Can Inflammatory Index Parameters be an Indicator

of Complexity in Perianal Fistula?

Osman Celik
Kayseri City Hospital
Ersin Gundogan
Kayseri City Hospital
Gamze Turk
Kayseri City Hospital
Sedat Carkit

Erciyes University
Tamer Ertan
Kayseri City Hospital

Research Article

Keywords: Perianal fistula, Inflammatory index, Magnetic Resonance Imaging, Recurrence.

Posted Date: April 30th, 2024

DOI: https://doi.org/10.21203/rs.3.rs-4319070/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License.
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Additional Declarations: No competing interests reported.

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Abstract
Purpose: To investigate the relationship between preoperative inflammatory parameters and disease
severity in patients operated for perianal fistula in our clinic between 2013-2021.

Methods: Patients between the ages of 16-78 who were operated on with the diagnosis of perianal fistula
in Kayseri Şehir Training and Research Hospital between 2013-2021 and who were followed up afterward
were included in the study by retrospective file search method without gender discrimination. Preoperative
demographic data, laboratory parameters (platelet, neutrophil, lymphocyte, monocyte, leukocyte, CRP,
albumin), surgical procedures, perioperative and postoperative complications, length of stay, and
recurrences were noted.

Results: 134 patients with perianal fistula were included in the study. It was determined that 71.6% (n=96)
were male, and the mean age was 44.6±13.8 years. Inflammatory parameters such as crp/albumin,
neutrophil/lymphocyte, lymphocyte/crp, neutrophil/crp, lymphocyte/monocyte, platelet/lymphocyte were
compared with tract length, tract thickness, presence of perifistular inflammation and presence of
abscess as criteria for complex fistula formation and cut of values were created. Among these scoring
values, crp/albumin, lymphocyte/crp, and neutrophil/crp ratios were statistically significant in predicting
the tract characteristics defined for high recurrence and complex fistula.

Conclusion: Inflammation-based scores such as crp/albumin, lymphocyte/crp, and neutrophil/crp ratios

can differentiate complex fistula from simple fistula.

1- Introduction
Although perianal fistulas are benign diseases, they may cause morbidity and loss of active labor force
due to the age range in which they are frequently seen (1). The diagnosis of perianal fistula is made by
visualization of the fistula tract and the external mouth. This diagnostic method may lead to incorrect
and incomplete evaluation of the fistula course in complex fistulas (2). MRI demonstrates high sensitivity
and specificity for the number and location of fistula tracts and detects complexity often missed on
clinical examination (3).

A simple perianal fistula is diagnosed by physical examination, and imaging modalities such as MRI are
used in cases where a complex perineal fistula is considered. Some fistulas thought to be simple on
clinical examination may be complex fistulas due to the presence of secondary tracts or long course and
deep localization (4). In one study, the preoperative diagnosis changed in half of simple fistulas with MRI
(5).

MRI is a drawback because of the cost per patient and difficulty accessing the examination. However, it is
known that lack of preoperative diagnosis is one of the most significant factors in postoperative
recurrence. Therefore, evaluating patients preoperatively and performing additional imaging for fistula

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morphology is essential. Our study aimed to find patients who may require further imaging with
preoperative routine laboratory parameters.

2- Materials and Methods

2.1. Study Design and Eligibility Criteria

The study was initiated with the ethics committee decision numbered 2021/412. Patients between the
ages of 16-78 years who were operated on for perianal fistula in the General Surgery Clinic of Kayseri
Şehir Training and Research Hospital between 2013-2021 and who were followed up afterward were
included in the study by retrospective file search method without gender difference.

Patients whose information could not be reached, who were lost to follow-up, who had discrepancies in
inflammatory parameter values, and who could not be subjected to adequate examination on MRI due to
technical reasons were excluded from the study. Preoperative demographic data, laboratory parameters
(platelet, neutrophil, lymphocyte, monocyte, leukocyte, c-reactive protein (CRP), albumin), surgical
procedure and dates, perioperative and postoperative complications, length of hospitalization, and
recurrences were noted. A single radiologist reinterpreted MRI images within the scope of the study.
According to MRI findings, the fistula type (according to its position in the sphincter) was classified as
intersphincteric, transsphincteric, extrasphincteric, and suprasphincteric.

