CASE REPORT
Disseminated systemic Nocardia farcinica infection
complicating alefacept and infliximab therapy in a
patient with severe psoriasis
Jaffar A. Al-Tawfiq
a,*
, Adil A. Al-Khatti
ba
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
b
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 Corresponding Editor: William Cameron, Ottawa, Canada
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 immuno-compromised hosts. The infection is usually acquired through the skin or the respiratory tract. The most common presen-tation is pulmonary infection, which may be followed by dissemination to multiple sites.2 Nocardia spp have a ten-dency to disseminate hematogenously from the primary site of infection to the brain, kidneys, joints, bones, and eyes.3 Dissemination of nocardiosis is associated with immuno-compromised states, including those in diabetes mellitus,
http://intl.elsevierhealth.com/journals/ijid KEYWORDS Nocardia farcinica; Anti-TNF; Psoriasis; Infliximab; Alefacept; Brain abscess
Summary Nocardiosis is a cause of significant morbidity and mortality in the immunocompro-mised host, and is an infrequent complication of tumor necrosis factor alpha (TNF-a) 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 uncom-mon 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, ciproflox-acin, amoxicillin—clavulanic acid, linezolid, sulfamethoxazole, and amikacin. It was resistant to clarithromycin, ceftriaxone, and tobramycin and was intermediately susceptible to imipenem. #2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +966 3 877 3524; fax: +966 3 877 3790. E-mail addresses:[email protected],
[email protected](J.A. Al-Tawfiq).
1201-9712/$36.00 # 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.03.017
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-a) blockers in chronic inflammatory diseases. A total of eight cases of nocardiosis were identified among approxi-mately 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 inflix-imab therapy6,7and disseminated disease following etaner-cept therapy.8However, 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 alefa-cept and infliximab.
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 hyper-tension. The psoriasis was quite refractory to topical treat-ment, 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, 15 mg intramuscularly weekly for 12 weeks, with no improvement. Two months before pre-sentation, she was given 100 mg 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 8C (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 8C and there was no peripheral lymphadenopathy. The skin showed slight hyperpigmentation and a few small psoriatic lesions. Cardi-ovascular and lung examinations were normal. The abdomen was soft with slight non-rebound left upper quadrant tender-ness and normal bowel sounds. There was no synovitis.
Laboratory investigations showed leukocytosis of 13.7 109/l primarily due to neutrophilia. Hemoglobin was 12.8 g/dl and platelets were 263 109/l. C-reactive
protein was 14 mg/dl and the erythrocyte sedimentation rate was 104 mm/h. Lactate dehydrogenase was 838 mg/dl (normal range 321—597). Alanine aminotransferase, aspar-tate aminotransferase, and alkaline phosphatase were normal. Serology for Brucella and HIV 1 and 2 were nega-tive. 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. Uri-nalysis 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 2.5 cm left adrenal mass and a 2.2 1.2 cm right adrenal mass (Figure 1). There were multiple retroperitoneal and mesenteric lymphadenopathies with a maximal diameter of 1.8 cm. 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 immunocompro-mised patient; however the first abdominal imaging appeared to favor a neoplastic process. While awaiting hor-monal studies to exclude an adrenal cortical tumor or pheo-chromocytoma, fever persisted. After one week, naproxen was started and the fever resolved within 24 hours, 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 enlarge-ment of both adrenal masses to 6.4 cm on the left associated with a small amount of fluid, and 4.7 cm on the right (Figure 3).
Magnetic resonance imaging of the brain showed numer-ous 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 multi-focal areas of leptomeningeal enhancement.
Aspiration and biopsy of the left adrenal lesion yielded 8 ml 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—
Figure 1 A computerized axial tomography scan of the abdo-men showing a 4.6 2.5 cm left adrenal mass and a 2.2 1.2 cm right adrenal mass.
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 avail-able one week after the patient’s death and showed Nocar-dia 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 (0.25 mg/ml), gatifloxacin
(0.25 mg/ml), ciprofloxacin (0.5 mg/ml), amoxicillin—cla-vulanic acid (8/4 mg/ml), linezolid (2 mg/ml), sulfamethox-azole (4 mg/ml), and amikacin (2 mg/ml). The organism was resistant to clarithromycin (32 mg/ml), ceftriaxone (64 mg/ml), and tobramycin (16 mg/ml) and was interme-diately susceptible to imipenem (8 mg/ml).
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 mod-erate to severe plaque psoriasis in adults who are candidates for systemic therapy. An alefacept-induced decline in circu-lating 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
manufac-turer recommends stopping alefacept when the CD4+ lym-phocyte count falls below 0.25 109/l. Alefacept appears to
be a safe medication.9A 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-a monoclonal antibody. It binds soluble TNF-a and TNF-a receptors on macrophages
Figure 3 A repeat computed axial tomography of the abdo-men, 16 days after the initial study, showing enlargement of both adrenal masses to 6.4 cm on the left and 4.7 cm on the right.
Figure 4 Magnetic resonance imaging of the brain showing numerous round peripherally enhancing lesions involving super-ficial and deep white matter.
Figure 2 Computed axial tomography of the brain showing multiple ring enhancing lesions scattered throughout the brain and slight surrounding edema.
and T cells, and results in apoptosis of macrophages and T cells. It is very effective in the treatment of resistant psor-iasis.11Increased susceptibility to opportunistic infections is a recognized side effect of infliximab therapy.12
Dissemi-nated and cutaneous nocardiasis have been reported follow-ing anti-TNF therapy.4—7,13A case of pulmonary nocardiosis
has also been described in a patient receiving adalimumab therapy for refractory rheumatoid arthritis14and a
dissemi-nated disease following etanercept therapy.8However, dis-seminated nocardiosis remains an uncommon complication of these agents.
