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Nothing to Sneeze At: Efficacy and Cost-Effectiveness of the Influenza Vaccine in Patients Receiving Long-term Dialysis
Editorial Nothing to Sneeze At: Efficacy and Cost-Effectiveness of the Influenza Vaccine in Patients Receiving Long-term Dialysis Related Articles, p. 716 and p. 724 I had a little bird And its name was Enza I opened the window And in-flew-Enza. Children’s song, circa 1918, quoted in1
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atients treated with long-term dialysis are immunosuppressed. Both cellular and humoral immunity are affected by the uremic state, and dialysis patients are more likely to contract and die of infection. Although the most common infections in this population are associated with dialysis access, there is also increased morbidity and mortality due to viral infections, including influenza. Unfortunately, as chronic kidney disease progresses, patients are also less able to develop a protective immune response to some vaccines. This is well demonstrated in the case of the hepatitis B vaccine, but is less clear for the seasonal influenza vaccine. Many dialysis patients seem to develop adequate protection with standard influenza vaccine dosing regimens, although the overall strength of the immune response may be less than that of healthy adults.2 In hemodialysis patients, protective immune response rates to seasonal influenza vaccine are highly variable among studies, ranging from 36% to over 90%, which may be related to the degree of immunosuppression associated with the uremic state as well as the immunogenicity of the antigens used in the seasonal vaccine3-7 Despite this, analysis of data from the US Renal Data System has shown that influenza vaccination in hemodialysis patients is associated with a reduced risk of hospitalization and death,8 and the Centers for Disease Control and Prevention recommends that dialysis patients should receive the vaccine annually. What remains unanswered, however, is whether such vaccination is cost-effective, and specifically which vaccination strategy is best from a cost perspective. This question is of even greater urgency in the long forecast, and now arrived, “era of limits.” In this issue of the American Journal of Kidney Diseases, 2 articles are presented that address the clinical efficacy9 and cost-effectiveness10 of adjuvanted influenza vaccine in hemodialysis patients. Dikow et al9 conducted a nonrandomized trial in several outpatient dialysis facilities in Germany. They compared the efficacy of 1- and 2-dose courses of AS03A-adjuvanted H1N1 vaccine in 292 patients with 123 patients who refused vaccination. The 1-dose Am J Kidney Dis. 2011;57(5):651-653
course (64 patients) produced a 64% protective response rate, and the 2-dose course (105 patients) produced an 89% protective response rate, compared with 35% in patients who refused vaccination. By contrast, the predicted protective response rate in healthy adults after one dose is 98%. Lee et al10 designed an economic stochastic decision analytic simulation model of cost-effectiveness in qualityadjusted life-years (assuming a societal perspective) of the use of either adjuvanted or nonadjuvanted seasonal influenza vaccine in long-term hemodialysis patients in the United States over a single influenza season. These authors found that adjuvanted vaccine would be cost-effective if the adjuvant added no more than $1 to the cost of the standard vaccine and if it overcame the difference in response between hemodialysis patients and healthy adults by ⱖ60%. Mortality rates among long-term dialysis patients who develop seasonal influenza are uncertain, in part due to underdiagnosis and reporting of actual cases and nonspecific coding for cause of death. The Centers for Disease Control and Prevention estimates mortality due to seasonal influenza for the general population using a statistical method that estimates excess deaths due to “influenza and pneumonia” during the influenza season. It is clear, however, that patients with diabetes and the elderly have an increased risk of death from pneumonia and influenza over that of the general population—in the range of 0.2%-0.3%.11 Compared with the general population, dialysis patients have approximately a 10-fold higher annual mortality risk due to pneumonia and influenza.12Notably, pandemic H1N1 influenza was associated with mortality as high as 5% in dialysis patients followed by a single outpatient dialysis provider in Latin America and Europe.13 In another recently published study, Temin et al demonstrated that single-dose adjuvanted vaccine for pandemic H1N1 influenza was effective in inducing an immune response in ⬎90% of a cohort of 70 dialysis patients who had been vaccinated 5 weeks Address correspondence to Kevin C. Abbott, MD, MPH, Department of Nephrology, Walter Reed Army Medical Center, 6900 Georgia Ave, Washington, DC 20307. E-mail: Kevin.Abbott@ amedd.army.mil Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. 0272-6386/$0.00 doi:10.1053/j.ajkd.2011.02.380 651
