Vaccine 32 (2014) 6601–6606

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Vaccine administration in children with chronic kidney disease Susanna Esposito ∗ , Maria Vincenza Mastrolia, Elisabetta Prada, Carlo Pietrasanta, Nicola Principi Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda 9 20122, Milano, Italy

a r t i c l e

i n f o

Article history: Received 2 May 2014 Received in revised form 23 June 2014 Accepted 19 September 2014 Available online 29 September 2014 Keywords: Chronic kidney disease Dialysis Renal transplantation Vaccination Vaccines

a b s t r a c t Pediatric patients with severe chronic kidney disease (CKD) on conservative treatment, on dialysis, and those with renal transplantation are at a higher risk for infectious diseases as the result of impaired immune responses against infectious agents. Infections in these patients can have drastic consequences for disease morbidity and mortality. Immunization is a crucial preventive strategy for disease management in this pediatric population. However, vaccination coverage among children with CKD remains low due to safety concerns and doubts about vaccine immunogenicity and efficacy. In this study, we reviewed why children with CKD are at higher risk of infections, the importance of vaccinations among these children, barriers to vaccinations, and recommend the best vaccination schedules. Overall, vaccines have acceptable immunogenicity, efficacy, and safety profiles in children with CKD. However, in some cases, the protective antibody levels induced by vaccines and the benefits and risks of booster vaccine doses must be individually managed. Furthermore, close contacts and household members of these children should complete age-appropriate vaccination schedules to increase the child’s indirect protection. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction Children are at an increased risk for infection, particularly in their first years of life, due to their immature immune systems [1]. Pediatric patients with severe chronic kidney disease (CKD), particularly those in stages 3–5 of the Kidney Disease Improving Global Outcomes workgroup classification [2] who are on conservative treatment, on dialysis, or have received renal transplantation (RT), are at an even higher risk because of their defective immune system responses against infectious agents [3–14]. Vaccines are the safest and most effective method for reducing the risks for many common severe infections. Immunization recommendations for children with CKD typically reflect those for healthy children but also include influenza and pneumococcal vaccines. The latter two vaccines are often recommended due to possible influenza and pneumococcal infection-related complications [13,15–17]. However, live vaccines are not recommended for patients receiving highly immunosuppressive therapy, including RT patients [16,17]. Despite recommendations, vaccination coverage in children with CKD is much lower than desired. In the US, a 2013 study showed that influenza and pneumococcal vaccinations among children

∗ Corresponding author. Tel.: +39 02 55032498; fax: +39 02 50320206. E-mail address: [email protected] (S. Esposito). http://dx.doi.org/10.1016/j.vaccine.2014.09.038 0264-410X/© 2014 Elsevier Ltd. All rights reserved.

with chronic renal failure remained low [18] despite the inclusion of these vaccines as quality and performance indicators for ESKD facilities by Medicaid [19]. Only a third of children on dialysis or with RT who were 14 years or younger received the influenza vaccine between 2008 and 2011 [18]. Influenza vaccination rates were higher (43%) among adolescents aged 15–19 years and did not significantly vary by race. Among adolescents, vaccination rates were generally higher in children on hemodialysis than those on peritoneal dialysis or undergoing RT [18]. Pneumococcal vaccination rates were even lower during the same time period; about 20% of adolescents and just 10% of children received pneumococcal vaccinations [18]. In this review, we discuss why children with CKD are at a higher risk for infections, the importance of vaccinations among these children, barriers to vaccinations, and recommend the best vaccination schedules for different groups of children with CKD. 2. Children with CKD are at an increased risk for infections There are several reasons behind the increased risk for infections in children with CKD. Peripheral edema and the loss of complement pathway factors in the urinary tract contribute to the risk for infection in nephrotic syndrome [3]. Moreover, a number of kidney diseases, including idiopathic glomerular diseases and autoimmune-related kidney diseases, are managed with systemic

