The Use of Vaccines in Adult Patients With Renal Disease

REVIEWS

The Use of Vaccines in Adult Patients With Renal Disease Mara Dinits-Pensy, MD, Graeme N. Forrest, MD, Alan S. Cross, MD, and Michael K. Hise, MD ● In patients with renal disease, infection remains among the most common causes of morbidity and mortality. Alterations in the function of the immune system, as well as unique exposures of this patient population, account for the increased risk. Vaccination is an invaluable tool in preventing many infectious diseases. Unfortunately, responsiveness to vaccination in patients with renal disease can be diminished. In the present review, we examine the available evidence on the use of vaccinations in adult patients at different stages of chronic kidney disease. We address efficacy, clinical outcomes, and potential costs of individual vaccinations and provide our recommendations based on the literature reviewed. We also identify areas in which additional research is needed. Am J Kidney Dis 46:997-1011. © 2005 by the National Kidney Foundation, Inc. INDEX WORDS: Immunization; vaccine; renal disease; dialysis; renal transplantation.

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NFECTION IS an important cause of death in patients with renal disease, ranking third after cardiovascular insults and miscellaneous events in patients on long-term dialysis. Patients with chronic kidney disease (CKD) are more likely to be hospitalized for bacteremia and/or septicemia than patients without CKD.1 Six-month mortality in patients with CKD hospitalized with bacteremia is 10 times greater than that in patients without bacteremia and exceeds mortality for cardiovascular admissions, including acute myocardial infarction and congestive heart failure. Thus, it is imperative that we take advantage of all potential mechanisms to prevent infectious complications in patients with renal disease. Perhaps one of the easiest mechanisms is vaccine use. Unfortunately, many dialysis centers and nephrology practices are reluctant to administer vaccines, in part because of a lack of understanding regarding their risk-benefit profiles. In a pediatric survey, only 60% of facilities suggested that pneumococcal vaccine be administered.2 Similarly, 10% to 15% did not recommend even standard killed vaccines for children with renal disease.2 In renal transplant recipients, there have been theoretical concerns that vaccination may trigger rejection. These concerns have not been substantiated in the literature. The most comprehensive source for information regarding vaccinations in all groups is the Morbidity and Mortality Weekly Report published by the Centers for Disease Control and Prevention (CDC).3 These recommendations take into consideration published information from the Advisory Committee on Immunization Practices (ACIP), the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and

the American College of Physicians–American Society of Internal Medicine. Unfortunately, no concise guidelines designed specifically for immunization of patients at different stages of kidney disease are available. Patients with renal disease represent a special population because of their immunosuppressed status and unique exposures. Multiple problems contribute to the increased risk for infectious complications in these patients, including the use of vascular access catheters, long-term peritoneal dialysis catheters, and immunosuppression after transplantation. Equally important are defects in immune function that are secondary to the uremic state per se. Various aspects of host defenses are affected by uremia and its metabolic consequences, including neutrophil function, antigen processing, antibody formation, and cellmediated immune responses. Neutrophils show From the Department of Medicine and Center for Vaccine Development, University of Maryland Medical Center, Baltimore, MD. Received April 15, 2005; accepted in revised form August 23, 2005. Originally published online as doi:10.1053/j.ajkd.2005.08.032 on November 3, 2005. The data reported here have been supplied by the US Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government. Address reprint requests to Mara Dinits-Pensy, MD, Department of Medicine, Division of Nephrology N3W143, University of Maryland Medical System, Baltimore, MD 21201. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4606-0002$30.00/0 doi:10.1053/j.ajkd.2005.08.032

American Journal of Kidney Diseases, Vol 46, No 6 (December), 2005: pp 997-1011

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Table 1. Vaccinations for Patients on Renal Replacement Therapy Vaccine

Administration and Schedule

Booster Doses

Contraindications and Precautions

Comments

Engerix, 40 ␮g IM at 0, 1, 2, 6 mo Recombivax, 40 ␮g IM at 0, 1, 6 mo

When anti-HBs titer ⬍ 10 mU/L

Hypersensitivity to yeast, latex, or any component of the vaccine; multiple sclerosis

There must be 4 wk between doses 1 and 2 and 8 wk between doses 2 and 3 (Recombivax); brands may be used interchangeably

Influenza trivalent inactivated vaccine

0.5 mL IM annually, preferably in October or November

Not recommended

Hypersensitivity to eggs; latex allergy; acute febrile illness

Can be administered at the same time as pneumococcal vaccine; live influenza vaccine is not recommended

Streptococcus pneumoniae 23-valent polysaccharide vaccine

0.5 mL SC or IM

Revaccination 5 y after first dose

Hypersensitivity to any component of the vaccine; acute febrile illness; severely compromised cardiovascular or pulmonary function

May be administered at the same time as influenza vaccine; currently, revaccination after a second dose is not routinely recommended

Tetanus toxoid

Primary immunization: 3 doses of 0.5 mL of either tetanus toxoid or tetanus/diphtheria toxoid IM with 4-8 wk between doses 1 and 2 and 6-12 mo between doses 2 and 3

0.5 mL every 10 y

Hypersensitivity to thimerosal; neurological reactions to tetanus toxoid; acute febrile illness; latex allergy

In areas where diphtheria poses a risk, tetanus/diphtheria toxoid may be preferred to tetanus toxoid

Varicella live attenuated vaccine

0.5 mL (minimum, 1,350 PFU) SC; second dose of 0.5 mL 4-8 weeks later

Not recommended

Severe immunodeficiency, including immunosuppressive therapy, human immunodeficiency virus, leukemia, lymphoma, or other blood dyscrasias. Anaphylaxis to neomycin or hypersensitivity to any vaccine component including gelatin.

Not routinely recommended; consider for patients awaiting renal transplantation; recipients of vaccine may be capable of transmitting the vaccine virus to close contacts for up to 6 weeks

Hepatitis A inactivated vaccine

1 mL of Havrix or Vaqta IM into the deltoid

6-12 mo later

Hypersensitivity to any component of the vaccine, including neomycin; latex allergy; febrile illness

Not routinely recommended; administer to patients with chronic liver disease, traveling to endemic areas, with intravenous drug use and male patients who have sex with men

Abbreviations: IM, intramuscular; SC, subcutaneous.