The presence of secondary tract, presence of single or multiple tracts, tract length, tract thickness,
presence of abscess, presence of perifustular inflammation, Lymphocyte/CRP (LCO),
Neutrophil/Lymphocyte (NLO), Lymphocyte/Monocyte (LMO), Platelet/Lymphocyte (TLO) and
CRP/albumin (CAO) values were compared with the preoperative MRI findings on each parameter. The
statistically significant correlation between these MRI-detected criteria and preoperative inflammatory
parameters was evaluated. No special tests or interventions were performed, and routine tests and
examinations were analyzed.

2.2. Statistical Analysis

SPSS (Statistical Package for the Social Sciences) 23.0 program was used for statistical data analysis.
Categorical measurements were evaluated as numbers and percentages; continuous measurements were
assessed as mean and standard deviation (median and minimum-maximum where necessary). Chi-
square and Fisher Exact tests were used to analyze categorical expressions. Shapiro-Wilk test was used
to determine whether the parameters in the study showed normal distribution. Independent Student's t-
test was used for normally distributed parameters, and the Whitney u-test was used for non-normally
distributed parameters. Multiple logistic regression models and Spearman and Pearson correlation tests
were also used. The statistical significance level was taken as 0.05 in all tests.

3- Results

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Of the patients included in the study, 72% (n=96) were male, and the mean age was 44.6±13.8 years
(Median: 44, Range: 16-78). 38 (31%) patients had abscess, and 63 (53%) patients had perifollicular
inflammation. The sphincter relationship was intersphincteric in 90 (75%) and transsphincteric in 30
(25%) patients. The mean tract length of the fistulas was 39.7 mm, the mean tract thickness was 3.5 mm,
and the mean number of tracts was 1.1. Intraoperative internal orifice was found in 103 (79%) patients,
and recurrence was observed in 33 (25%) patients.

The cutoff values of LCO, NLO, TLO, CAO, LMO, and NCO were analyzed using ROC analysis, according to
the presence of abscess. As a result of the analysis, it was found that the cutoff value calculated for the
LCO value was below 0.28 (86% sensitivity, 71% specificity), the cutoff value calculated for the CAO value
was 1.52 and above (71% sensitivity, 73% specificity), and the cutoff value calculated for the NCO value
was below 0.43 (98% sensitivity, 59% specificity), which was statistically significant in distinguishing the
presence of abscess (p<0.001).

The cutoff values of LCO, NLO, TLO, CAO, LMO, and NCO were analyzed by ROC according to perifollicular
inflammation. As a result of the analysis, it was found that the cutoff value calculated for the LCO value
was 0.45 and below (59% sensitivity, 68% specificity), the cutoff value calculated for the CAO value was
1.39 and above (56% sensitivity, 74% specificity). The cutoff value calculated for the NCO value was 0.5
and below (93% sensitivity, 41% specificity), which was statistically significant in distinguishing
perifistular inflammation (p<0.001).

The cutoff values of LCO, NLO, TLO, CAO, LMO, and NCO were analyzed using ROC analysis according to
tract thickness. As a result of the analysis, the cutoff value calculated for the LCO value was 0.4 and
below (66% sensitivity, 69% specificity), the cutoff value calculated for the CAO value was 1.71 and above
(50% sensitivity, 86% specificity), and the cutoff value calculated for the NCO value was 0.53 and below
(90% sensitivity, 47% specificity).

The cutoff values of the patients' LCO, NLO, TLO, CAO, LMO, and NCO were analyzed using ROC analysis
according to tract length. As a result of the analysis, it was found that the cutoff value calculated for the
LCO value was 0.19 and below (35% sensitivity, 97% specificity), the cutoff value calculated for the CAO
value was 1.71 and above (52% sensitivity, 87% specificity). The cutoff value calculated for the NCO
value was 0.5 and below (42% sensitivity, 90% specificity) were statistically significant (p<0.001).

