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Pneumococcal meningitis and etanercept—chance or association?
Journal of Infection (2005) 51, e49–e51
www.elsevierhealth.com/journals/jinf
CASE REPORT
Pneumococcal meningitis and etanercept—chance or association? B. Killingley*, V. Carpenter, K. Flanagan, G. Pasvol Department of Infection and Tropical Medicine, Lister Unit, Northwick Park Hospital, Watford Road, London HA1 3UJ, UK Accepted 7 August 2004 Available online 30 September 2004
KEYWORDS Etanercept; Rheumatoid arthritis; Pneumococcal meningitis; Streptococcus pneumoniae
Abstract Rheumatoid arthritis is a severe deforming chronic disease which has major implications for mortality and quality of life. Agents with anti-tumour necrosis factor alpha (TNFa) activity are a new modality of therapy, which can significantly reduce the acute inflammation in this condition. However, TNFa is a cytokine involved in initiating the protective immune response; consequently, patients receiving this therapy are at increased risk of infection. Etanercept is a recombinant form of the p75 TNF receptor (TNF-RII) dimerised by fusion with a portion of the human IgG1 Fc tail with anti-TNFa activity. We report the first case of a patient with rheumatoid arthritis who developed pneumococcal meningitis whilst on etanercept, suggesting a possible association between etanercept and this severe life threatening infection. Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
Case history A 52-year-old woman with seropositive rheumatoid arthritis (RA) diagnosed in 1992, presented in April 2003 via the Accident and Emergency Department with a fever of 40 8C and drowsiness. In the past she had required frequent intra-articular steroid injections and in 1995, was commenced on regular low dose prednisolone (5 mg daily). She had also taken disease-modifying anti-rheumatic drugs (DMARDs), including gold, sulphasalazine and ciclosporin.
* Corresponding author. Address: Dr Ben Killingley, Ian Charleson Centre, Royal Free Hospital, Pond Street, London NW3 2GG, UK. Tel.: C44-20-8216-4000. E-mail address: [email protected] (B. Killingley).
Despite these therapies, her disease remained active with continued deterioration. Surgical interventions had included bilateral knee replacements (left in 1998, right in 2000), bilateral wrist fusions (both in 1998), C1/C2 fusion (1999), and right shoulder joint replacement (2001). Other medical problems had included gastro-oesophageal reflux, hypertension, osteopenia, depression and alcohol excess (90 units a week in 1995, reducing to 30 units a week at the start of 2003). In June 2002 (10 months before presentation), anti-tumour necrosis factor (TNF) therapy was initiated with etanercept (Enbrel, Wyeth), 25 mg subcutaneously twice weekly. She responded well, gaining good symptomatic relief. She had felt well the previous day, but on the morning of presentation developed a non-specific
0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2004.08.015
e50 febrile illness. She had telephoned a friend who arrived at her home within few hours to find her drowsy and disorientated. Medications on admission were etanercept (as above), prednisolone 4 mg daily, ibuprofen 600 mg daily, amitriptyline 25 mg at night, omeprazole 10 mg daily, fosinopril 10 mg daily and Calcichew D3w with didronel cycles. On examination she had a Glasgow Coma Score of 11/15 (motor 5/6, eyes 4/5 and verbal 2/4). She had no visible rash. She was tachycardic (120 beats/min), had a respiratory rate of 36 but was haemodynamically stable with a blood pressure of 195/105 mm Hg. Her heart sounds were normal. Auscultation of her chest revealed reduced air entry bilaterally but with no added sounds. Most noticeable was the neck stiffness. There was frank pus in the external auditory meatus of her right ear. Laboratory results showed a white blood cell count of 14.7!109 lK1 (neutrophil count 13.2! 