Cocaine-Induced Midline Destructive Lesions

Abstract

Introduction Habitual nasal insufflation of pulverized cocaine may cause mucosal lesions. Mild changes cause nasal stuffiness, headache, or hyposmia. If cocaine use becomes chronic and compulsive, progressive damage of the mucosa and perichondrium leads to ischemic necrosis of the septal cartilage and perforation of the nasal septum. Occasionally, cocaine-induced lesions cause extensive destruction of the osteocartilaginous structures of the nose, sinuses, and palate that mimics the clinical picture of other diseases associated with necrotizing midfacial lesions (1,4,17,20,31,38,43,49,58,62,63,66,74). The mucosal damage induced by cocaine is multifactorial. The vasoconstrictive effect of the drug is thought to be the most important factor (8,17,20,38). However, the irritant effect of adulterants of the drug, the traumatic effect on the mucosa caused by cocaine crystals insufflated at high velocity, and recurrent nasal infections all seem to contribute to chronic tissue destruction (20,38). Progressive nasal obstruction, epistaxis with crusting, and ulceration of the nasal mucosa with or without septal perforation are also characteristic manifestations of nasal involvement by Wegener granulomatosis (WG). The differentiation of cocaine-induced midline destructive lesions (CIMDL) and limited WG may be difficult, particularly if the patients do not readily admit to their substance abuse. Antineutrophilic cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) or myeloperoxidase (MPO) are sensitive and specific markers for the idiopathic small vessel vasculitides including WG (30). It is generally believed that the presence of a positive ANCA test result with either of the 2 antigen specificities facilitates the differential diagnosis of WG. However, instances of positive ANCA test results have been reported in patients with lesions attributed to cocaine abuse (4,29). We found positive ANCA test results in an unexpectedly large proportion of patients with CIMDL. In several instances their lesions were clinically indistinguishable from WG limited to the upper respiratory tract (28). This seems to limit the usefulness of routine ANCA testing for the unequivocal differentiation of cocaineinduced nasal lesions from limited WG. We performed the present study to identify clinical, radiographic, and histopathologic features that allow the distinction of patients with severe CIMDL from those with WG and to further characterize their ANCA. Patients and Methods Patients Between January 1991 and December 1999, 18 cocaine abusers with midline destructive lesions were evaluated in the Department of Otolaryngology of the University of Brescia, Italy (Table 1). The patients ranged in age from 22 to 66 years (median, 37 yr). Ten were men and 8 women. The follow-up period ranged from 12 to 108 months (median, 34 mo). At the time of first observation, all patients except 1 admitted to cocaine use. In 7 patients reliable information on abuse duration and dose could not be obtained, 2 patients had a history of abuse with an undetermined dose lasting 6 and 8 years, respectively. One patient had been using 1–3 g per week irregularly. The remaining 8 patients had been using cocaine for 2–30 years, at a dose ranging from 1 to 15 g per week.TABLE 1: Clinical features and laboratory values at presentation of patients with CIMDL and WGThe control population consisted of all 21 consecutive WG patients who underwent a nasal biopsy in the Department of Otolaryngology of the University of Brescia during the same time frame (see Table 1). Patients’ ages ranged from 30 to 64 years (median, 45 yr). Nine were men and 12 women. The follow-up period ranged from 13 to 108 months (median, 52 mo). Nineteen patients were evaluated at the time of first diagnosis, 2 at the time of their first relapse. Five WG patients had generalized disease with renal involvement, 3 had limited disease involving only the nasal and tracheal mucosa. The remaining 13 patients had lung involvement and other systemic symptoms but no kidney involvement. All patients had biopsy-proven WG or satisfied the Chapel Hill Consensus Conference definition (35) of the disease. Clinical and laboratory evaluations Physical examination included inspection of the face, oral cavity, and oropharynx; inspection of the nasal cavities and nasopharynx using 0° and 30° rigid telescopes, 4 mm in diameter, and the flexible fiberscope. Multiple biopsies and samples for bacterial and fungal cultures were taken under endoscopic guidance. To monitor the clinical course of the disease, digital images of the relevant endoscopic features were archived. