Necrotizing cutaneous lesions complicating treatment with pegylated-interferon alfa in an HIV-infected patient

ARTICLE

Pegylated interferon alfa is a pegylated formulation of recombinant human interferon alpha[IFN-alpha] conjugated with molecules of polyethylene-glycol (PEG). The major advantages of this formulation, compared to standard, nonpegylated, IFN-alpha, are a prolonged half-life which allow for once-weekly injection and high and stable serum concentrations of the molecule. During the course of HIV infection, the antiviral efficacy of PEG-IFN-alpha2b in terms of reducing the plasma virus load and modification of the patient's immune status is currently being evaluated in open, prospective pilot studies in patients with or without ongoing antiretroviral therapy [1].

To the best of our knowledge, we describe herein the first observation of cutaneous necrosis at the sites of PEG-IFN injection in an HIV-infected patient. We review the literature on previously reported cases of cutaneous necrosis following standard or pegylated IFN-alpha injection and discuss the different pathophysiological mechanisms that might be involved.

Case report

A 50-year-old man was followed for HIV infection, diagnosed in September 1996 and treated since that time with antiretroviral bitherapy combining zidovudine and didanosine. Otherwise, his prior medical history was unremarkable. In March 1999, his CD4⁺ lymphocyte count was 564 cells/mm³ with a T4/T8 ratio of 1.2 and virus load was 10,702 copies/ml, i.e., 4 log/ml (Amplicor HIV 1, Monitor Roche).

Once-weekly subcutaneous injections of PEG-IFN-alpha2b (ViraferonPeg, Schering-Plough) were started at a dose of 1.5 mug/kg. Nine months later, the patient noted the appearance of an indurated, painful, erythematous plaque overlying the usual area of injection on the right side of the abdomen. One week later, a painful black escarotic lesion developed at the center of the plaque and expanded progressively. The patient continued to inject himself at the same site, alternating with the left side of the abdomen. One month later, the same cutaneous lesion appeared on the left side of the abdomen, again overlying the injection zone. He continued to inject the product at the same sites over the next 3 months, while the cutaneous lesions continued to expand progressively and were accompanied by severe pain of the abdominal wall muscles.

At admission, the patient had a temperature of 38° C, and 2 inflammatory plaques on the abdomen, about 40 mm in diameter, symmetrically situated on either side of the navel (Fig. 1A). The lesions were poorly delimited, indurated, painful and infiltrated at palpation with a central necrotic zone (Fig. 1B). Removal of the black eschars revealed deep atonic ulcerations with fibrinous and purulent contents. Histological examination of a specimen taken from the edge of one of the lesions showed superficial and deep lymphocytic and neutrophilic infiltrates of the dermis. Septal and lobular inflammatory lesions of the hypodermis including lymphocytic and neutrophilic wall-infiltration of venule without vasculitis were also noted (Fig. 2). Blood and bacteriological tissue, mycobacterial, parasitic and mycological cultures were negative. The erythrocyte sedimentation rate was elevated, 104 mm/1st h; C-reactive protein was 8 times the normal. The complete blood count, calcemia, serum phosphate, uremia and creatininemia were normal. Hepatitis C virus serology was negative and HBs antigen was not detected. His CD4⁺ lymphocyte count was 501/mm³ with a T4/T8 ratio of 2.8 and virus load was 20 copies/ml, i.e., 1.3 log/ml. Lupus coagulant was detected without anticardiolipin or anti-beta2-glycoprotein 1 antibodies. The levels of prothrombin, coagulation factors, protein C, protein S, antithrombin III, plasma homocysteine, and resistance to activated protein C were normal. Polymorphism 20210 of the factor II gene was normal. The search for an anomaly of fibrinolysis, cryoglobulinemia or cryofibrinogenemia was negative. A computed tomography scan detected a discreet heterogeneous densification of abdominal fat without involvement of the underlying muscle wall.

The lesions resolved slowly over the next 2 months with local treatment that combined antibiotic-containing gauze and hydrocolloid bandages and gave rise to hypopigmented and atrophic scar tissue. PEG-IFN-alpha2b continued to be injected subcutaneously into the thigh, without interruption or dose modification. Since changing the injection site, no new cutaneous lesions, at the injection site or elsewhere, have been observed.

Discussion

To the best of our knowledge, this is the first documented case of cutaneous necroses associated with PEG-IFN injections in an HIV-infected patient. Other potential causes of cutaneous necrosis could easily be eliminated for our patient: protein C or S deficiency, calciphylaxis (vascular calcification-cutaneous necrosis syndrome), cryoglobulinemia, cryofibrinogenemia. Furthermore, the clinical picture differed from those of the rare cases of widespread cutaneous necrosis associated with antiphospholipid syndrome [2]. The possibility of ecthyma gangrenosum, necrotizing fasciitis or an infectious pathology of bacterial, mycobacterial, fungal or parasitic origin was eliminated by appropriate cultures of skin biopsies.

