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Rheumatology 2001; 40: 949-952
© 2001 British Society for Rheumatology
Letters to the Editor |
Disseminated nocardiosis presenting as a flare of Behçet's disease
1 Service de Médecine interne, Centre Hospitalier de Moulins-Yzeure, 10 avenue du général de Gaulle, BP 609, 03006 Moulins cedex,
2 Service de Médecine interne, Hôpital de la Pitié-Salpêtrière, 47–83 boulevard de l'Hôpital, 75651 Paris cedex 13 and
3 Service de Médecine interne, Centre Hospitalier Inter Communal de Tarbes-Vic en Bigorre, Boulevard de Lattre de Tassigny, BP 1330, 65013 Tarbes cedex 9, France
SIR, Behçet's disease (BD) is an inflammatory disorder characterized by the classic triad of recurrent oral and genital aphthae and uveitis, and by possible multisystem involvement (e.g. central nervous system, pulmonary system, digestive tract) and an increased tendency to thrombosis. Its relapsing course often requires immunosuppressive therapy.
Nocardiosis is mainly an opportunistic infection due to aerobic actinomycetes and is characterized by a primary respiratory focus and potential haematogenic dissemination, mainly to the brain and skin. We report the occurrence of disseminated nocardiosis due to Nocardia asteroides in an immunosuppressed patient who presented with a neurological deficit, visual deterioration and cutaneous nodular lesions mimicking a flare of BD despite immunosuppressive therapy.
A 45-yr-old man, born in Portugal, was referred to the hospital in October 1998 with a suspected BD flare. He had suffered recurrent oral aphthosis and painful genital ulcerations since the age of 10 yr. A sural thrombophlebitis occurred in 1985. In 1991, the onset of right uveitis led to the diagnosis of BD. He was treated with high-dose corticosteroids; he showed a high degree of corticodependence and annual relapses, and needed adjunction of immunosuppressive therapy in 1992. This consisted successively of chlorambucil, azathioprine, cyclosporin A and, since May 1998, monthly intravenous pulses of cyclophosphamide (dose 750 mg). Three weeks after the sixth bolus, when the prednisone dose had been tapered to 30 mg/day, he developed night sweats and fatigue, progressive visual loss, recent headaches and brachiofacial paresis. He was hospitalized in the department of internal medicine at Tarbes. His temperature was 37.8°C. Clinical examination displayed a slight motor deficit involving the right arm and hemiface without sensory disturbance or changes in sensitivity; there was anterior inflammation of the right eye, with an epiretinal membrane without papillar oedema and truncal folliculitis. Blood pressure was 130/80 mmHg and the pulse rate was 90/min. The chest radiograph showed a dense parahilar right infiltrate. A cranial computed tomograph (CT) scan showed two round hypodensities in the left parieto-occipital and temporal areas, without a mass effect. Blood and urine cultures were sterile. Flare of BD was suspected and the patient was referred to our department after institution of 50 mg intravenous methylprednisolone per day.
Clinical examination disclosed folliculitis and painful deep inflammatory nodular lesions of the left side of the thorax. Laboratory tests showed a white blood cell count 21.6x109/l [polymorphonuclear neutrophils (PMN) 18.8x109/l, lymphocytes: 1.3x109/l], haemoglobin 12.7 g/dl, platelet count 181x109/l, erythrocyte sedimentation rate 26 mm/h, C-reactive protein (CRP) concentration 128 mg/l, uraemia 14 mmol/l and serum creatinine concentration 136 µmol/l. Magnetic resonance imaging (MRI) evidenced two round areas of low signal on the T1-weighted image, with peripheral high signal and central low signal, and high signal on the T2-weighted image, with peripheral gadolinium enhancement; in addition, two other frontal high signals were discovered on the T2-weighted image (Fig. 1
). Lumbar puncture showed normal cerebrospinal fluid with normal lactate dehydrogenase and interferon levels. Polymerase chain reactions for detection of herpes simplex virus, Varicella zoster virus (VZV), cytomegalovirus (CMV) and Epstein–Barr virus in cerebrospinal fluid (CSF) were negative, as were Chinese ink, Ziehl–Neelsen and May–Grünwald–Giemsa (MGG) stainings. Blood, urine, sputum, perbronchoscopic samples and CSF cultures were negative, including tests for Aspergillus, Candida and CMV antigens. Serological testing for HIV was negative. Chest X-rays and CT scanning showed an excavated infiltrate of the middle lobe. Bronchoscopy and transoesophageal echocardiography were normal. Subcutaneous fine-needle aspiration yielded a few altered PMN that contained liquid but no microorganisms on direct examination after Gram, Ziehl–Neelsen and MGG staining. However, the cultures grew Gram-positive rods on standard media at 7 days; these were identified as N. asteroides (Institut Pasteur Paris, France). The antibiogram demonstrated the susceptibility of the strain to amoxicillin clavulanate, imipenem, third-generation cephalosporins, trimethoprim-sulfamethoxazole, aminoglycosides, minocyclin and quinolones. An antibiotic combination of ceftriaxone (2 g every 12 h), amikacin (1 g every 24 h, progressively tapered to 0.75 g every 24 h) and trimethoprim-sulfamethoxazole (intravenously 1.2 g every 12 h) was prescribed. Prophylactic anticonvulsive therapy (oral disodium valproate) was added and corticosteroids were maintained at the same dose. Cutaneous lesions disappeared within 1 week and chest opacity within 2 weeks. Almost complete neurological recovery was achieved within 1 month (there was mild residual facial palsy). WBC, fibrinogen and CRP normalized within 5 days. One month later, amikacin was stopped; ceftriaxone was withdrawn in June 1999 and trimethoprim-sulfamethoxazole has been maintained until the present. Delayed regression of the cerebral abscesses on MRI was noticed only in February 1999 and complete disappearance in September 1999. At the 21-month follow-up, the patient was well, under treatment with trimethoprim-sulfamethoxazole and prednisone 20 mg/day, with no relapse of BD. Immunosuppressive therapy was not reintroduced.
