Malani, Anurag N. MD; Aronoff, David M. MD
Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI.
Supported by the National Institutes of Health Grant HL078727 (D.M.A.).
Address correspondence and reprint requests to David M. Aronoff, MD, The University of Michigan Health System, 5220-D MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-6400. E-mail: email@example.com.
Anti-tumor necrosis factor alpha (TNF-α) therapy has been associated with an increased risk of granulomatous infections. We present a case of osteomyelitis and soft tissue abscess caused by Pseudomonas aeruginosa following the use of etanercept, a recombinant protein composed of the TNF-α receptor fused to human immunoglobulin (IgG). The patient recently developed P. aeruginosa osteomyelitis of the left femur 7 months after starting etanercept therapy for rheumatoid arthritis. The infection developed in an area of retained shrapnel deposited traumatically during the Vietnam War. Etanercept was withheld and the patient improved after medical and surgical therapy. Although it is possible that retained shrapnel fostered a dormant infection that was reactivated by pharmacological immunosuppression, an occult transcutaneous or bacteremic inoculation could not be ruled out. Patients receiving anti-TNF-α therapy may be at increased risk of common bacterial pathogens such as Pseudomonas, leading to severe bone and soft tissue infections.
Targeted anti-tumor necrosis factor α (TNF-α) therapy is an important advance in the treatment of autoimmune diseases, including rheumatoid arthritis.1 There are 3 TNF-α sequestering agents that have been approved by the US Food and Drug Administration for clinical use: infliximab, a chimeric monoclonal anti-TNF-α antibody; etanercept, a recombinant human protein composed of the human TNF-α receptor fused to human immunoglobulin (IgG); and adalimumab, a human monoclonal anti-TNF-α antibody. It is estimated that more than 500,000 individuals have received one of these agents.2
With the increasing use of these medicines, it has become clear that the selective blockade of TNF-α is associated with a reduced host response to certain infections, particularly granulomatous infections caused by fungal and mycobacterial pathogens.2,3 The degree (if any) to which anti-TNF-α therapy increases the risk of infection by routine bacterial pathogens remains unclear.4-6 Recently, 2 cases of Pseudomonas aeruginosa infection were reported in patients receiving anti-TNF-α drugs.4,5 We now report a complicated P. aeruginosa bone and soft tissue infection in a patient who, years earlier during the Vietnam War, experienced a complicated shrapnel injury in the same anatomic location that possibly served as the source for the present infection.
A 53-year-old man experienced traumatic, bilateral, and above-the-knee amputations (with retained shrapnel) while engaged in combat in the Republic of Vietnam on December 23, 1970. According to his military medical records, he developed extensive osteomyelitis of the right stump, requiring combined medical and surgical therapy. Wound cultures yielded P. aeruginosa, although antimicrobial susceptibility data (if performed) were not available to us.
The patient was well until 30 years later when he was diagnosed with rheumatoid arthritis and treated with hydroxychloroquine, celecoxib, and prednisone (10 mg QD). On this oral regimen, he had no infections requiring hospitalization or intravenous antibiotics. However, these medications failed to control the patient's joint pain and stiffness. Destructive and erosive changes of both wrists and hands progressed. Therefore, etanercept (25 mg sc twice weekly) was added in September, 2003. Seven months later, the patient noted the gradual onset of edema, tenderness, and warmth of the left stump over the period of several weeks. He did not recall any recent injury or trauma to the stump. On presentation to his local hospital, the patient was afebrile and the distal left stump was edematous and tender, without marked erythema. Laboratory tests revealed the following values: white blood cell count, 12.1×109/L (normal range, 4.8-10.8×109/L); C-reactive protein 1.0 mg/dL (normal ≤1 mg/dL), and a Westergren sedimentation rate of 10 mm/h (normal range 0-20 mm/h).