It is possible that exposure to alefacept, and then inflix-imab, 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, espe-cially 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 spe-cies 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.19In
addi-tion, 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.21An increase in mortality may be
associated with delayed diagnosis or difficulties in cultur-ing Nocardia spp.21 To facilitate the rapid diagnosis,
sev-eral 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 intracer-ebral 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.
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.
References
1. McNeil MM, Brown JM. The medically important actinomycetes: epidemiology and microbiology. Clin Microbiol Rev 1994;7:357— 417.
2. Burgert SJ. Nocardiosis: a clinical review. Infect Dis Clin Pract 1999;8:27—32.
3. Sabuncuog˘lu H, Cibali Ac¸ikgo ZZ, Caydere M, Ustu¨n H, Semih Keskil I. Nocardia farcinica brain abscess: a case report and review of the literature. Neurocirugia (Astur) 2004;15: 600—3.
4. Wallis RS, Broder M, Wong J, Beenhouwer D. Granulomatous infectious diseases associated with tumor necrosis factor antago-nists. Clin Infect Dis 2004;38:1261—5.
5. Wallis RS, Broder M, Wong J, Beenhouwer D. Granulomatous infections due to tumor necrosis factor blockade: correction. Clin Infect Dis 2004;39:1254—5.
6. Fabre S, Gibert C, Lechiche C, Jorgensen C, Sany J. Primary cutaneous Nocardia otitidiscaviarum infection in a patient with rheumatoid arthritis treated with infliximab. J Rheumatol 2005; 32:2432—3.
7. Singh SM, Rau NV, Cohen LB, Harris H. Cutaneous nocardiosis complicating management of Crohn’s disease with infliximab and prednisone. CMAJ 2004;171:1063—4.
8. Menon KV, Stadheim L, Kamath PS, Wiesner RH, Gores GJ, Peine CJ, et al. A pilot study of the safety and tolerability of etaner-cept in patients with alcoholic hepatitis. Am J Gastroenterol 2004;99:255—60.
9. Scheinfeld NJ. Alefacept: its safety profile, off-label uses, and potential as part of combination therapies for psoriasis. J Der-matolog Treat 2007;18:197—208.
10. Prasertsuntarasai T, Bello EF. Mycobacterium avium complex olecranon bursitis in a patient treated with alefacept. Mayo Clin Proc 2005;80:1532—3.
11. Vamvouris T, Hadi S. A review of the treatment of psoriasis with infliximab. Rev Recent Clin Trials 2006;1:201—5.
12. Toruner M, Loftus Jr EV, Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008;134:929—36.
13. Wendling D, Murad M, Mathieu S, Berger E, Rumbach L. Systemic nocardiosis in a case of rheumatoid arthritis treated with tumor necrosis factor blockers. J Rheumatol 2008;35: 539—42.
14. Doraiswamy VA. Nocardia infection with adalimumab in rheu-matoid arthritis. J Rheumatol 2008;35:542—3.
15. Torres OH, Domingo P, Pericas R, Boiron P, Montiel JA, Va´zquez G. Infection caused by Nocardia farcinica: case report and review. Eur J Clin Microbiol Infect Dis 2000;19:205—12.
16. Wauters G, Avesani V, Charlier J, Janssens M, Vaneechoutte M, Delmee M. Distribution of Nocardia species in clinical samples and their routine rapid identification in the laboratory. J Clin Microbiol 2005;43:2624—8.
17. Cercenado E, Marin M, Sanchez-Martinez M, Cuevas O, Martinez-Alarcon J, Bouza E. In vitro activities of tigecycline and eight other antimicrobials against different Nocardia species identi-fied by molecular methods. Antimicrob Agents Chemother 2007;51:1102—4.
18. Wallace Jr RJ, Steele LC, Sumter G, Smith JM. Antimicrobial susceptibility patterns of Nocardia asteroides. Antimicrob Agents Chemother 1988;32:1776—9.
19. Aydoslu B, Tug˘rul HM. Nocardia spp isolated from immunocom-promised patients in Trakya University Medical Faculty Hospital and their antibiotic susceptibilities. Mikrobiyol Bul 2007;41: 529—35.
20. Dodds EM, Echandi LV, Puente SI, Kaufman S. Subretinal abscess due to Nocardia farcinica resistant to trimethoprim—sulfa-methoxazole in a patient with systemic lupus erythematosus. Ocul Immunol Inflamm 2006;14:249—51.
21. Mamelak AN, Obana WG, Flaherty JF, Rosenblum ML. Nocardia brain abscess: treatment strategies and factors influencing out-come. Neurosurgery 1994;35:622—31.
22. Steingrube VA, Brown BA, Gibson JL, Wilson RW, Brown J, Black-lock Z, et al. DNA amplification and restriction endonuclease analysis for differentiation of 12 different species and taxa of Nocardia, including recognition of four new taxa within the Nocardia asteroides complex. J Clin Microbiol 1995;33:3096— 101.
23. Iannotti CA, Hall GS, Procop GW, Tuohy MJ, Staugaitis SM, Weil RJ. Solitary Nocardia farcinica brain abscess in an immunocom-petent adult mimicking metastatic brain tumor: rapid diagnosis by pyrosequencing and successful treatment. Surg Neurol 2008. [Epub ahead of print].
