Fournier’s Gangrene: Clinical, Biochemical, Bacteriologic,Immunologic Study and Treatment Outcome

Abstract

Back ground: Fournier’s disease is a pathologic diagnosis necrotizing fasciitis and a clinical condition of deep perineal sepsis, which has diversionary treatment and variable outcomewith high morbidity and mortality.

Aim of the study: Evaluation of risk factors and prognostic variables that affect survival of patients with Fournier's disease and Study of Cell mediated immunity in Fournier's disease.

Methods: Fournier’s gangrene “thirty four” patients were treated between 2003 & 2006. Data were collected about medical history, physical findings, metabolic tests, bacteriologic typing, immunologic screening for T cell function, serum IL-2, ICAM-I and gIFN with their management.

Results: The disease had polymicrobial nature and low serum albumin (3.3 ± 0.6 mg/dl). Inadequate T-cell function in patients (11347.1 ± 3332.3) compared to controls (18255.3 ± 1641 CPM) and high ICAM-I, IL-2, gIFN (35.9 ± 5.7, 309.6 ± 34.1, 368.4 ± 11.3) compared to controls (10.5 ± 0.7, 93.3 ± 1.6, 131 ± 2 pg/ml) respectively were detected in Fournier’s disease. The mortality rate was (17.6%), that associated with older patients’ age, P = 0.0001, late presentation timing, P = 0.001, extensive disease extent, P = 0.0001, septic shock, P = 0.01, severe multi-organ dysfunction syndrome “MODS” ,P = 0.001, lower serum albumin, P = 0.0001 and lower IL-2,P = 0.0001.

Conclusion: Fournier’s disease has a high mortality rate. Large series are required to explore the prognostic variables of this disease. Such as; patient age, presence of systemic risk factors, urological source of infection, the immunologic status of the patient and the extent of the disease, all exert an impact upon the prognosis of Fournier’s gangrene.

Received: 6 May 2009

Accepted: 1st referee: 11 June 2009

2nd referee: 15 July 2009

 

 

Fournier’s Gangrene: Clinical, Biochemical, Bacteriologic,
Immunologic Study and Treatment Outcome

Elham Ragab Abd El Samee*, Saleh El Awady**, Wael Khafagy**, Mohamed Faryd**, Mohamed Abd El-Raof***

Clinical Pathology*, Surgery**, Mansoura University Mansoura General Hospital***, Egypt

                                                                                                                                                                                                         

Abstract

Back ground: Fournier’s disease is a pathologic diagnosis necrotizing fasciitis and a clinical condition of deep perineal sepsis, which has diversionary treatment and variable outcomewith high morbidity and mortality.

Aim of the study: Evaluation of risk factors and prognostic variables that affect survival of patients with Fournier's disease and Study of Cell mediated immunity in Fournier's disease.

Methods: Fournier’s gangrene “thirty four” patients were treated between 2003 & 2006. Data were collected about medical history, physical findings, metabolic tests, bacteriologic typing, immunologic screening for T cell function, serum IL-2, ICAM-I and gIFN with their management.

Results: The disease had polymicrobial nature and low serum albumin (3.3 ± 0.6 mg/dl). Inadequate T-cell function in patients (11347.1 ± 3332.3) compared to controls (18255.3 ± 1641 CPM) and high ICAM-I, IL-2, gIFN (35.9 ± 5.7, 309.6 ± 34.1, 368.4 ± 11.3) compared to controls (10.5 ± 0.7, 93.3 ± 1.6, 131 ± 2 pg/ml) respectively were detected in Fournier’s disease. The mortality rate was (17.6%), that associated with older patients’ age, P = 0.0001, late presentation timing, P = 0.001, extensive disease extent, P = 0.0001, septic shock, P = 0.01, severe multi-organ dysfunction syndrome “MODS” ,P = 0.001, lower serum albumin, P = 0.0001 and lower IL-2,P = 0.0001.

Conclusion: Fournier’s disease has a high mortality rate. Large series are required to explore the prognostic variables of this disease. Such as; patient age, presence of systemic risk factors, urological source of infection, the immunologic status of the patient and the extent of the disease, all exert an impact upon the prognosis of Fournier’s gangrene.