109 lK1, lymphocyte count 0.7!109 lK1), haemoglobin 12.1 g/dl and platelets 226!109 dlK1. Her plasma sodium was 134 mmol/l, potassium 4.9 mmol/l, urea 4.5 mmol/l, creatinine 81 mmol/l, C reactive protein 288 mg/l, alanine transferase 81 IU/l and bilirubin 33 mmol/l. Coagulation was normal. Arterial blood gas analysis (on 15 l of oxygen) showed a PaO2 21.6 kPa, PaCO2 3.88 kPa, pH 7.40, base excess of K6.2 mmol/l and bicarbonate 18.3 mmol/l. An urgent CT scan of her head was performed and was normal. She was clinically diagnosed as having bacterial meningitis with possible malignant otitis externa. She was accordingly commenced on intravenous antibiotics (ceftriaxone 2 g twice daily and ciprofloxacin 500 mg twice daily). An ear, nose and throat opinion was sought, but surgical intervention was not considered necessary. Two hours after presentation she had a tonic clonic seizure and her GCS fell to 7/15. She was intubated and transferred to the intensive care unit (ICU). It was thought that a lumbar puncture would be unsafe. Twenty-four hours after admission, blood cultures grew Grampositive cocci in chains, which were identified as S. pneumoniae, sensitive to penicillin. It was therefore concluded that she had developed pneumococcal meningitis secondary to acute otitis media. Ciprofloxacin was discontinued and ceftriaxone was continued for 12 days. On day 2 she required haemofiltration for acute renal failure. She made a slow but a sustained improvement and was discharged from ICU on day 12. Following a period of intensive rehabilitation she was discharged home on day 63. She suffered no long-term neurological sequelae and functionally returned to her preadmission state.
B. Killingley et al.
Discussion This case report describes a patient on anti-TNF therapy (etanercept) for the treatment of severe rheumatoid arthritis, who developed acute pneumococcal meningitis secondary to a middle ear infection. It is well recognised that anti-TNF therapies are a risk factor for a number of infections, but as far as we are aware, this is the first case describing an association between the use of etanercept and S. pneumoniae meningitis using Medline (1966 to the present) and Embase. Etanercept is a genetically engineered TNFa receptor fusion protein, which is able to bind TNFa and reduce its bioavailability.1 It was first approved for the treatment of moderate to severe RA in November 1998 and is now also used in psoriatic arthritis and juvenile RA. TNFa is a cytokine produced primarily by monocytes and macrophages, which has numerous physiological activities, including a central role in the inflammatory response.2 Overproduction or inappropriate release of TNF has been implicated in the pathogenesis of certain chronic inflammatory diseases such as rheumatoid arthritis3 and Crohn’s disease.4 Novel anti-TNF therapies have, therefore, been developed for use in such conditions. TNFa, however, also plays an important role in host defence against various micro-organisms and therefore increased susceptibility to infection is a potential adverse outcome of using anti-TNF agents. Pyogenic bacterial infections reported to date in patients receiving the anti-TNF drug, etanercept, have included pyelonephritis, bronchitis, septic arthritis, osteomyelitis, cellulitis, abscesses and septicaemia.5 Other bacterial infections, notably mycobacterial, viral, fungal and protozoal infections have all been reported to the Adverse Event Reporting System (AERS) of the Food and Drugs Administration (FDA), a post-marketing database of adverse events associated with products approved by the FDA.6 Interestingly, clinical trials involving over 700 patients showed no significant difference in infection rates between patients with rheumatoid arthritis who received either etanercept or methotrexate, a DMARD not acting via TNFa blockade.7–9 The current case report suggests that the immunosuppressive effect of etanercept increased our patient’s susceptibility to severe pneumococcal infection. Since TNFa is known to enhance the bactericidal activity of neutrophils in response to pneumococcal infection,10 the current observation is consistent with this hypothesis rather than our case being just a chance event. To our knowledge,
Pneumococcal meningitis and etanercept—chance or association? this is the first report linking etanercept with pneumococcal meningitis. The manufacturers of etanercept and the WHO11 both recommend vigilance for signs of sepsis in patients receiving this drug and the cessation of anti-TNF therapy in the event of any serious infection. This case report indicates that invasive pneumococcal disease should be added to the list of infections consequent upon etanercept therapy. General practitioners and patients need to be aware of the potential risks of infection associated with anti-TNF therapies. They should monitor for signs and symptoms of infection and institute prompt and aggressive intervention if infection develops. Fortunately, the patient we describe made an excellent recovery, but as a consequence of her illness has elected not to have further etanercept treatment at present.
