Influenza vaccination in patients with end-stage renal disease.

Review

Influenza vaccination in patients with end-stage renal disease Nicola Principi†, Susanna Esposito for the ESCMID Vaccine Study Group (EVASG)

1.

Introduction

2.

Are patients with ESRD at increased risk of infections?

3.

Is influenza a well-demonstrated risk for

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Emory University on 07/29/15 For personal use only.

ESRD patients? 4.

Immunogenicity of influenza vaccines in ESRD patients

5.

Effectiveness and safety of influenza vaccine in patients with ESRD

6.

Conclusion

7.

Expert opinion

Universit a degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Milano, Italy

Introduction: Patients with end-stage renal disease (ESRD) are considered at higher risk of influenza-related complications and are listed worldwide among the subjects for whom yearly influenza vaccination is strongly recommended. However, influenza vaccination coverage of patients with ESRD is significantly lower than desired. Areas covered: This paper explores why compliance with official recommendations for influenza vaccination is poor in patients with ESRD and analyzes the true risk of infection as well as the immunogenicity, the effectiveness and the safety of influenza vaccination in these patients. Expert opinion: Epidemiological and clinical data support the importance of influenza in conditioning clinical deterioration of patients with ESRD, particularly in relation to their level of immunosuppression. However, the variable levels of immunodeficiency detected in patients with ESRD may reduce the immune response to influenza vaccination, which appears to be lower than that usually found in healthy subjects. However, few studies are available, and they are difficult to compare for several reasons. Additionally, limited data have been collected on influenza vaccine effectiveness, although the available studies support positive results of vaccination on outcomes of severe disease. Despite such limitations, it is important to highlight that all the available studies have confirmed the good safety and tolerability of inactivated influenza vaccines. These findings, together with the risks associated with influenza in these patients, support annual influenza vaccination in patients with ESRD as well as vaccination of their close contacts and should be presented in educational programs organized for nephrologists and patient associations. Keywords: end-stage renal disease, influenza, influenza prevention, influenza vaccination, influenza vaccine, vaccine safety Expert Opin. Drug Saf. (2015) 14(8):1249-1258

1.

Introduction

Patients who undergo renal replacement therapy for end-stage renal disease (ESRD) are at increased risk of infections [1]. Globally, despite significant improvements in recent years regarding preventive and therapeutic measures of infectious diseases, infections remain the second most important cause of hospitalization and death of patients treated with hemodialysis (HD), peritoneal dialysis (PD) and kidney transplantation (KT) [2,3]. Data reported by the United States Renal Data System highlight the importance of infections in these patients. In the USA, where every year since 2002, the number of incident cases of ESRD patients was > 100,000, the hospitalization rates in 2012 of all subjects on HD or PD or with KT varied from 1.6 to 1.8 per patient-year in which 50% of the cases were for an infectionrelated problem [4]. Moreover, it was calculated that in the same year in comparison 10.1517/14740338.2015.1053459 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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N. Principi & S. Esposito

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Patients with ESRD are at increased risk of infections and are considered at higher risk of influenza-related complications. Patients with ESRD are listed worldwide among the subjects for whom yearly influenza vaccination is strongly recommended; however, their vaccination coverage is significantly lower than desired. Uremia, volume overload, comorbidities, iron accumulation and malnutrition play a role in negatively influencing immune system function in patients with ESRD. A global evaluation of the available data seems to indicate that in patients with ESRD, the immune response to influenza vaccination is lower than that usually found in healthy subjects. Pooled analysis of data on influenza vaccine effectiveness in patients with ESRD initially seemed very satisfactory because most of the outcomes were found to be positively influenced by TIV administration; however, the quality of the studies appeared low. All the inactivated influenza vaccines appeared safe because no risk for transplant rejection or renal function deterioration has been documented after vaccination. Influenza prevention through vaccination appears to be a priority in patients with ESRD, and further studies along with educational programs are needed to prevail upon nephrologists and patients. It is also extremely important to vaccinate close contacts and household members of ESRD patients to further protect these vulnerable subjects.