Introduction

Fournier’s disease is a necrotizing soft tissue infection of the perineum and genitalia that rapidly progress to gangrene(1,2) with rising reports due to awareness and longevity(3). Necrotizing fasciitis elicits variable immune response (innate & adaptive), triggering cytokines and adhesive molecules activation(4). The relative contribution of T helper 1 (Th1) and T helper 2 (Th2) cytokines determine the outcome, from eradication till multi-organ dysfunction syndrome (MODS)(5,6). The Fournier’s disease continues to challenge surgeons regarding its aetio-pathogenesis and management(7); also its predictive and prognostic factors are still lacking (Fournier’s gangrene severity index scoring (FGSIS)(8). Recently, severe cases suffering from toxic shock or necrotizing fasciitis had higher frequencies of IL2, IL6, and TNF-alpha producing cells in their circulation compared to non-severe cases(9), similarly Lungstras -Bufler et al(10), found significantly higher gamma interferon in Fournier’s gangrene patients.In the present work, thirty four Fournier’s gangrene male patients were studied as regard their clinical, metabolic, bacteriologic, immunologic associations together with their prognostic value.

Patients & Methods

34 Fournier’s gangrene male patients admitted to Mansoura University hospital and Mansoura General Hospital were included in a prospective study with the control group of 18 age matched, healthy male, blood donors. Patients were informed about the study and if accepted they signed a written consent.The clinical data include age, medical history (co-morbid, predisposing illness) and consultation time. The disease extent was classified according to Mansoura Colorectal Surgery Unit (M-CRSU) policy for disease extent created by modifying burn score as, isolated (penis – scrotum – scrotum till coccyx), limited (all perineum – a region of ischial tuberosity) and extensive (more than a region of ischial tuberosity- beyond the perineum) (Figs 1 & 2). The medical, surgical, biochemical, bacteriological, immunological procedures and statistics were done. The patients received their management in the surgery departments (within the Isolation unit, that had special barriers, aprons, masks, gowns and gloves under Mansoura University Microbiology Diagnostics and Infection Control Unit) unless complicated with septic shock or MODS “mild & severe” (defined and staged according to the American College of Chest Physicians and Society of Critical Care Medicine Consensus Panel in 1991 after Sharma et al(11), when they were transferred to surgical intensive care unit. The medical treatment was stepwise resuscitation and 3rd generation cephalosporin “Claforan 1 gm vial, Aventis company”, together with metronidazole : Flazol 500 mg /100 ml bottle “El–Nile company”, then specified according to culture and sensitivity(12).

The surgical treatment involved:

Aggressive excision of all non-viable tissues every 48 hours under short time anesthesia “when indicated” till all remaining tissues were adherent and viable, only skin grafts were required in 6 patients(13). Resection of gangrenous testes (2 patients) and gangrenous penis (2 patients) were done. Suprapubic cystostomy for urinary extravasations (2 patients) was done. Colostomy in morbid obese (2 patients), “had massive anorectal infection protracted from defecation.”

Laboratory investigations include:

Serum albumin, CBC, Blood sugar and creatinine were estimated. The bacteriologic study involved; sample collection as pus from the wound depth or wound edges swabbing, direct Gram film staining and culture both Blood Agar aerobic & anaerobic in gas pack jar(10), colony identification morphologically, Gram stain and antibiotic sensitivity testing using disc diffusion method(11). The immunologic study entailed (a) Serum sample stored at –70ºC till assay of some cytokines and adhesion molecules such as, detection of serum interleukin-2 (IL2) (14), gamma interferon (γIFN)(15), intercellular adhesive molecule-1 (ICAM-1)an indicator of T cell homing at the infection site , (5) using the enzyme linked immunosorbent assay(12). The kits are supplied from Diaclone E research company, France, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. . Results are expressed as picogram per milliliter (pg/ml). (b) Heparinized sample of T cell function(16), using in vitro peripheral lymphocytes separation and culture with phytohaemagglutenin mitogenic stimulation, that stimulation is studied by measuring DNA synthesis as evidenced by triated thymidine uptake of the proliferating cells. The results are expressed as count per minute (CPM)(12). The PMNCs separation according to Boyum(17) using Ficol-Hepaque centrifugation method, adjusting the count and culture with PHA for 72 hours then addition of H3 Thymidine for another 18 hours and harvest the proliferating cells on glass fiber filter and the triated Thymidine counted using B counter. The patients outcome was morbidity rate [local (L) massive anorectal infection protracted from defecation & urinary extravasations & gangrenous testes & gangrenous penis, systemic (S) Septic shock, MODS (mild& sever), local & systemic (L+S)] and the finite end point was the in-hospital mortality [survive – died]. Data were computed using Microsoft statistical software package version 10 [SPSS, 10], for comparison the Chi-square, student t-test and one way ANOVA test were used, and the binary logistic regression for prediction, P £ 0.05 is significant.

