Scandinavian Journal of Infectious Diseases, 2013; Early Online: 1–3
CASE REPORT
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Herpes simplex virus encephalitis during treatment with etanercept
ROBBERT H. J. CRUSIO1,2, STEPHANIE V. SINGSON3, FAYSAL HAROUN2, HETAL H. MEHTA3 & DAVID M. PARENTI1,2 From the 1Division of Infectious Diseases, Department of Medicine, George Washington University Medical Center, 2Department of Medicine, George Washington University Medical Center, and 3George Washington University School of Medicine, Washington DC, USA
Abstract Tumor necrosis factor alpha (TNF-α) inhibitors are widely used for the treatment of various inflammatory conditions. They are associated with an increased risk for infections. We report a case of herpes simplex virus type 1 (HSV-1) encephalitis in a patient receiving etanercept and review the literature on TNF-α and TNF-α inhibitors, and their importance in the pathophysiology of herpes simplex encephalitis.
Keywords: TNF alpha inhibitor, encephalitis, HSV
Introduction
Case report
Anti-tumor necrosis factor alpha (TNF-α) agents are widely used for the treatment of various rheumatologic conditions, as well as inflammatory bowel disease [1,2]. Currently, 5 anti-TNF-α agents are available worldwide to treat inflammatory conditions. The prime immunologic defect caused by these drugs is in the cell-mediated immune response. Patients have an increased susceptibility to certain infections, of which tuberculosis (TB) has received the most attention. An increased susceptibility has also been suggested for various other organisms, including bacteria, viruses, and fungi [1,2]. There have only been a few reports of viral encephalitis in this population [3,4]. Herpes simplex virus (HSV) can lead to a severe necrotizing encephalitis, which has a mortality of up to 70% if left untreated. It is associated with significant morbidity even with adequate treatment [5]. We present a case of HSV type 1 (HSV-1) encephalitis in a patient who was receiving etanercept and give a review of the literature on TNF inhibitors and HSV encephalitis.
A 57-y-old man with psoriatic arthritis presented to the emergency department with a 6-day history of fevers up to 39.2°C. He soon developed right-sided retro-orbital headaches and hiccups. Two days prior to presentation he had become lethargic and was constantly sleeping as reported by his wife. He had been receiving weekly etanercept injections for 9 y. On presentation he was lethargic and difficult to arouse. He had slurring of speech and a tangential thought process. Vital signs on presentation included a temperature of 38.7°C, blood pressure of 123/69 mmHg, pulse of 60 beats/min, and a respiratory rate of 18/min. A computed tomography (CT) scan of the brain showed an ill-defined hypodensity in the right frontotemporal region with an ill-defined hyperdense rim and a slight midline shift. Subsequent magnetic resonance imaging (MRI) demonstrated edema of the right frontotemporoparietal region with faint enhancement of the left basal ganglia and a 5-mm right-to-left midline shift (Figure 1). Laboratory studies revealed a white blood cell count of 7000 cells/mm3 (63% neutrophils, 16%
Correspondence: R. H. J. Crusio, Division of Infectious Diseases, 2150 Pennsylvania Avenue, NW, Washington, DC 20037, USA. Tel: ⫹ 1 202 741 2234. Fax: ⫹ 1 202 741 2241. E-mail: [email protected] (Received 10 September 2013 ; accepted 17 September 2013) ISSN 0036-5548 print/ISSN 1651-1980 online © 2013 Informa Healthcare DOI: 10.3109/00365548.2013.849816
2
R. H. J. Crusio et al. temporal lobe without enhancement and a smaller area of encephalomalacia in the same region, consistent with prior encephalitis.
Scand J Infect Dis Downloaded from informahealthcare.com by Universitaets- und Landesbibliothek Duesseldorf on 12/01/13 For personal use only.
Discussion
Figure 1. Magnetic resonance image on day 1 showing an enhancing lesion within the right frontotemporoparietal region with vasogenic edema and a 5-mm right-to-left midline shift. There is a smaller focus of hyperintensity within the left basal ganglia.
