients considered is too low to obtain certain results. The number of ileal-pouch anal anastomosis fistula patients treated with fibrin glue is very low as well, but in these patients the results seem to be good. On the other hand it was possible to estimate the prognostic value of the anatomical characteristics of the fistula, particularly comparing simple or complex fistulas (Table 4) 1215161920232425262728. Our analysis shows that simple fistulas have a better healing rate than complex fistulas.

Recent articles report encouraging results, which will need further studies to be confirmed, in the repair of anal fistulas by using Surgisis AFP (Anal Fistula Plug: Cook Medical Incorporated, Bloomington, IN), a bioabsorbable plug derived from porcine small submucosa (SIS) 2930. The plug is placed into the fistula tract and sutured to the internal opening. SIS promotes tissue remodelling while being slowly incorporated into the body during a 3 to 6-month period. Surgisis AFP long-term closure rate is significantly higher in patients with simple fistulas than complex ones and with non-Crohn disease versus Crohn disease 22. The major complication of Anal Fistula Plug is a severe perianal sepsis (14.7% Ky 2008 - 29% Lawes 2008) requiring surgical drainage and removal of the plug 2230.

Nowadays the laying-open, seton insertion, staged fistulotomy and sliding flap advancement are still the main pillar of perianal fistula surgery, while fibrin glue alone or in combination with intra-adhesive antibiotics and the anal fistula plug would rather be used in the patients with high risk of postoperative disturbance of anal continence. In literature we found only two randomized controlled trials comparing conventional surgical management versus fibrin glue treatment in patients with anal fistulas. Although from our statistical analysis we could not find any statistically significant result, the healing rate is higher in the patients who underwent the conventional surgical treatment (P = 0,68), and the anal incontinence rate is very low in the fibrin glue treatment group (P = 0,08). Anyway these limited data do not support the use of fibrin glue. Besides, in our subgroup analysis the use of fibrin glue in combination with intra-adhesive antibiotics does not improve the healing rate (P = 0.65), whereas the anal fistula plug treatment compared to the fibrin glue treatment shows good results (P = 0,02), although the poor number of patients treated does not lead to any significant conclusion. Our systematic review underlines the need of new RCTs upon this issue.

The Authors state that none of the authors involved in the manuscript preparation has any conflicts of interest towards the manuscript itself, neither financial nor moral conflicts. Besides none of the authors received support in the form of grants, equipment, and/or pharmaceutical items.

All authors contributed equally to this work, read and approved the final manuscript.