4- Discussions
A perianal fistula is an epithelialized tract that connects the luminal surface of the anal canal or rectum
with the perineal skin. Tract formation in anal fistula requires disruption of the epithelial barrier and anal
mucosa-associated immune cells; the precise mechanism of this physical disruption and immunologic
obstacles to the development of anal fistulas have yet to be determined. However, there were hints that
matrix metalloproteinases and cytokines, defined as epithelial-mesenchymal transition, may all play a
role (6, 7). Anal fistula disease is thought to be caused by activation of the inflammatory process
independently of the abscess; most of these studies are based on preclinical studies of fistulas
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associated with Crohn's disease, whose inflammatory processes are relatively well characterized.
Currently, inflammatory markers such as CRP are used in scoring systems to determine the severity of
uncomplicated Crohn's disease (8). In addition, many publications have proven CRP's efficacy in
evaluating the perianal fistula activity (9, 10). CAO ratio, a combination of markers for systemic
inflammation and nutritional status, has been extensively studied as an independent prognostic marker in
infection, malignancy, and other inflammatory diseases (11-13). In addition, NLO and CAO ratios in
patients with acute cholecystitis (14), NLO ratio in patients with acute appendicitis (15), and CAO ratio in
patients with acute pancreatitis (16) were significant as prognosis and severity scores. In colorectal
cancers, the LCO ratio was an excellent prognostic marker (17-19). In our study, CAO, NLO, LCO, LCO, NCO,
LMO, and TLO parameters were compared separately with tract length, tract thickness, presence of
perifistular inflammation, and presence of abscess, which are the criteria for complex fistula formation,
and cutoff values were created. Among these scoring values, CAO, LCO, and NCO ratios were statistically
significant in predicting the tract characteristics defined for complex fistula with a high probability of
recurrence.

Fistula morphology and the relationship between the fistula and the anal sphincter complex are crucial in
determining the feasibility of any surgical treatment. The optimal surgical strategy should offer the best
chance of cure with the lowest risk of recurrence and an acceptable risk of continence disturbance.
Fistulas can be categorized as simple or complex. Simple fistulas are intersphincteric or low trans
sphincteric fistulas and involve less than 30% of the external sphincter complex. Complex fistulas include
high trans sphincteric, suprasphincteric, extrasphincteric, recurrent and horseshoe fistulas, multiple
fistulas, inflammatory bowel disease, radiation history, and those associated with pre-existing
incontinence or chronic diarrhea (20). In addition, another defined form of complex anal fistula is a fistula
that is difficult to manage, carries a higher risk of recurrence, and poses a more significant threat to
continence (21). The definition of complex fistula includes high localization of the fistula, multiple tracts,
tract length, sphincter relationship, presence of an associated abscess, absence of an internal orifice,
presence of concomitant disease, and recurrent fistulas (21). In our study, it was found that all of the
criteria defined as components of complex fistula showed a homogenic correlation with each other; in
patients with more than one tract, trans sphincteric sphincter relationship, presence of abscess and
presence of perifollicular inflammation were found to be more frequent, and the tract length was also
found to be higher. In patients with perifistular inflammation, trans sphincteric fistula and the presence of
abscess were more frequent, and the thickness of the tract was higher. Therefore, these criteria were
compared with inflammatory indices separately.