Results

The evaluated thirty four (34) male patients had their mean age 40.5 ± 14.7 years (range 3 – 67) and the mean duration till presentation was 3.7 ± 1.8 days (range 1–8). Seventeen patients (50%) had co-morbid diseases mainly diabetes as thirteen (76.5%) out of the seventeen (50%) were diabetics, and the predisposing illness was commonly anorectal sources; 13 (38.2%), while the necrotizing process extent was mainly limited; 19 (55.9%) (Table 1, Fig 1). The bacteriologic study defined 86 isolates [aerobic (4) patients, anaerobic (7) patients and mixed (23) patients] with E coli & group A streptococci predominance each; 15 patients (44.1%). The isolates per case were 2–3 organisms ranked as 2 organisms in 10 patients [5 identical, 5 different] & 3 organisms in 18 patients [10 identical, 8 different] & 4 organisms in 15 patients [3 identical, 12 different] & 5 organisms in single patient, (Table 2). The patients had low serum albumin level (mean ± SD 3.3 ± 0.6 mg/dl),but statistically in the Fournier’s gangrene patients the serum levels of IL-2, ICAM-1 gIFN tended to be greater (P = 0.0001) with lowered T cell function (P = 0.0001) compared to control group(Table 3). Patients with co- morbid diseases had more extensive disease compared to those without (P = 0.02), otherwise the clinical, bacteriologic and immunologic data were insignificant. Surgical debridements were performed 61 times (mean was 1.8, range 1-5), 15 patients required single debridement and 19 patients required multiple debridement (mean was 2.4, range 2-5). The disease morbidity were 22 events (63.4%) (Occurred only in twenty patients) [Septic shock; 4, 11.7% & mild MODS; 6, 17.6% & severe MODS; 4, 11.7% & local; 8, 23.5%] and by its grades (L, S, L+S) achieved significant difference with T cell function (P = 0.0001), serum IL-2 (P = 0.0001) and gIFN (P = 0.0001), also with serum albumin P = 0.0001 (Table 4). The mortality rate was 6 patients, 17.6% [4 patients due to multi-organ dysfunction syndrome “MODS” and two due to single organ dysfunction syndrome “SODS” acute liver cell failure]. Patients who survived were younger [mean ± SD, 36.17 years ± 12.18] than those who died [mean ± SD, 60.66 years ± 5.28] (P = 0.0001), similarly the difference in duration before consultation between both groups was significant (P = 0.0001). Also the statistically significant parameters for bad prognosis were extensive disease (P = 0.0001), local complications (P = 0.01), septic shock (P = 0.0001) and severe MODS (P = 0.0001). Survived patients had higher serum albumin, serum IL-2 [3.3 ± 0.5 mg/dl, 321.5 ± 22.1 pg/ml respectively] compared to those died [1.9 ± 0.1 mg/dl, 251.6 ± 14 pg/ml] and the differences were statistically significant (P = 0.0001) (Table 5). Neither the bacteriologic typing nor the frequency of surgical debridement [survivors underwent 1-3 times, the mean was 2.6, single attack in 12 & two attacks in 13 & three attacks in 3 and non-survivors underwent 1-5 times, the mean was 2.3, single attack in 3 & three attacks in 2 & 5 attacks in single patient, P=0.68] had affected the outcome, also the logistic regression of the studied parameters was insignificant.

 

Fig. 1             Isolated Fournier’s gangrene (active stage)

 

 

 

 

 

 

 

 

 

 

 

 

 

Fig 2.             Cancer rectum complicated by extensive Fournier’s gangrene (healing stage) and perineal fistulae

 

 

 

Table 1.    Patients “clinical data”

 

No.

