TRANSFUSION COMPLICATIONS Incidence and natural history of intravenous immunoglobulin– induced aseptic meningitis: a retrospective review at a single tertiary care center Vighnesh Bharath,1 Kathleen Eckert,2 Matthew Kang,3 Ian H. Chin-Yee,3,4 and Cyrus C. Hsia3
BACKGROUND: Aseptic meningitis is a rare but significant complication of intravenous immunoglobulin (IVIG) therapy. The majority of literature is limited to case reports, so the true incidence of this complication is uncertain. STUDY DESIGN AND METHODS: A retrospective review of all cases of IVIG-associated adverse transfusion reactions was performed at London Health Sciences Centre (LHSC) from January 1, 2008, to December 31, 2013. All reported transfusion reactions were evaluated to identify cases of aseptic meningitis due to IVIG. All documented IVIG infusions and lumbar punctures performed during the study period were reviewed; patients with both interventions were identified and further chart review was performed to identify aseptic meningitis. RESULTS: During our study period, 1324 unique patients received a total of 11,907 IVIG infusions (554,566 g) for various conditions. Eight cases of aseptic meningitis were identified, suggesting an overall incidence of 0.60% for all patients and 0.067% for all IVIG infusions. Patients presented with symptoms within 24 to 48 hours of the infusion and were treated with antibiotics initially. The reactions were self-limited, as symptoms self-resolved within 5 to 7 days. Treatment was supportive, with subsequent IVIG infusions likely requiring preinfusion medication or possibly a switch in product formulation. CONCLUSION: This review of IVIG-induced aseptic meningitis over a 6-year period identifies a more robust estimate of incidence and risk of 0.60% and 0.067% for all patients and infusions, respectively. Given that this complication can mimic infectious meningitis and cause considerable morbidity, physicians need to be aware of this rare but important condition.
A
septic meningitis is a rare but significant complication of intravenous immunoglobulin (IVIG) therapy.1,2 This underrecognized condition clinically resembles infectious meningitis and causes considerable patient morbidity.1,3 As there are only a number of case reports and few thorough reviews, the true incidence and natural history of this adverse reaction are unknown; the literature suggests an incidence of 0% to 1%, with one reported exception of 11% in a 1994 study by Sekul and colleagues.2-4 IVIG is an expensive blood product containing polyvalent immunoglobulin (Ig)G antibodies pooled from thousands of plasma donors and is used in the treatment of primary immunodeficiencies and a variety of autoimmune and inflammatory disorders.2,5-7 The primary immunomodulatory mechanism of IVIG is still unknown, but postulated to involve the inhibition of reticuloendothelial macrophages via the Fc receptor, the suppression of cytokines and complement uptake, and the induction of apoptosis.5 The most frequent side effects are mild headache, fever, myalgias, nausea, and vomiting—these are often managed conservatively or with adjustment in ABBREVIATIONS: LHSC 5 London Health Sciences Centre; LP(s) 5 lumbar puncture(s); NSAID(s) 5 nonsteroidal antiinflammatory drug(s); TRAC 5 Transfusion Reaction Course. From the 1Department of Medicine; 2Blood Transfusion Laboratory; and the 3Division of Hematology, Department of Medicine, London Health Sciences Centre, Victoria Hospital; and the 4Canadian Blood Services, London, Ontario, Canada. Address reprint requests to: Vighnesh Bharath, Department of Medicine, London Health Sciences Centre/Western University, Room E6-102, 800 Commissioners Road East, London, Ontario, N6A 5W9, Canada; e-mail: [email protected]. Received for publication February 10, 2015; revision received May 3, 2015; and accepted May 10, 2015. doi:10.1111/trf.13200 C 2015 AABB V
TRANSFUSION 2015;55;2597–2605 Volume 55, November 2015 TRANSFUSION 2597