Although many surgical methods have been tried to treat perianal fistula, recurrence rates are variable
and do not tend to decrease (recurrence rates are 3-57%) (22). The reasons for recurrence in the literature
include previous anal surgery, fistulas related to Crohn's disease, patients receiving immunosuppressive
therapy, diabetes mellitus, steroid users, high trans sphincteric fistulas, wrong choice of surgical
procedure, failure to reveal the internal patency completely, presence of secondary tract, presence and
persistence of abscess pouches, and inability to remove the primary tract (23, 24). Our study observed
recurrence in 33 (25%) patients. In addition, recurrence rates were found to be more frequent in patients
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with perifistular inflammation and increased tract thickness. One of the main perioperative problems is
the inability to detect the inner mouth of the fistula in the anal epithelium and the presence of a second
tract that is not detected by imaging methods (21). In our study, the internal opening could not be
detected intraoperatively in 16 (22%) patients. In addition, a secondary tract was observed in 14 (11%)
patients. Therefore, the importance of preoperative diagnosis of complex fistula and the importance of
utilizing routine examination methods that may raise the suspicion of complex fistula in terms of
preoperative preparation-diagnosis algorithm were seen.

In some cases of perianal fistula, in addition to superficially located acute abscess foci, there may be
collections in chronic abscess formation that cause deep recurrences or formation of other fistula tracts
that cannot be detected by complicated physical examination. In our study, the trans sphincteric sphincter
relationship and perifistular inflammation were observed more frequently in abscess patients. We also
found that abscess patients had more extended hospital stays and more frequent recurrences. Our study
also found that the distributions between the history of previous abscess drainage and tract thickness
were homogeneous. This was another indicator of the link between abscess and complex fistula.

In various publications, recurrence and incontinence rates have been reported to be lower with surgeries
performed by considering MRI findings; the most important reason for this is that the surgical plan is
shaped according to the preoperative fistula tract course (25-27). However, one of the most commonly
used methods for intraoperative visualization of the internal orifice is determining where it will exit
through the lumen by giving colored fluids through the external orifice. However, this method may not be
adequate in all patients. In such a case, it is recommended to advance the probe to the dentate line and
perforate the mucosa closest to the epithelium. However, this method is highly likely to find a false
internal orifice. It has been reported that such a method is the most important cause of recurrence (28).
Determination of the fistula tract is vital in determining the presence of additional fistula tracts and
determining the patients to be further investigated in terms of preoperative shaping of the surgical
procedure to be applied. Our study with routine inflammatory parameters showed us that based on this
information, the presence of abscess, tract length, tract thickness, tract thickness, number of tracts,
presence of highly located tracts, additional inflammatory disease, and perifistular inflammation are the
main factors that increase the likelihood of complex fistulas. As a result, these factors closely affect the
possibility of recurrence, and our study has shown that inadequate preoperative and perioperative patient
evaluation increases the likelihood of recurrence regardless of the type of technique used. Based on this
information, preoperative differentiation of complex/straightforward fistula, identification of the fistula
tract, determination of the presence of additional fistula tracts, and identification of patients to be further
investigated for preoperative shaping of the surgical procedure to be performed are of significant
importance.

5- Conclusions
The wide range of recurrence rates of anal fistula has led to the need for standardization in diagnosis and
treatment. LCO, CAO, and NCO prognostic indices can optimize diagnostic conditions and identify
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patients requiring further imaging. With these indices, diagnosis and treatment plans can be made by
predicting patients who may have complex fistula.

Declarations
Acknowledgments

Funding: None

Conflicts of Interest: The authors have no conflicts of interest to declare.

Author contribution: Osman Celik and Ersin Gundogan designed the study. Osman Celik, Ersin Gundogan
and Sedat Carkit wrote the manuscript; Osman Celik, Ersin Gundogan, Sedat Carkit, Gamze Turk and
Tamer Ertan refined the study protocol and study implementation. O.C and G.T. provided methodological
and statistical expertise. Tamer Ertan critically reviewed and edited the manuscript. All authors read and
approved the final manuscript.

Consent for publication: Written informed consent to publish the clinical details and images of the patient
was obtained.

Ethical Statement: This study complied with the Declaration of Helsinki and was approved by the
Institutional Review Board of Kayseri City Training and Research Hospital (protocol code: 2021/ 412).
Written informed consent will be obtained from all patients. All patients will be informed in writing about
the details of the study (purpose, procedure and potential risks) and informed consent will be signed
before allocation.

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