Kevin C. Abbott
earlier, significantly greater than that in 20 healthy young adult controls.14 In contrast, in the study by Dikow et al, dialysis patients required 2 doses of AS03A-adjuvanted H1N1 vaccine to develop protective antibody titers with the frequency seen after one dose in healthy adults. Nonresponders were also more likely to be nonresponders to the hepatitis B vaccine. The effectiveness of the adjuvanted vaccine in both studies is reassuring in light of what is known regarding the effects of H1N1 on hemodialysis patients during the 2009 epidemic. Marcelli et al13 described their experience with the epidemic in a group of Fresenius Medical Care dialysis units in South America and Europe where 3.4% of patients developed clinical symptoms consistent with H1N1 influenza, and 34% of these required hospital admission— primarily with pneumonia. Of the patients who contracted influenza, 5% died, and those with diabetes were 3 times more likely to develop pneumonia. Notably, those older than 65 years were less likely to develop H1N1 influenza, probably due to the presence of immunity acquired early in life. Dikow et al were able to demonstrate that this was true in their unvaccinated patients, in whom positive anti-H1N1 antibody titers correlated significantly with older age.9 The H1N1 vaccine used in 2009 was delivered with one of several adjuvants, because the supply of antigen was not adequate in the face of the H1N1 epidemic. The use of adjuvant allowed for smaller amounts of delivered antigen in the vaccine, and the use of one dose only in healthy adults. Although adjuvanted seasonal influenza vaccine would be theoretically more effective at producing protective antibodies than the standard vaccine in dialysis patients, it does not follow that such a vaccine will be costeffective, especially if the increase in the proportion of patients achieving protective antibody titers is relatively modest, and the cost of the adjuvant is high. Lee et al10 have developed a very useful model to assess this, providing vaccine cost and efficacy thresholds that certainly should serve as a decision-making guide to both vaccine developers and public health officials. Without such information, policy makers would largely be “flying blind”—a factor that may contribute more to rising medical costs than we know. However, it is very important to be aware of the potential pitfalls of using a model such as that of Lee et al in making decisions about influenza vaccines in dialysis patients. First of all, this model reflects a steady-state situation as seen with seasonal influenza. It cannot be used as a model for epidemic influenza (such as the 2009 H1N1 epidemic), which may be associated with unpredictable patterns of spread, higher mortality and morbidity in the general population, low to nonexistent natural immunity, and the potential for 652
overwhelming medical and pharmaceutical providers. In such a situation, vaccination is used as a defensive “wall” to minimize infection rates in the entire population—and societal benefit is based not only on reducing individual costs among dialysis patients, but in preventing the spread of infection generally. Moreover, the conclusions reached by the model are dependent on the assumptions used, some of which are not specific for hemodialysis patients (eg, the mortality risk used is for patients with diabetes). If these should change substantially over time (eg, the risk of contracting influenza, dialysis population demographics, costs of treatment, hospitalization risk, and efficacy of the nonadjuvanted vaccine), cost and efficacy thresholds could change as well. However, the model allows for considerable variation, nicely summarized in the second of the article.10 Because of this, it