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infusion rates with or without premedication.1,2,4,6 More serious and fortunately uncommon complications include acute hemolytic and anaphylactic reactions, infections, thrombotic and thromboembolic events such as myocardial infarction and stroke, volume overload, transfusionassociated lung injury, Stevens-Johnson syndrome and other skin reactions, and aseptic meningitis.1,4,6,8 Aseptic meningitis usually manifests as meningismus, fevers, chills, nausea, and vomiting—resembling infectious meningitis.1,2 Reported drug associations include nonsteroidal anti-inflammatory drugs (NSAIDs), azathioprine, intrathecal agents, and antimicrobials such as isoniazid and trimethoprim-sulfamethoxazole, but the etiologic role of drugs in these reactions is unclear.3,9,10 The first association with IVIG was reported in 1988, and more than 30 such reports have followed.1 Scribner and coworkers11 suggest that the “aseptic meningitis syndrome” may in fact represent part of a disease continuum that begins with a headache. The exact mechanism of this complication remains unknown, but may involve an acute leptomeningeal hypersensitivity reaction or serum IgG crossing the blood–brain barrier.2,3,9 There have been no extensive case series or reviews to date that examine the true incidence and natural history of this condition. In this study, we conducted a thorough retrospective review of all IVIG-associated adverse reactions to determine an accurate incidence of IVIG-induced aseptic meningitis and evaluate its natural history.
MATERIALS AND METHODS A retrospective review of all cases of IVIG-induced aseptic meningitis at the London Health Sciences Centre (LHSC), a tertiary care center in London, Ontario, was performed using two separate methods from January 1, 2008, to December 31, 2013. As per the Public Health Agency of Canada (PHAC) database and Transfusion Transmitted Injury Surveillance System (TTISS; http://www.phac-aspc. gc.ca/hcai-iamss/ttiss-ssit/index-eng.php), IVIG-induced aseptic meningitis was defined as headache with meningismus or deterioration in mental status after receiving IVIG, with or without accompanying fever, nausea, vomiting, pharyngitis, photophobia, and/or diarrhea. IVIG headache was defined as a headache during or shortly after administration of IVIG; this was not included in our review. For our inclusion criteria, we included all patients less than 1 year old to 99 years old who had an underlying diagnosis for which they received IVIG and developed aseptic meningitis during the study period. Patients were excluded if they did not receive IVIG (for example, if they received subcutaneous immunoglobulin) or if they did not develop aseptic meningitis. In our first method, we evaluated all reported transfusion reactions (as per our local Transfusion Reaction Course [TRAC] system for reporting) to identify possible 2598 TRANSFUSION Volume 55, November 2015
or probable aseptic meningitis due to IVIG. TRAC is our local institutional process for reporting of all transfusion reactions; all transfusion reactions are required to be reported to the local transfusion safety officer or the blood transfusion laboratory via this system. In our second method, we reviewed and cross-referenced all documented IVIG infusions and lumbar punctures (LPs) performed at LHSC during the study period. At LHSC, the Transfusion Medicine Laboratory Information System contains all infusion episodes and data on IVIG utilized within the study period, including all inpatient and outpatient IVIG utilization at all hospital sites (i.e., University Hospital and Victoria Hospital of the LHSC and St Joseph’s Health Care Centre). This database was queried for all patients that had an LP tested and had also received IVIG during our study period; these patients were identified and further chart review was performed to determine if they had aseptic meningitis due to IVIG. The results from these two separate methods were then reviewed along with denominator data on the total number of unique patients and IVIG infusions during the study period to determine the true incidence of this condition. Individual identified cases were reviewed to speculate on the natural history and pathophysiology of this condition. Descriptive statistics were used to determine the incidence of aseptic meningitis based on the total number of patients receiving IVIG and the total number of infusions of IVIG during the study period. We calculated the 95% confidence interval (CI) for proportions using Wilson’s estimates on www.openepi.com. This study was performed initially as part of a quality assurance project at the blood transfusion laboratory at LHSC. Subsequently, local institutional ethics review board approved this study as part of a larger ongoing study called the extraction of blood utilization data (HSREB#103638).