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The patient presented with prominent central nervous and cutaneous features mimicking a flare of BD. The dermohypodermal nodules, folliculitis and recent visual loss were consistent with this hypothesis. However, the nodules, which are present in 30–40% of cases, involved mainly the lower limbs and the pustules were aseptic [1]. Brain CT scanning and MRI can show features specific to BD. The classical appearance is of areas of low signal on T1-weighted images and high signal on T2-weighted images, involving the brainstem cerebellum, basal ganglia region or periventricular white matter. During the acute phase, very large lesions with gadolinium enhancement and occasionally a mass effect may be observed, mimicking a tumour. With time, the lesions decrease in size and small signal abnormalities persist [2]. Various mechanisms have been suspected: true vasculitis with necrosis and effraction of blood–brain barrier [3], meningoencephalitis with perivascular inflammatory infiltration, necrosis and oedema with gadolinium enhancement [2, 4]. The fortuitous discovery of a pulmonary infiltrate does not fit with the usual feature of BD pulmonary involvement. It consists of pulmonary arteritis, which is usually revealed by fever, haemoptysis, dyspnoea and chest pain [5, 6]. Although CRP can increase in cases of erythema nodosum, ocular or neurological manifestations of BD are not significantly correlated with an elevated CRP concentration [7]. In the present case, the absence of fever contrasting with an elevated CRP concentration suggests an infectious complication with cutaneous, pulmonary and brain foci. Moreover, the occurrence of BD flare during immunosuppressive therapy is unlikely. Thus, the main infectious causes suggested by the association of pulmonary, cerebral and cutaneous involvements were nocardiosis, systemic fungaemia, tuberculosis and infective endocarditis.
Pathogenic Nocardia species are ubiquitous aerobic environmental actinomycetes [8]. Human nocardiosis results mainly from inhalation or direct seeding of superficial tissues by contaminated soil or dust particles. It presents more often as a subacute or chronic pulmonary infection with secondary haematogenous dissemination, especially to the central nervous system, and less commonly to the soft tissues, including cutaneous [9] and intra-abdominal abscesses [8].
Nocardia asteroides accounts for 66–86% of nocardial isolates in Europe in the last 20 yr [10, 11]. It is responsible for 71% of cases of pulmonary nocardiosis and 80% of cases of central nervous system and systemic infections [10]. An immunocompromised status or a chronic respiratory disease are encountered in 60–90% of cases of nocardiosis [8]. Immunological defects that predispose the patient to nocardiosis can result from both the disease and its treatment: these defects may include impaired anatomical barriers, hypogammaglobulinaemia, altered PMN and macrophage functions (in our case, defective oxidative burst or abnormal migration related to steroids, colchicine and alkylating agents or BD itself), and overall qualitative impairment of T-cell responses. Corticosteroids are an established risk factor for nocardiosis [8] and their use correlates with higher mortality [12].
The main underlying conditions described in association with nocardiosis are malignancies, immunosuppression associated with organ transplantation, connective tissue diseases, HIV infection, intravenous drug abuse and other disorders, such as chronic granulomatous diseases, dysgammaglobulinaemia, diabetes, alcoholism, chronic nephropathy and hepatopathy [8]. Bronchopulmonary, central nervous system or disseminated nocardiosis, mainly caused by N. asteroides, has been described as a rare complication of uveitis [13] and different connective tissue diseases (especially systemic lupus erythematosus and rheumatoid arthritis [9, 14, 15]). Among 147 cases of nocardiosis, all 13 patients with autoimmune diseases had respiratory involvement and eight of these (61%) had disseminated disease [12]. To the best of our knowledge, this case is the first description of disseminated nocardiosis in a patient with BD. As clinical symptoms and signs of both BD and nocardiosis are non-specific, skin puncture or biopsy of cutaneous nodules appears essential for aetiological diagnosis, preventing resort to more invasive procedures. The long-term antibiotic course was justified in this case by the patient's severely immunocompromised status and the central nervous system septic metastases. A total duration of treatment of more than 12 months is warranted in such cases [9].
Disseminated nocardiosis is a rare and serious complication of immunosuppressive therapy in multisystem inflammatory diseases. Physicians need to be aware of the possible resemblance between BD and nocardial infection, which share ocular, cutaneous and central nervous system involvement. These equivocal aetiologies must be distinguished on the basis of systematic microbiological testing.
Notes
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