lymphocytes, and 20% monocytes), hematocrit of 39%, and platelet count of 175,000 platelets/mm3. The erythrocyte sedimentation rate was 12 mm/h and C-reactive protein was 21.5 mg/l, creatinine 0.9 mg/dl, total protein 5.4 g/dl, and glucose 119 mg/dl. Lumbar puncture showed 362 leukocytes/mm3, of which 95% were lymphocytes, 133 erythrocytes/ mm3, a total protein of 274 mg/dl, and glucose of 61 mg/dl. The opening pressure was 21 cmH2O. Empiric therapy with intravenous acyclovir (10 mg/ kg every 8 h) was initiated due to the concern for HSV encephalitis. High-dose dexamethasone 10 mg intravenously every 6 h was started to treat the vasogenic edema with midline shift given the severe clinical presentation. Levetiracetam was started for seizure prophylaxis. Serological studies including HIV antibodies and rapid plasma reagin (RPR) yielded negative results. Bacterial culture of the cerebrospinal fluid (CSF) remained negative. PCR of CSF was positive for HSV-1. His clinical condition improved significantly during the hospitalization, with complete resolution of his fevers on day 2 and near resolution of the neurological deficits by day 5. He completed a 3-week course of intravenous acyclovir and then continued with oral valacyclovir 2 g three times daily. He received a tapering course of corticosteroids for 1 week, while levetiracetam for seizure prophylaxis was discontinued after discharge. His clinical course continued to improve and he has returned to work and completely retained his functional status. An MRI of the brain 3 months later demonstrated an abnormal signal of the right
Herpes simplex encephalitis (HSE) is a rare but lifethreatening infection of the central nervous system. It is the most common cause of viral encephalitis in the USA [5]. Typically, HSE is a result of reactivation of HSV; however primary HSV infection is identified in a third of patients with HSE. Approximately 90% of cases are caused by HSV-1. Patients typically present with an acute onset of fever and headache, which can be further complicated by impaired consciousness, seizures, or focal neurological deficits [5]. The diagnosis of HSE can be made by the combination of a compatible clinical scenario, suggestive brain imaging, and the examination of CSF. MRI is more sensitive than CT, not only for early diagnosis but also for defining the extent of cerebral injury [5]. PCR analysis of the CSF for the presence of HSV DNA has a high sensitivity and specificity (⬎ 95% and near 100%, respectively) and has replaced viral culture from a brain biopsy as the gold standard for making the diagnosis [5]. Treatment with acyclovir may reduce mortality from 70% to approximately 20% [5]. The role of corticosteroids remains unclear, but is currently being evaluated with a randomized controlled trial [6]. Our patient exhibited rapid improvement with acyclovir and a dexamethasone taper to reduce edema and inflammation. TNF-α plays a critical role in the cell-mediated immune response. TNF-α stimulates the expression of adhesion molecules on endothelial cells and activates neutrophils and macrophages. TNF-α inhibitors are used in the treatment of rheumatologic conditions, as well as inflammatory bowel disease. Currently 5 different TNF-α inhibitors are approved for clinical use: infliximab, certolizumab, adalimumab, golimumab, and etanercept. All agents except etanercept are anti-TNF-α monoclonal antibodies or fragments thereof [7]. Etanercept is a genetically engineered fusion protein that is a dimer of the extracellular domain of human TNF receptor 2 (TNFR2) fused to the Fc portion of human IgG. It binds equally well to both TNF-α and lymphotoxin-α (TNF-β). Lymphotoxin-α is considered to have an important role in controlling infection and tumor growth independent of TNF activity [7]. Although TNF-α inhibitors have been shown to be clinically useful, they are associated with serious adverse effects including infections [1,2]. The most notable infection associated with the use of TNF-α inhibitors is TB [8]. An increased risk for infections due to HSV and varicella zoster virus has also been
Scand J Infect Dis Downloaded from informahealthcare.com by Universitaets- und Landesbibliothek Duesseldorf on 12/01/13 For personal use only.