Acknowledgements We would like to thank Drs R.A. Wall and R.N. Davidson for their help.
References 1. Bazzoni F, Beutler B. The tumour necrosis factor ligand and receptor families. N Engl J Med 1996;334:1717–25.
e51
2. Pasparakis M, Alexopoulou L, Episkopou V, Kollias G. Immune and inflammatory responses in TNFa deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers and in the maturation of the humoral immune response. J Exp Med 1996;184:1397–411. 3. Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344: 907–16. 4. Plevy SE, Landers CJ, Prehn J, et al. A role for TNFa and mucosal T helper-1 cytokines in the pathogenesis of Crohns disease. J Immunol 1997;159:6276–82. 5. Bresnihan B, Cunnane G. Infection complications associated with the use of biologic agents. Rheum Dis Clin N Am 2003; 29:185–202. 6. Food and drug administration medicinal watch program. http//www.fda.gov/medwatch. 7. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586–93. 8. Weinblatt ME, Kremer JM, Bankurst AD, et al. A trial of etanercept, a recombinant tumour necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340:253–9. 9. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomised, controlled trial. Ann Intern Med 1999;130:478–86. 10. Van Der Poll T, Keogh CV, Buurman WA, Lowry SF. Passive immunisation against TNFa impairs host defence during pneumococcal pneumonia in mice. Am J Respir Crit Care Med 1997;155:603–8. 11. Anonymous. Etanercept and sepsis. WHO Drug Inf 1999; 13(2):92.
www.elsevierhealth.com/journals/jinf
CASE REPORT
Pneumococcal meningitis and etanercept—chance or association? B. Killingley*, V. Carpenter, K. Flanagan, G. Pasvol Department of Infection and Tropical Medicine, Lister Unit, Northwick Park Hospital, Watford Road, London HA1 3UJ, UK Accepted 7 August 2004 Available online 30 September 2004
KEYWORDS Etanercept; Rheumatoid arthritis; Pneumococcal meningitis; Streptococcus pneumoniae
Abstract Rheumatoid arthritis is a severe deforming chronic disease which has major implications for mortality and quality of life. Agents with anti-tumour necrosis factor alpha (TNFa) activity are a new modality of therapy, which can significantly reduce the acute inflammation in this condition. However, TNFa is a cytokine involved in initiating the protective immune response; consequently, patients receiving this therapy are at increased risk of infection. Etanercept is a recombinant form of the p75 TNF receptor (TNF-RII) dimerised by fusion with a portion of the human IgG1 Fc tail with anti-TNFa activity. We report the first case of a patient with rheumatoid arthritis who developed pneumococcal meningitis whilst on etanercept, suggesting a possible association between etanercept and this severe life threatening infection. Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
Case history A 52-year-old woman with seropositive rheumatoid arthritis (RA) diagnosed in 1992, presented in April 2003 via the Accident and Emergency Department with a fever of 40 8C and drowsiness. In the past she had required frequent intra-articular steroid injections and in 1995, was commenced on regular low dose prednisolone (5 mg daily). She had also taken disease-modifying anti-rheumatic drugs (DMARDs), including gold, sulphasalazine and ciclosporin.
* Corresponding author. Address: Dr Ben Killingley, Ian Charleson Centre, Royal Free Hospital, Pond Street, London NW3 2GG, UK. Tel.: C44-20-8216-4000. E-mail address: [email protected] (B. Killingley).