This box summarizes key points contained in the article.

to the previous year, whereas hospital admissions due to other causes decreased, those due to infections globally rose by 21.8%. The highest increase was evidenced among HD patients, for whom hospitalization rose by 34% [4]. These data, notable per se, probably underestimate the total burden of infectious diseases in ESRD patients because mild-to-moderate infections are frequently managed outside the hospital and are not considered in the number of those included in the official surveys. The same seems to be true for that proportion of serious infections for which patients may receive intravenous and/or intraperitoneal antibiotics outside the hospital [5]. Fortunately, mortality rates for infections in ESRD patients declined by 36% from 2003 to 2012; however, they remained a significant medical and social problem because in 2012, ~ 140 cases of death per 1000 patient-years occurred [6]. Most of these deaths were due to bacterial infections, mainly pneumonia and sepsis, which have been demonstrated to occur 10- [7] and 100-fold [8] more frequently than in the general population, respectively. Influenza is a common infectious disease that affects a great number of people worldwide every year. Periodic pandemics due to previously unknown viruses may cause millions of deaths [9]. Seasonal influenza due to viral strains already 1250

known or with marginal genetic variations from those previously circulating generally cause mild-to-moderate disease in healthy subjects. However, in young children, in the elderly and in patients with chronic underlying disease of any age, seasonal influenza and its complications may be very severe and may lead to an increased number of hospitalizations, admissions to intensive care units (ICU) and deaths [10-12]. Patients with ESRD are considered at higher risk of influenza-related complications and are worldwide included in the list of subjects for whom yearly influenza vaccination is strongly recommended [13]. However, as frequently occurs in subjects at increased risk of influenza-related complications [14], influenza vaccination coverage of patients with ESRD is significantly lower than desired. Official US data indicate that despite having slowly improved over the past decade, in the last 3 years, the vaccination rates of subjects with ESRD remained ~ 65%, without any further incremental increase [15]. Coverage was highest in older age groups and was only 40% among pediatric patients. The vaccination rate was slightly higher in patients with HD (72%) than in those in PD (68%), whereas KT patients received the vaccine only in ~ 50% of the cases [15]. The main aim of this paper is to attempt to investigate why compliance with the official recommendations for influenza vaccination is poor in ESRD patients. The problems that must be solved to convince nephrologists that influenza vaccination is an essential preventive measure for patients with ESRD will be discussed. In particular, the true risk of infection as well as the immunogenicity, the effectiveness and the safety of influenza vaccination in these patients will be analyzed.

Are patients with ESRD at increased risk of infections?

2.

It has been established that with the development of renal insufficiency, significant modifications of immune system function invariably occur. Their importance increases in parallel to uremia and reaches the highest level when renal replacement therapy is required [16]. Uremia leads to immune system activation and dysfunction in association with systemic inflammation, oxidative stress and a significant reduction of host defenses. Inflammation and oxidative stress are the consequences of the activation of the innate immune system and contribute to atherosclerosis, cardiovascular disease and cachexia that are constantly present in ESRD patients [16]. The development of inflammation and oxidative stress is associated with overall expansion of the monocyte population, increases in Toll-like receptor (TLR)-2 and TLR-4 expression, increased cytokine production and increased reactive oxygen species (ROS) generation [17,18]. Moreover, strongly contributing to the development of these conditions are the impaired inhibitory activity of regulatory T cells [19,20], the activation of polymorphonuclear leukocytes, the upregulation of the ROS production machinery [21] and the increased pro-inflammatory

Expert Opin. Drug Saf. (2015) 14(8)