HSV encephalitis and etanercept described. The odds ratio for cutaneous herpes zoster is 1.8, which increases further with concomitant methotrexate and corticosteroid use [9]. Three cases of HSE and 1 case of herpes zoster encephalitis in patients receiving TNF-α inhibitors have been reported in the literature [3,4]. Several more cases of HSE were reported to the FDA Adverse Events Reporting System (FAERS) during post-marketing surveillance [10]. The immune response to HSV involves neutralizing antibody, the cell-mediated immune response (CD4/CD8 cells), and the innate immune response (natural killer (NK) cells, plasmacytoid dendritic cells). TNF-α plays an important role in the cellmediated response. Herpesviridae actually encode genes that target TNF-related cytokines and receptors in an attempt to evade the immune response [11]. The importance of TNF-α was shown in an HSV encephalitis study with TNF-α knock-out mice. Mortality due to encephalitis was significantly higher in knock-out mice than in wild-type mice, which was attenuated following TNF-α replacement. This effect seemed to be independent of TNFR1 and TNFR2 [12]. In another study, knockout mice lacking TNFR1 developed a rapidly fatal encephalitis following direct intra-cerebral HSV inoculation and had a significantly increased viral titer compared with wild-type mice. Brain pathology showed increased neuronal damage and less inflammatory infiltrates in the mice lacking TNFR1. Intravital microscopy showed less leukocyte adhesion and rolling compared with wild-type mice [13]. Sequential CSF analyses in humans have shown increased levels of TNF-α, interferon gamma (IFN-γ), and interleukin 6 (IL-6) following HSE. CSF cytokine levels were markedly increased compared to serum, and remained elevated for months to years, arguing for ongoing low-level chronic infection [14]. Therefore, one could argue for a more prolonged antiviral treatment. Currently, a trial is underway evaluating high-dose valacyclovir given for 90 days after conventional intravenous treatment. Preliminary results have not shown a benefit for prolonged treatment [15]. In conclusion, patients receiving TNF-α inhibitors are at increased risk for certain infections including HSV encephalitis. HSE should be high in the differential diagnosis in these patients when presenting with fever and headache, and especially when neurological symptoms are present. Prompt diagnosis and treatment significantly improve survival and morbidity.
3
Declaration of interest: No conflicts of interest to disclose. No funding. References [1] Furst DE, Keystone EC, Braun J, Breedveld FC, Burmester GR, De Benedetti F, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010. Ann Rheum Dis 2011;70(Suppl 1):i2–36. [2] D’Haens GR, Panaccione R, Higgins PD, Vermeire S, Gassull M, Chowers Y, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol 2011;106:199–212. [3] Buccoliero G, Lonero G, Romanelli C, Loperfido P, Resta F. Varicella zoster virus encephalitis during treatment with antitumor necrosis factor-alpha agent in a psoriatic arthritis patient. New Microbiol 2010;33:271–4. [4] Bradford RD, Pettit AC, Wright PW, Mulligan MJ, Moreland LW, McLain DA, et al. Herpes simplex encephalitis during treatment with tumor necrosis factor-alpha inhibitors. Clin Infect Dis 2009;49:924–7. [5] Whitley RJ, Lakeman F. Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations. Clin Infect Dis 1995;20:414–20. [6] Hacke W. German trial of Acyclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE). ISRCTN Register. Available at: http://www.controlledtrials.com/ ISRCTN45122933 (accessed 19 February 2013). [7] Benucci M, Saviola G, Manfredi M, Sarzi-Puttini P, Atzeni F. Tumor necrosis factors blocking agents: analogies and differences. Acta Biomed 2012;83:72–80. [8] Patkar NM, Teng GG, Curtis JR, Saag KG. Association of infections and tuberculosis with antitumor necrosis factor alpha therapy. Curr Opin Rheumatol 2008;20:320–6. [9] Kim SY, Solomon DH. Tumor necrosis factor blockade and the risk of viral infection. Nat Rev Rheumatol 2010;6: 165–74. [10] FDA Adverse Events Reporting System (FAERS). Available at: http://www.fda.gov (accessed 16 August 2012). [11] Benedict CA, Ware CF. Virus targeting of the tumor necrosis factor superfamily. Virology 2001;289:1–5. [12] Lundberg P, Welander PV, Edwards CK 3rd, van Rooijen N, Cantin E. Tumor necrosis factor (TNF) protects resistant C57BL/6 mice against herpes simplex virus-induced encephalitis independently of signaling via TNF receptor 1 or 2. J Virol 2007;81:1451–60. [13] Vilela MC, Lima GK, Rodrigues DH, Lacerda-Queiroz N, Mansur DS, de Miranda AS, et al. TNFR1 plays a critical role in the control of severe HSV-1 encephalitis. Neurosci Lett 2010;479:58–62. [14] Aurelius E, Andersson B, Forsgren M, Sköldenberg B, Strannegård O. Cytokines and other markers of intrathecal immune response in patients with herpes simplex encephalitis. J Infect Dis 1994;170:678–81. [15] A phase III double-blind, placebo-controlled trial of long term therapy of herpes simplex encephalitis (HSE): an evaluation of valacyclovir. Study identifier: NCT00031486. Available at: http://www.clinicaltrials.gov (accessed 19 February 2013).
