Acta Orthop. Belg., 2018, 84, 17-24 ORIGINAL STUDY

Diagnostic pitfalls in the differentiation between and

Yves Fortems, Pieter De Witte, Erwin Jansegers

From the Department of Orthopedics, “Groep Orthopedie”, GZA Hospitals, Campus Sint-Augustinus, Wilrijk and Sint-Jozef Hospital, Malle, Belgium

Pyoderma gangrenosum and necrotizing fasciitis couple of years the mortality of this life-threatening are two rare pathologic entities with a similar infection is still 9.3% (3). Pyoderma gangrenosum clinical image, but a who require a very different (PG), first described in 1908 by Brocq, is a primarily management. In general physicians, orthopedics, sterile inflammatory neutrophilic dermatosis. Due dermatologists, plastic surgeons will hardly ever see to the possible similar clinical image it can be it, but when they do it is very important to distinguish easily misplaced by NF. Although the etiology of between both. In this paper with the focus on the practical approach ,we expose the diagnostic pitfalls PG is unknown, a number of familial PG cases have in the differential diagnosis, explain how to prevent been reported, suggesting that genetic factors might them and summarize the evidence on therapeutic be involved in the pathomechanism of PG. For management. To achieve this we use a case where example PG occurs by the association of a JAK2 the diagnosis was rather difficult and utilize reviews mutation that activates the JAK-STAT pathway, a where the clinical features, early diagnostic tools and common mechanism involved in the pathogenesis treatment options are explained. of inflammatory and hematologic diseases. Another Keywords : necrotizing fasciitis; pyoderma gangrenosum. example are mutations in the PSTPIP1 gene, typically present in patients with PAPA syndrome, a rare auto inflammatory disorder including pyogenic sterile arthritis and acne with autosomal dominant INTRODUCTION inheritance (11,12). The peak of incidence occurs between 20 to 50 years with women being more Necrotizing fasciitis (NF) is a rapidly spreading affected then men. The general incidence has soft-tissue infection first described by Hippocrates been estimated to be between 3 and 10 per 10^6 in the 5th century BCE which typically follows an injury to the involved site. Toxin producing virulent bacteria like group A beta-hemolytic streptococci (NF type 2) are often the causative n P. De Witte, JMS. agent. Multibacterial (NF type 1) and Marine n Y. Fortems, MD. n Vibrio species (NF type 3) are also described. The E. Jansegers, MD. Department of Orthopedics, GZA Hospitals Campus Sint- infection usually presents at the extremities, but NF Augustinus, Wilrijk, Belgium. can affect any body part. The incidence proportion Correspondence : GZA Ziekenhuizen, Campus Sint- is 4 cases per 10^6 persons per year. Despite more Augustinus, Oosterveldlaan 24, 2610 Wilrijk, Belgium. effective and faster therapeutic treatment the last E-mail : [email protected] © 2018 Acta Orthopaedica Belgica

No benefits or funds were received in support of this study. The authors report no conflict of interests. Acta Orthopædica Belgica, Vol. 84 - 1 - 2018