would be optimal if the model could be made available to be “reloaded” as necessary, as facts about cost and efficacy change over time. The data contained in the studies of Dikow et al9 and Marcelli et al13 are exactly the kind of information that could be used in the model by Lee et al10 to assess the cost-effectiveness of the H1N1 AS03A-adjuvanted vaccine as natural immunity increases in the general population and it becomes part of the seasonal influenza vaccine. Ultimately, the clinical decision analysis research community should agree on a way to make simulation models “living documents” that are easily available to be revisited to assist in public health decision making. This has been done in some areas in the biological and physical sciences, which have open databases containing protein structures, nucleic acid sequences, and astronomic data. Detailed information on ongoing and completed clinical trials is now available at ClinicalTrials.gov. Such a system would be invaluable in the area of clinical decision analysis, greatly enhancing the future usefulness of models such as that of Lee et al. Kevin C. Abbott, MD, MPH Christina M. Yuan, MD Walter Reed Army Medical Center Washington, DC Jessica L. Lee, MD National Naval Medical Center Bethesda, Maryland
ACKNOWLEDGEMENTS The views expressed in this paper are those of the authors and do not reflect the official policy of the National Institutes of Health, US Department of Army, Department of Defense, or the US government. Financial Disclosure: Dr Abbott reports having stock in Johnson & Johnson. All remaining authors declare they have no relevant financial interests. Am J Kidney Dis. 2011;57(5):651-653
Editorial
REFERENCES 1. Navy Department Library. A Forgotten Enemy: PHS’s [Public Health Service] Fight Against the 1918 Influenza Pandemic. Available at: http://www.history.navy.mil/library/online/ influenza_forgot.htm#fn6. Accessed February 17, 2011. 2. Kausz AT, Gilbertson DT. Overview of vaccination in chronic kidney disease. Adv Chronic Kidney Dis. 2006;13(3):209-214. 3. Scharpe J, Peetermans WE, Vanwalleghem J, et al. Immunogenicity of a standard trivalent influenza vaccine in patients on long-term hemodialysis: an open-label trial. Am J Kidney Dis. 2009;54(1):77-83. 4. Brydak LB, Roszkowska-Blaim M, Machala M, Leszczynska B, Sieniawska M. Antibody response to influenza immunization in two consecutive epidemic seasons in patients with renal diseases. Vaccine. 2000;18(28):3280-3286. 5. Vogtlander NP, Brown A, Valentijn RM, Rimmelzwaan GF, Osterhaus AD. Impaired response rates, but satisfying protection rates to influenza vaccination in dialysis patients. Vaccine. 2004;22(17-18):21992201. 6. Cavdar C, Sayan M, Sifil A, et al. The comparison of antibody response to influenza vaccination in continuous ambulatory peritoneal dialysis, hemodialysis and renal transplantation patients. Scand J Urol Nephrol. 2003;37(1):71-76. 7. Antonen JA, Hannula PM, Pyhala R, Saha HH, Ala-Houhala IO, Pasternack AI. Adequate seroresponse to influenza vaccination in dialysis patients. Nephron. 2000;86(1):56-61.
Am J Kidney Dis. 2011;57(5):651-653
8. Gilbertson DT, Unruh M, McBean AM, Kausz AT, Snyder JJ, Collins AJ. Influenza vaccine delivery and effectiveness in endstage renal disease. Kidney Int. 2003;63(2):738-743. 9. Dikow R, Eckerle I, Ksoll-Rudek D, et al. Immunogenicity and efficacy in hemodialysis patients of a AS03A-adjuvanted vaccine for 2009 pandemic influenza A(H1N1): a nonrandomized trial. Am J Kidney Dis. 2011;57(5):716-723. 10. Lee BY, Stalter RM, Bacon KM, et al. Cost-effectiveness of adjuvanted versus nonadjuvanted influenza vaccine in adult hemodialysis patients. Am J Kidney Dis. 2011;57(5):724-732. 11. Valdez R, Venkat Narayan KM, Geiss LS, Engelgau MM. Impact of diabetes mellitus on mortality associated with pneumonia and influenza among non-hispanic black and white US adults. Am J Public Health. 1999;89(11):1715-1721. 12. Sarnak MJ, Jaber BL. Pulmonary infections mortality among patients with end stage renal disease. Chest. 2001;120(6):18831887. 13. Marcelli D, Marelli C, Richards N. Influenza A(H1N1)v pandemic in the dialysis population: first wave results from an international survey. Nephrol Dial Transplant. 2009;24(12):35663572. 14. Temiz G, Kasifoglu N, Kiris A, et al. Immune response after a single vaccination against 2009 influenza A(H1N1) in hemodialysis patients. Ren Fail. 2010;32(6):716-720.