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Hepatitis B recombinant vaccine

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Table 2. Vaccinations for Adult Renal Transplant Recipients Vaccine

Administration and Schedule

Comments

Hepatitis B

Administer before transplantation

Not routinely recommend posttransplantation

Influenza

0.5 mL IM annually, preferably in October or November

Household contacts also should be immunized

S pneumoniae

0.5 mL SC or IM

Revaccination recommended 5 y after first dose

Tetanus toxoid

See Table 1

Administer booster every 10 y and after penetrating wound if last administration ⬎5 y

Varicella vaccine

Not recommended after transplantation

Consider immunizing seronegative household contacts; no isolation of household contacts postvaccination is necessary unless a rash develops

Hepatitis A

1 mL of Havrix or Vaqta IM into the deltoid

Not routinely recommended; for selected populations only; see Table 1

Abbreviations: IM, intramuscular; SC, subcutaneous.

decreased chemotaxis, phagocytosis, and intracellular killing. Ingestion and oxidative metabolism are decreased markedly and are not improved by hemodialysis. T-cell, B-cell, and monocyte function are impaired, resulting in faulty presentation of antigens for immune recognition. Alterations in the functional capacity of lymphocytes result in impaired responsiveness to vaccination. A comprehensive review of immunologic defects in patients with chronic renal failure was published by Pesanti4 and is beyond the scope of this review.

The Kidney Disease Outcomes Quality Initiative provides evidence-based clinical practice guidelines for different aspects of management of patients at all stages of CKD. However, no guidelines are available yet for preventive care in patients with CKD, including the use of vaccines. Data about immunization of patients with renal disease are limited and obtained predominantly from retrospective studies. There are few studies comparing immunization outcomes in patients at different stages of CKD or patients on

Table 3. Vaccinations for Patients With CKD Not on Renal Replacement Therapy Vaccine

Administration and Schedule

Comments

Hepatitis B

For patients with stage 5 CKD, same schedule as in Table 1

Not routinely recommended; consider for patients at high likelihood for progression to ESRD

Influenza

0.5 mL IM annually, preferably in October or November

Can be administered at the same time as pneumococcal vaccine

S pneumoniae

0.5 mL SC or IM

Revaccination recommended 5 y after first dose

Tetanus toxoid

See Table 1

Administer a booster every 10 y and after penetrating wound if last administration ⬎5 y

Varicella vaccine

0.5 mL (minimum, 1,350 PFU) SC; second dose of 0.5 mL 4-8 weeks later

Consider for patients awaiting renal transplantation; may be beneficial in zoster prevention if administered before transplantation

Hepatitis A

1 mL of Havrix or Vaqta IM into the deltoid

Not routinely recommended; for selected population only; see Table 1

Abbreviations: IM, intramuscular; SC, subcutaneous.

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dialysis. Data obtained from patients on hemodialysis frequently are extrapolated to patients on peritoneal dialysis. We performed a PubMed literature search to examine the current state of knowledge on the use of vaccination for prevention of infectious complications in patients with renal disease. A detailed review of individual vaccines commonly used in adults is provided next. Tables 1 through 3 summarize our recommendations for the immunization of patients with CKD, those receiving dialysis, and patients after renal transplantation. HEPATITIS B

Hepatitis B virus (HBV) has been a public health issue in dialysis units since the advent of hemodialysis in the 1960s, and it has remained the main infectious target of vaccination in the dialysis population. HBV is transmitted by percutaneous or mucosal exposure to infectious blood or body fluids. It is relatively stable in the environment, remaining viable on environmental surfaces at room temperature for at least 7 days. Therefore, blood-contaminated surfaces such as equipment, supplies, multidose drug vials, gloves, and hands of the dialysis staff can aid in the transmission of infection.5 In addition to being at greater risk for acquiring HBV infection, dialysis patients also appear to be at greater risk for becoming chronic carriers, thus serving as a potential reservoir of infection.6 The CDC began conducting national surveillance for hemodialysis-associated hepatitis in 1972. In 1974, the incidence of newly acquired HBV infection in hemodialysis patients in the United States was 6.2%, and in some centers, as high as 30%.5 In 1977, the first recommendations for control of hepatitis B in hemodialysis centers were published.7 They included monthly testing of all susceptible patients for HBV surface antigen (HBsAg), isolation of HBsAg-positive patients in a separate room with separate staff and equipment, glove changes between each patient, assignment of a supply tray to each patient regardless of serological status, cleaning and disinfection of nondisposable items before use on another patient, and routine cleaning and disinfection of equipment and environmental surfaces. By 1980, widespread implementation of these guidelines was associated with a sharp decrease in the incidence of

HBV infection, with the nationwide incidence in hemodialysis patients decreasing to 1%. In 1982, hepatitis B vaccination was recommended for all susceptible hemodialysis patients and staff members. By 2001, 60% of patients and 89% of staff members had been vaccinated, with the incidence of HBV infection decreasing to 0.05% and the prevalence of HBsAg positivity in dialysis patients decreasing to 0.9%.8 Screening of blood products and, later, the decrease in numbers of blood transfusions with the advent of recombinant erythropoietin also contributed to the marked decrease in incidence of hepatitis B. No outbreaks of HBV infection in the United States have been reported in outpatient dialysis centers since 1994, and hospital units, since 1996.9,10 HBV vaccines currently available in the United States are the recombinant vaccines: Recombivax HB (Merck, Whitehouse Station, NJ) and Engerix-B (GlaxoSmithKline; GlaxoSmithKline Biologicals, Rixensart, Belgium). Recommended doses for adults on dialysis are either 40 ␮g of Recombivax HB administered at 0, 1, and 6 months or 40 ␮g of Engerix-B administered at 0, 1, 2, and 6 months. This is a greater dose than the regular dose of 10 ␮g of Recombivax HB or 20 ␮g of Engerix-B administered at 0, 1, and 6 months to immunocompetent patients. Despite a greater dose of vaccine, hemodialysis patients are less likely to achieve protective antibody titers, defined as 10 mIU/mL or greater.11 The median response rate to vaccination in hemodialysis patients is 64% (range, 34% to 88%) with the 3-dose schedule compared with 90% to 95% in adults with normal immune status.5 To assess the response to HBV vaccination in dialysis patients, HBV surface antibody (anti-HBs) testing should be performed 1 to 2 months after the primary series is completed.5 In patients who do not respond to the primary 3-dose series of vaccine, an additional 3-dose series is recommended, with a 40% to 50% response to revaccination.5 Given the low incidence of HBV infection in the United States today, the efficacy of HBV vaccine is difficult to establish. A case-control trial showed that the risk for HBV infection was 70% less in vaccinated compared with unvaccinated longterm hemodialysis patients.12 Antibody levels in patients on dialysis therapy decrease rapidly after immunization until they are undetectable in up to 42% of patients at 1