Influenza vaccination in patients with end-stage renal disease

activity of low-density lipoproteins, along with the reduced anti-inflammatory capacity of high-density lipoproteins [22,23]. Impaired immune system function leads to poor responses to antigen stimulation, including those strictly linked to vaccine administration, and to impaired host defenses against infectious agents. Innate immunity impairment is marked by the decreased phagocytic activity of monocytes, macrophages and neutrophils [24], along with a depleted and dysfunctional population of dendritic cells [25]. Impaired adaptive immunity is marked by a reduced CD4/CD8 ratio, an increased Th1/ Th2 ratio and the depletion of naive and central memory CD4+ and CD8+ T cells. Down-regulated antigen receptors, such as CD28 and CD69, may also lead to weakened T-cell responses to microorganisms [26]. Moreover, the higher Th1 to Th2 ratio increases IL-4 and IL-10 secretion, which inhibits cellular immune responses [27]. Additionally, ESRD is accompanied by the aging of both the CD4+ and CD8+ T-cell populations. Lymphopenia, which is often observed, is the primary condition associated with decreases in the number of naive T cells due to decreased T-cell production and increased apoptosis in the thymus [28]. Finally, the B-cell population may also be depleted, leading to impaired humoral immunity [28]. However, uremia is the most important but not the only reason that explains the insufficiency of immune system activities in patients with ESRD. Volume overload, comorbidities such as hyperparathyroidism, iron accumulation and malnutrition play a role in negatively influencing immune system function [29]. Moreover, dialysis is an independent factor that further reduces immunity. Both PD and HD disrupt the cutaneous barrier against infectious agents and are associated with increased risk for bacteremia, exit-site infections or peritonitis [30-32]. Moreover, they frequently cause severe hypogammaglobulinemia due to immunoglobulin loss in the dialysate [33]. Age may add further limitations, particularly when ESRD occurs in aged individuals with senescence of the immune system [34] or in very young children who already have a physiologically immature immunity [35]. Finally, in subjects receiving strong immunosuppressive regimens, particularly KT patients in the first months after transplantation, drugs induce further immune problems that effectively preclude adequate host responses against infectious agents or vaccine antigens [36].

Is influenza a well-demonstrated risk for ESRD patients?

3.

An association between influenza infection and acute kidney allograft rejection has been repeatedly reported [37-39], suggesting a strict relationship between the influenza virus infection and the development of a severe clinical problem in KT patients. This conclusion cannot be modified by the results of the studies that have evaluated the impact of influenza on morbidity and mortality of KT patients even if they have not always been in agreement with those regarding rejection.

Kumar et al., who studied the impact of the recently emerged A/H1N1v pandemic virus infection in a group of 237 adults and children with solid organ transplantation (37% KT), reported that morbidity and mortality were independent from the type of transplant with consequent hospitalization, admission to the ICU and death in 71, 16 and 4% of the cases, respectively [40]. In a small group of adult KT recipients, Vilchez et al. observed that the risk of hospitalization during a seasonal epidemic was 4.3 cases/1000 person-years, a value not different from those historically reported for the population >65 years of age but significantly higher than those found in the healthy population of the same mean age as the KT recipients [41]. Conversely, quite different results were obtained in the study by Camargo et al., who retrospectively reviewed and compared the clinical presentation, morbidity and mortality of all KT and healthy subjects (non-KT) admitted for at least 12 h with a diagnosis of influenza virus infection in a single hospital during the 2009 pandemic and who found similar characteristics and outcome of the disease in the two groups of subjects [42]. Moreover, no differences in the rate of ICU admission (22.7 vs 22.6%, respectively) or hospital mortality (9.1 vs 7.5%, respectively) were observed. The data are scarce and conflicting regarding the total burden of influenza in ESRD patients on HD or PD. In a review published in 2009 regarding influenza in immunocompromised populations, Kunisaki and Janoff reported that no previous study regarding the specific frequency of influenza infection and influenza-specific mortality rates in HD and PD patients could be identified in the scientific literature [43]. Only after the development of the most recent influenza pandemic have some data been collected in this regard. Marcelli et al. compared the mean hospitalization rate and mortality of the general, previously healthy population with those of patients in dialysis after the first wave of the pandemic [44]. They found that whereas in healthy individuals the hospitalization rate was estimated to be from 5 to 7% of infected people with a mortality rate of 0.2 -- 0.5%, these values were significantly higher in dialysis patients in whom they were 34% and ~ 5%, respectively. Data on influenza in HD patients were collected in subjects in several developing countries and compared with those reported for the general population in industrialized geographic areas by other authors [45,46]. Although these data showed the increased risk of influenza-related complications in HD patients, considering that infection control is less efficient in developing countries than in those with well-developed health systems, it is not possible to compare patients evaluated in different settings.