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immunosuppressive therapy that predisposes to infection [4]. The same is true of RT patients who take immunosuppressive drugs for long periods of time [5]. Most patients with CKD suffer from malnutrition, increased intracellular calcium, iron overload, and uremic toxins, all of which contribute to impaired innate and adaptive immune responses. Impaired innate immunity is marked by decreased phagocytic activity of monocytes, macrophages, and neutrophils [6,7] as well as a depleted and dysfunctional population of dendritic cells [8]. Impaired adaptive immunity is marked by abnormal B and T cells, particularly the Th cell population of CD4+ T cells. Downregulated antigen receptors, such as CD28 and CD69, may also lead to weakened T cell responses to microorganisms [9]. Changes in subpopulations of Th cells can also occur; a higher Th1 to Th2 ratio increases interleukin (IL)-4 and IL-10 secretion, which inhibits cellular immune responses [10]. In addition, end-stage renal failure 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 naïve T cells due to decreased T cell production and increased apoptosis in the thymus. Finally, the B cell population can also be depleted, leading to impaired humoral immunity [11]. Dialysis contributes a number of potential risks for infection. Both peritoneal dialysis and hemodialysis disrupt the cutaneous barrier against infectious agents and is associated with increased risk for bacteremia, exit-site infections, or peritonitis [12–14]. Moreover, dialysis frequently results in severe hypogammaglobulinemia due to immunoglobulin loss in the dialysate [12–14]. Infections in children with CKD on conservative treatment, on dialysis, or with RT can have drastic consequences. Infections are the second leading cause of morbidity and mortality in children with chronic renal failure and account for 25 deaths per 1000 patient-years. The highest incidence of infection-associated morbidity and mortality is found in patients less than 2 years old who are undergoing dialysis [20]. Hospitalization for infections is common in all these patients and has significant medical, social, and economic costs. In the USA, rates of hospitalization for infections were 500 and 600 per 1000 patient-years for children with renal failure between 2001 and 2005 and 2006 and 2010, respectively; rates were highest among children younger than 9 years old who were undergoing peritoneal dialysis [18].

3. Vaccine-preventable infections in children with CKD Most studies of infectious diseases among children with CKD were conducted several years ago when vaccine availability and coverage was significantly lower than in recent years, even in industrialized countries. These studies reported that vaccinepreventable infectious diseases were more common in children with CKD on conservative treatment, on dialysis, or undergoing RT [15,21–28]. In recent years, widespread vaccination in the general pediatric population has significantly reduced the circulation of vaccine-preventable infections, which indirectly reduces the risk for infections in children with chronic renal failure. However, the number of children with chronic renal failure at an increased risk for severe infections remains high since vaccination coverage among these children is poor [18]. Furthermore, influenza, measles, varicella, and hepatitis B (HB) vaccination are not universally recommended or included in the immunization schedules of infants and children [29–32]. This further exacerbates the problem for children with chronic renal failure since the proportion of the general pediatric population vaccinated against these diseases remains low.

4. Barriers to vaccination among children with CKD Several factors can explain the poor vaccination coverage among children with CKD. Frequent hospitalizations can hinder recommended immunization schedules and explain delays in vaccination. In addition, vaccines that are not provided by the national health system for free cannot be obtained by many families due to their relatively high cost. Limited knowledge among families and health care providers about the importance of vaccination may also contribute to poor vaccination coverage. However, the most important explanation for low vaccination coverage may be concerns about the safety, immunogenicity, and efficacy of vaccines [33]. 4.1. Vaccine safety Vaccine safety among children with CKD is comprised of four potential risks: graft rejection after RT, reduced dialysis efficacy, acceleration of renal function decline, and live vaccine-induced infection in severely immunocompromised patients. Fortunately, many studies have addressed these concerns. The use of any inactivated or live attenuated vaccines in children with RT has not been found to increase rates of graft rejection [13,34–37]. Similarly, vaccinations have not been shown to reduce dialysis efficacy [13,25,35]. Studies have also not found negative associations between vaccination and renal deterioration [13,25,36]; however, children with nephrotic syndrome may be at an increased risk of relapse when receiving polysaccharide conjugate or HB vaccines. One study reported a higher number of relapses among children with steroid sensitive nephrotic syndrome (SSNS) who received the meningococcal C (MC) vaccine, which is comprised of a bacterial polysaccharide conjugated to a carrier protein [38]. This led to the hypothesis that complex antigens, such as that of the MC vaccine, could stimulate T cells, leading to cytokine disturbances, increased glomerular damage, and clinical relapse. However, no associations with relapse have been reported for other vaccines comprised of “complex antigens”, including Haemophilus influenzae type b, pneumococcal, and ACYW135 meningococcal vaccines [39,40]. Moreover, another study did not observe an increased number of SSNS relapses before and after children received the same MC vaccine [40]. The increased risk for relapse in children with nephrotic syndrome has also been reported for the HB vaccine [41,42]. The relapse rates of 41 children with SSNS were lower pre-vaccination (0.12 ± 0.19 per month) than post-vaccination (0.4 ± 0.12 per month; p = 0.002). However, these data should not limit the use of the HB vaccine in children with nephrotic syndrome since immunocompromised individuals are at a higher risk of chronic HB virus infection [43]. Chronic HB virus infection in patients with SSNS is particularly high, especially in endemic areas [44]. The same conclusion can be drawn for conjugate vaccines since children with nephrotic syndrome are at a higher risk of infections caused by capsulated bacteria, particularly Streptococcus pneumoniae [45]. Most of the available data indicates that live attenuated vaccines are safe in children with CKD on conservative treatment or on dialysis [46]. Live attenuated vaccines are not recommended for children receiving high-dose, long-term immunosuppressive treatment before and after RT [16,17]. However, several studies have suggested that live attenuated vaccines are safer than previously expected in such children. In one study, none of the 17 renal RT recipients (2–18 years old) who received a single dose of the varicella vaccine developed chicken pox during the immediate post-vaccination period [47]. Similarly, in another study, none of the adolescent RT recipients who received a booster vaccination against measles, mumps, and rubella (MMR) suffered adverse events [13]. Finally, in the third study, none of the six children who had recently undergone RT and received one or two doses of