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per year. It affects usually the trunk and the lower negative results. Repeat cultures remaid negative. extremities, but also here other body parts can be The patient’s medical history illustrated besides involved (13,17). Powell et al. (14) classified PG into a meningitis in childhood an important treatment 4 major clinical types (Table I). for a presumed NF at chest level 14 years earlier. A removal of a considerable part of the pectoralis Table I. — The different clinical types of PG muscle was necessary and a skin graft was applied. Clinical variants Typical findings In consideration with the patient his family he Ulcerative PG Ulceration with rapidly evolving puru- was transferred to the hospital where he was lent wound ground treated 14 years ago. Remarkably the patient’s Pustular PG Discrete pustules, sometimes self-lim- brother had been treated at that hospital for similar ited, commonly associated with inflam- symptoms. However, his final diagnosis was not a matory bowel disease NF but rather a PG. By arrival an antibiotic scheme Bullous PG Superficial bullae with development of of clindamycin 3x600mg IV and cefepim 3x2g ulcerations IV and rehydration therapy (1l sodium chloride Vegetative PG Erosions and superficial ulcers 0.9% per 12h) was applied. Supportive analgesic therapy contained paracetamol 4x1g IV and PATIENTS AND METHODS tramadol 3x100mg/ml orally. That night an urgent contrast MRI of the left forearm was taken showing A 48-year old men presented at the emergency evidence of NF. According that result a surgical department with fever (39,1°C) and pain localized release, decompression and debridement of the left at his left hand and forearm. Two weeks prior to arm was performed. The next day there was already this he sutained a multifragmentary diaphyseal an enlargement of the lesions and a revision was midshaft humeral fracture at the same side after necessary. During surgical revision however the a fall. A Sarmiento brace was applied in order to clinical aspect of a part of the wound could fit by PG. obtain a healing by conservative means . By clinical High dose steroids (IV 120mg methylprednisolone) examination the hand and forearm were swollen. were adjusted. From a pathologic point of view the No penetration or pressure wound could be found histologic correlate fitted more the diagnosis of a as possible agent for infection. The Sarmiento NF at the first operation and of PG at the revision brace was loosened, but the swelling persisted. . Because of the suggestive clinical appearance A deep venous thrombosis could be excluded ,the steroid treatment was continued together with by a negative duplex scan. Laboratory findings the latter described medication scheme. From then showed a C-reactive protein (CRP) of 328 mg/dl, on the situation remained stable enough to apply a hemoglobin level of 12,0 g/dl, a white blood cell a vacuum assisted closure (VAC) to stimulate count of 16700/µl with left shift, an INR of 1,09, granulation of the wound. One week later the patient a creatinine level of 0,75mg/dl, and an LDH of was stable enough to leave the intensive care unit. 701U/l. Urine cultures, blood cultures and a thoracic Antibiotics were stopped and steroids were further X-ray taken during fever episode at the emergency downgraded. Another week later split-thickness department showed no peculiarities. A hospital autografts at the left thigh region were preleased stay was advocated . 24 hours later an increase in and applied. Postoperatively the graft showed a pain and a bullous formation with augmentation favorable growth into the original tissue. During of swelling was noticed. A puncture was done and the next visits the grafted zone further evolved in the fluid sent for culture. A medication scheme of a positive way and the donor site was almost fully diclofenac 75mg intramuscular (IM), paracetamol cured. The left arm was progressively mobilized 4x1g intravenous (IV), and flucloxacillin 6x1g IV with the professional help of a physiotherapist and in a 20cc sodium chloride solution was applied. adequate wound management remained. During The fever disappeared and new blood cultures and also after his stay the patient could always were taken. The day after all samples showed count on professional psychologic support.

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DISCUSSION described as dishwater , non-contractile muscles and minimal changes in the dermis of the skin. In Background our patient deep forming and a necrotizing process over the full length of the skin was apparent. NF is mainly a clinical diagnosis. In the medical Thrombotic formation was not present. Despite history 31,4% of the cases have a former trauma antibiotic use NF will evolve very quickly. The of which 4,3 % is caused by surgical wounds. best way to diagnose NF macroscopically is by Diabetes mellitus is the most common co morbidity applying the ‘finger test’. Under local anesthesia a involving 44,5% of patients. Other co morbidities 2 cm incision is made down to the deep fascia and who also result in an immunocompromised a gloved finger is inserted to its base. The index status like obesity, peripheral vascular diseases, finger dissecting the subcutaneous tissue easily intravenous drug abuse, alcohol abuse, malnutrition, from the fascia defines a positive test. Together with smoking, chronic cardiac disease, chronic immune histopathologic findings direct inspection from the suppression, steroid therapy, cancer and age are fascia during surgery remains the golden standard also risk factors for NF. Although numerous risk in diagnosing NF (9). factors have been identified half of all cases of The following described diagnostic tools could NF occur in previously healthy individuals (3). help to support the diagnosis, but never should delay The triad of pain (79,0%), swelling (80,8%) and medical intervention and therapy. Microbiologically erythema (70,7%) which also could be observed Wong et al. (19) created a score (Laboratory Risk in our patient is very characteristic. Other features Indicator for Necrotizing Fasciitis or LRINEC) to are showed in Table II (9). Initially the pain is discriminate between NF and non necrotizing soft- inordinate with the present swelling and erythema. tissue infection (Table III). A total score of 6 as in our case predicts a probability between 50 and 75%. Table II. — Typical features of NF