USE OF VACCINES IN RENAL DISEASE

year postimmunization.5 In immunocompetent individuals, effective immunity after HBV vaccination is sustained, even when anti-HBs levels decrease to less than 10 mIU/mL.13 In the dialysis population, protection against HBV from the vaccine may be diminished or lost when antiHBs titers decrease to less than this level.14 The current CDC recommendation is to test levels of anti-HBs annually in dialysis patients. If anti-HBs titers decrease to less than 10 mIU/mL, a booster dose is recommended. A recent decision analysis showed that the current practice of screening for HBV immunity before immunization is more cost-effective than administration of a yearly booster without screening.15 To improve immunogenicity of the HBV vaccine in dialysis patients, alternative routes of vaccine administration have been attempted. The intradermal route may offer a greater seroconversion rate, but is technically more difficult to administer.16,17 It is not recommended by the current CDC guidelines, but may be the preferred route in patients who do not respond to the primary vaccination series.18 HBV vaccine currently is not licensed for the intradermal route. Other methods to improve the immune response to HBV vaccination include administration of adjuvants such as interleukin 2 and granulocyte-macrophage colonystimulating factor, have produced variable results and are not recommended.19-21 Administration of cytosine-guanine oligodeoxynucleotide has shown promise in animals and stage I to II trials of healthy volunteers.22-24 However, no data are available for patients with renal disease. There is evidence that vaccination of patients before the initiation of dialysis may result in greater success rates.25-27 A recent prospective study examined the response to HBV vaccination based on the stage of CKD in a cohort of predialysis patients. Patients with higher levels of kidney function, based on Cockcroft-Gault and Modification of Diet in Renal Disease equations, were more likely to respond to HBV vaccination, and the level of kidney function was an independent predictor of seroconversion.26 Long-term immunogenicity and cost implications of this strategy need to be investigated further. A simulated model showed that for the predialysis immunization strategy to become cost-effective, the price of the vaccine needed to decrease substantially.28

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The cost-effectiveness of HBV vaccination in general recently was questioned. Arguments against the universal immunization of dialysis patients include the low incidence of HBV infection in the dialysis population today, the wide use of infection-control measures, the low likelihood of dialysis patients surviving long enough to develop HBV-related complications, and the high cost of immunization and follow-up of immunity. A prospective study examining the impact of vaccination on the relative risk for HBV seroconversion and the cost-effectiveness of vaccination strategy is needed, but may not be feasible given current practice guidelines and the low incidence of HBV infection. Patients who are potential transplant candidates may derive the greatest benefit from HBV vaccination because of the increased morbidity and mortality associated with HBV infection after renal transplantation. Mathurin et al29 showed that 10-year graft and patient survival was lower in HBsAg-positive than HBsAg-negative renal transplant recipients. Response to HBV vaccination after renal transplantation appears to be poor.30,31 Lefebure et al,31 using 40 ␮g of HBV vaccine, reported a conversion rate of only 36%. Conversely, patients vaccinated before transplantation who were administered a booster of 40 ␮g of the vaccine posttransplantation had a conversion rate of 86%. Therefore, HBV immunization should be administered before transplantation. In 1991, the ACIP recommended a comprehensive strategy to eliminate HBV transmission in the United States that included universal immunization of infants.32 More recently, the ACIP recommended that all persons younger than 18 years be administered hepatitis B immunization. The duration of immune response to HBV vaccination in patients who were immunized as infants and children and who develop renal failure later in life will need to be addressed. STREPTOCOCCUS PNEUMONIAE

Pneumonia remains a major cause of morbidity and mortality in patients with renal disease. According to the most recent US Renal Data System (USRDS) report, rates of pneumonia during the first year of hemodialysis have increased gradually from 24.8 admissions/100 patient-years at risk in 1991 to 30.6 admissions/100 patient-years at risk in 2001.1 Slinin et al33

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Fig 1. Adjusted mortality rates in dialysis patients after the first pneumonia event. Data obtained from 194,374 incident dialysis patients, 1996 to 2000. Rates adjusted for age, sex, race, primary diagnosis, and vintage. Patients without pneumonia were used as the reference cohort. Data from USRDS 2004 Annual Data Report.1

reported an overall pneumonia hospitalization rate of 84.4 admissions/1,000 patient-years in 14,859 prevalent hemodialysis patients. S pneumoniae is responsible for up to 53% of reported pneumonia cases in dialysis patients.34 In renal transplant recipients, a pneumonia incidence of 2.62 episodes/100 patient-years recently was reported.35 Mortality rates after pneumonia in dialysis patients remain high, with up to 14- to 16-fold greater mortality compared with the general population.36 Six-month mortality rates after pneumonia in patients during the first year of dialysis were 78.3/100 patient-years in 2001 (Fig 1).1 The relative risk for death at 6 months in first-year dialysis patients who experienced an episode of pneumonia was 5.1 (95% confidence interval [CI], 4.9 to 5.2; P ⬍ 0.0001) compared with patients who did not. The increase in mortality persisted even 48 months after the event, with an adjusted relative risk for death in patients with pneumonia of 1.82 (95% CI, 1.66 to 2.0; P ⬍ 0.0001) compared with patients without pneumonia (Fig 1). Relative risk for cardiovascular events in the first 6 months also was greater at 3.02 (95% CI, 2.87 to 3.02; P ⬍ 0.0001) in dialysis patients with pneumonia compared with those without pneumonia (Fig 2). Despite the high mortality and increased cardiovascular event rates associated with pneumonia, immunization rates of patients with endstage renal disease (ESRD) with pneumococcal vaccine remain low. In 2001, pneumococcal