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complete and differential blood counts, liver and kidney function tests, urinalysis and microscopy, and serology for hepatitis virus B and C and human immunodefiency virus (HIV), were performed in every patient. In addition, antinuclear antibodies (ANA), rheumatoid factor (RF), and complement levels were determined in most patients. ANCA determination All sera from CIMDL and WG patients were tested for ANCA in 3 different laboratories. ANCA tests were first performed at the time of the patients’ clinical evaluation in the laboratory of the Department of Clinical Immunology of Spedali Civili, University of Brescia, Italy. Sera were analyzed by indirect immunofluorescence microscopy (IIF) on ethanol-fixed blood donor neutrophils following the standard procedure delineated at the first ANCA workshop (77). Sera were further tested by enzyme-linked immunosorbent assays (ELISA) for the presence of antibodies reacting with PR3 (PR3-ANCA) and MPO (MPO-ANCA). PR3, purified as previously described (65), and MPO obtained from a commercial source (Calbiochem Biosciences, Inc. La Jolla, CA) served as antigens in the assays. Aliquots of the sera were subsequently analyzed at the Mayo Clinic (Rochester, MN) by IIF and ELISA for MPO-ANCA following a standardized test algorithm (68). For some of the WG patients only convalescent sera were available for testing at Mayo (see Table 2). In addition, the sera were analyzed in the research laboratory of 1 of the authors (US) by IIF for PR3-ANCA and human leukocyte elastase (HLE)-ANCA using ethanol-fixed HMC-1 cells that expressed recombinant PR3 (rPR3) or HLE (rHLE) (56,69). Furthermore, the sera were tested for PR3-ANCA by capture-ELISA using purified neutrophil PR3 (Athens Research, Athens, GA) as target antigen (71). IIF results obtained using neutrophils were expressed qualitatively as showing characteristic cytoplasmic staining (C-ANCA) or perinuclear staining (P-ANCA). IIF results using HMC-1 cells expressing rPR3 or rHLE were reported as positive when characteristic IIF staining was detected at a serum dilution of 1:4 or higher that was not detectable on sham-transfected HMC-1 (HMC-1/VEC) control cells (69). Solid-phase assay results were expressed in arbitrary units.TABLE 2: ANCA test results in 18 patients with CIMDL and 21 patients with nasal destructive lesions caused by WG *Imaging studies Sixteen of the 18 CIMDL patients underwent cross-sectional imaging. A total of 24 examinations were evaluated: 7 computed tomography (CT) studies in 5 patients, and 17 magnetic resonance (MR) studies in 11 patients. Four patients had 1 study Sixteen of the 21 WG patients were evaluated by cross-sectional 2 by and by The studies were obtained the endoscopic examination in all patients the CIMDL patients, 4 patients had examinations during the follow-up mo). All studies were performed at the Department of of the University of Brescia using In all or were with All examinations were performed without of 5 studies were performed at the Department of the at different All studies were by 1 of the authors We analyzed the of septal that obtained by the of the of nasal structures nasal and of the nasal and A was obtained by 1 for We evaluated changes of of the mucosa on and In addition, evaluated changes in and of and of the and studies obtained at the time of the first endoscopic studies were evaluation A total of mucosal biopsies from nasal cavities and were evaluated from the 18 CIMDL patients. Five patients had 1 biopsy were with staining was to and and were to identify and respectively. were to identify were for and for protein 1 and were performed using and in respectively. nasal biopsies were obtained from 21 patients with WG and evaluated in the same all antibodies were from was performed using the The histopathologic the 2 were using the The the 2 were using the test and the For all values of or were Clinical and laboratory All patients with CIMDL an of symptoms including nasal obstruction, and severe The most at the first were necrotizing extensive crusting, and septal of the and was found in all patients. In severe to the and and the of the The was in 3 patients. and palate were present at presentation in 2 patients and during follow-up in 3 patients 1). The lesions to and nasal and the patients’ of of progressive destruction of the midline structures is in 1: of palate perforation in patients with cocaine-induced midline destructive lesions. The from a small to a large involving the palate and to the 2: of a midline destructive in a patient with cocaine-induced midline destructive lesions 3 In a large palate perforation was at inspection of the oral resonance (MR) studies also destruction of the and on and of the 1999, the had to destruction of the of the The and are in the endoscopic picture taken with a the presence of a of the CIMDL patients of symptoms or lung involvement at the course of the disease, 2 patients with severe destruction symptoms caused by infections associated with and One patient a lung All lesions with At symptoms as as as or were in patient and of the patients had symptoms or laboratory that a systemic disease The clinical presentation of patients with WG was The of nasal destruction was severe in patients with and of other involvement were present in most