Number of patients 1463 Table III. — LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) (1) Symptoms (%) Erythema 70,7 Value Score Our case Warmth 44.0 Pain 79.0 C-reactive protein (mg/l) 328 Swelling 80.8 <150 0 Bullae 25.6 >150 4 Crepitus 20.3 White blood cell count (cells/µl) 16700 Skin necrosis 24.1 <15000 0 Fever >37,5°C 40.0 15000-25000 1 Hypotension 21.1 > 25000 2 Gas on X-ray (%) 24.8 Hemoglobin level (g/dL) 12.0 Microbiology (%) >13.5 0 Positive wound culture 76.5 11-13.5 1 46.5 <11 2 Monomicrobial Sodium level (mmol/L) 138 >/= 135 0 The increase in skin sensibility is typically due <135 2 enzymes and toxins spreading through the fascia Creatinine level (mg/dL) 0.75 beneath the skin. The affected wound margins are lymphangitis of the > 1.6 2 skin itself is hardly present because of the deep Glucose level (mg/dL) 100 presenting infection. Further presenting features 180 1 thrombotic veins, a thin watery foul-smelling fluid Total: 6

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The serum creatinine phosphokinase level (CPK) and accelerate the disease process (7). In our in the early diagnosis can help to distinguish the case initially there wasn’t a pathergy phenomenon type of NF more specifically. Significant highly detected. Although afterwards one may question the elevated CPK values direct towards a group A beta- precise reason why revision was necessary. Typical hemolytic streptococci infection (NF type 2, or the clinical features of PG are recurrent cutaneous so called flesh-eating bacteria) (15). In our patient ulcers with mucopurulent or hemorrhagic exudate. a CPK value of 54U/l made the diagnosis of NF The wound margins are regular and violaceous. Su type 2 unlikely. In 24.8% of all cases gas in soft WP et al. (16) proposed two major and four minor tissue could be detected by plain radiographs. CT criteria, strictly to be used in a clinical setting scans are sensitive in identifying soft tissue edema to diagnose an ulcerative type of PG. A positive and are more useful in evaluating the margins of diagnosis requires both major criteria and at least infection. Fascial fluid detected on T2-weighted two minor criteria (Table IV). One may notice MRI images have a sensitivity between 93 and that in this classification they assume an irregular 100 % in diagnosing NF. This fascial fluid together wound margin as a key criterion. Contrary to with edematous formation of the subcutis and the NF there are no diagnostic laboratory criteria or surrounding muscle tissue was clearly visualized typical histopathologic findings. This makes PG in our patient. Besides several abscess collections more a diagnosis of exclusion. Table V presented could be found. Frozen-section biopsies can, when by Mahajan AL et al. (10) shows both entities in a the diagnosis is unclear and the patient is stable, clarifying summary also be used for diagnostic work up. 60% of the PG cases are associated with Table IV. — Criteria of classic, ulcerative PG underlying systemic diseases like inflammatory Major criteria bowel disease, rheumatological or hematological 1. Rapid progression of a painful necrolytic cutaneous ulcer with an irregular, violaceous and undermined border disorders and malignancies. In 1930 this link 2. Other causes of cutaneous ulceration have been excluded was already described by Brunsting et al. (5) Minor criteria although they thought that PG could be explained 1. History suggestive of pathergy or clinical finding of crib- by a streptococci or staphylococci infection in an riform scarring immune suppressed patient. Secondary infection 2. Systemic disease associated with PG or invasion by commensal bacteria is possible 3. Histopathologic findings (sterile dermal neutrophilia +/- mixed inflammation +/- lymphocytic vasculitis) though and can harden the diagnostic work up. 4. Treatment response (rapid response to systemic steroid In 1985 Fulbright et al. (8) formulated the now treatment) generally accepted hypothesis where PG is seen as an aberrant immune response on still to be Approach and treatment identified contributing factors. A cross-reaction with underlying disease where the pathways There are five important pillars of therapy for NF: protecting the epidermis from the neutrophilic early diagnosis and aggressive debridement, broad- infiltration are insufficiently working, would form spectrum antibiotics, aggressive resuscitation, the cutaneous manifestation (17). Because of the frequent re-evaluation and comprehensive latter it is important to take the medical history nutritional support. Surgical debridement is the into the diagnostic process. In our case there cornerstone of management because it is the fastest wasn’t a known systemic disease. Moreover there and most effective way to reduce the bacterial should be noticed that these associated diseases load and halt the necrotic process. This is the only could also align ulcers due to other disease intervention proven to increase the rate of survival. conditions (18). Pathergy occurs in 25-50% of Hereby it is of great importance to remove all cases, where dermatologic lesions develop at the necrotic tissue even if this leads to a necessary site of minor trauma. Surgical debridement is amputation. Daily careful management of the therefore contraindicated as it would aggravate extensive wounds is critical and these should be