Despite these therapies, her disease remained active with continued deterioration. Surgical interventions had included bilateral knee replacements (left in 1998, right in 2000), bilateral wrist fusions (both in 1998), C1/C2 fusion (1999), and right shoulder joint replacement (2001). Other medical problems had included gastro-oesophageal reflux, hypertension, osteopenia, depression and alcohol excess (90 units a week in 1995, reducing to 30 units a week at the start of 2003). In June 2002 (10 months before presentation), anti-tumour necrosis factor (TNF) therapy was initiated with etanercept (Enbrel, Wyeth), 25 mg subcutaneously twice weekly. She responded well, gaining good symptomatic relief. She had felt well the previous day, but on the morning of presentation developed a non-specific
0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2004.08.015
e50 febrile illness. She had telephoned a friend who arrived at her home within few hours to find her drowsy and disorientated. Medications on admission were etanercept (as above), prednisolone 4 mg daily, ibuprofen 600 mg daily, amitriptyline 25 mg at night, omeprazole 10 mg daily, fosinopril 10 mg daily and Calcichew D3w with didronel cycles. On examination she had a Glasgow Coma Score of 11/15 (motor 5/6, eyes 4/5 and verbal 2/4). She had no visible rash. She was tachycardic (120 beats/min), had a respiratory rate of 36 but was haemodynamically stable with a blood pressure of 195/105 mm Hg. Her heart sounds were normal. Auscultation of her chest revealed reduced air entry bilaterally but with no added sounds. Most noticeable was the neck stiffness. There was frank pus in the external auditory meatus of her right ear. Laboratory results showed a white blood cell count of 14.7!109 lK1 (neutrophil count 13.2! 109 lK1, lymphocyte count 0.7!109 lK1), haemoglobin 12.1 g/dl and platelets 226!109 dlK1. Her plasma sodium was 134 mmol/l, potassium 4.9 mmol/l, urea 4.5 mmol/l, creatinine 81 mmol/l, C reactive protein 288 mg/l, alanine transferase 81 IU/l and bilirubin 33 mmol/l. Coagulation was normal. Arterial blood gas analysis (on 15 l of oxygen) showed a PaO2 21.6 kPa, PaCO2 3.88 kPa, pH 7.40, base excess of K6.2 mmol/l and bicarbonate 18.3 mmol/l. An urgent CT scan of her head was performed and was normal. She was clinically diagnosed as having bacterial meningitis with possible malignant otitis externa. She was accordingly commenced on intravenous antibiotics (ceftriaxone 2 g twice daily and ciprofloxacin 500 mg twice daily). An ear, nose and throat opinion was sought, but surgical intervention was not considered necessary. Two hours after presentation she had a tonic clonic seizure and her GCS fell to 7/15. She was intubated and transferred to the intensive care unit (ICU). It was thought that a lumbar puncture would be unsafe. Twenty-four hours after admission, blood cultures grew Grampositive cocci in chains, which were identified as S. pneumoniae, sensitive to penicillin. It was therefore concluded that she had developed pneumococcal meningitis secondary to acute otitis media. Ciprofloxacin was discontinued and ceftriaxone was continued for 12 days. On day 2 she required haemofiltration for acute renal failure. She made a slow but a sustained improvement and was discharged from ICU on day 12. Following a period of intensive rehabilitation she was discharged home on day 63. She suffered no long-term neurological sequelae and functionally returned to her preadmission state.