CASE REPORT
Scand J Infect Dis Downloaded from informahealthcare.com by Universitaets- und Landesbibliothek Duesseldorf on 12/01/13 For personal use only.
Herpes simplex virus encephalitis during treatment with etanercept
ROBBERT H. J. CRUSIO1,2, STEPHANIE V. SINGSON3, FAYSAL HAROUN2, HETAL H. MEHTA3 & DAVID M. PARENTI1,2 From the 1Division of Infectious Diseases, Department of Medicine, George Washington University Medical Center, 2Department of Medicine, George Washington University Medical Center, and 3George Washington University School of Medicine, Washington DC, USA
Abstract Tumor necrosis factor alpha (TNF-α) inhibitors are widely used for the treatment of various inflammatory conditions. They are associated with an increased risk for infections. We report a case of herpes simplex virus type 1 (HSV-1) encephalitis in a patient receiving etanercept and review the literature on TNF-α and TNF-α inhibitors, and their importance in the pathophysiology of herpes simplex encephalitis.
Keywords: TNF alpha inhibitor, encephalitis, HSV
Introduction
Case report
Anti-tumor necrosis factor alpha (TNF-α) agents are widely used for the treatment of various rheumatologic conditions, as well as inflammatory bowel disease [1,2]. Currently, 5 anti-TNF-α agents are available worldwide to treat inflammatory conditions. The prime immunologic defect caused by these drugs is in the cell-mediated immune response. Patients have an increased susceptibility to certain infections, of which tuberculosis (TB) has received the most attention. An increased susceptibility has also been suggested for various other organisms, including bacteria, viruses, and fungi [1,2]. There have only been a few reports of viral encephalitis in this population [3,4]. Herpes simplex virus (HSV) can lead to a severe necrotizing encephalitis, which has a mortality of up to 70% if left untreated. It is associated with significant morbidity even with adequate treatment [5]. We present a case of HSV type 1 (HSV-1) encephalitis in a patient who was receiving etanercept and give a review of the literature on TNF inhibitors and HSV encephalitis.
A 57-y-old man with psoriatic arthritis presented to the emergency department with a 6-day history of fevers up to 39.2°C. He soon developed right-sided retro-orbital headaches and hiccups. Two days prior to presentation he had become lethargic and was constantly sleeping as reported by his wife. He had been receiving weekly etanercept injections for 9 y. On presentation he was lethargic and difficult to arouse. He had slurring of speech and a tangential thought process. Vital signs on presentation included a temperature of 38.7°C, blood pressure of 123/69 mmHg, pulse of 60 beats/min, and a respiratory rate of 18/min. A computed tomography (CT) scan of the brain showed an ill-defined hypodensity in the right frontotemporal region with an ill-defined hyperdense rim and a slight midline shift. Subsequent magnetic resonance imaging (MRI) demonstrated edema of the right frontotemporoparietal region with faint enhancement of the left basal ganglia and a 5-mm right-to-left midline shift (Figure 1). Laboratory studies revealed a white blood cell count of 7000 cells/mm3 (63% neutrophils, 16%
Correspondence: R. H. J. Crusio, Division of Infectious Diseases, 2150 Pennsylvania Avenue, NW, Washington, DC 20037, USA. Tel: ⫹ 1 202 741 2234. Fax: ⫹ 1 202 741 2241. E-mail: [email protected] (Received 10 September 2013 ; accepted 17 September 2013) ISSN 0036-5548 print/ISSN 1651-1980 online © 2013 Informa Healthcare DOI: 10.3109/00365548.2013.849816
2
R. H. J. Crusio et al. temporal lobe without enhancement and a smaller area of encephalomalacia in the same region, consistent with prior encephalitis.
Scand J Infect Dis Downloaded from informahealthcare.com by Universitaets- und Landesbibliothek Duesseldorf on 12/01/13 For personal use only.
