Pyoderma Gangrenosum With Common Variable Immunodeficiency

   Pyoderma gangrenosum (PG) is a rare ulcerative skin disease of unknown etiology. It can be seen on normal skin or secondary to traumas such as injections and biopsies. Half of reported cases are associated with systemic diseases such as arthritis, inflammatory bowel diseases, hematological disorders, hepatic disease, and necrotizing vasculitis. Lesions often occur on the trunk and extremities. Abscess drainage, debridement, or necrosectomy are contraindicated in PG, and false management of these indications aggravates the lesion. A diagnosis of PG is based on medical history as well as physical and laboratory examination according to standard criteria. Presented here is a case of a male patient with a medical history of recurrent abscess of injection and splenectomy due to splenic abscess. The patient presented with a subcutaneous abscess which transformed rapidly to an ulcer after abscess drainage. Consequently, the patient received the final diagnosis of PG with common variable immunodeficiency and was treated accordingly.

Pyoderma gangrenosum (PG) is a rare ulcerative skin disease of unknown etiology that mimics other ulcerative lesions. It was first described by Brunsting et al¹ in 1930 as a rare neutrophilic ulcerative disorder of the skin. Today, PG is classified into 4 different types: ulcerative, which is the most common type; pustular; bullosus; and vegetative.² Approximately 50% of PG cases are associated with systemic diseases.³ It is a neutrophilic dermatosis that is considered to be an immunological abnormality.^3-5 Pathergy, which is the formation of a sterile papule or pustule on the site of a needlestick, is a skin hyperreactivity response.⁶ Pyoderma gangrenosum lesions may rapidly transform into a wide ulcer after surgical inventions, such as biopsy, drainage, or debridement, as a consequence of pathergy. Thus, early diagnosis is essential to prevent pathergy; however, it has been reported to be preventive in only 20% of patients with PG.^6,7

Common variable immunodeficiency (CVID) is one of the most common symptomatic primary immunodeficiency syndromes characterized by hypogammaglobulinemia and recurrent infections. The estimated incidence⁸ of CVID is between 1:10,000 and 1:50,000. Patients with CVID have an increased risk of malignancy, a higher incidence of autoimmune disease, and can develop granulamatous lesions on both the skin and organs.⁹

Presented here is a case of a 28-year-old man with a history of recurrent abscess who, after injection with various antibiotics and nonsteroidal anti-inflammatory drugs, underwent splenectomy due to splenic abscess. The patient had an abscess on the anterior abdominal wall that transformed rapidly to a wide ulcer after drainage. He received a diagnosis of PG with CVID. Systemic corticosteroid and azathioprine treatment led to complete resolution of the lesions, and intravenous immunoglobulin (IVIG) therapy deactivated his CVID.

A 28-year-old male patient with a medical history of recurrent injection abscesses presented to the emergency department of Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey, with a 2 cm x 2 cm abscess, hyperemic, and painful swelling which was fluctuating. The patient had been treated with hyperbaric oxygen, IVIG, and splenectomy due to splenic abscesses at another hospital and had a familial background of delay in wound healing. His body temperature and vital signs were stable at presentation. Routine blood tests showed a white blood cell count of 17.66*103/mm³ and C-reactive protein of 20.07 mg/L. Superficial tissue ultrasonography of the lesion revealed an epidermal and subepidermal edema, a dense cystic structure of 15 cm x 10 cm, which may have been an abscess, a folliculitis, or an infected sebaceous cyst. The abscess was drained and the patient was discharged with oral ciprofloxacin and metronidazole treatment.

A week later, the patient presented to the clinic with an increase of hyperemic swelling of the abscess site. Medical examination showed a hyperemic lesion that was 10 cm x 8 cm in size with necrotic fields, fluctuation, and a purple halo. The patient’s blood pressure was 120/70 mm Hg with a pulse of 80 per minute; his temperature was 35°C. Blood work results showed a white cell count of 37.1*103/mm³ and C-reactive protein level of 254 mg/L. Colleagues from the institution’s Department of Infectious Diseases suggested tazobactam-piperacillin and teicoplanin antibiotherapy, which was started preoperatively. The patient’s lesional cutaneous and subcutaneous tissue, along with necrotic areas, was excised and debrided on the same day. Histopathological examination identified a nonspecific mixed inflammatory cell infiltration with areas of necrosis and vascular changes. Cultures of the debrided tissue were negative for bacteria, mycobacteria, and fungi.