B. Killingley et al.
Discussion This case report describes a patient on anti-TNF therapy (etanercept) for the treatment of severe rheumatoid arthritis, who developed acute pneumococcal meningitis secondary to a middle ear infection. It is well recognised that anti-TNF therapies are a risk factor for a number of infections, but as far as we are aware, this is the first case describing an association between the use of etanercept and S. pneumoniae meningitis using Medline (1966 to the present) and Embase. Etanercept is a genetically engineered TNFa receptor fusion protein, which is able to bind TNFa and reduce its bioavailability.1 It was first approved for the treatment of moderate to severe RA in November 1998 and is now also used in psoriatic arthritis and juvenile RA. TNFa is a cytokine produced primarily by monocytes and macrophages, which has numerous physiological activities, including a central role in the inflammatory response.2 Overproduction or inappropriate release of TNF has been implicated in the pathogenesis of certain chronic inflammatory diseases such as rheumatoid arthritis3 and Crohn’s disease.4 Novel anti-TNF therapies have, therefore, been developed for use in such conditions. TNFa, however, also plays an important role in host defence against various micro-organisms and therefore increased susceptibility to infection is a potential adverse outcome of using anti-TNF agents. Pyogenic bacterial infections reported to date in patients receiving the anti-TNF drug, etanercept, have included pyelonephritis, bronchitis, septic arthritis, osteomyelitis, cellulitis, abscesses and septicaemia.5 Other bacterial infections, notably mycobacterial, viral, fungal and protozoal infections have all been reported to the Adverse Event Reporting System (AERS) of the Food and Drugs Administration (FDA), a post-marketing database of adverse events associated with products approved by the FDA.6 Interestingly, clinical trials involving over 700 patients showed no significant difference in infection rates between patients with rheumatoid arthritis who received either etanercept or methotrexate, a DMARD not acting via TNFa blockade.7–9 The current case report suggests that the immunosuppressive effect of etanercept increased our patient’s susceptibility to severe pneumococcal infection. Since TNFa is known to enhance the bactericidal activity of neutrophils in response to pneumococcal infection,10 the current observation is consistent with this hypothesis rather than our case being just a chance event. To our knowledge,
Pneumococcal meningitis and etanercept—chance or association? this is the first report linking etanercept with pneumococcal meningitis. The manufacturers of etanercept and the WHO11 both recommend vigilance for signs of sepsis in patients receiving this drug and the cessation of anti-TNF therapy in the event of any serious infection. This case report indicates that invasive pneumococcal disease should be added to the list of infections consequent upon etanercept therapy. General practitioners and patients need to be aware of the potential risks of infection associated with anti-TNF therapies. They should monitor for signs and symptoms of infection and institute prompt and aggressive intervention if infection develops. Fortunately, the patient we describe made an excellent recovery, but as a consequence of her illness has elected not to have further etanercept treatment at present.
Acknowledgements We would like to thank Drs R.A. Wall and R.N. Davidson for their help.
References 1. Bazzoni F, Beutler B. The tumour necrosis factor ligand and receptor families. N Engl J Med 1996;334:1717–25.
e51
2. Pasparakis M, Alexopoulou L, Episkopou V, Kollias G. Immune and inflammatory responses in TNFa deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers and in the maturation of the humoral immune response. J Exp Med 1996;184:1397–411. 3. Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344: 907–16. 4. Plevy SE, Landers CJ, Prehn J, et al. A role for TNFa and mucosal T helper-1 cytokines in the pathogenesis of Crohns disease. J Immunol 1997;159:6276–82. 5. Bresnihan B, Cunnane G. Infection complications associated with the use of biologic agents. Rheum Dis Clin N Am 2003; 29:185–202. 6. Food and drug administration medicinal watch program. http//www.fda.gov/medwatch. 7. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586–93. 8. Weinblatt ME, Kremer JM, Bankurst AD, et al. A trial of etanercept, a recombinant tumour necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340:253–9. 9. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomised, controlled trial. Ann Intern Med 1999;130:478–86. 10. Van Der Poll T, Keogh CV, Buurman WA, Lowry SF. Passive immunisation against TNFa impairs host defence during pneumococcal pneumonia in mice. Am J Respir Crit Care Med 1997;155:603–8. 11. Anonymous. Etanercept and sepsis. WHO Drug Inf 1999; 13(2):92.