vaccine was offered to patients at only 58.5% of US dialysis centers. Overall, the estimated percentage of dialysis patients vaccinated for S pneumoniae in 2001 was 26.2%.8 The pneumococcal vaccine currently in use for adults in the US is the 23-valent polysaccharide vaccine (Pneumovax 23; Merck; and PnuImmune23; Lederle Laboratories, Pearl River, NY). A 7-valent conjugate vaccine (Prevnar; Wyeth-Ayerst, Philadelphia, PA) was developed in 2000 and currently is recommended for immunization of children younger than 2 years. In the general population, pneumococcal vaccine is protective against invasive bacteremic disease, but it may not be effective in protecting from other types of pneumococcal infection.37,38 There are no recent data regarding the use of pneumococcal vaccine in patients with renal disease. Studies from the 1980s showed that dialysis patients achieved lower postvaccination antibody titers and that there was a rapid decline in antibody level within 6 months to 5 years after vaccination.39-41 Fuchshuber et al42 observed a protective response to pneumococcal vaccination 4 weeks after immunization in 83% of children and young adults with CKD, on dialysis, and after transplantation. Only 68% of patients retained protective antibody levels at 6 months, and only 48%, at 1 year. Revaccination at 1 year produced a significant response in 50% of the patients reimmunized, but antibody levels decreased rapidly within 6 months.42 Little information is available on clinical outcomes after

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Fig 2. Adjusted cardiovascular event rates in dialysis patients after the first pneumonia event. Data obtained from 78,262 incident dialysis patients, 1996 to 2000. Rates adjusted for age, sex, race, primary diagnosis, and vintage. Patients without pneumonia were used as the reference cohort. Data from USRDS 2004 Annual Data Report.1

pneumococcal vaccination in patients with kidney disease. Most studies examine protective antibody responses, that are not well established for adults. Information on the use of pneumococcal vaccination in renal transplant recipients also is very limited. Kumar et al43 performed a randomized doubleblinded trial comparing responses to pneumococcal conjugate and polysaccharide vaccines in 60 renal transplant recipients. Functional antibody responses were not different between the 2 groups. In both groups, overall response rates to each individual serotype of the vaccine were poor (13% to 50%). This response was much lower than in earlier studies, but at that time, different immunosuppressive protocols were used.44,45 Currently, the ACIP recommends administration of a single 0.5-mL dose of the 23-valent pneumococcal vaccine intramuscularly or subcutaneously to all patients with CKD older than 2 years. Revaccination is recommended for adult patients 5 years after the first dose.46 The timing of revaccination in the dialysis population may need to be readdressed. Vaccine failures have been reported as early as 2 years after the primary vaccination series.47 In a small study, administration of repeated booster doses every 2 years was safe and resulted in an increase in antibody titers.47 INFLUENZA

Influenza epidemics have been responsible for an average of 36,000 deaths/y in the United States between 1990 and 1999.48 Patients on

dialysis therapy are at greater risk for influenzarelated mortality.49 Influenza vaccination is associated with decreases in influenza-related respiratory illness, physician visits in all age groups, hospitalization and death in persons at high risk, otitis media in children, and work absenteeism in adults.48 Although influenza vaccination rates in the general population have been increasing, vaccination rates in the ESRD population have remained well below the target of Healthy People 2010. This lower rate of immunization occurs despite greater access to care and lack of a copayment for influenza vaccination in the dialysis population. Lower rates of vaccination in patients on dialysis may be caused in part because the efficacy of influenza vaccination in this population has been a point of debate. Earlier studies showed an impaired response to influenza vaccination in patients with renal disease.50-52 The more recent literature showed that although the overall antibody response to influenza vaccination is diminished in patients on dialysis, a significant number of these patients are able to mount protective antibody titers.53,54 Repeated vaccination in consecutive years may enhance the protective value of vaccination.55 To examine the clinical protective effect of influenza vaccination, Gilbertson et al used the USRDS to compare outcomes among vaccinated and unvaccinated persons for the 1997 to 1998 and the 1998 to 1999 influenza seasons.56 The combined vaccination rate for hemodialysis and peritoneal dialysis patients was less than 50% for

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Table 4. ORs and 95% CIs for the Impact of Influenza Vaccination on Mortality and Hospitalization in Patients on Peritoneal Dialysis and Hemodialysis Hemodialysis

Peritoneal Dialysis

Outcome

1997-1998

1998-1999

1997-1998

1998-1999

Any-cause hospitalization Any-cause mortality Cardiac mortality

0.95 (0.92-0.98) 0.75 (0.71-0.80) 0.84 (0.77-0.92)

0.93 (0.90-0.95) 0.77 (0.73-0.81) 0.82 (0.76-0.88)

0.90 (0.83-0.98) 0.70 (0.59-0.82) 0.77 (0.61-0.98)

1.01 (0.93-1.11) 0.83 (0.71-0.97) 0.90 (0.72-1.13)

Data from Gilbertson et al.56

each season. Vaccination rates were lower in patients on peritoneal dialysis compared with hemodialysis. Younger patients, nonwhites, and women had lower rates of vaccination. In hemodialysis patients, influenza vaccination was associated with a statistically significant decreased risk for death and hospitalization for any cause (Table 4). In peritoneal dialysis patients, vaccination was associated with a decreased risk for death from any cause. Risk for any-cause hospitalization in peritoneal dialysis patients was decreased in the 1997 to 1998 cohort and unchanged in the 1998 to 1999 cohort (Table 4). Examination of causespecific mortality showed that in hemodialysis patients, there was a significant decrease not only in all-cause and influenza and/or pneumonia– related mortality, but also in cardiac mortality. Previous studies of patients without ESRD showed an association between influenza vaccination and decreased risk for acute myocardial infarction, cardiac death, and hospitalization for heart disease.57-59 In a case-control study of 218 patients with coronary heart disease, influenza vaccination was associated with a significantly decreased risk for myocardial infarction (odds ratio [OR], 0.33; 95% CI, 0.13 to 0.82; P ⫽ 0.017).59 Gurfinkel et al, in a prospective randomized pilot study of 200 patients with acute coronary syndromes, found a similar decrease in cardiovascular mortality associated with influenza immunization (OR, 0.25; 95% CI, 0.07 to 0.86; P ⫽ 0.01).58 A cohort study of elderly community-dwelling adults found a decrease in risk for hospitalization for cardiac disease, cerebrovascular disease, and death from all causes in patients who received influenza vaccination.57 Given the high risk for cardiovascular events in patients with CKD, patients on dialysis therapy, and patients following renal transplantation, it would be interesting to prospectively examine