On the second postoperative day the patient’s blood pressure and pulse remained the same, but his temperature increased to 38.6°C. Inflammatory parameters including white blood count (34.5*103/mm³) and C-reactive protein (297.3 mg/L) were elevated. Blood cultures were negative. The patient was diagnosed with PG (Figures 1 and 2). After dermatological consultation, prednisolone (80 mg/day) was started, and azathioprine 150 mg/day was added 2 weeks later.

Figure 1. The appearance of the lesion upon admission, 1week after drainage of the abscess.

Figure 2. The 3-dimensional computed tomography image of the lesion.

Radiological and laboratory examinations were conducted to identify the probable associated diseases. Examinations of the chest, x-rays of the abdomen, and electrocardiograms revealed no significant findings. An abdominal tomography investigation was negative for inflammatory bowel disease and intestinocutenous fistula. Serum protein electrophoresis demonstrated alpha dominance, and the erythrocyte sedimentation rate was 11 mm/hour. Titers reflecting liver, renal, and thyroid functions were within normal limits. Antinuclear antibody, rheumatoid factor, beta microglobulin, anticardiolipin antibody, anti-double stranded DNA, C3, C4, antineutrophil cytoplasmic antibody, CA19.9, carcinoembryonic antigen, CA12.5 markers, and serology were negative. Only myeloperoxidase antineutrophil cytoplasmic antibody was positive. Analyses for the JAK2 and V617F genes were normal. Peripheric blood microscopy revealed hypersegmented neutrophils, erythroblasts with vacuoles, and stimulated monoblasts. The patient’s chemotactic index, oxidative burst, and phagocytosis values were within the normal range. Immunoglobulin (Ig) G (429 mg/dL), IgA (58.2 mg/dL), and IgM (27.5 mg/dL) levels were less than the normal range. The patient was referred to the hematology department and diagnosed with CVID. Monthly immunoglobulin replacement was started.

Two days after the initiation of steroid therapy, the patient’s inflammatory parameters decreased dramatically and his lesion improved within a month. The prednisolone dose was tapered by 50% over the course of a month. The ulcerated area was completely epithelialized 4 months later (Figure 3). The patient developed pustular acne on his face, which was considered to be an adverse effect of the steroid treatment.

Figure 3. The condition of the lesion 4 months after discharge.

Pyoderma gangrenosum is a rare ulcerative skin disease of unknown etiology. It can be seen in otherwise normal skin or secondary to previous lesions that have healed, often following intradermal skin tests, pathergy tests, prick tests, infections, insect bites, tattoo applications, and biopsies.^10,11 A large proportion (95%) of PG lesions occur on the trunk and extremities, and occasionally on the neck, abdominal wall, face, scrotum or penis, gluteal area, or the pretibial area of the legs.^5,10 Histopathologic assessments are limited for the diagnosis of PG, so diagnoses rely primarily on clinical features. Histology of the lesion is characterized by extensive neutrophilic infiltration mainly through the dermis; abscesses with necrosis and ulceration; and perivascular lymphatic inflammation at the periphery of the lesion. Some reports show vasculitis with fibroid deposits inside vessel walls and erythrocyte extravasation.^2,3,5,12 Patients occasionally present with a painful pustule or small abscess, which transforms rapidly and spontaneously to an ulcer or after the drainage of abscess. Abscess drainage, debridement, or necrosectomy are contraindicated in PG and this kind of management may aggravate the patient’s clinical condition.^13,14 Pyoderma gangrenosum can mimic many other ulcerative lesions, thus delaying diagnosis and proper treatment. The authors have noted PG diagnosis is mostly based on clinical criteria, such as medical history and physical examination; however, biopsies are helpful in ruling out other diagnoses. The primary purpose of a biopsy is to exclude other causes of ulceration.¹⁴ A clinical diagnosis of PG can be made upon meeting the 2 major criteria and at least 2 minor criteria. Major criteria include: 1) an inflammatory lesion with violaceous border; and 2) the exclusion of relevant differential diagnoses (eg, venous, arterial, vasculitis). Minor criteria include: 1) a histological examination showing neutrophil-rich dermal infiltrate; 2) deposits of immunoglobulins or complement factors, or both; 3) the presence of associated diseases; 4) little or no response to conventional treatments; and 5) a response to immunosuppressive treatment.¹⁰

