International Journal of Infectious Diseases
Volume 14, Issue 2 , Pages e153-e157, February 2010

Disseminated systemic Nocardia farcinica infection complicating alefacept and infliximab therapy in a patient with severe psoriasis

  • Jaffar A. Al-Tawfiq

      Affiliations

    • Internal Medicine Services Division, PO Box 76, Room A-428-2, Building 61, Dhahran Health Center, Saudi Aramco Medical Services Organization, Saudi Aramco, Dhahran 31311, Saudi Arabia
    • Corresponding Author InformationCorresponding author. Tel.: +966 3 877 3524; fax: +966 3 877 3790.
    • ,
  • Adil A. Al-Khatti

      Affiliations

    • Oncology Services Division, Dhahran Health Center, Saudi Aramco Medical Services Organization, Saudi Aramco, Dhahran, Saudi Arabia

Received 8 December 2008; received in revised form 3 March 2009; accepted 17 March 2009. published online 08 June 2009.

Corresponding Editor: William Cameron, Ottawa, Canada

Article Outline

Summary 

Nocardiosis is a cause of significant morbidity and mortality in the immunocompromised host, and is an infrequent complication of tumor necrosis factor alpha (TNF-α) blockers in chronic inflammatory diseases. Nocardiosis occurs at a rate of 3.55 and 0.88 per 100 000 patients treated with infliximab or etanercept, respectively. Disseminated nocardiosis remains an uncommon complication of these agents. Here, we present a fatal case of disseminated systemic nocardiosis in a patient with psoriasis following sequential therapy with alefacept and then infliximab therapy. The patient developed disseminated disease involving the brain, lymph nodes, and adrenal glands. The diagnosis was made by blood culture and aspiration of the adrenal gland abscess, which revealed Gram-positive bacilli and later grew Nocardia farcinica. The organism was identified by DNA sequencing, and was susceptible to moxifloxacin, gatifloxacin, ciprofloxacin, amoxicillin–clavulanic acid, linezolid, sulfamethoxazole, and amikacin. It was resistant to clarithromycin, ceftriaxone, and tobramycin and was intermediately susceptible to imipenem.

Keywords: Nocardia farcinica, Anti-TNF, Psoriasis, Infliximab, Alefacept, Brain abscess

 

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Introduction 

Nocaxdia infection is not rare, as has generally been assumed, and the associated mortality rate is high. Nocardia spp can be isolated from plants and soil in most regions of the world. The infection ranges from a self-limiting, sub-clinical process to acute life-threatening and disseminated disease.1 Nocardia may cause infection in either normal or immunocompromised hosts. The infection is usually acquired through the skin or the respiratory tract. The most common presentation is pulmonary infection, which may be followed by dissemination to multiple sites.2 Nocardia spp have a tendency to disseminate hematogenously from the primary site of infection to the brain, kidneys, joints, bones, and eyes.3

Dissemination of nocardiosis is associated with immunocompromised states, including those in diabetes mellitus, alcoholism, chronic granulomatous disease, malignancy, corticosteroid therapy, HIV infection, organ transplant, and the use of tumor necrosis factor inhibitors. Nocardiosis is an infrequent complication of tumor necrosis factor alpha (TNF-α) blockers in chronic inflammatory diseases. A total of eight cases of nocardiosis were identified among approximately 300 000 patients treated with anti-TNF agents with a rate of 3.55 and 0.88 per 100 000 patients treated with infliximab or etanercept, respectively.4, 5 Additionally, cutaneous nocardiosis has been reported following infliximab therapy6, 7 and disseminated disease following etanercept therapy.8 However, disseminated nocardiosis remains an uncommon complication of these agents. Here, we present a case of disseminated systemic nocardiosis in a patient with psoriasis and sequential therapy with alefacept and infliximab.

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Case report 

The patient was a 66-year-old woman who had had psoriasis for 8 years and had diabetes mellitus type 2 and essential hypertension. The psoriasis was quite refractory to topical treatment, including ultraviolet light therapy. One year before presentation, the psoriasis became extensive and covered 60% of her body surface area. Six months before presentation, she was treated with alefacept, 15mg intramuscularly weekly for 12 weeks, with no improvement. Two months before presentation, she was given 100mg infliximab weekly for two weeks with marked improvement of the psoriasis. On the day of admission to hospital, she presented with a fever reaching 39°C (associated with rigors and profuse sweating). There was no weight loss. She had left upper quadrant abdominal pain that had started a week before admission. There was no history of recent travel or history of raw milk ingestion. The patient had no known epidemiological risk factors for nocardiosis such as gardening.