Immunogenicity of influenza vaccines in ESRD patients

4.

A great number of studies have evaluated the immunogenicity of influenza vaccination in patients with ESRD on HD, PD or KT. Only the inactivated vaccines, both the traditional


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inactivated trivalent influenza vaccine (TIV) and the recently developed monovalent pandemic A/H1N1v vaccines, were tested [47-60]. The live attenuated influenza vaccine, despite being more immunogenic than the inactivated form, was not evaluated because it is based on live viruses and it is not licensed for use in immunocompromised patients because of the risk of inducing severe influenza disease [61]. A global evaluation of the available data seems to indicate that in patients with ESRD, the immune response to influenza vaccination is lower than that usually found in healthy subjects. Only a minority of the studies concluded that the immune response was equivalent between patients and healthy controls [62-67]. In most of the cases, lower seroprotection and seroconversion rates and lower geometric mean antibody titers (GMT) were evidenced. This was observed with both TIV and pandemic vaccines, in adults and children, with whichever vaccine was used [57,68-70]. A good example with respect to the use of the traditional TIV is provided by the study by Vogtla¨nder et al., who found that TIV administration was associated with a fourfold rise in serum HI titers in significantly lower percentages of HD adult patients than in healthy controls (p < 0.05) [68]. Regarding the administration of A/H1N1v pandemic vaccine, the data collected by Chang et al. indicate that the efficacy of a standard single 15-µg dose of non-adjuvanted monovalent A/H1N1v vaccine in 110 vaccine-naive HD patients and 173 healthy participants was significantly lower than that found in healthy controls [57]. The seroconversion rates and the fold increase in GMT after vaccination were 25.4% and 1.8 in the adult (18 -- 60 years old) HD subgroup, and 23.4% and 1.8 in the elderly (>60 years old) HD subgroup, whereas in the corresponding healthy control subgroups, they were 92.5% and 32.9 in adults and 73.6% and 10.8 in aged individuals (p < 0.001 for both subgroups), respectively. Similar differences were reported with the same vaccine by Ott et al. [69] and Lertdumrongluk et al. [70]. No more satisfactory were the results of the studies that have evaluated the immunogenicity of the pandemic vaccine in children and adolescents with ESRD. Satisfactory results were obtained only in studies in which few children were enrolled and in which no control group of healthy subjects was included [71,72]. Gavalda et al. [71] and Donmez et al. [72] studied 17 KT children and 25 pediatric patients on HD or PD who received a dose of an adjuvanted vaccine and a dose of non-adjuvanted vaccine, respectively. In both cases, the seroconversion and seroprotection rates were considered adequate, although some children, particularly those with KT, did not develop protective titers. By contrast, negative results were reported by Kelen et al. [73] and Esposito et al. [74]. Kelen et al. used a monovalent whole-virus vaccine and monitored the immune response of 37 children and adolescents with KT, concluding that a single injection might not be sufficient to achieve protection [73]. Esposito et al. evaluated the immunogenicity of the pandemic influenza A/H1N1v MF59-adjuvanted vaccine administered sequentially or 1252