PEG-IFN alpha-2b is a pegylated formulation of recombinant human IFN-alpha2b conjugated with monomethoxy polyethylene-glycol. The major advantage of this formulation, compared to nonpegylated IFN-alpha2b, is a ten-fold prolonged half-life (40 hrs vs 4 hrs) by reducing renal clearance, which allows for once-weekly injection. Its antiviral efficacy in association with ribavirin as a new standard treatment of chronic hepatitis C has been recently documented [3, 4]. During the course of HIV infection, preliminary results in open, prospective pilot studies in patients showed a significant antiretroviral activity in addition to a suboptimal antiretroviral therapy [1]. The most commonly reported adverse events of PEG-IFN in clinical trials are similar to standard IFN: asthenia, headache, flu-like symptoms, myalgia and fatigue/malaise. Inflammation without serious reactions at the site of injections has been noted in approximately 40-45%. Only one previous report described multiple cutaneous ulcerations occurring at the site of injection of PEG-IFN-alpha associated with visual disturbances in a patient with malignant melanoma [5].

Our observation can be added to the previously reported cases of cutaneous necrosis following standard IFN-alpha injection [6-22]. These cutaneous necroses occur without age or sex predominance and regardless of whether the IFN injections were given subcutaneously or intramuscularly [11]. Although most frequently reported to arise on the abdominal wall and the anterior surfaces of the thighs, they can also been seen overlying the deltoid or triceps when these are the sites of injection [14]. Among the various diseases treated, Kaposi's sarcoma during acquired immunodeficiency syndrome, chronic hepatitis C, hairy-cell leukemia, chronic myeloid leukemia, renal carcinoma, none is significantly associated with cutaneous necroses. The delay to the appearance of the lesions is most often 2-3 months after the onset of treatment, but can vary from several weeks to years [13, 17]. It is not usually correlated to the dose or frequency of administration. According to the typical clinical presentation, the lesion appears
1-2 days after injection, but sometimes more than 1 month later. Only the first report mentioned the appearance of cutaneous necrosis within several hours following injection [6]. The skin lesion starts at the injection site as an erythematous or orange-colored painful macule or nodule, that becomes necrotic within several days. The necrosis spreads progressively and forms a dry, black escarotic plaque with irregular borders, often angular and well defined. The size of the ulcerations varies from several millimeters to 10 cm in diameter. The edge of the ulceration is comprised of a large inflammatory plaque, infiltrated on palpation, poorly delimited. Removal of the scab reveals an atonic ulceration. The lesions can be multiple. Resolution under treatment is slow, taking several months and giving rise to a hyperpigmented and atrophic scar. Histological examination of skin biopsied at the edge of the ulceration showed neutrophilic, lymphocytic and histiocytic infiltration of the superficial and deep dermis, sometimes associated with lobular panniculitis. Venular thromboses in the deep dermis and subcutis can be seen but usually a deep biopsy, sometimes of the center of the ulceration, is required. No histological vasculitic lesion is reported to be associated in most cases. Rare bacterial secondary infections with Staphylococcus aureus, Pseudomonas aeruginosa have been noted [14]. Medical treatment is mostly based on the application of hydrocolloid bandages to hasten healing, associated with local and systemic antibiotics in rare cases of infection. It is sometimes necessary to resort to surgical debridement and excision of the lesion followed by direct suturing or grafting. Continuation of IFN injections far from the site of necrosis is possible for most patients, but can be complicated by the appearance of new cutaneous necroses at the new injection sites which necessitate discontinuation of the drug [15]. Prevention requires competent training in self injection, with as much variation as possible of the injection site, and particular vigilance in cases of erythema which shows persistance for several days at the injection site.

Several pathogenic mechanisms may be involved in IFN-alpha-induced cutaneous necroses (Table I). In our observation, the detection of lupus anticoagulant that might be associated with HIV disease or induced by IFN treatment could have played a favoring or aggravating role. Moreover, because of clinical similarities with drug-induced necroses such as heparin and warfarin, the development of cutaneous necroses associated with IFN therapy requires a complete hemostasis work-up, including laboratory tests for factors of congenital or acquired thrombophilia with, in particular, dosages of proteins C and S, and the search for an antiphospholipid-anti-beta2-glycoprotein 1 syndrome. A local vasospastic effect due to direct IFN-alpha toxicity on the vascular endothelium is another possibility. The action could be facilitated by the increased local concentration of IFN attributable to the repeated injections at the same site and the pharmacokinetics of the PEG-IFN formulation. Continued administration of the injections into inflammatory or periulcerated areas constitutes a frequently mentioned triggering or aggravating factor [9, 10]. This hypothesis of a direct vasospastic effect of IFN-alpha could account for the previously reported cases of IFN-induced Raynaud's syndrome [23, 24] or severe visceral ischemic manifestations [25], and supports the preventive proscription of the drugs favoring arteriolar vasospasms, such as beta-blockers or dihydroergotamine.

Article accepted on 10/9/01

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