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Table V. — Table comparing features of PG and NF

Features Pyoderma gangrenosum Necrotizing fasciitis Pain Superficial Deep Associated systemic disease (IBD°, Yes (60%) No arthritis,…) Early lesions Pustule/nodule Cellulitic-like Established lesions Well defined violaceous ulcer edge Poorly defined border Multiple lesions Yes No Satellite lesions Yes No Pathergy Yes (20-40%) No Disease progression Progresses gradually over days Progresses within hours Hemodynamic instability No Yes Positive cultures No Yes Inflammatory infiltrate Predominantly neutrophilic Mixed infiltrate including neutrophils Vessel thrombosis Yes Yes Necrosis Yes Yes Response to steroids Yes No Response to surgery and antibiotics No Yes ° IBD: Inflammatory bowel disease

kept covered to protect against secondary infection, and recombinant human-activated protein encourage the formation of granulation tissue C for sepsis therapy (3). The best documented and absorb inflammatory exudates. Both alginate treatments for PG are systemic corticosteroids and hydrogel dressings with or without negative and cyclosporine. According Brooklyn et al. (4) pressure have been used successfully. Once an urgent referral to the dermatology department the infection has resolved and a bed of healthy is needed once suspect signs are presenting. Oral granulation tissue is present, the wound may be corticosteroids (with or without minocycline) are closed with skin flaps or split-thickness grafts. One recommended as first line treatment. If patients do week after debridement this procedure was also not respond promptly, infliximab is used as this has done in our case. Antibiotic therapy cannot be the fewer recognized side effects than cyclosporine sole treatment because fascia is poorly vascularized and has been used widely in inflammatory bowel and the disease process further reduces its blood disease and rheumatoid arthritis. An induction dose supply. Despite having little effect on the wound regimen of 5mg/kg at weeks 0, 2 and 6, followed itself, its value lies in the power to reduce the by further treatments as necessary, depending on bacterial load and termination of toxin production. response are recommended. Azathioprine, another It also protects against organ failure. In table VI immunosuppressant should be given at the same the widely accepted antibiotic scheme is presented. time as infliximab. While this approach is not Besides antibiotics and surgical debridement an strictly evidence based, it is now accepted practice adequate fluid resuscitation, nutritional support and in other inflammatory conditions, such as Crohn blood pressure support are essential. Furthermore disease. So the main therapeutic treatment of PG one may underline the huge importance of an beholds several factors. First of all one should be adequate analgesic therapy. Adjunctive therapies aware of associated diseases if there are. Generally include intravenous immunoglobulin G (IVIG) the treatment then consists out of two parts: local to inhibit the activation of T-cells and cytokine and systemic. Local therapeutic options include production, the use of hyperbaric oxygen (HBO) debridement, dressings of hydrocolloid type and/or

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Fig 1. – Algorithm according Ayestaray et al. This algorithm is a help for the surgical course, but cannot replace the medical discussion for each clinical situation. although immunosuppressive treatment may worsen the evolution of a NF to start with corticosteroids in association with antibiotics. As clinical and biological improvement is noticed after starting corticosteroids and histological results make a NF unlikely the antibiotics could be stopped.