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varicella vaccine experienced severe adverse events following vaccination [48]. In addition, only a limited number of mild adverse events were reported among pediatric patients who received MMR vaccines 1.5–173 months after liver or small intestine transplantation, and no relevant infections were reported [48–51]. The most important mild adverse effects in these studies were fever and skin rash, both of which were spontaneously resolved in few days [47–50]. Despite their low risk for relevant clinical problems after receiving live attenuated vaccines, pediatric solid organ transplant recipients should only be administered these vaccines with caution. One prudent approach could be to wait for 1 year after transplant before administering live attenuated vaccines; furthermore, patients taking highly immunosuppressive regimens or exhibiting any evidence of acute rejection should be excluded [52]. Alternatively, live attenuated vaccines could follow current vaccine recommendations for children with major primary immunodeficiency disorders (i.e., children with ≥500 CD4 cells/␮L, ≥200 CD8 cells/␮L, and a normal mitogen response or those with CD4 cells/␮L ≥25%) [53]. 4.2. Vaccine immunogenicity Many studies have evaluated the immunogenicity of vaccines in children with CKD. In most of the cases, children with CKD on conservative treatment or on dialysis did not have significantly different vaccine immune responses than healthy subjects. Protective immune responses were observed for both primary vaccination series and booster shots as well as both inactivated vaccines and live attenuated vaccines, which suggests that these children are generally protected from all vaccine-preventable diseases [54–59]. However, children suffering from nephrotic syndrome may have reduced antibody production and could remain unprotected after standard vaccine administration. In one study, most children with idiopathic nephrotic syndrome who received the heptavalent pneumococcal conjugate vaccine (PCV7) developed serotype-specific antibodies which persisted for 12–14 months, although it was at lower levels for four of the seven serotypes. Inferior immunogenicity for three of the seven serotypes was observed in children who were also taking immunomodulators [39]. Reduced immune responses have also been reported in children with SSNS who received the HB vaccine [42]. In that study, HB seroconversion rates and the number of subjects with a protective titer of 10 mIU/mL or greater for antibody against HBsAg (anti-HBs) were lower among children who were taking steroids and also those who were not taking immunosuppressants; this suggested that SSNS was the major cause of their impaired immune responses. Children on dialysis also have a reduced immune response to PCV7 with post-vaccination antibody concentrations only 40% higher than baseline concentrations [60]. Similarly, the MMR vaccine was able to induce adequate antibody responses to all the antigens in only three of ten children on dialysis although antibody responses were observed to measles in eight children, mumps in five children, and rubella in eight children [61]. The duration of protection offered by standard vaccine administration is shorter for children with CKD on conservative treatment and those with ESKD on dialysis than for healthy children [62,63]. In one study, only 26% of children with ESKD on dialysis had protective antibodies against measles, mumps, rubella, varicella, HB, diphtheria, and tetanus [62]. Protection against HB was particularly low, and children younger than 4 years had significantly lower protective antibody titers than older children for almost all the vaccine-preventable diseases. Another study showed that children who were completely vaccinated 6 months to 6 years prior to RT had higher protective antibody titers against all pathogens than