of the WG patients. All 21 patients with nasal crusting, but only 3 with a septal of the WG patients had involvement of the nasal or A of the is in of in cocaine-induced midline destructive lesions (CIMDL) and Wegener granulomatosis patients. The the proportion of patients of that had involvement of the patients with nasal symptoms were only 1 of several Clinical of involvement of other and were detected in all patients. symptoms and in the blood tests were in only 2 WG patients at the time of were with as the only of the disease. All other patients had symptoms and or The and were the other most were in WG CIMDL patients. the 21 WG patients of chronic disease was found in of blood in and of in levels of and were detected in 15 and of the WG patients, respectively. the 18 CIMDL patients, 2 had 5 had blood counts, and 2 had and values were found in and 8 CIMDL patients, but the values were those found in WG patients (see Table 1). and were present in 13 of 21 WG patients, in the presence of serum WG patients also had of 18 or of 11 All CIMDL patients had liver and renal function test results and tested for hepatitis B hepatitis and of 17 CIMDL patients tested at the had positive nasal cultures for of 21 WG patients were on at the time of diagnosis were not tested for Five of the remaining 7 WG patients not to had positive nasal ANCA results All patients were tested for ANCA at presentation WG was in the differential diagnosis of all necrotizing nasal lesions. A large of ANCA tests were positive in patients with CIMDL. The ANCA test results are in Table 5 of the 18 CIMDL patients were by all ANCA tests In 8 patients, IIF was positive for All sera were for MPO-ANCA by of the sera with and 4 were positive in 1 or of the tests performed to PR3-ANCA or IIF on of the sera with HLE and of the sera were for PR3-ANCA and Five patients with CIMDL had by All of were positive for PR3-ANCA in at 2 of the target assays. The IIF of in the 5 patients was indistinguishable from that found in WG. IIF and ELISA assay were as high as those in WG patients. of the 5 sera also with were in the PR3-ANCA ELISA in the other PR3-ANCA assays. the 21 WG patients, only 2 were ANCA (see Table 2). were the patients with biopsy-proven disease only the and Four patients had a with positive MPO-ANCA ELISA test and had a with 1 WG patient with MPO but not PR3, a that been reported of the sera from WG patients with the that routine ANCA testing not allow the differentiation cocaine-induced and nasal lesions. However, of ANCA specificities that the ANCA in patients with CIMDL from that in WG patients. In WG is To identify that to cocaine-induced lesions from analyzed the cross-sectional studies obtained at presentation in patients of (Table CIMDL patients had septal of had at destruction of the was in Ten of the cocaine abusers had or total destruction of at 1 was in of the was in 2 patients. The nasal was in 5 of the patients. All had destruction of the in 1 patient the to the The of the nasal was in 4 of patients In 1 of the involvement to the In the studies obtained at presentation in WG patients a nasal septal perforation in only 2 of The in of nasal septal perforation was with a positive of for CIMDL. The involvement of a nasal in to the nasal was the 2 as was present in of CIMDL patients but not in of the WG patients. the of structures was higher in CIMDL patients with WG patients A was present the of nasal perforation 2 and the The was in CIMDL patients and in WG patients In addition, the of palate perforation in CIMDL patients was with the destruction of or In CIMDL patients, of an of nasal or mucosa as on and or were detected on 4 and 6 of the 11 respectively. the obtained in WG patients, on and or were present in 3 and 6 patients, respectively. of the nasal mucosa were detected in CIMDL in WG patients, the was not However, when only the mucosa of the that the nasal and the and was or was in CIMDL in WG patients of the mucosa of the was in WG in CIMDL patients but the was not of the or was found on the studies in of CIMDL patients. It was associated with small tissue in most chronic changes of the were in WG patients of were detected in only 1 CIMDL patient but in 5 WG patients All had different of In 1 of the WG patients, tissue the was detected to be tissue destruction of the The of not studies were obtained in 4 of the CIMDL patients. All of admitted to cocaine abuse. All progressive of nasal In 1 patient was progressive involvement of the nasal and with destruction of the and complete of the and The of the was also (see 2). of the detected in CIMDL and WG patients the clinical that the of tissue destruction is severe in CIMDL in WG patients. To histopathologic features are for CIMDL and all nasal biopsy of patient. the biopsy obtained from the CIMDL patients, changes of with or extensive The remaining biopsies (Table In all a of cells with neutrophils and was was The cells the of and in of of the The to as was found in of the biopsies involving the of were