simultaneously with seasonal virosomal-adjuvanted influenza vaccine in 32 pediatric KT recipients and 32 controls [74]. They found that when the pandemic vaccine was administered sequentially to the seasonal vaccine, it was significantly less immunogenic than in controls (p < 0.05). Interestingly, when it was administered together with the seasonal vaccine, the immune responses of both the patients and the controls were significantly greater than when it was administered sequentially (p < 0.05 in both groups) [74]. However, despite the increase, antibody levels in the KT group remained significantly lower than that of the controls. The poor immune response of ESRD patients to influenza vaccines seems to be further confirmed by the studies in which adjuvanted preparations of the pandemic vaccine were used. In healthy subjects, the addition of adjuvants permits the development of an antibody response that is quite similar to that evoked by the standard amount of influenza virus antigens even if the antigen dose is reduced to one-quarter [75]. A number of studies have found that vaccines with this composition were not effective in patients with ESRD, and to obtain a satisfactory immune response, the amount of antigens could not be reduced below 50% of the standard dose [53-55]. Labriola et al. [53], Broeders et al. [54], and Crespo et al. [55] tested in HD patients and in healthy controls a vaccine containing only 3.75 µg of each of the viral antigens together with a squalene-based adjuvant and found that whereas the seroprotection rates of healthy subjects were 93.8, 90.0 and 81.8%, those of patients with ESRD were only 64.2, 57.0 and 33.0%, respectively. Differences were no more evident in the study by Temiz et al. who, using an adjuvanted vaccine containing 7.5 µg hemagglutinin of each antigen, observed a positive response in 97.1% of the HD patients [52]. Alternatively, the need for an amount of antigens significantly higher than that used in healthy subjects to obtain satisfactory immune responses to influenza vaccine in HD patients has been suggested previously by Rautenberg et al. using TIV [76]. Finally, the poor immune response of ESRD subjects to influenza vaccines is confirmed by the demonstration that the administration of booster doses does not significantly increase seroconversion and seroprotection rates or the GMT titers obtained after the first dose [68,77,78]. Tanzi et al. [77] and Versluis et al. [78], using an adjuvanted and a nonadjuvanted TIV, respectively, reported that the booster dose was accompanied only by a marginal, statistically insignificant increase in all the studied immune parameters. Finally, Vogtla¨nder et al. reported that the booster administration was associated with a significant increase in the seroprotection rate only against the A/H3N2 strain but not against the other strains [78]. However, in some of the apparently negative studies, the antibody production after booster administration was deemed high enough to allow protection in a satisfactory number of cases [67,79].



Effectiveness and safety of influenza vaccine in patients with ESRD


5.

Several studies were performed to evaluate whether the immune response evoked by influenza vaccines in ESRD patients could be translated into the prevention of influenza disease and its complications. Regarding those studies that considered patients with HD or PD, a recent systematic review and meta-analysis has demonstrated that only five studies could be considered for a reliable evaluation of the true efficacy/effectiveness of influenza in these subjects because they included not only patients receiving the vaccine, but also control participants who were either unvaccinated or received placebo [80-85]. Different clinical outcomes were studied. All-cause mortality, all-cause hospitalization and hospitalization due to influenza or pneumonia were addressed by at least two studies, whereas outcomes such as cardiac death, infectious death, hospitalization due to bacteremia, viremia or septicemia, hospitalization due to respiratory infection, ICU admission or the development of influenza-like illness were reported by one study each. Pooled analysis initially seemed very satisfactory because most of the outcomes were found to be positively influenced by TIV administration. All-cause mortality and cardiac death were significantly reduced in vaccinated patients with a vaccine effectiveness (VE) of 32% (95% CI 24 -- 39) and 16% (95% CI 2 -- 29), respectively. Moreover, regarding hospitalization, significant protective effects of influenza vaccination against hospitalization due to influenza or pneumonia and ICU admission were evidenced. In these cases, VE rates were 14% (95% CI 7 -- 20) and 81% (95% CI 63 -- 86), respectively. However, when the risk of bias in the included studies and the quality of the respective body of evidence were assessed, it was demonstrated that all the studies had some problems [80]. Risk of bias was high in four studies and unclear in the fifth. Moreover, the quality of the body of evidence was graded as very low. Inappropriate adjustment for confounders and unclear baseline imbalance of unvaccinated subpopulations were the most important methodological problems. Moreover, some results could per se indicate the presence of residual confounding factors. McGrath et al., who found a protective effect of TIV against all-cause mortality, reported a similar significant protective effect for the same outcome also in the period during which influenza virus did not circulate (VE 55%, 95% CI 50 -- 59) [81]. Similarly, a positive effect of TIV was found offseason for the effect on hospitalization due to pneumonia (VE 26%, 95% CI 15 -- 36) [81]. Finally, the effect on influenzalike illness was higher off-season than during influenza season [81]. When all these problems were considered, Remschmidt et al. concluded that evidence for the protective effect of TIV in patients with ESRD treated with HD or PD had to be considered as limited and of very low quality and only further studies using a randomized or quasiexperimental design would be required to solve the problem

