Disseminated Nocardiosis Complicating Medical Therapy in Crohn's Disease

Immunosuppressive therapy using 6-mercaptopurine, azathioprine, and cyclosporine are widely used for severe, steroid-dependent Crohn's disease, with an improvement seen in 60-70% of patients (1). These medications are usually well tolerated, although therapy may be complicated by their immunosuppressive effects (2). 6-Mercaptopurine and cyclosporine have inhibitory effects on T-cell function (3,4). Immunosuppression from corticosteroids occurs at multiple sites, including affecting T cells (5). We describe a patient with severe Crohn's disease who developed disseminated nocardiosis, a potentially life-threatening condition, while being treated with prednisone and 6-mercaptopurine. CASE REPORT Our patient was a 16-year-old girl in whom Crohn's disease was diagnosed 6 months before her acute presentation with nocardiosis. She had a 2-year history of intermittent abdominal pain, 6 months of diarrhea, and 2 months of grossly bloody stools at her initial presentation. She had lost 16 lb in the previous 4 months. She was pale and ill looking. Her abdomen was tender in the right lower quadrant, but no mass was palpated. A skin tag was present, and her stool had gross blood. A small-bowel series showed nothing abnormal, although the colonoscopy revealed patchy erythema with aphthous ulcers throughout the colon with rectal sparing. Biopsies were consistent with inflammatory bowel disease, and granulomas were seen. Initial therapy with sulfasalazine (50 mg/kg/day) and prednisone (1 mg/kg/day) was only partially successful. Eight weeks after diagnosis, ciprofloxacin and ranitidine were added to the patient's therapeutic regimen to help control her Crohn's colitis and possible acid peptic disease. Because of the inability to taper the patient's steroid use without an increase in abdominal pain and diarrhea, administration of 6-mercaptopurine (1 mg/kg/day) was started 6 weeks before she was diagnosed with nocardiosis. Four weeks before her presentation with nocardiosis, she received therapy for a dental abscess that included extraction of a broken tooth and administration of oral penicillin. Other than mild headaches, she felt well. Her steroid dose was tapered from 60 to 30 mg/day. However, 3 days before the acute presentation, the steroid dosages were increased back to 60 mg for severe ankle pain, thought to represent extraintestinal manifestation of the Crohn's disease. During the next 3 days, the patient experienced excruciating headaches, vomiting, and worsening of ankle pain. On the day of the admission she had a syncopal attack followed by a generalized seizure. She was afebrile but extremely agitated, tachycardic, and hypertensive. Her musculoskeletal examination was remarkable for an abscess below the right calf. Neurological examination was nonfocal, and there was no papilledema. Her abdomen was soft and nontender. Computed tomography (CT) scans of the head and magnetic resonance scans made on the same day revealed multiple brain abscesses (Fig. 1), with a large left cerebellar abscess compressing the fourth ventricle and brainstem. A CT scan of the abdomen and pelvis revealed a peripherally enhancing lesion in the posterior musculature suggestive of an abscess (Fig. 2). Chest radiography and CT revealed no abnormalities. The dental examination revealed two teeth requiring extraction for extensive caries but no abscess. At admission the patient's white blood cell count was 18.8 with 74% neutrophils. Her immunoglobulin profile and lymphocyte screen were normal. Tests for delayed hypersensitivity and mitogen response to phytohemagglutinin, concanavalin A, and pokeweed mitogen were also normal. The left cerebellar and right calf abscesses were drained. No fluid could be obtained from the lesion in the back. Nocardia asteroides and Staphylococcus aureus were isolated from the brain abscess, whereas N. asteroides alone was cultured from the calf abscess. Nocardia was sensitive to ceftriaxone, penicillins, and trimethoprim-sulfamethoxazole. The initial antimicrobial regimen included intravenous trimethoprim-sulfamethoxazole and ceftriaxone for N. asteroides, nafcillin for S. aureus, and penicillin for a polymicrobial abscess potentially of dental origin. She was hyperventilated for 4 days after surgery. Steroids were administered intravenously for cerebral edema, and 6-mercaptopurine