the effect of influenza vaccination on rates of acute myocardial infarction, hospitalization for cardiovascular events, and cardiac mortality in each of these patient populations. Currently, the CDC recommends influenza vaccination for all patients with renal dysfunction and persons who can transmit influenza to those at high risk (household contacts, physicians, nurses, and other personnel in both hospital and outpatient-care settings).48 Patients with renal disease should receive inactivated influenza vaccine in early October. For patients who have not received influenza vaccination early in the season, vaccine should continue to be offered throughout the influenza season because influenza activity has not reached peak levels in the majority of recent seasons until late December to early March.48 In adult patients, a single dose containing 0.5 mL of vaccine is administered intramuscularly into the deltoid muscle. No dose adjustment has been recommended for patients on dialysis. There were earlier concerns about influenza immunization triggering acute rejection episodes in recipients of renal transplants. This has not been substantiated in the literature. However, influenza infection itself was associated with acute rejection in 62% of 30 patients with influenza documented in solid-organ transplant recipients at the University of Pittsburgh between 1990 and 2000.60 The response to influenza vaccination in recipients of renal transplants appears to be diminished. Sanchez-Fructuoso et al immunized 49 patients with a 1-year functioning transplant and compared them with 37 healthy family members.61 The proportion of renal transplant patients able to produce protective antibodies in response to the vaccine was lower compared with healthy controls. However, the incidence of illness was similar in both groups. Postvaccina-

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tion renal function remained stable, and there were no cases of acute rejection after vaccination. Live attenuated cold-adapted trivalent influenza vaccine (CAIV-T; FluMist, MedImmune Vaccines, Inc, Gaithersburg, MD) was approved by the Food and Drug Administration in June 2003 for use in healthy persons aged 5 to 49 years. CAIV-T is specifically indicated to prevent influenza in persons without underlying high-risk conditions and it has not been tested in patients with advanced renal disease. TETANUS AND DIPHTHERIA

Since the introduction of vaccination with tetanus toxoid in the 1940s, tetanus has been a rare disease in the United States, with an overall incidence of 0.02 cases/100,000 population during the late 1990s.46 The majority of cases reported occurred in persons who had not completed a 3-dose primary tetanus toxoid vaccination or for whom vaccination histories were uncertain. Adults aged 60 or older are at greatest risk for tetanus and tetanus-related mortality, with an incidence of 0.03 cases/100,000 population and a case-fatality ratio of 31%. Currently, the ACIP recommends routine tetanus vaccination in adults who have not been immunized as children with a 3-dose primary series (0, 4 to 8 weeks, and 6 to 12 months) and a booster dose every 10 years after the primary dose. As with other immunizations, literature for patients with CKD is limited. Girndt et al vaccinated seronegative patients with chronic renal failure not on dialysis, patients on long-term hemodialysis, patients after kidney transplantation and compared them with healthy controls.62 Only 55% of patients in the chronic renal failure group and 69% of patients in the dialysis group reached protective antibody levels. Kidney transplant recipients showed normal seroconversion rates, but lower overall antibody titers. More recently, Kruger et al showed similar findings, with 65% of dialysis patients remaining protected at 1 year.63 After 5 years, 71% of patients in that study maintained protective antibody levels. The increase in overall protection rate after 5 years occurred because significantly more patients died in the initial nonresponder group.63 Guerin et al found much greater rates of protective antibody levels in 66 hemodialysis patients, with 95.6% of

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patients achieving protective levels after a booster dose.64 However, antibody titers decreased rapidly, with only 68% of patients maintaining protective titers after 6 months. In transplant recipients, Huzly et al found much better response rates to tetanus vaccination, with all 150 patients achieving protective antibody levels.65 Antibody levels, although decreased, remained protective in all patients 12 months after vaccination. Data for diphtheria boosters in patients with renal disease are even more limited. Diphtheria is extremely rare in the United States, and a literature search did not yield any case reports of diphtheria in patients with preexisting renal disease. The ACIP currently recommends administration of diphtheria toxoid booster together with tetanus toxoid booster as a Td preparation to adults every 10 years. Surveys of the general population in the United States indicated that 22% to 62% of adults aged 18 to 39 years and 41% to 84% of adults older than 60 years may lack protective antibody levels against diphtheria.66 The recent outbreak of diphtheria in the former Soviet Union emphasized the need for achieving and maintaining high levels of diphtheria immunity in both adults and children.67,68 Patients on dialysis show an impaired response to diphtheria vaccination, with a seroconversion rate of only 37%; 33% of patients retain protective levels 5 years after booster administration.63 Transplant recipients may have an adequate response to booster administration, with protection rates as high as 89% to 95%, but with a rapid decrease in antibody levels within the first year.65,69 Lower rates of protection in transplant recipients after a diphtheria booster were found by other investigators.63 There were no episodes of acute rejection or decreased graft function associated with tetanus or diphtheria vaccination. HEPATITIS A

In most industrialized countries, there are low levels of endemic hepatitis A virus (HAV) transmission. Because most of the population in these countries are susceptible to HAV infection, outbreaks occur.70 In the United States, this is becoming more apparent with the importation of food that may be tainted.70,71 HAV causes both acute disease and asymptomatic infection, but does not cause chronic infec-