Computed tomography scan revealed a 6-cm thick-rimmed, cystic abscess containing multiple scattered, small, metallic pieces of shrapnel abutting the distal femur (Fig. 1). The distal femur exhibited cortical thickening consistent with osteomyelitis. Aspiration of the distal stump yielded pus from which P. aeruginosa was isolated (it was sensitive to aminoglycosides, carbapenems, fluoroquinolones, aztreonam, and anti-pseudomonal β-lactams). Mycobacterial and fungal cultures were negative. The patient underwent surgical debridement with complete removal of the abscess, which was adhered to the distal femur. Shrapnel associated with the infection was removed, although uninvolved neighboring tissues retained foreign bodies. Etanercept therapy was held and the patient received 6 weeks of parenteral meropenem (500 mg QD) combined with oral ciprofloxacin (750 mg BID), with complete resolution. Because of the severity of his arthritis, etanercept was resumed along with a suppressive regimen of oral ciprofloxacin (500 mg BID). Both of these agents were discontinued approximately 1 year later in May 2005, when the patient developed a sterile, serous fluid collection of the stump that required surgical drainage. He has had no further complications.
P. aeruginosa is a versatile Gram-negative bacterium that is widespread in nature, growing in soil, marshes, and coastal marine habitats, as well as on plant and animal tissues. Herein we report the possible reactivation of a latent pseudomonal infection of the bone and soft tissues in an immunocompromised host after the initiation of etanercept therapy. The use of etanercept and other TNF-α sequestrants (infliximab and adalimumab) has significantly advanced the treatment of autoimmune inflammatory disorders such as rheumatoid arthritis.1 However, they seem to impair host resistance to granulomatous infections, such as tuberculosis, histoplasmosis, listeriosis, candidiasis, and aspergillosis.7 An increased risk of infection with Pseudomonas species has not been proven, although 2 cases of Pseudomonas infection after anti-TNF-α therapy have been reported recently.4,5 In one report, a fatal case of sepsis associated with purulent otitis media developed in a 45-year old etanercept-treated rheumatoid arthritis patient.5 Cultures from the ear grew P. aeruginosa and Streptococcus pneumoniae, although it was unclear if P. aeruginosa caused the patient's sepsis.5 In another, Pseudomonas pneumonia occurred in a smoker after anti-TNF-α therapy. Important details of this case, such as the specific anti-TNF-α agent used and the time course after institution of the drug were not published.4
The timing of our patient's infection, 7 months after the institution of etanercept therapy, accords with other infections associated with anti-TNF-α drugs reported in the literature.3 It has been noted that the occurrence of bacterial infections is generally unrelated to the exact duration of TNF-α blockade and that such patients seem to remain at risk for the duration of immunosuppression.3 Both skin/soft tissue infections and bone/joint infections caused by pyogenic (ie, nongranulomatous) bacterial pathogens have been reported with TNF-α blockade.8-11
Because of the severe and progressive nature of our patient's rheumatoid arthritis, it was felt that etanercept therapy should be resumed, despite the recent Pseudomonas infection. There is little information and no formal recommendations available regarding the reinstitution of anti-TNF-α medications after the resolution of treatment-associated nonmycobacterial infections. However, a recent update of the British Society for Rheumatology guidelines for prescribing TNF-α blockers in adults with rheumatoid arthritis states, "anti-TNF therapy should be discontinued in the presence of serious infections, but can be recontinued once the infection has completely resolved."12 We elected, in the absence of data, to place our patient on prophylactic ciprofloxacin to prevent relapse during the reinstitution of etanercept. We arbitrarily chose a dose (500 mg BID) that is less than what we would use to treat active osteomyelitis (750 mg BID) to minimize the risk of adverse effects. In contrast to our approach, infliximab was prescribed to control rheumatoid arthritis in a patient following a staphylococcal prosthetic joint infection, despite the retention of the joint, and the patient neither received prophylactic antibiotics nor relapsed during 3 years of follow up.13
We do not know with certainty how our patient's stump became infected with P. aeruginosa. It is possible that the patient experienced minor trauma to the left stump that inoculated the soft tissues with Pseudomonas. A hematogenous route of infection can also not be ruled out, although the patient denied systemic complaints to suggest significant Gram negative bacteremia. The broad antibiotic sensitivity of the pseudomonal isolate suggests that it was not acquired nosocomially. The lack of evidence for a recent injury of his stump and the continued presence of shrapnel within the area of infection suggest the possibility that this represents the reactivation of an indolent infection. Although it is tempting to postulate that the present illness represents a reactivation of a latent infection that was seeded during the Vietnam War, such a conclusion remains speculative. It is notable that the patient initially experienced osteomyelitis of the right stump whereas the latest episode involved the contralateral femur. It is possible that both femurs were inoculated with similar bacteria at the time of the inciting injury, but the right stump manifested clinical signs of infection sooner than the left. Antimicrobial therapy for the evident infection in 1970 might have treated a subclinical process on the left side. Our ability to tie the present infection together with the past episode is further hampered by the lack of antibiotic susceptibility data on the original (1970) pathogen and our inability to perform molecular comparisons (eg, pulse field gel electrophoresis) of the 2 strains.