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atients treated with long-term dialysis are immunosuppressed. Both cellular and humoral immunity are affected by the uremic state, and dialysis patients are more likely to contract and die of infection. Although the most common infections in this population are associated with dialysis access, there is also increased morbidity and mortality due to viral infections, including influenza. Unfortunately, as chronic kidney disease progresses, patients are also less able to develop a protective immune response to some vaccines. This is well demonstrated in the case of the hepatitis B vaccine, but is less clear for the seasonal influenza vaccine. Many dialysis patients seem to develop adequate protection with standard influenza vaccine dosing regimens, although the overall strength of the immune response may be less than that of healthy adults.2 In hemodialysis patients, protective immune response rates to seasonal influenza vaccine are highly variable among studies, ranging from 36% to over 90%, which may be related to the degree of immunosuppression associated with the uremic state as well as the immunogenicity of the antigens used in the seasonal vaccine3-7 Despite this, analysis of data from the US Renal Data System has shown that influenza vaccination in hemodialysis patients is associated with a reduced risk of hospitalization and death,8 and the Centers for Disease Control and Prevention recommends that dialysis patients should receive the vaccine annually. What remains unanswered, however, is whether such vaccination is cost-effective, and specifically which vaccination strategy is best from a cost perspective. This question is of even greater urgency in the long forecast, and now arrived, “era of limits.” In this issue of the American Journal of Kidney Diseases, 2 articles are presented that address the clinical efficacy9 and cost-effectiveness10 of adjuvanted influenza vaccine in hemodialysis patients. Dikow et al9 conducted a nonrandomized trial in several outpatient dialysis facilities in Germany. They compared the efficacy of 1- and 2-dose courses of AS03A-adjuvanted H1N1 vaccine in 292 patients with 123 patients who refused vaccination. The 1-dose Am J Kidney Dis. 2011;57(5):651-653
course (64 patients) produced a 64% protective response rate, and the 2-dose course (105 patients) produced an 89% protective response rate, compared with 35% in patients who refused vaccination. By contrast, the predicted protective response rate in healthy adults after one dose is 98%. Lee et al10 designed an economic stochastic decision analytic simulation model of cost-effectiveness in qualityadjusted life-years (assuming a societal perspective) of the use of either adjuvanted or nonadjuvanted seasonal influenza vaccine in long-term hemodialysis patients in the United States over a single influenza season. These authors found that adjuvanted vaccine would be cost-effective if the adjuvant added no more than $1 to the cost of the standard vaccine and if it overcame the difference in response between hemodialysis patients and healthy adults by ⱖ60%. Mortality rates among long-term dialysis patients who develop seasonal influenza are uncertain, in part due to underdiagnosis and reporting of actual cases and nonspecific coding for cause of death. The Centers for Disease Control and Prevention estimates mortality due to seasonal influenza for the general population using a statistical method that estimates excess deaths due to “influenza and pneumonia” during the influenza season. It is clear, however, that patients with diabetes and the elderly have an increased risk of death from pneumonia and influenza over that of the general population—in the range of 0.2%-0.3%.11 Compared with the general population, dialysis patients have approximately a 10-fold higher annual mortality risk due to pneumonia and influenza.12Notably, pandemic H1N1 influenza was associated with mortality as high as 5% in dialysis patients followed by a single outpatient dialysis provider in Latin America and Europe.13 In another recently published study, Temin et al demonstrated that single-dose adjuvanted vaccine for pandemic H1N1 influenza was effective in inducing an immune response in ⬎90% of a cohort of 70 dialysis patients who had been vaccinated 5 weeks Address correspondence to Kevin C. Abbott, MD, MPH, Department of Nephrology, Walter Reed Army Medical Center, 6900 Georgia Ave, Washington, DC 20307. E-mail: Kevin.Abbott@ amedd.army.mil Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. 0272-6386/$0.00 doi:10.1053/j.ajkd.2011.02.380 651