of the true effectiveness of influenza vaccines in these subjects [80]. With respect to safety, no study comparing safety outcomes between vaccinated and unvaccinated ESRD patients was ever performed, which does not permit drawing definitive conclusions in this regard. However, considering that in healthy subjects influenza vaccines are generally safe and well tolerated and that in those studies in which the impact of influenza vaccine administration was compared between ESRD patients and healthy subjects, no difference in the incidence of adverse events was evidenced, it could be concluded that the risk of development of influenza vaccine-related severe clinical problems in ESRD patients is very low. This seems to be true for both adults and children [67,86-91]. Moreover, these studies have shown that, contrary to what has been anecdotally suggested, there is no clinical association between influenza vaccination and acute rejection in KT patients and no risk of decrease in renal function after influenza vaccination. 6.

Conclusion

Although patients with ESRD are considered at risk of influenza-related complications, and for this reason they are included among the high-risk patients for whom annual influenza vaccination is recommended by health authorities, their vaccination coverage remains very low. Several factors could explain this low compliance to the official recommendation, although the concerns regarding the actual immunogenicity, the effectiveness and the safety of influenza vaccines in these patients by patients themselves, their parents and their physicians play the major role. A good example in this regard is given by the study by Printza et al., who evaluated the acceptance of pandemic influenza A 2009 vaccination in a group of high-risk children with chronic renal diseases and found that vaccination rates were 57.1% for KT patients, 61.5% for patients on PD, 36.4% for patients with various stages of chronic renal disease and 26.7% for patients with glomerulonephritis on immunosuppressive therapy [92]. Children with KT or on PD had a fourfold higher rate of being vaccinated than children with nephritis (p = 0.04). Causes of denying vaccination included fear of adverse effects (48.9%), lack of sufficient data on the new vaccine (31.9%) and others (19.2%). Patients being vaccinated were all urged by their pediatric nephrologist (100%), while patients not vaccinated were negatively influenced by media (41.4%), friends (24.1%), pediatrician (20.7%) and others (13.8%). The pediatric nephrologists had the most significant positive influence in contrast to the media which had the most negative influence. However, the behavior of physicians that negatively influence acceptance of vaccination seems not justified because immunogenicity and effectiveness of influenza vaccines appear acceptable, particularly if influenza risks are adequately considered. Moreover, all the inactivated influenza vaccines appeared safe because no risk of transplant rejection or renal function deterioration has been documented after


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vaccination. Consequently, influenza prevention through vaccination appears to be an absolute priority in these patients. Furthermore, it is extremely important to vaccinate their close contacts and household members to further protect these vulnerable subjects.


7.

Expert opinion

Patients with ESRD regardless of their age are at increased risk of infections due to high uremia and several other underlying conditions that may reduce the efficiency of their immune system. This explains why the use of preventive measures is extremely relevant to avoid severe preventable infectious complications. Epidemiological and clinical data support the importance of influenza in conditioning clinical deterioration of these patients, particularly in relation to their level of immunosuppression. However, the variable levels of immunodeficiency detected in patients with ESRD are able to reduce the immune response of influenza vaccination, which appears to be lower than that usually found in healthy subjects. Unfortunately, the available studies are scarce and difficult to compare for several reasons. First, tested vaccines were frequently quite different from each other in general characteristics (i.e., whole virus, split and sub-unit vaccines), antigen content and the presence and type of adjuvants. Second, evaluation of the immune response was not uniform because in some cases, it was limited to the analysis of seroconversion and/or seroprotection rates and in other cases extended to the measurement of the cell-mediated response. Moreover, different methods for antibody response evaluation were used. Third, the importance of the preexisting level of specific antibodies and the mismatch between circulating influenza strains and those included in the tested vaccine were not always adequately considered. Finally, whereas in all of the studies patients with ESRD were included, their characteristics were frequently quite different regarding the duration of kidney replacement therapy and/or the drugs they were receiving when the vaccine response was evaluated. Additionally, limited data have been collected on influenza vaccine effectiveness, although the available studies support the positive results of vaccination on outcomes of severe disease.