RESULTS During the study period, a total of 1324 unique patients (1921 total patients with duplications) with an average age of 47 years (range,
BACKGROUND: Aseptic meningitis is a rare but significant complication of intravenous immunoglobulin (IVIG) therapy. The majority of literature is limited to case reports, so the true incidence of this complication is uncertain. STUDY DESIGN AND METHODS: A retrospective review of all cases of IVIG-associated adverse transfusion reactions was performed at London Health Sciences Centre (LHSC) from January 1, 2008, to December 31, 2013. All reported transfusion reactions were evaluated to identify cases of aseptic meningitis due to IVIG. All documented IVIG infusions and lumbar punctures performed during the study period were reviewed; patients with both interventions were identified and further chart review was performed to identify aseptic meningitis. RESULTS: During our study period, 1324 unique patients received a total of 11,907 IVIG infusions (554,566 g) for various conditions. Eight cases of aseptic meningitis were identified, suggesting an overall incidence of 0.60% for all patients and 0.067% for all IVIG infusions. Patients presented with symptoms within 24 to 48 hours of the infusion and were treated with antibiotics initially. The reactions were self-limited, as symptoms self-resolved within 5 to 7 days. Treatment was supportive, with subsequent IVIG infusions likely requiring preinfusion medication or possibly a switch in product formulation. CONCLUSION: This review of IVIG-induced aseptic meningitis over a 6-year period identifies a more robust estimate of incidence and risk of 0.60% and 0.067% for all patients and infusions, respectively. Given that this complication can mimic infectious meningitis and cause considerable morbidity, physicians need to be aware of this rare but important condition.
A
septic meningitis is a rare but significant complication of intravenous immunoglobulin (IVIG) therapy.1,2 This underrecognized condition clinically resembles infectious meningitis and causes considerable patient morbidity.1,3 As there are only a number of case reports and few thorough reviews, the true incidence and natural history of this adverse reaction are unknown; the literature suggests an incidence of 0% to 1%, with one reported exception of 11% in a 1994 study by Sekul and colleagues.2-4 IVIG is an expensive blood product containing polyvalent immunoglobulin (Ig)G antibodies pooled from thousands of plasma donors and is used in the treatment of primary immunodeficiencies and a variety of autoimmune and inflammatory disorders.2,5-7 The primary immunomodulatory mechanism of IVIG is still unknown, but postulated to involve the inhibition of reticuloendothelial macrophages via the Fc receptor, the suppression of cytokines and complement uptake, and the induction of apoptosis.5 The most frequent side effects are mild headache, fever, myalgias, nausea, and vomiting—these are often managed conservatively or with adjustment in ABBREVIATIONS: LHSC 5 London Health Sciences Centre; LP(s) 5 lumbar puncture(s); NSAID(s) 5 nonsteroidal antiinflammatory drug(s); TRAC 5 Transfusion Reaction Course. From the 1Department of Medicine; 2Blood Transfusion Laboratory; and the 3Division of Hematology, Department of Medicine, London Health Sciences Centre, Victoria Hospital; and the 4Canadian Blood Services, London, Ontario, Canada. Address reprint requests to: Vighnesh Bharath, Department of Medicine, London Health Sciences Centre/Western University, Room E6-102, 800 Commissioners Road East, London, Ontario, N6A 5W9, Canada; e-mail: [email protected]. Received for publication February 10, 2015; revision received May 3, 2015; and accepted May 10, 2015. doi:10.1111/trf.13200 C 2015 AABB V
TRANSFUSION 2015;55;2597–2605 Volume 55, November 2015 TRANSFUSION 2597
BHARATH ET AL.