Discussion
Figure 1. Magnetic resonance image on day 1 showing an enhancing lesion within the right frontotemporoparietal region with vasogenic edema and a 5-mm right-to-left midline shift. There is a smaller focus of hyperintensity within the left basal ganglia.
lymphocytes, and 20% monocytes), hematocrit of 39%, and platelet count of 175,000 platelets/mm3. The erythrocyte sedimentation rate was 12 mm/h and C-reactive protein was 21.5 mg/l, creatinine 0.9 mg/dl, total protein 5.4 g/dl, and glucose 119 mg/dl. Lumbar puncture showed 362 leukocytes/mm3, of which 95% were lymphocytes, 133 erythrocytes/ mm3, a total protein of 274 mg/dl, and glucose of 61 mg/dl. The opening pressure was 21 cmH2O. Empiric therapy with intravenous acyclovir (10 mg/ kg every 8 h) was initiated due to the concern for HSV encephalitis. High-dose dexamethasone 10 mg intravenously every 6 h was started to treat the vasogenic edema with midline shift given the severe clinical presentation. Levetiracetam was started for seizure prophylaxis. Serological studies including HIV antibodies and rapid plasma reagin (RPR) yielded negative results. Bacterial culture of the cerebrospinal fluid (CSF) remained negative. PCR of CSF was positive for HSV-1. His clinical condition improved significantly during the hospitalization, with complete resolution of his fevers on day 2 and near resolution of the neurological deficits by day 5. He completed a 3-week course of intravenous acyclovir and then continued with oral valacyclovir 2 g three times daily. He received a tapering course of corticosteroids for 1 week, while levetiracetam for seizure prophylaxis was discontinued after discharge. His clinical course continued to improve and he has returned to work and completely retained his functional status. An MRI of the brain 3 months later demonstrated an abnormal signal of the right
Herpes simplex encephalitis (HSE) is a rare but lifethreatening infection of the central nervous system. It is the most common cause of viral encephalitis in the USA [5]. Typically, HSE is a result of reactivation of HSV; however primary HSV infection is identified in a third of patients with HSE. Approximately 90% of cases are caused by HSV-1. Patients typically present with an acute onset of fever and headache, which can be further complicated by impaired consciousness, seizures, or focal neurological deficits [5]. The diagnosis of HSE can be made by the combination of a compatible clinical scenario, suggestive brain imaging, and the examination of CSF. MRI is more sensitive than CT, not only for early diagnosis but also for defining the extent of cerebral injury [5]. PCR analysis of the CSF for the presence of HSV DNA has a high sensitivity and specificity (⬎ 95% and near 100%, respectively) and has replaced viral culture from a brain biopsy as the gold standard for making the diagnosis [5]. Treatment with acyclovir may reduce mortality from 70% to approximately 20% [5]. The role of corticosteroids remains unclear, but is currently being evaluated with a randomized controlled trial [6]. Our patient exhibited rapid improvement with acyclovir and a dexamethasone taper to reduce edema and inflammation. TNF-α plays a critical role in the cell-mediated immune response. TNF-α stimulates the expression of adhesion molecules on endothelial cells and activates neutrophils and macrophages. TNF-α inhibitors are used in the treatment of rheumatologic conditions, as well as inflammatory bowel disease. Currently 5 different TNF-α inhibitors are approved for clinical use: infliximab, certolizumab, adalimumab, golimumab, and etanercept. All agents except etanercept are anti-TNF-α monoclonal antibodies or fragments thereof [7]. Etanercept is a genetically engineered fusion protein that is a dimer of the extracellular domain of human TNF receptor 2 (TNFR2) fused to the Fc portion of human IgG. It binds equally well to both TNF-α and lymphotoxin-α (TNF-β). Lymphotoxin-α is considered to have an important role in controlling infection and tumor growth independent of TNF activity [7]. Although TNF-α inhibitors have been shown to be clinically useful, they are associated with serious adverse effects including infections [1,2]. The most notable infection associated with the use of TNF-α inhibitors is TB [8]. An increased risk for infections due to HSV and varicella zoster virus has also been
Scand J Infect Dis Downloaded from informahealthcare.com by Universitaets- und Landesbibliothek Duesseldorf on 12/01/13 For personal use only.