In this case, the patient’s lesion transformed rapidly to an ulcer after drainage due to a pathergy reaction. Medical and family background are the most important parameters when diagnosing PG. Approximately 50% of cases are associated with systemic diseases like arthritis, inflammatory bowel diseases (eg, ulcerative colitis and, less frequently, Crohn’s disease), hematological disorders (eg, leukemia and myeloma), immunological diseases such as monoclonal gammopathy, hepatic disease such as chronic active hepatitis, HIV infection, diverticulosis, necrotizing vasculitis, inflammatory pulmonary disease, neurofibromatosis, and leukocyte adhesion deficiency.^2,5,14-17 It can also be idiopathic and can occur spontaneously after surgery; PG is most commonly diagnosed in relation to incisions and stoma following colectomy or trauma surgery.^14,18-20

As far as the authors know, there is no case presentation of PG associated with CVID in the literature. Common variable immunodeficiency is a heterogeneous disorder described as resulting from defective antibody production and recurrent bacterial infections. The incidence of PG is between 1/10000 and 1/50000, it affects both sexes similarly, and is diagnosed in patients in their second and third decades of life. The pathogenesis of the disease still remains unclear and genetic investigations showed no evidence of any genetic abnormality.^8,21-23 Immunoglobulin G levels of these patients tend to be low. Immunoglobulin M, IgA, and circulating B-cell levels can be normal or low. Common variable immunodeficiency must be considered as a possible diagnosis of patients with recurrent infections and hypogammaglobulinemia. The most important approach to prevent organ disorders and complications is early diagnosis and treatment. The incidence of lymphoma and gastric carcinoma is increased in these patients. Standard treatment of CVID is intravenous or subcutaneous Ig replacement.^21-23

High doses of corticosteroids and cyclosporine are the main treatments for PG and should be considered as first-line therapies.^24,25 Infections must be ruled out as the etiology to prevent any systemic infections due to planned immunosuppressive therapy. Recently, good outcomes have been reported for treatments based on mycophenolate mofetil, tacrolimus, infliximab, plasmapheresis, azathioprine, methotrexate, granulocyte-monocyte adsorption apheresis, IVIG therapy, thalidomide, alkylating agents, dapsone, interferon alpha, and phendimetrazine.²⁴ Topical agents, such as intralesional corticosteroid, tacrolimus, cromolyn sodium, intralesional cyclosporine, doxycycline, topical 5-aminosalicylic acid, nitrogen mustard, benzoyl peroxide, and platelet-derived growth factor, have limited use and are only considered as a supportive treatment in individual cases or small case series.^24-26 Surgical treatment has only limited use in PG cases; however, skin graft, muscular flap, and cultured keratinocyte autografting techniques are the most preferred, and surgical interventions must be performed while the patient is under immunosuppressive therapy regardless of the disease activity. Radiotherapy and electron beam irradiation have little use in PG treatment and are not included in the current therapy algorithm.^24-26 In some articles,²⁷ hyperbaric oxygen therapy was added as an adjuvant therapy and resulted in good cicatrization of the lesion, even if there is no compelling evidence about benefits in cases of PG and very little issue in the literature supporting this therapy.²⁷

Common variable immunodeficiency should be considered in cases of repeated infections, granulomatous skin infections, such as PG, and delayed wound healing. Instead of giving priority to biopsy, which may cause pathergy, as a diagnostic parameter, Ig levels should be assessed as demonstrated in the presented case.

Osman Simsek, MD; Kivilcim Ulusan, MD; Anil Orhan, MD; Tolga Kırıs, MD; Ahmet Kocael, MD; Pinar Kocael, MD, are from the Department of General Surgery, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey

Address correspondence to:
Ahmet Kocael, MD
İstanbul Üniversitesi
Cerrahpasa Tıp Fakültesi
Genel Cerrahi Anabilim Dalı
34098 Cerrahpasa
Istanbul, Turkey
akocael147@yahoo.com

Disclosure: The authors disclose no financial or other conflicts of interest.