Kevin C. Abbott
earlier, significantly greater than that in 20 healthy young adult controls.14 In contrast, in the study by Dikow et al, dialysis patients required 2 doses of AS03A-adjuvanted H1N1 vaccine to develop protective antibody titers with the frequency seen after one dose in healthy adults. Nonresponders were also more likely to be nonresponders to the hepatitis B vaccine. The effectiveness of the adjuvanted vaccine in both studies is reassuring in light of what is known regarding the effects of H1N1 on hemodialysis patients during the 2009 epidemic. Marcelli et al13 described their experience with the epidemic in a group of Fresenius Medical Care dialysis units in South America and Europe where 3.4% of patients developed clinical symptoms consistent with H1N1 influenza, and 34% of these required hospital admission— primarily with pneumonia. Of the patients who contracted influenza, 5% died, and those with diabetes were 3 times more likely to develop pneumonia. Notably, those older than 65 years were less likely to develop H1N1 influenza, probably due to the presence of immunity acquired early in life. Dikow et al were able to demonstrate that this was true in their unvaccinated patients, in whom positive anti-H1N1 antibody titers correlated significantly with older age.9 The H1N1 vaccine used in 2009 was delivered with one of several adjuvants, because the supply of antigen was not adequate in the face of the H1N1 epidemic. The use of adjuvant allowed for smaller amounts of delivered antigen in the vaccine, and the use of one dose only in healthy adults. Although adjuvanted seasonal influenza vaccine would be theoretically more effective at producing protective antibodies than the standard vaccine in dialysis patients, it does not follow that such a vaccine will be costeffective, especially if the increase in the proportion of patients achieving protective antibody titers is relatively modest, and the cost of the adjuvant is high. Lee et al10 have developed a very useful model to assess this, providing vaccine cost and efficacy thresholds that certainly should serve as a decision-making guide to both vaccine developers and public health officials. Without such information, policy makers would largely be “flying blind”—a factor that may contribute more to rising medical costs than we know. However, it is very important to be aware of the potential pitfalls of using a model such as that of Lee et al in making decisions about influenza vaccines in dialysis patients. First of all, this model reflects a steady-state situation as seen with seasonal influenza. It cannot be used as a model for epidemic influenza (such as the 2009 H1N1 epidemic), which may be associated with unpredictable patterns of spread, higher mortality and morbidity in the general population, low to nonexistent natural immunity, and the potential for 652
overwhelming medical and pharmaceutical providers. In such a situation, vaccination is used as a defensive “wall” to minimize infection rates in the entire population—and societal benefit is based not only on reducing individual costs among dialysis patients, but in preventing the spread of infection generally. Moreover, the conclusions reached by the model are dependent on the assumptions used, some of which are not specific for hemodialysis patients (eg, the mortality risk used is for patients with diabetes). If these should change substantially over time (eg, the risk of contracting influenza, dialysis population demographics, costs of treatment, hospitalization risk, and efficacy of the nonadjuvanted vaccine), cost and efficacy thresholds could change as well. However, the model allows for considerable variation, nicely summarized in the second of the article.10 Because of this, it would be optimal if the model could be made available to be “reloaded” as necessary, as facts about cost and efficacy change over time. The data contained in the studies of Dikow et al9 