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allograft installation to support re-epithelialization, margins at the revision in addition with the success topical agents and intralesional injection of steroids of steroid treatment in highly suggestive for the rare or cyclosporine. Systemic therapy typically diagnosis of Pyoderma Gangrenosum. comprises oral prednisone (40-120mg/d). It is administered in high doses until lesional clearance is obtained. Subsequently, a low maintenance REFERENCES dose is used to maintain remission (6). A quick 1. Anaya DA, Dellinger EP. Necrotizing soft-tissue infection: intervention is anyhow of primordial importance. Diagnosis and management. Clin Infect Dis 2007, 44: 705- That is why Ayestaray et al. (2) suggested an 710. algorithm as a help for the therapeutic decision in 2. Ayestaray B, Dudrap E, Chartaux E, Verdier E, Joly the differential diagnosis of both pathologic entities P. Necrotizing pyoderma gangrenosum: an unusual when the final diagnosis is yet unclear (Figure 1). differential diagnosis of necrotizing fasciitis. JPRAS 2010, The problematic phase is the therapeutic strategy 63:e655-658. 3. Bellapianta JM, Ljungquist K, Tobin E, Uhl R. during the period where antibiotics are (not) yet Necrotizing fasciitis. J Am Acad Orthop Surg 2009, 17: effective and histological diagnosis is uncertain. 174-182. These authors recommend in case of doubt, Fig 1, 4. Brooklyn T, Dunnil G, Probert C. Diagnosis and treatment Algorithm according Ayestaray et al. This algorithm of pyoderma gangrenosum. BMJ 2006, 333: 181-184. is a help for the surgical course, but cannot replace 5. Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma gangrenosum: clinical and experimental observations in the medical discussion for each clinical situation. five cases occurring in adults. Arch Dermatol 1930, 22: although immunosuppressive treatment may worsen 655. the evolution of a NF to start with corticosteroids 6. Crowson AN, Mihm Jr MC, Magro C. Pyoderma in association with antibiotics. As clinical and gangrenosum: a review. J Cutan Pathol 2003, 30: 97-107. biological improvement is noticed after starting 7. De Thomasson E, Caux I. Pyoderma gangrenosum corticosteroids and histological results make a NF following an orthopedic surgical procedure. Orthop Traumatol Surg Res 2010, 96: 600-602. unlikely the antibiotics could be stopped. 8. Fullbright RK, Wolf JE, Tschen JA. Pyoderma gangrenosum at surgery sites. J Dermatol Surg Oncol 1985, 11: 883-886. CONCLUSION 9. Goh T, Goh LG, Ang CH, Wong H. Early diagnosis of necrotizing fasciitis. BJS 2014, 101: e119-e125. One may conclude that is essential to put all the 10. Mahajan AL, Ajmal N, Barry J, Barnes L, Lawlor clinical and pathological findings together to make D. Could your case of necrotizing fascitis be pyoderma a correct diagnosis. Even done adequately it can gangrenosum? Br J Plast Sur 2005, 58: 409-412. 11. Nesterovitch AB, Hoffman MD, Simon M, Petukhov still be extremely difficult to become a conclusive PA, Tharp MD, Glan TT. Mutations in the PSTPIP1 gene result. In our case the blood cultures who kept and aberrant splicing variants in patients with pyoderma remaining negative, the first surgical debridement gangrenosum. Clin Exp Dermatol. 2011, 36: 889,895. that didn’t succeed, the observed violaceous wound 12. Palanivel JA, Macbeth AE, Levell NJ. Pyoderma margin during revision and the patient’s brother gangrenosum in association with Janus kinase 2 who had similar problems after trauma which was (JAK2V617F) mutation. Clin Exp Dermatol 2012, 38: 44-46. treated effectively with corticosteroids are all 13. Powell FC, Schroeter AL, Su WP, et al. Pyoderma strong arguments against NF. On the other hand the gangrenosum a review of 86 patients. Q J Med 1985, 55: patient ‘s medical history, the absence of a systemic 173-186. disease, the first histological result directing towards 14. Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: NF and the positive medical imaging ensured that classification and management. J Am Acad Dermatol 1996, 34: 395-409. the original work up diagnose of NF maintained 15. Simonart T, Nakafusa J, Narisawa Y. The importance of originally maintained . However the presence of serum creatine phosphokinase level in the early diagnosis the brother‘s history ,negative cultures, a positive and microbiological evaluation of necrotizing fasciitis. J second histologic report and the violaceous wound Eur Acad Dermatol Venereol 2004, 18: 687-690.

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16. Su WP, Davis MD, Weenig RH, Powell FC, Perry HO. 19. Wong CH, Khin LW, Heng KS, Tan KC, Low CO. pyoderma gangrenosum: clinicopathologic correlation and The LRINEC (Laboratory Risk Indicator for Necrotizing proposed diagnostic criteria. Int J Dermatol 2004, 43: 790- Fasciitis) score: A tool for distinguishing necrotizing 800. fasciitis from other tissue infections. Crit Care Med 2004, 17. Van den Driesch P. Pyoderma gangrenosum: a report of 44 32: 1535-1541 cases with follow up. Br J Dermatol 1997, 137: 1000-1005. 18. Weenig RH, Davis MD, Dahl PR, et al. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Eng J Med 2002, 347: 1412-1418.

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