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Several new influenza vaccines have been developed in recent years. Unfortunately, live attenuated influenza vaccines do not seem to be appropriate for patients with ESRD due to their immunodeficiency. By contrast, adjuvanted or intradermal vaccines with an increased amount of antigens appear to have the ideal characteristics to increase the immune response and the potential efficacy of vaccination in these patients. These new formulations could be used also when additional antigens are included in the vaccine, as in the quadrivalent inactivated influenza vaccination. However, only adequate controlled studies may address this issue, although such studies are difficult to perform due to the large number of patients required. Alternatively, specific studies could be useful in persuading nephrologists and the patients themselves of the utility of influenza vaccination. These studies should consider different age groups (i.e., children, adults and the elderly), various ESRD categories (i.e., patients treated with HD, PD and KT), different immunosuppressive treatments and previous influenza vaccination status (i.e., patients previously unvaccinated and those vaccinated annually for several years). These studies should include immunogenicity, safety and tolerability evaluations, along with analyses of efficacy and the cost/benefit ratio. Despite the limitations reported above, it is important to highlight that all the available studies confirmed the good safety and tolerability of inactivated influenza vaccines. These findings, together with the risks associated with influenza in these patients, support their annual influenza vaccination as well as the vaccination of their close contacts and should be presented in educational programs organized for nephrologists and patient associations.

Declaration of interest This work was supported by Italian Ministry of Health (Bando Giovani Ricercatori 2009). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed



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Affiliation

Nicola Principi†, Susanna Esposito for the ESCMID Vaccine Study Group (EVASG) † Author for correspondence Universita degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Via Commenda 9 20122, Milano, Italy Tel: +39 02 55032203; Fax: +39 02 50320206; E-mail: [email protected]

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Cefpodoxime proxetil in patients with endstage renal failure on hemodialysis.

Renal transplantation dramatically reduces IgA anti-beta-2-glycoprotein I antibodies in patients with endstage renal disease.

Influenza vaccination perception and coverage among patients with malignant disease.

The Endstage Renal Disease Severity Index (ESRD-SI).

Influenza vaccination in asthmatic patients.

Influenza vaccination in oncology patients.

Influenza vaccination coverage in children with inflammatory bowel disease.

Immunogenicity of Influenza Vaccination in Patients With Cancer.

Influenza vaccination in north Indian patients with heart failure.

Swine influenza virus vaccination in patients with multiple sclerosis.

Safety and tolerability of intradermal influenza vaccination in patients with cardiovascular disease.

Influenza and Pneumococcal Vaccination Rates in Patients With Inflammatory Bowel Disease.

Coeliac lung disease and influenza vaccination.

Acute renal failure after influenza vaccination: a case report.

Influenza vaccination in patients with cancer: factors associated with vaccination practices for patients and their household members.

New technique for the treatment of endstage renal failure.

Influenza vaccination in adults with cystic fibrosis.

Apolipoprotein B attenuates albuminuria-associated cardiovascular disease in prevention of renal and vascular endstage disease (PREVEND) participants.

Influenza vaccination of primary healthcare physicians may be associated with vaccination in their patients: a vaccination coverage study.

Henoch-Schönlein purpura in a renal transplant recipient with prior IgA nephropathy following influenza vaccination.

Influenza vaccination.

Influenza vaccination in asthma.

Influenza vaccination in asthma.

Influenza vaccination in children at high risk of respiratory disease.