use was discontinued and sulfasalazine therapy restarted as soon as the patient was able to tolerate oral feedings. Her neurological examination continued to show normal results throughout the hospital stay. Nafcillin and penicillin use were discontinued after 8 weeks. The patient was discharged home 8 weeks after admission with a regimen of intravenous trimethoprim-sulfamethoxazole, ceftriaxone, sulfasalazine, 6-mercaptopurine (50 mg/day), and prednisone (10 mg/day). Multiple CT scans performed thereafter revealed progressive improvement in the brain abscesses. A CT scan performed 4 months after the start of therapy showed almost complete resolution of the brain abscesses. The patient's neurological examination continues to show normal results, and her Crohn's disease is in remission. DISCUSSION Species of the genus Nocardia are aerobic actinomycetes and common inhabitants of the soil. N. asteroides is the species most often isolated from clinical specimens, although N. brasiliensis and N. caviae have also been implicated in human infections. Nocardiosis usually occurs as an opportunistic infection in immunocompromised patients (6,7), although localized skin and subcutaneous infections have been seen after trauma in immunocompetent hosts (8). Cell-mediated immunity and activated macrophages are the defense mechanisms of the body against disseminated infections (9). 6-Mercaptopurine has been associated with an increased incidence of infections, although a large proportion of these patients were reported to be taking steroids as well (2). Most of these infections were viral. Nocardiosis occurs in patients receiving 6-mercaptopurine along with other immunosuppressive drugs, including corticosteroids (10,11), and has been seen with use of corticosteroids as a single agent as well (6,12). Both corticosteroids and 6-mercaptopurine affect cell-mediated immunity, which is the primary immune mechanism against Nocardia. Disseminated nocardiosis has an incidence of 500-1,000 cases annually in United States (13). Although the lung is often the primary site of infection, the source of infection in our patient is unclear, because there were no lesions seen on chest radiographs or CT. However, there are reports of transient or subclinical pulmonary disease that presents as disseminated infection (14). Oral cavity lesions resulting in dissemination have been reported (15). Our patient had a dental abscess 4 weeks before presentation, which may have served as a portal of entry for Nocardia. CNS disease is associated with extraneural disease in 66% of patients (16). This patient had a calf abscess at the time of presentation of the cranial abscesses. The treatment of choice for Nocardia is sulfonamides (17). Amikacin, ceftriaxone, imipenem, ciprofloxacin, and minocycline have also been used alone or in combination in patients who are allergic or intolerant to sulfonamides (18-22). Surgical drainage for large or life-threatening brain abscesses may be necessary (16). In patients with CNS disease, the mortality rate approaches 55% in immunocompromised patients and 20% in immunocompetent patients (16). In immunocompromised patients, any combination of headache, meningismus, altered mental status, and focal neurological deficit should raise the suspicion of an intracranial disease (23). Our patient had complained of headaches, which were thought to be secondary to sulfasalazine use. We were unable to find any reports of disseminated nocardiosis in patients receiving 6-mercaptopurine or azathioprine alone. Despite extensive use of these agents, this is the first report of disseminated nocardiosis in a patient with Crohn's disease who was taking a combination of 6-mercaptopurine and corticosteroids. It is difficult to be sure which of the two agents used was more responsible for this opportunistic infection, and perhaps it is the combination of the two that made her more susceptible (24). The development of Nocardia in one patient with Crohn's disease should not alter the indications for use of steroids or immunosuppressive agents. However, clinicians should keep in mind all the potential side effects of these drugs when treating patients.FIG. 1.: Axial MRI of the brain with multiple high-signal ring lesions in the parenchyma with surrounding edema.FIG. 2.: Axial CT scan of the abdomen reveals a peripherally enhancing lesion with a fluid center in the posterior musculature.