Whether patients harboring shrapnel from traumatic injuries are at increased risk of reactivation of bacterial infections in the wake of anti-TNF-α therapy remains to be seen, and a causative role of etanercept in our patient's infection has not been firmly established. We were unable to identify other published cases in the literature involving shrapnel-associated infections after anti-TNF-α therapy, although a case of a Staphylococcus aureus prosthetic joint infection after anti-TNF-α treatment has been reported.14 We advise clinicians prescribing anti-TNF-α medications to patients harboring retained foreign bodies to be alert for signs and symptoms of infection at retention sites.
1. Hochberg MC, Tracy JK, Hawkins-Holt M, et al. Comparison of the efficacy of the tumour necrosis factor alpha blocking agents adalimumab, etanercept, and infliximab when added to methotrexate in patients with active rheumatoid arthritis. Ann Rheum Dis. 2003;62(suppl 2): ii13-ii16.
2. Giles JT, Bathon JM. Serious infections associated with anticytokine therapies in the rheumatic diseases. J Intensive Care Med. 2004;19:320-334.
3. Crum NF, Lederman ER, Wallace MR. Infections associated with tumor necrosis factor-alpha antagonists. Medicine (Baltimore). 2005;84:291-302.
4. Kiely PD. Symptom concealment-a new phenomenon in patients treated with biological therapies? Rheumatology (Oxford). 2004;43:114-115.
5. Kling A, Mjorndal T, Rantapaa-Dahlqvist S. Sepsis as a possible adverse drug reaction in patients with rheumatoid arthritis treated with TNF-alpha antagonists. J Clin Rheumatol. 2004;10:119-122.
6. Kroesen S, Widmer AF, Tyndall A, et al. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology (Oxford). 2003;42:617-621.
7. Deepe GS Jr, Smelt S, Louie JS. Tumor necrosis factor inhibition and opportunistic infections. Clin Infect Dis. 2005;41(suppl 3):S187-S188.
8. Chan AT, Cleeve V, Daymond TJ. Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J. 2002;78:47-48.
9. Elwood RL, Pelszynski MM, Corman LI. Multifocal septic arthritis and osteomyelitis caused by group A Streptococcus in a patient receiving immunomodulating therapy with etanercept. Pediatr Infect Dis J. 2003;22:286-288.
10. Colombel JF, Loftus EV Jr, Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. Gastroenterology. 2004;126:19-31.
11. Schett G, Herak P, Graninger W, et al. Listeria-associated arthritis in a patient undergoing etanercept therapy: case report and review of the literature. J Clin Microbiol. 2005;43:2537-2541.
12. Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford). 2005;44:157-163.
13. Fernandez-Castro M, Andreu JL, Munoz P, Silva L. Sepsis of a prosthetic joint and biological therapies. Rheumatology (Oxford). 2005;44:1076-1077; author reply 1075.
14. Phillips K, Husni ME, Karlson EW, et al. Experience with etanercept in an academic medical center: are infection rates increased? Arthritis Rheum. 2002;47:17-21.
© 2007 Lippincott Williams & Wilkins, Inc.