found in biopsies with necrosis was in only 7 biopsies changes detected in 7 biopsies consisted of or changes of the In 4 the It is that the and only in a or or tissue necrosis with were not found in biopsy of the CIMDL features in nasal biopsies from 18 patients with CIMDL and 21 patients with features of nasal biopsies from cocaine-induced midline destructive lesions and Wegener granulomatosis and patients. the without destruction of the vessel to as The is particularly and the of the is necrosis and identify The of a small is by from an the and features only in WG lesions are cells a and associated with tissue necrosis All biopsies were with and for the histopathologic features of CIMDL patients with and without ANCA were that of was in the patients However, the not The of the cells a of with a and of B were or not All biopsies were for as as for and in studies at the of virus antigen and were also not The histopathologic changes in biopsies obtained from the WG patients are also in Table were in 22 biopsies A with and to those found in the CIMDL was was in all biopsies changes consisted of in the with necrosis and or histopathologic features as cells or and with necrosis were detected in and of respectively. In biopsies with changes were in CIMDL in WG patients but the was not in the and were with in and necrosis to be in WG However, when the was on the of the in patients no was in 6 of 18 CIMDL and in of 21 WG patients In changes of with and necrosis were features in WG The abuse of cocaine may cause that septal perforation was first reported in the abuse of of CIMDL are and To only 24 with clinical and have been reported to 5 of the ANCA test most of were The 2 of positive ANCA test results do not target antigen on high for the small vessel vasculitides including a positive ANCA test result was thought to be of differential in In most of patients with CIMDL had ANCA. of were at to be as WG. some were with to no the of clinical, radiographic, and histopathologic features that allow a distinction the 2 is Clinical and differentiation of CIMDL and WG the clinical and in patients with CIMDL with those of WG patients that the and of changes the 2 Furthermore, of the necrosis from the nasal the nasal was in CIMDL patients. In to the nasal most CIMDL patients had of 1 or of the only in patients who also had involvement. 18 reported in the with 1 or were in all patients, and 1 or were in The may and destruction of the midfacial involving the nasal or nasal structures palate palate was associated with involvement of and The of is by the the of septal perforation and the of nasal structures In of structures of the midline was WG patients and was limited to the nasal septum. The of mucosal detected on studies may further the of mucosa and on and or have been as markers for and in WG In 2 were not only detected in WG but also cocaine abusers with In patient mucosal changes of the were However, in CIMDL patients, were in the nasal and the The structures the of drug In the lesions had a in and changes of tissue of the chronic changes were in cocaine testing at the of chronic or systemic liver and kidney function and markers of no in CIMDL patients, a the severe destruction of the and an It be that the clinical and CIMDL and WG It is that patients with cocaine-induced lesions only tissue damage In WG patients may be for several including symptoms in other However, when severe destruction of nasal and of the tissue of the are in the of systemic substance abuse be and differentiation of CIMDL and WG the of diagnosis for particularly in patients with disease limited to the upper respiratory of the and have a limited on the of histopathologic features of WG in the changes including in the of and have been as characteristic features of WG that be in and biopsy We found changes including chronic and in the of CIMDL patients In addition, of and was found in the of or the changes in a large proportion of biopsies from patients with CIMDL be as with studies of CIMDL reported mucosal biopsies showing tissue necrosis and or chronic in the of or This is to the and the of the biopsies were not It is that at biopsies were performed in the disease and that the were The of in nasal biopsies from cocaine abusers is not been reported to in other as the and the and lesions have been found in the tract Furthermore, in have of neutrophils and to of and and of and that have also been in in nasal biopsies of WG CIMDL patients, the not CIMDL. Furthermore, have detected in a of nasal biopsies from WG histopathologic is of and for WG. is by a that the and the and the It is not associated with or but have been reported in with different ranging from chronic of the vessel to changes We found the in all biopsies from is was not detected in of the biopsy of WG patients, in with the results of In to the the of the changes is and of necrosis were in a large proportion of WG but not in of the biopsies obtained from cocaine In a differential diagnosis CIMDL and WG be on the