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tion. It confers lifelong immunity from future HAV infection.72 Patients with chronic liver disease have an increased risk for fulminant hepatitis and death during acute HAV superinfection.73 Given the greater prevalence of hepatitis B and C in the dialysis population, this becomes important when devising immunization strategies for these patients. The Food and Drug Administration has licensed 2 inactivated vaccines in the United States, Havrix (GlaxoSmithKline) and Vaqta (Merck). Approximately 97% to 100% of children, adolescents, and adults develop protective antibody levels within 1 month after the first dose of the vaccine. Essentially 100% of vaccinees develop protective antibody levels with high geometric mean concentrations after completing the 2-dose series.74,75 Both Havrix and Vaqta have shown a considerable safety profile.76 However, these results are in a healthy patient population. There is very little information on the efficacy and long-term response of hepatitis A vaccines in patients requiring dialysis.77,78 These patients are at increased risk for developing severe hepatitis.5,79 Fleishmann et al vaccinated 43 consecutive dialysis patients with the Havrix vaccine.80 Thirty patients received vaccination on a nondialysis day intramuscularly (group A), and 13 patients received vaccination on the day of dialysis subcutaneously (group B). The 30 patients in group A and 12 of 13 patients in group B developed protective antibodies. There were no adverse events in either group. Responses in both groups were similar to those in healthy individuals. However, there was no long-term follow-up to evaluate the duration of immunity in these patients. The response to HAV vaccination in hemodialysis patients appears to be similar to that in patients after liver transplantation and greater than that in renal transplant recipients.72,79 After 2 doses of the vaccine, 72% of renal transplant recipients developed protective antibody levels.72 Because of the low incidence of hepatitis A in the United States, universal vaccination of dialysis patients against hepatitis A is not recommended. Based on CDC guidelines, hepatitis A vaccination should be administered to dialysis patients with chronic liver disease, including patients with active hepatitis B and C, patients in outbreak epidemics or those traveling into known endemic areas; patients using intravenous drugs;

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and male patients who have sex with men. There is no dose adjustment recommended for patients on dialysis. VARICELLA VACCINE

Approximately 4 million varicella cases with 4,000 to 9,000 hospitalizations and 100 deaths were reported annually in the United States before the approval of varicella vaccine in 1995 (Varivax; Merck). Although less than 5% of these cases occurred in adults older than 20 years, 55% of varicella-related deaths occurred in this age group.81 The incidence of varicella infection in patients with renal disease is not clearly defined. Although varicella is not a significant contributor to morbidity in dialysis patients, varicella in immunosuppressed renal transplant recipients is a serious and potentially life-threatening infection. Complications of varicella infection after renal transplantation include disseminated infection, allograft rejection, and mortality rates up to 34%.82 There have been no major studies of varicella vaccine efficacy in adult patients with renal disease. Several studies of children with ESRD showed the vaccine to be efficacious and safe. In a study of 17 pediatric patients with ESRD and 17 patients with functioning renal transplants who were immunized with a single 1,000–plaqueforming unit (PFU) dose of the vaccine, 85% of patients with ESRD developed antibodies within the first 6 months and 76% of patients with ESRD had protective antibody titers at 1 year. Three children acquired varicella 2 to 4 years after immunization, although in all cases, the disease was in an attenuated form.83 A retrospective review of 212 children administered a single dose of vaccine reported an 87% seroconversion rate.84 Only 62% of children had protective antibody titers 1 year after immunization, with an additional decrease to 52% at the time of transplantation. Nevertheless, the incidence of varicella in the transplant population decreased from 45% to 12% after the introduction of immunization. Disease in the vaccinated group was mild, whereas there were 3 deaths in the nonimmunized group. Webb et al immunized 32 children with advanced renal disease (25 children on dialysis and 7 children with a glomerular filtration rate ⬍20 mL/min/1.73 m2 [⬍0.33 mL/s/1.73 m2]) with no

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previous history of varicella.85 Two doses (2,000 PFU) of live attenuated varicella vaccine were administered 3 months apart.85 All children experienced seroconversion, and the incidence of side effects was low. Of 28 survivors administered 2 doses of vaccine, 82% had protective antibody titers at an average follow-up of 20 months. Immunization before transplantation resulted in 10 of 11 children having protective antibody titers at the time of transplantation, and of the 3 children who subsequently lost their protective titers, 2 children had immunity for the first 12 months after engraftment, when immunosuppressive therapy was the greatest. There were no episodes of varicella infection despite a number of well-documented episodes of exposure to wildtype varicella zoster virus. A retrospective analysis of solid-organ transplantations performed between 1994 and 1999 at the University of Alberta reported a 7.4% incidence of herpes zoster after renal transplantation.86 Infection caused by herpes zoster was associated with significant morbidity in the form of postherpetic neuralgia (42.7%) and cutaneous scarring (18.7%). An interesting finding of this study is that subjects who developed zoster pretransplantation experienced no recurrence after transplantation. A prospective trial of adult patients is needed to examine the utility of pretransplantation administration of varicella vaccine on the incidence and morbidity of herpes zoster. The use of varicella vaccine in patients after renal transplantation remains controversial and is not recommended at this time. Hata et al, in a randomized controlled trial, immunized 53 bone marrow transplant recipients who were seropositive for varicella zoster with live attenuated vaccine 30 days before and 30, 60, and 90 days after transplantation.87 Risk for zoster was 13% in vaccinated patients compared with 33% in controls.87 The American Academy of Pediatrics recommends immunization of seronegative household contacts of transplant recipients against varicella. However, vaccinees who develop a rash should avoid contact with transplant recipients.88 At this time, data for varicella vaccination in adult patients with renal disease are insufficient. Based on pediatric data, patients with renal disease awaiting transplantation who lack serological evidence of previous varicella infection should

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be immunized to prevent disseminated varicella posttransplantation. Studies of adults are needed to address the utility of pretransplantation varicella vaccine administration as a means to decrease the incidence and morbidity of herpes zoster in patients with previous varicella infection. STAPHYLOCOCCUS AUREUS VACCINE