On examination, her temperature was 38.8°C and there was no peripheral lymphadenopathy. The skin showed slight hyperpigmentation and a few small psoriatic lesions. Cardiovascular and lung examinations were normal. The abdomen was soft with slight non-rebound left upper quadrant tenderness and normal bowel sounds. There was no synovitis.

Laboratory investigations showed leukocytosis of 13.7×109/l primarily due to neutrophilia. Hemoglobin was 12.8g/dl and platelets were 263×109/l. C-reactive protein was 14mg/dl and the erythrocyte sedimentation rate was 104mm/h. Lactate dehydrogenase was 838mg/dl (normal range 321–597). Alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were normal. Serology for Brucella and HIV 1 and 2 were negative. A skin test with purified protein derivative (PPD) showed no induration. One out of five blood cultures was initially reported to grow a diphtheroid species. Urinalysis and culture were negative. CD4+ lymphocytes were 0.14×109/l (normal range 0.41–1.59×109/l) compared to CD4+ counts of 0.49–0.70×109/l before and during alefacept therapy.

A chest radiograph was normal, but computed tomography (CT) of the abdomen showed a 4.6×2.5cm left adrenal mass and a 2.2×1.2cm right adrenal mass (Figure 1). There were multiple retroperitoneal and mesenteric lymphadenopathies with a maximal diameter of 1.8cm. There was partial left renal vein thrombosis and a wedge-shaped splenic lesion that most likely represented an infarction.

The initial impression was infection in an immunocompromised patient; however the first abdominal imaging appeared to favor a neoplastic process. While awaiting hormonal studies to exclude an adrenal cortical tumor or pheochromocytoma, fever persisted. After one week, naproxen was started and the fever resolved within 24hours, and she temporarily felt much better. Later, the patient had a decrease in the level of consciousness that progressed to deep coma over a few days. CT of the head showed multiple ring enhancing lesions scattered throughout the brain, with slight surrounding edema (Figure 2). A repeat CT scan of the abdomen, 16 days after the initial study, showed enlargement of both adrenal masses to 6.4cm on the left associated with a small amount of fluid, and 4.7cm on the right (Figure 3).

  • View full-size image.
  • Figure 3. 

    A repeat computed axial tomography of the abdomen, 16 days after the initial study, showing enlargement of both adrenal masses to 6.4cm on the left and 4.7cm on the right.

Magnetic resonance imaging of the brain showed numerous round peripherally enhancing lesions involving superficial and deep brain matter and white matter (Figure 4). The lesions were surrounded by mild vasogenic edema and demonstrated intense restricted diffusion. Several lesions also demonstrated evidence of hemorrhage. Post-contrast imaging demonstrated an enhancement pattern and multifocal areas of leptomeningeal enhancement.

Aspiration and biopsy of the left adrenal lesion yielded 8ml of pus. Gram stain showed many pus cells and Gram-positive bacilli. These were initially identified as diphtheroid species, but later confirmed by modified acid-fast stain and cultures to be Nocardia species. Mycobacterial smears and cultures were negative. Biopsy revealed necrotic tissue and flow cytometry showed cellular debris.

Vancomycin and ampicillin were started initially, and later ampicillin was stopped and meropenem and voriconazole were given. Once Nocardia spp was suspected, the patient was treated with trimethoprim–sulfamethoxazole (TMP–SMX) and linezolid. Although she partially improved, she never regained full consciousness up to the time of her death. Two and a half months after admission, the patient developed seizure and cardiopulmonary arrest and died. A CT of the brain shortly before death showed no significant change in the appearance of the brain lesions.

The final culture and susceptibility results were available one week after the patient's death and showed Nocardia farcinica. The organism was identified by DNA sequencing at the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA. The organism was susceptible to moxifloxacin (0.25μg/ml), gatifloxacin (0.25μg/ml), ciprofloxacin (0.5μg/ml), amoxicillin–clavulanic acid (8/4μg/ml), linezolid (2μg/ml), sulfamethoxazole (4μg/ml), and amikacin (2μg/ml). The organism was resistant to clarithromycin (32μg/ml), ceftriaxone (64μg/ml), and tobramycin (16μg/ml) and was intermediately susceptible to imipenem (8μg/ml).