HSV encephalitis and etanercept described. The odds ratio for cutaneous herpes zoster is 1.8, which increases further with concomitant methotrexate and corticosteroid use [9]. Three cases of HSE and 1 case of herpes zoster encephalitis in patients receiving TNF-α inhibitors have been reported in the literature [3,4]. Several more cases of HSE were reported to the FDA Adverse Events Reporting System (FAERS) during post-marketing surveillance [10]. The immune response to HSV involves neutralizing antibody, the cell-mediated immune response (CD4/CD8 cells), and the innate immune response (natural killer (NK) cells, plasmacytoid dendritic cells). TNF-α plays an important role in the cellmediated response. Herpesviridae actually encode genes that target TNF-related cytokines and receptors in an attempt to evade the immune response [11]. The importance of TNF-α was shown in an HSV encephalitis study with TNF-α knock-out mice. Mortality due to encephalitis was significantly higher in knock-out mice than in wild-type mice, which was attenuated following TNF-α replacement. This effect seemed to be independent of TNFR1 and TNFR2 [12]. In another study, knockout mice lacking TNFR1 developed a rapidly fatal encephalitis following direct intra-cerebral HSV inoculation and had a significantly increased viral titer compared with wild-type mice. Brain pathology showed increased neuronal damage and less inflammatory infiltrates in the mice lacking TNFR1. Intravital microscopy showed less leukocyte adhesion and rolling compared with wild-type mice [13]. Sequential CSF analyses in humans have shown increased levels of TNF-α, interferon gamma (IFN-γ), and interleukin 6 (IL-6) following HSE. CSF cytokine levels were markedly increased compared to serum, and remained elevated for months to years, arguing for ongoing low-level chronic infection [14]. Therefore, one could argue for a more prolonged antiviral treatment. Currently, a trial is underway evaluating high-dose valacyclovir given for 90 days after conventional intravenous treatment. Preliminary results have not shown a benefit for prolonged treatment [15]. In conclusion, patients receiving TNF-α inhibitors are at increased risk for certain infections including HSV encephalitis. HSE should be high in the differential diagnosis in these patients when presenting with fever and headache, and especially when neurological symptoms are present. Prompt diagnosis and treatment significantly improve survival and morbidity.
3
Declaration of interest: No conflicts of interest to disclose. No funding. References [1] Furst DE, Keystone EC, Braun J, Breedveld FC, Burmester GR, De Benedetti F, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010. Ann Rheum Dis 2011;70(Suppl 1):i2–36. [2] D’Haens GR, Panaccione R, Higgins PD, Vermeire S, Gassull M, Chowers Y, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol 2011;106:199–212. [3] Buccoliero G, Lonero G, Romanelli C, Loperfido P, Resta F. Varicella zoster virus encephalitis during treatment with antitumor necrosis factor-alpha agent in a psoriatic arthritis patient. New Microbiol 2010;33:271–4. [4] Bradford RD, Pettit AC, Wright PW, Mulligan MJ, Moreland LW, McLain DA, et al. Herpes simplex encephalitis during treatment with tumor necrosis factor-alpha inhibitors. Clin Infect Dis 2009;49:924–7. [5] Whitley RJ, Lakeman F. Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations. Clin Infect Dis 1995;20:414–20. [6] Hacke W. German trial of Acyclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE). ISRCTN Register. Available at: http://www.controlledtrials.com/ ISRCTN45122933 (accessed 19 February 2013). [7] Benucci M, Saviola G, Manfredi M, Sarzi-Puttini P, Atzeni F. Tumor necrosis factors blocking agents: analogies and differences. Acta Biomed 2012;83:72–80. [8] Patkar NM, Teng GG, Curtis JR, Saag KG. Association of infections and tuberculosis with antitumor necrosis factor alpha therapy. Curr Opin Rheumatol 2008;20:320–6. [9] Kim SY, Solomon DH. Tumor necrosis factor blockade and the risk of viral infection. Nat Rev Rheumatol 2010;6: 165–74. [10] FDA Adverse Events Reporting System (FAERS). Available at: http://www.fda.gov (accessed 16 August 2012). [11] Benedict CA, Ware CF. Virus targeting of the tumor necrosis factor superfamily. Virology 2001;289:1–5. [12] Lundberg P, Welander PV, Edwards CK 3rd, van Rooijen N, Cantin E. Tumor necrosis factor (TNF) protects resistant C57BL/6 mice against herpes simplex virus-induced encephalitis independently of signaling via TNF receptor 1 or 2. J Virol 2007;81:1451–60. [13] Vilela MC, Lima GK, Rodrigues DH, Lacerda-Queiroz N, Mansur DS, de Miranda AS, et al. TNFR1 plays a critical role in the control of severe HSV-1 encephalitis. Neurosci Lett 2010;479:58–62. [14] Aurelius E, Andersson B, Forsgren M, Sköldenberg B, Strannegård O. Cytokines and other markers of intrathecal immune response in patients with herpes simplex encephalitis. J Infect Dis 1994;170:678–81. [15] A phase III double-blind, placebo-controlled trial of long term therapy of herpes simplex encephalitis (HSE): an evaluation of valacyclovir. Study identifier: NCT00031486. Available at: http://www.clinicaltrials.gov (accessed 19 February 2013).