S aureus remains a major cause of morbidity in hemodialysis patients. An annual incidence of bacteremia caused by S aureus of 3% to 4% in hemodialysis patients was reported in the early 1990s.89 Most recent USRDS data showed that adjusted septicemia rates in the first year of dialysis therapy increased from 13.96/100 patients in 1991 to 26.16/100 patients in 2001 (Fig 3), with S aureus as the most common specified organism.3 Danese et al recently showed that septicemia caused by S aureus was associated with significantly greater in-hospital and postdischarge mortality compared with any other specified organism (OR of mortality, 1.33; 95% CI, 1.21 to 1.46).90 An increasing percentage of S aureus isolates are resistant to methicillin, and strains resistant to vancomycin are emerging. Preventing infection caused by S aureus remains an issue of major importance. Immunotherapy for S aureus has been in development for several decades with various vaccine approaches. In the early 1990s, a killed wholecell S aureus vaccine combined with ␣-toxin (Staphypan; Berna Biotech, Switzerland) was administered to 124 patients undergoing continuous ambulatory peritoneal dialysis by using a complex immunization series during a 12-month period.91 Although vaccination induced a significant increase in serum and dialysate levels of antibodies to S aureus, rates of peritonitis, exitsite infection, and S aureus asymptomatic carriage did not differ between vaccine recipients and saline-immunized controls. Based on the success of vaccines targeted against the polysaccharide capsule (S pneumoniae and Haemophilus influenza type b), the discovery of polysaccharide capsule in S aureus isolates revived the search for a S aureus vaccine. There are 12 known types of S aureus capsular polysaccharides, with types 5 and 8 accounting for approximately 85% of bacteremic isolates in humans. A conjugate S aureus vaccine directed against cap-

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Fig 3. Hospital admission rates for septicemia during the first year on peritoneal dialysis (PD) or hemodialysis (HD), 1991 to 2001. Septicemia rates in patients on hemodialysis therapy continue to increase, whereas rates in peritoneal dialysis patients have remained stable and are consistently lower. Rates adjusted for age, sex, race, and primary diagnosis. Data from USRDS 2004 Annual Data Report.1

sular polysaccharides 5 and 8 was developed (StaphVAX; Nabi, Rockville, MD). A randomized, double-blinded, placebo-controlled trial evaluated the efficacy and safety of StaphVAX in 1,804 adult patients with ESRD.92 The study found the vaccine to be safe, with adverse effects limited to local reactions, malaise, and myalgias. There was no statistically significant difference between immunized and nonimmunized groups in numbers of episodes of bacteremia caused by S aureus during the originally designed follow-up period (weeks 3 to 54 after vaccine administration). In the post hoc analysis evaluating performance of the vaccine through various times, there was a 57% decrease in bacteremia caused by S aureus (95% CI, 10 to 81; P ⫽ 0.02) for weeks 3 to 40 after vaccine administration and 64% decrease for weeks 3 to 32 (P ⫽ 0.02). An unexpected finding was the emergence of another capsular polysaccharide, type 336, in approximately 20% of all blood isolates. Another phase III clinical trial of StaphVAX is underway to examine the effect of a booster dose administered at 8 months on antibody levels and efficacy. At this time, there are insufficient data to recommend administration of S aureus vaccine to patients on renal replacement therapy. Although StaphVAX vaccine appears to be safe and may have some efficacy over a limited period, additional studies are needed and are underway to investigate potential prolongation of the protective effect with booster doses of the vaccine.

CONCLUSION

Vaccines remain an underused tool for the prevention of infectious complications in patients with renal disease. Nephrologists frequently serve as primary care physicians for their patients and thus need to be familiar with the data for commonly used adult vaccinations. Although patients with renal disease may have an impaired immunologic response, successful vaccination of this patient population is possible and can decrease the risk for complications from vaccine-preventable diseases. Recent data suggest an association between influenza vaccination and decreased cardiac mortality. Given the markedly increased risk for cardiovascular events in patients with renal disease, there is an urgent need to investigate further the effects of influenza vaccination on this high-risk population. Well-designed studies examining clinical outcomes of patients with renal disease after pneumococcal vaccination also are needed. The use of varicella vaccine before renal transplantation as a means of decreasing the incidence and morbidity of herpes zoster is of interest. We are hopeful that our review provides a stimulus for additional research on the use of vaccines in patients with renal disease. REFERENCES 1. US Renal Data System: USRDS 2004 Annual Data Report. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2004

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2. Furth SL, Neu AM, Sullivan EK, Gensler G, Tejani A, Fivush BA: Immunization practices in children with renal disease: A report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 11:443-446, 1997 3. Recommended adult immunization schedule—US, 10/ 2004-9/05. MMWR Morb Mortal Wkly Rep 53:Q1-Q4, 2004 4. Pesanti EL: Infections in patients with CRF. Infect Dis Clin North Am 15:1-15, 2001 5. Recommendations for preventing transmission of infections among chronic HD patients. MMWR Morb Mortal Wkly Rep 50:1-43, 2001 6. Ribot S, Rothstein M, Goldblat M, Grasso M: Duration of hepatitis B surface antigenemia (HBsAg) in hemodialysis patients. Arch Intern Med 139:178-180, 1979 7. US Department of Health, Education and Welfare Public Health Services, CDC: Hepatitis: Control Measures for Hepatitis B in Dialysis Centers. Atlanta, GA, CDC, HEW publication no. 78-8358, 1977 8. Tokars JI, Finelli L, Alter MJ, Arduino MJ: National surveillance of dialysis-associated diseases in the United States, 2001. Semin Dial 17:310-319, 2004 9. Outbreaks of hepatitis B infection among HD patients— California, Nebraska, Texas, 1994. MMWR Morb Mortal Wkly Rep 45:285-289, 1996 10. Hutin YJ, Goldstein ST, Varma JK, et al: An outbreak of hospital-acquired hepatitis B virus infection among patients receiving chronic hemodialysis. Infect Control Hosp Epidemiol 20:731-735, 1999 11. Palmovic D, Crnjakovic-Palmovic J: Vaccination against hepatitis B: Results of the analysis of 2000 population members in Croatia. Eur J Epidemiol 10:541-547, 1994 12. Miller ER, Alter MJ, Tokars JI: Protective effect of hepatitis B vaccine in chronic hemodialysis patients. Am J Kidney Dis 33:356-360, 1999 13. West DJ, Calandra GB: Vaccine induced immunologic memory for hepatitis B surface antigen: Implications for policy on booster vaccination. Vaccine 14:1019-1027, 1996 14. Stevens CE, Alter HJ, Taylor PE, Zang EA, Harley EJ, Szmuness W: Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efficacy. N Engl J Med 311:496-501, 1984 15. Saab S, Weston SR, Ly D, et al: Comparison of the cost and effectiveness of two strategies for maintaining hepatitis B immunity in hemodialysis patients. Vaccine 20:3230-3235, 2002 16. Charest AF, McDougall J, Goldstein MB: A randomized comparison of intradermal and intramuscular vaccination against hepatitis B virus in incident chronic hemodialysis patients. Am J Kidney Dis 36:976-982, 2000 17. Propst T, Propst A, Lhotta K, Vogel W, Konig P: Reinforced intradermal hepatitis B vaccination in hemodialysis patients is superior in antibody response to intramuscular or subcutaneous vaccination. Am J Kidney Dis 32:10411045, 1998 18. Fabrizi F, Andrulli S, Bacchini G, Corti M, Locatelli F: Intradermal versus intramuscular hepatitis B re-vaccination in non-responsive chronic dialysis patients: A prospec-