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Discussion 

This patient had a severe cellular immune defect secondary to exposure to alefacept and infliximab in succession. Her CD4+ lymphocytes were low at 0.14×109/l. She suffered from a fatal case of systemic nocardiasis, involving the central nervous system.

Alefacept is a recombinant, soluble leukocyte function-associated antigen-3-immunoglobulin fusion protein that binds to the T cell rosette receptor. Alefacept treatment results in decreases in circulating CD4+ CD45RO+ and CD8+ CD45RO+ lymphocytes. It is used for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. An alefacept-induced decline in circulating T lymphocytes may increase the risk of infection. In the current patient, the CD4+ lymphocyte count declined during alefacept therapy, from 0.70 to 0.49×109/l. The manufacturer recommends stopping alefacept when the CD4+ lymphocyte count falls below 0.25×109/l. Alefacept appears to be a safe medication.9 A patient treated with alefacept was reported to have developed Mycobacterium avium complex bursitis, when the CD4+ cell count was 0.298×109/l at the time of diagnosis.10

Infliximab is a chimeric anti-TNF-α monoclonal antibody. It binds soluble TNF-α and TNF-α receptors on macrophages and T cells, and results in apoptosis of macrophages and T cells. It is very effective in the treatment of resistant psoriasis.11 Increased susceptibility to opportunistic infections is a recognized side effect of infliximab therapy.12 Disseminated and cutaneous nocardiasis have been reported following anti-TNF therapy.4, 5, 6, 7, 13 A case of pulmonary nocardiosis has also been described in a patient receiving adalimumab therapy for refractory rheumatoid arthritis14 and a disseminated disease following etanercept therapy.8 However, disseminated nocardiosis remains an uncommon complication of these agents.

It is possible that exposure to alefacept, and then infliximab, increased immunosuppression and susceptibility to infection. However, CD4+ cells were above the recommended level at which alefacept should be discontinued. At the time of presentation with systemic Nocardia infection, the CD4+ cell count was very low at 0.14×109/l. The patient had diabetes mellitus, which might have contributed to the immune deficiency.

Nocardia species are aerobic Gram-positive bacteria that are ubiquitous in the environment. Infection usually occurs through inhalation or direct cutaneous inoculation of the organism. Systemic nocardiasis is most frequently seen in immunocompromised hosts. It has a high mortality, especially when the central nervous system is involved. Delay in diagnosis has been reported and may contribute to a worse prognosis. This case highlights the risk of these potent medications. It also highlights the difficulty in making a timely diagnosis of rare infections in immunocompromised patients.

N. farcinica appears to be more virulent than the other Nocardia spp and tends to result in disseminated disease.15 The distribution of Nocardia spp is different based on the geographic location. N. farcinica accounts for 27% of species in Japan and 44% in Belgium.16 Nocardia spp exhibit different in vitro susceptibility patterns, therefore it is important to obtain precise speciation and susceptibility testing of clinical isolates.17, 18 Two N. farcinica strains were found to be resistant to antimicrobial agents, but were susceptible to ceftriaxone and cefotaxime.19 In addition, TMP–SMX resistance has also been described in one patient.20 Of all reported cases, a mortality rate of 35% occurred in patients with N. farcinica. However, cerebral nocardiosis has been associated with mortality rates of 55% and 20% in immunocompromised and immunocompetent patients, respectively, and may be as high as 66% in those with multiple abscesses.21 An increase in mortality may be associated with delayed diagnosis or difficulties in culturing Nocardia spp.21 To facilitate the rapid diagnosis, several molecular techniques have been developed including 16S ribosomal DNA and hsp65 gene analysis,22 and more recently pyrosequencing.23

In conclusion, Nocardia spp are rare causes of intracerebral abscess related to the use of alefacept and infliximab therapy. Physicians need to be aware of this diagnosis in such patients, and prompt diagnosis and treatment are necessary to decrease mortality and morbidity.

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Acknowledgements 

The authors wish to acknowledge the use of Saudi Aramco Medical Services Organization (SAMSO) facilities for the data and study, which resulted in this paper. Opinions expressed in this article are those of the authors and not necessarily of SAMSO.

Conflict of interest: No conflict of interest to declare.

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PII: S1201-9712(09)00153-2

doi:10.1016/j.ijid.2009.03.017

International Journal of Infectious Diseases
Volume 14, Issue 2 , Pages e153-e157, February 2010

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