of changes on mucosal biopsies from the upper respiratory However, is the specific changes of WG are This the of changes in the diagnosis of WG It also that WG is a necrotizing granulomatosis and a a that was by Wegener and ANCA in CIMDL The high of ANCA in patients with CIMDL was and their their and be from the ANCA in WG. The positive ANCA tests in patients with CIMDL may to a clinical particularly if only IIF testing or are performed in studies and have for the use of IIF and target only the and of ANCA testing for of with and with have been reported in seem to only of the found in CIMDL patients with all found in the WG control population as with testing that 4 of the found in CIMDL patients with PR3, a been reported to but not in patients with biopsy-proven WG of the sera with and 2 of were positive for PR3 and or of different ANCA in the same target of the sera a from the in WG or The 5 sera found in CIMDL patients of a all with PR3 in at 2 target assays. testing that 2 of also with The of of may the ANCA of CIMDL from those of have been described in but are in 1 study using an ELISA for their reported 8 patients with 108 WG patients and 15 patients In the WG population no was the same tested a of consecutive patients evaluated for and no in that patient population the that 2 of the 5 sera were in the ELISA further ANCA from those found in WG. PR3-ANCA for the on PR3 that is by the an that is by of PR3-ANCA from WG patients The cause of ANCA in CIMDL patients In the that 4 of the 13 CIMDL patients but of the WG patients is ANCA reacting with target antigens at the same time have previously been in patients with ANCA and in the ANCA in CIMDL patients is the result of by cocaine or drug adulterants to that induced by and It is also that ANCA in CIMDL patients are to with was in most of the patients. This is with the presence of nasal in cocaine abusers to a high of including nasal The mucosal damage caused by or by may cocaine to the of chronic with WG patients’ nasal mucosa is also with and the been to a higher rate as as to ANCA have been to the of in ANCA in to be thought to cells and B cells in an by the Furthermore, of are to be that could B cells to ANCA. studies have reported ANCA in infections in For the target antigens for the ANCA were not PR3 or MPO However, reacting with PR3 have been in bacterial and in were in 5 of the 7 reported patients are also to All patients on and ANCA of the In chronic infections of the CIMDL are to This may contribute to the of ANCA in patients. and MPO-ANCA have been in the of small vessel in At of ANCA in CIMDL patients seems to against a of ANCA of the CIMDL patients of Furthermore, the clinical presentation and histopathologic features not CIMDL patients with ANCA and those However, is that different ANCA may have different large studies performed during the that only ANCA reacting with the target antigens PR3 or and not those directed against other target are to the of in In addition, PR3-ANCA and MPO-ANCA from patients to a of PR3-ANCA as those on the of PR3, seem to with of the ANCA detected in CIMDL patients with target antigens other those associated with and that the PR3-ANCA found a different of the PR3-ANCA in WG. We found a high of positive ANCA test results in patients who for an evaluation of severe necrotizing nasal lesions associated with nasal cocaine the drug use history by patients is may the differentiation of cocaine-induced lesions from necrotizing of the upper respiratory tract associated with WG. radiographic, and histopathologic examination of the CIMDL patients and all WG patients with nasal during the same time frame the The destruction of nasal and structures is severe in of systemic are were found in biopsy of CIMDL patients and are not in the differential However, and cells are histopathologic of WG. routine ANCA testing not the ANCA found in some CIMDL patients from those of WG patients, the ANCA of the 2 patient We the clinical, radiographic, and histopathologic features of 18 consecutive patients who with cocaine-induced midline destructive lesions (CIMDL) with those of all 21 patients with Wegener granulomatosis with nasal involvement evaluated during the same time ANCA tests were positive in 13 of 18 CIMDL patients with of 21 WG patients. Clinical and evaluation that destruction of midline structures was severe in CIMDL WG. In to was no other involvement and no laboratory systemic in CIMDL. evaluation the of and as and in CIMDL as as in WG. necrotizing and cells found in WG were of the ANCA found in CIMDL and WG patients the following 8 CIMDL with 4 with PR3, 3 with 2 of with PR3 and All of 5 CIMDL patients with of also with In all but 1 of the WG patients or respectively. In 1 WG patient the target antigen was of the WG patients routine ANCA testing not allow an unequivocal distinction CIMDL and nasal involvement of but the ANCA of the 2 patient We Department of University of for and in as as and Department of Clinical University of Brescia, for in ANCA