and Marcelli et al13 are exactly the kind of information that could be used in the model by Lee et al10 to assess the cost-effectiveness of the H1N1 AS03A-adjuvanted vaccine as natural immunity increases in the general population and it becomes part of the seasonal influenza vaccine. Ultimately, the clinical decision analysis research community should agree on a way to make simulation models “living documents” that are easily available to be revisited to assist in public health decision making. This has been done in some areas in the biological and physical sciences, which have open databases containing protein structures, nucleic acid sequences, and astronomic data. Detailed information on ongoing and completed clinical trials is now available at ClinicalTrials.gov. Such a system would be invaluable in the area of clinical decision analysis, greatly enhancing the future usefulness of models such as that of Lee et al. Kevin C. Abbott, MD, MPH Christina M. Yuan, MD Walter Reed Army Medical Center Washington, DC Jessica L. Lee, MD National Naval Medical Center Bethesda, Maryland
ACKNOWLEDGEMENTS The views expressed in this paper are those of the authors and do not reflect the official policy of the National Institutes of Health, US Department of Army, Department of Defense, or the US government. Financial Disclosure: Dr Abbott reports having stock in Johnson & Johnson. All remaining authors declare they have no relevant financial interests. Am J Kidney Dis. 2011;57(5):651-653
Editorial
REFERENCES 1. Navy Department Library. A Forgotten Enemy: PHS’s [Public Health Service] Fight Against the 1918 Influenza Pandemic. Available at: http://www.history.navy.mil/library/online/ influenza_forgot.htm#fn6. Accessed February 17, 2011. 2. Kausz AT, Gilbertson DT. Overview of vaccination in chronic kidney disease. Adv Chronic Kidney Dis. 2006;13(3):209-214. 3. Scharpe J, Peetermans WE, Vanwalleghem J, et al. Immunogenicity of a standard trivalent influenza vaccine in patients on long-term hemodialysis: an open-label trial. Am J Kidney Dis. 2009;54(1):77-83. 4. Brydak LB, Roszkowska-Blaim M, Machala M, Leszczynska B, Sieniawska M. Antibody response to influenza immunization in two consecutive epidemic seasons in patients with renal diseases. Vaccine. 2000;18(28):3280-3286. 5. Vogtlander NP, Brown A, Valentijn RM, Rimmelzwaan GF, Osterhaus AD. Impaired response rates, but satisfying protection rates to influenza vaccination in dialysis patients. Vaccine. 2004;22(17-18):21992201. 6. Cavdar C, Sayan M, Sifil A, et al. The comparison of antibody response to influenza vaccination in continuous ambulatory peritoneal dialysis, hemodialysis and renal transplantation patients. Scand J Urol Nephrol. 2003;37(1):71-76. 7. Antonen JA, Hannula PM, Pyhala R, Saha HH, Ala-Houhala IO, Pasternack AI. Adequate seroresponse to influenza vaccination in dialysis patients. Nephron. 2000;86(1):56-61.
Am J Kidney Dis. 2011;57(5):651-653
8. Gilbertson DT, Unruh M, McBean AM, Kausz AT, Snyder JJ, Collins AJ. Influenza vaccine delivery and effectiveness in endstage renal disease. Kidney Int. 2003;63(2):738-743. 9. Dikow R, Eckerle I, Ksoll-Rudek D, et al. Immunogenicity and efficacy in hemodialysis patients of a AS03A-adjuvanted vaccine for 2009 pandemic influenza A(H1N1): a nonrandomized trial. Am J Kidney Dis. 2011;57(5):716-723. 10. Lee BY, Stalter RM, Bacon KM, et al. Cost-effectiveness of adjuvanted versus nonadjuvanted influenza vaccine in adult hemodialysis patients. Am J Kidney Dis. 2011;57(5):724-732. 11. Valdez R, Venkat Narayan KM, Geiss LS, Engelgau MM. Impact of diabetes mellitus on mortality associated with pneumonia and influenza among non-hispanic black and white US adults. Am J Public Health. 1999;89(11):1715-1721. 12. Sarnak MJ, Jaber BL. Pulmonary infections mortality among patients with end stage renal disease. Chest. 2001;120(6):18831887. 13. Marcelli D, Marelli C, Richards N. Influenza A(H1N1)v pandemic in the dialysis population: first wave results from an international survey. Nephrol Dial Transplant. 2009;24(12):35663572. 14. Temiz G, Kasifoglu N, Kiris A, et al. Immune response after a single vaccination against 2009 influenza A(H1N1) in hemodialysis patients. Ren Fail. 2010;32(6):716-720.
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