infusion rates with or without premedication.1,2,4,6 More serious and fortunately uncommon complications include acute hemolytic and anaphylactic reactions, infections, thrombotic and thromboembolic events such as myocardial infarction and stroke, volume overload, transfusionassociated lung injury, Stevens-Johnson syndrome and other skin reactions, and aseptic meningitis.1,4,6,8 Aseptic meningitis usually manifests as meningismus, fevers, chills, nausea, and vomiting—resembling infectious meningitis.1,2 Reported drug associations include nonsteroidal anti-inflammatory drugs (NSAIDs), azathioprine, intrathecal agents, and antimicrobials such as isoniazid and trimethoprim-sulfamethoxazole, but the etiologic role of drugs in these reactions is unclear.3,9,10 The first association with IVIG was reported in 1988, and more than 30 such reports have followed.1 Scribner and coworkers11 suggest that the “aseptic meningitis syndrome” may in fact represent part of a disease continuum that begins with a headache. The exact mechanism of this complication remains unknown, but may involve an acute leptomeningeal hypersensitivity reaction or serum IgG crossing the blood–brain barrier.2,3,9 There have been no extensive case series or reviews to date that examine the true incidence and natural history of this condition. In this study, we conducted a thorough retrospective review of all IVIG-associated adverse reactions to determine an accurate incidence of IVIG-induced aseptic meningitis and evaluate its natural history.
MATERIALS AND METHODS A retrospective review of all cases of IVIG-induced aseptic meningitis at the London Health Sciences Centre (LHSC), a tertiary care center in London, Ontario, was performed using two separate methods from January 1, 2008, to December 31, 2013. As per the Public Health Agency of Canada (PHAC) database and Transfusion Transmitted Injury Surveillance System (TTISS; http://www.phac-aspc. gc.ca/hcai-iamss/ttiss-ssit/index-eng.php), IVIG-induced aseptic meningitis was defined as headache with meningismus or deterioration in mental status after receiving IVIG, with or without accompanying fever, nausea, vomiting, pharyngitis, photophobia, and/or diarrhea. IVIG headache was defined as a headache during or shortly after administration of IVIG; this was not included in our review. For our inclusion criteria, we included all patients less than 1 year old to 99 years old who had an underlying diagnosis for which they received IVIG and developed aseptic meningitis during the study period. Patients were excluded if they did not receive IVIG (for example, if they received subcutaneous immunoglobulin) or if they did not develop aseptic meningitis. In our first method, we evaluated all reported transfusion reactions (as per our local Transfusion Reaction Course [TRAC] system for reporting) to identify possible 2598 TRANSFUSION Volume 55, November 2015
or probable aseptic meningitis due to IVIG. TRAC is our local institutional process for reporting of all transfusion reactions; all transfusion reactions are required to be reported to the local transfusion safety officer or the blood transfusion laboratory via this system. In our second method, we reviewed and cross-referenced all documented IVIG infusions and lumbar punctures (LPs) performed at LHSC during the study period. At LHSC, the Transfusion Medicine Laboratory Information System contains all infusion episodes and data on IVIG utilized within the study period, including all inpatient and outpatient IVIG utilization at all hospital sites (i.e., University Hospital and Victoria Hospital of the LHSC and St Joseph’s Health Care Centre). This database was queried for all patients that had an LP tested and had also received IVIG during our study period; these patients were identified and further chart review was performed to determine if they had aseptic meningitis due to IVIG. The results from these two separate methods were then reviewed along with denominator data on the total number of unique patients and IVIG infusions during the study period to determine the true incidence of this condition. Individual identified cases were reviewed to speculate on the natural history and pathophysiology of this condition. Descriptive statistics were used to determine the incidence of aseptic meningitis based on the total number of patients receiving IVIG and the total number of infusions of IVIG during the study period. We calculated the 95% confidence interval (CI) for proportions using Wilson’s estimates on www.openepi.com. This study was performed initially as part of a quality assurance project at the blood transfusion laboratory at LHSC. Subsequently, local institutional ethics review board approved this study as part of a larger ongoing study called the extraction of blood utilization data (HSREB#103638).
RESULTS During the study period, a total of 1324 unique patients (1921 total patients with duplications) with an average age of 47 years (range,