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51. Ortbals DW, Marks ES, Liebhaber H: Influenza immunization in patients with chronic renal disease. JAMA 239: 2562-2565, 1978 52. Osanloo EO, Berlin BS, Popli S, et al: Antibody responses to influenza vaccination in patients with chronic renal failure. Kidney Int 14:614-618, 1978 53. Antonen JA, Hannula PM, Pyhala R, Saha HH, AlaHouhala IO, Pasternack AI: Adequate seroresponse to influenza vaccination in dialysis patients. Nephron 86:56-61, 2000 54. Vogtlander NP, Brown A, Valentijn RM, Rimmelzwaan GF, Osterhaus AD: Impaired response rates, but satisfying protection rates to influenza vaccination in dialysis patients. Vaccine 22:2199-2201, 2004 55. Ahmed AE, Nicholson KG, Nguyen-Van-Tam JS: Reduction in mortality associated with influenza vaccine during 1989-90 epidemic. Lancet 346:591-595, 1995 56. Gilbertson DT, Unruh M, McBean AM, Kausz AT, Snyder JJ, Collins AJ: Influenza vaccine delivery and effectiveness in end-stage renal disease. Kidney Int 63:738-743, 2003 57. Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M: Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med 348:1322-1332, 2003 58. Gurfinkel EP, de la Fuente RL, Mendiz O, Mautner B: Influenza vaccine pilot study in acute coronary syndromes and planned percutaneous coronary interventions: The FLU Vaccination Acute Coronary Syndromes (FLUVACS) Study. Circulation 105:2143-2147, 2002 59. Naghavi M, Barlas Z, Siadaty S, Naguib S, Madjid M, Casscells W: Association of influenza vaccination and reduced risk of recurrent myocardial infarction. Circulation 102:3039-3045, 2000 60. Vilchez RA, McCurry K, Dauber J, et al: Influenza virus infection in adult solid organ transplant recipients. Am J Transplant 2:287-291, 2002 61. Sanchez-Fructuoso AI, Prats D, Naranjo P, et al: Influenza virus immunization effectivity in kidney transplant patients subjected to two different triple-drug therapy immunosuppression protocols: Mycophenolate versus azathioprine. Transplantation 69:436-439, 2000 62. Girndt M, Pietsch M, Kohler H: Tetanus immunization and its association to hepatitis B vaccination in patients with chronic renal failure. Am J Kidney Dis 26:454-460, 1995 63. Kruger S, Muller-Steinhardt M, Kirchner H, Kreft B: A 5-year follow-up on antibody response after diphtheria and tetanus vaccination in hemodialysis patients. Am J Kidney Dis 38:1264-1270, 2001 64. Guerin A, Buisson Y, Nutini MT, Saliou P, London G, Marchais S: Response to vaccination against tetanus in chronic haemodialysed patients. Nephrol Dial Transplant 7:323-326, 1992 65. Huzly D, Neifer S, Reinke P, et al: Routine immunizations in adult renal transplant recipients. Transplantation 63:839-845, 1997 66. Diphtheria, tetanus, and pertussis: Recommendations for vaccine use and other preventive measures: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Morb Mortal Wkly Rep 40:2-28, 1991

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67. Update: Diphtheria epidemic—New independent states of the Former Soviet Union. MMWR Morb Mortal Wkly Rep 45:693-691, 1996 68. Vitek CR, Wharton M: Diphtheria in the former Soviet Union: Reemergence of a pandemic disease. Emerg Infect Dis 4:539-550, 1998 69. Enke BU, Bokenkamp A, Offner G, Bartmann P, Brodehl J: Response to diphtheria and tetanus booster vaccination in pediatric renal transplant recipients. Transplantation 64:237-241, 1997 70. Leach CT: Hepatitis A in the United States. Pediatr Infect Dis J 23:551-552, 2004 71. Niu MT, Polish LB, Robertson BH, et al: Multistate outbreak of hepatitis A associated with frozen strawberries. J Infect Dis 166:518-524, 1992 72. Stark K, Gunther M, Neuhaus R, et al: Immunogenicity and safety of hepatitis A vaccine in liver and renal transplant recipients. J Infect Dis 180:2014-2017, 1999 73. Keeffe EB: Is hepatitis A more severe in patients with chronic hepatitis B and other chronic liver diseases? Am J Gastroenterol 90:201-205, 1995 74. Werzberger A, Mensch B, Kuter B, et al: A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N Engl J Med 327:453-457, 1992 75. Werzberger A, Kuter B, Nalin D: Six years’ follow-up after hepatitis A vaccination. N Engl J Med 338: 1160, 1998 76. Niu MT, Salive M, Krueger C, Ellenberg SS: Twoyear review of hepatitis A vaccine safety: Data from the Vaccine Adverse Event Reporting System (VAERS). Clin Infect Dis 26:1475-1476, 1998 77. Kuramoto I, Fujiyama S, Matsushita K, Sato T: Immune response after hepatitis A vaccination in haemodialysis patients: Comparison with hepatitis B vaccination. J Gastroenterol Hepatol 9:228-231, 1994 78. Lemon SM, Thomas DL: Vaccines to prevent viral hepatitis. N Engl J Med 336:196-204, 1997 79. Keeffe EB: Vaccination against hepatitis A and B in patients with chronic liver disease. Viral Hepat Rev 5:77-88, 1999 80. Fleishmann EH, Kruppenbacher J, Bock HL, Weber M: Active immunization against hepatitis A in dialysis patients. Nephrol Dial Transplant 17:1825-1828, 2002

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