%

Co-morbid disease

+ve

17

50

 

Diabetic

13

38.2

 

Cardiac

4

11.7

 

Hepatic

4

11.7

 

Renal

4

11.7

 

-ve

17

50

Disease source

Idiopathic

6

17.6

 

Known

28

82.4

 

Ano-rectal

13

38.2

 

Uro-genital

9

26.5

 

Dermatologic

6

17.6

Disease extent

Isolated

9

26.5

 

Limited

19

55.9

 

+ Extensive

6

17.6

17 patients were co morbid diseases –ve, 17 patients were co morbid diseases +ve [12 patients had single Co- disease & 4 patients had two Co- diseases &1 patients had three Co- diseases]. Anorectal source: Haemorrhoidectomy (5), Fistulectomy (3), Abscess (3), Cancer rectum (2) Urological: Post TUR (4), Hydrocele surg (1), Varicocelectomy (3), circumcision (1).Dermatologic: Perineal laceration (2), scrotal hematoma (2), Burn (1), IM injection (1) + Extensive: ant. abdominal wall (2), Thigh (2), buttocks (2).(Mansoura CRSU score).

 

 

 

Table 2.    Bacteriologic study

 

 

No

%

i) Aerobic

E-coli G –ve

15

44.1

 

Group A strept G +ve

15

44.1

 

Pseudomonas G –ve

9

26.4

 

Staph aureus G +ve

6

17.6

 

Citrobacter G –ve 

6

17.6

 

Klebsilla pneumonia G –ve 

6

17.6

 

Proteus mirabilis G –ve 

3

8.8

ii) Anaerobic

Bacteroids fragilis

8

23.5

 

Clostridium

6

17.6

 

Lactobacillus

6

17.6

 

Peptostreptococus

6

17.6

Isolates = 86: 2 organisms in 8 patients & 3 organisms in 10 patients & >3 organisms in 16 patients. Aerobic (4) patients, anaerobic (7) patients and mixed (23) patients.

 

 

 

Table 3.    Comparison of immunological parameters between patients and controls.

 

Patients (n=34) Mean ± SD

Controls (n=18) Mean ± SD

P value

T cells (CPM)

11347.1 ± 3332.3

18255.1 ± 1641

0.0001*

ICAM-1 pg/ml

35.9 ± 5.7

10.5 ± 0.7

0.0001*

IL-2 pg/ml

309.6 ± 34.1

93.3 ± 1.3

0.0001*

d IFN pg/ml

368.4 ± 11.3

131.1 ± 2.1

0.0001*

Student t test is used.

 

 

 

Table 4.    Morbidity association with the immunologic parameters and serum albumin.

 

Systemic (n=14)

Local (n=8)

Systemic & Local (n=2)

No Morbidity (n=14)

P value

T cells (CPM)

10192.3 ± 2863.6

12700.0 ± 226.7

5200.0 ± 130.9

13976.9 ± 530.8

0.0001*

ICAM-1 pg/ml

36.3 ± 0.8

36.2 ± 1.3

36.2 ± 0.4

35.3 ± 9.2

0.94

IL-2 pg/ml

297.3 ± 23.2

307.5 ± 11.0

252.5 ± 17.1

340.0 ± 17.3

0.0001*

d IFN pg/ml

364.2 ± 7.1

368.7 ± 4.4

348.0 ± 6.2

378.8 ± 2.9

0.0001*

Albumin mg %

2.8 ± 4.0

2.6 ± 0.1

1.9 ± 8.8

3.7 ± 0.2

0.0001*

One way ANOVA test P £ 0.05 is significant.

 

 

 

Table 5.    Significant outcome factors.

 

Survivors (n=28)

Dead (n=6)

P value

Age (years)

+

36.17 ± 12.18

60.66 ± 5.28

0.0001*

Time till consultation (days)

+

3.00 ± 1.11

7.00 ± 1.04

0.001*

Disease extent

 

 

 

 

Isolated

8

1

 

 

Limited

18

1

0.0001*

 

Extensive

2

4

 

Disease morbidity

 

 

 

 

Local

4

4

0.0001*

 

Septic shock

2

2

0.01*

 

Severe MODS

1

3

0.001*

Metabolic

+

 

 

 

 

Serum albumin mg%

3.30 ± 0.47

1.93 ± 0.11

0.0001*

Immunologic

+

 

 

 

 

Serum IL-2 pg/ml

321.96 ± 22.12

251.66 ± 14.03

0.0001*

           

+ data expressed as mean ± SD, student t test is used. ‡ Chi-square test.

4 patients due to “MODS” and two due to “SODS” acute liver cell failure.

 

 

Discussion

Fournier’s gangrene (FG) is the most serious life threatening infection of the perineum and genital organs(18,19), mostly reported in an ever aging population(20), and this study detected wide age range similar to Callard & Gearing(21) but our patients had lower average age as  Armerding et al,(22). Contradicting FG initial description, this study revealed co-morbid diseases conjugation similar to Geraci et al(23), and identifiable sources of infection like Spirnak et al,(24).In accordance with most studies(25,26), the bacteriologic study found the disease polymicrobial and reflecting the source of infection 'E coli' (anorectal), “group A streptococci” (urogenital)(27,28). Essentially this study declared novel observations which had not been previously reported (a) FG association with inadequate T cell function reflecting both poor microbial presentation and effector T cell tolerance related to T-cell anergy, apoptosis, decoy of interleukin receptors or inhibitory cytokines release(29), (b) FG was consistent with immunologic dissonance marked as (i) high gIFN (stimulate innate and Th2 cytokines, Th2 subset ofCD4 Th cells) (ii) raised ICAM-1 (T-cell recognition & co-stimulation, migration and homing) (iii) elevated IL-2 (clonal expansion of the committed CD4 Th cells)(30,31). Hence FG is a polarized Th2 immune response. This study recorded high disease morbidity as reported by Koneman et al(18). The systemic morbidity is related to the cytokines released, inciting wide spread endothelial and parenchymatous cell injury(32), while the local morbidity is attributed to the malignant intravascular inflammation(33). The association of morbidity rate with serum IL-2, gIFN and T cell function might be related to maladaptive cascade mediators release acting autocrine & paracrine(34), inciting auto destructive process through hypoxic & histotoxic hypoxia, apoptosis [anti- for inflammatory cells & pro- for host cells] and immune intolerance [Th1 suppression & Th2 excitation](35).Still the disease has an inherently high mortality reaching in our study 17.6% , that was less than previously reported (53%) by (28). The Triad for critical illness outcome is “patient” [co-morbid disease, its response to treatment], “disease” [nature & severity] and “treatment” given(36), herein, significantly survivors were younger than who died as observed by Aasen & Wang(37), = contradicting Rangel-Frausto(38). That’s might be related to age associated immunesenescence, malnutrition and immobilization, also the survivors searched for medical consultation earlier than the unsaved. This also reported by Dahm et al(39), of course early consultation enabled detection of early disease and co-morbid diseases management, But the necrotizing process in who died was extensive as reported by Jones & de Cossart(40), but Clayton et al(41), found the association equivocal and Tuncel et al(42) denied that association. Statistically, the co-morbid diseases, infection sources and bacteriologic typing didn’t affect the survival going with many reports(43,44), but the systemic and local complications worsened the prognosis similar to Rangel-Frausto(38). In accordance with Korkut et al(8), this study found survived patients had significantly higher serum albumin consequent to better patient’s metabolic reserve. Noteworthy, FG predilected with immune dysfunction, and survived patients had higher IL-2 level, that’s might be related to its functional role(45) in preventing and combating this devastating infection to be formulated as a cutoff point and added to Laor score, FGSIS-IL2.The frequency of surgical debridment did not affect the survival, but Bauer et al(20), found greater mortality with increased frequency so disease managing should be multidisplinary (Local & Systemic) as Palmer et al(46), suggested. The risk adjusted analysis of the relevant survival factors in this study using the logistic regression analysis were insignificant predictors of the outcome, similarly not all the risk scoring system Fournier’s  gangrene severity index scoring= (FGSIS) items were statistically significant as serum creatinine, co-morbid  diseases also other findings were significant as body surface area involved, serum IL-2, so surgical risk scale [mode of presentation, co-morbidity and procedure magnitude “sepsis related organ failure assessment SOFA”] together with the experience of the treatment team help to predict the outcome as no agreement as to the optimal approach [time & frequency of medical and surgical treatment] and judgment is required, that’s determined by local expertise and preference.

Conclusion

Fournier’s disease represents a T helper 2 maladaptive immune response with local gangrenous process associated with unbalanced metabolic status. Patients with co-morbid diseases had more extensive gangrene compared to those without. Also the disease carried poor outcome and the studied parameters (immune-metabolic-local disease extent) are important for disease management and outcome, Decision making should be performed by senior expert multidisplinary teams as neither the risk adjusted analysis nor the risk scoring system (FGSIS) were valid outcome predictors but the surgical risk scale may be valuable.

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