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those who were vaccinated more than six years before RT [63]. In Turkey, antibody titers were analyzed among children (mean age, 10.8 years; age range, 2–17 years) who had been admitted to a transplant center for RT. These children had received ageappropriate vaccinations but only 84.3% had antibodies positive for HB, 76.5% for hepatitis A, 72.5% for measles, 64.7% for mumps, 64.7% for rubella, and 72.5% for varicella [63]. The relevance of the moment of vaccine administration in conditioning duration of vaccine protection has been recently confirmed by Sheth et al. [64] who assessed HB immunity in a group of 202 CKD pediatric patients on dialysis and found that patients immunized after starting dialysis had a hazard ratio of 6.13 for HB immunity loss compared to patients immunized as infants (p < 0.001). All these data explain why several experts suggest that in these children antibody titers should be periodically monitored and eventually boosted with another vaccine dose if needed [62–64]. Children who received RT can have an even greater risk for moderately or severely impaired immune responses and can remain unprotected after vaccine administration. In one study, only 64% of children who received RT achieved seroprotection rates after receiving the HB vaccine compared to 100% and 94% of children with CKD on conservative treatment and those with ESKD on dialysis, respectively [65]. In addition, only 30% of children and adolescents who received RT achieved seroprotection to the A/H1N1 pandemic influenza vaccine for an overall seroconversion rate of 18.7% [66]. Antibody levels also decrease faster than expected in children after RT. In one German study, antibody titers against diphtheria, tetanus, and HB, but not varicella, significantly decreased between 1 year and 2 years after immunization in children who received RT, which led to a lack of protection in a significant number of children [67]. No correlation was observed between antibody titers and renal function or immunosuppressive regimen. In another study, antibody titers decreased within 6 months of RT in three and one of six children for measles and varicella, respectively; these children had been seroprotected before RT [68]. Similar evidence further indicates that children who have protective antibody titers before RT lose protection after RT [68]. Thus, antibody titers should be periodically monitored for all vaccine-preventable diseases in children after RT.

4.3. Vaccine efficacy Assessing vaccine efficacy requires large study cohorts that enroll thousands of patients and controls. The number of children with CKD is relatively low; therefore, very few studies have evaluated vaccine efficacy in this population. The available data indicate that, despite poor vaccination rates and rapid decreases in antibody titers, vaccines are effective for children with CKD. In countries where the HB vaccine is universally recommended, the incidence of HB infection, which was very common among children with ESKD on dialysis, has almost completely disappeared. Similarly, varicella vaccination before RT reduces the risk for acquiring the disease and also attenuated its severity [22,49,69]. In the largest study of varicella vaccination among children who received RT, only 12% of children who had routinely received the varicella vaccine acquired varicella after RT [22]. Varicella was only observed among children who never developed antibodies against varicella or lost protection, and the severity of the disease was significantly lower among vaccinated patients that did acquire it. This is consistent with the strict relationship between adequate vaccine-evoked immunity and actual protection. Finally, one study has also observed that the influenza vaccine was apparently effective for children with RT since none of the vaccinated patients required hospitalization for influenza complications [70].

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Table 1 Suggested vaccination schedule for children with chronic kidney disease (CKD). Vaccine

Patients with CKD

Remarks

Diphteria-tetanus-pertussis (DTP)

All according to the national schedule.

Efforts should be made to ensure that immunization with DTP and subsequent booster immunizations are provided in a timely fashion.

Hemophilus influenzae type b conjugate Hepatitis B

All according to the national schedule. All according to the national schedule.

Inactivated poliovirus vaccine Measles, mumps, rubella (MMR)

All according to the national schedule. Only patients who do not receive immunosuppressive therapy, including corticosteroids at a dose greater than 2 mg/kg or 20 mg total daily or on alternate days for more than 14 days. Only patients who do not receive immunosuppressive therapy, including corticosteroids at a dose greater than 2 mg/kg or 20 mg total daily or on alternate days for more than 14 days. All according to the national schedule.

Varicella zoster

Streptococcus pneumoniae

Influenza inactivated vaccine Rotavirus

Neisseria meningitidis Human papillomavirus Hepatitis A

All according to the national schedule. Only patients who do not receive immunosuppressive therapy, including corticosteroids at a dose greater than 2 mg/kg or 20 mg total daily or on alternate days for more than 14 days. All according to the national schedule. All according to the national schedule. Recommended in patients with Hepatitis C or liver disease.

5. Suggested vaccination approaches for children with CKD A rational vaccination approach can be recommended for children with CKD based on the available data. First, impaired immune responses are more common among children with ESKD on dialysis and those with RT than children with CKD on conservative treatment. Immune impairment affects the immediate vaccination response as well as the duration of protective antibody titers. Second, although age appears to condition the immune response, factors that predict the vaccine immune response and its duration of protection are not clear. Thus, patients with the highest risk for a poor vaccine immune response or for losing immunity cannot be readily identified. Third, vaccines are generally effective in children who develop adequate and persistent antibody responses. Fourth, inactivated vaccines are generally safe since the risks for significant deterioration in renal function or RT rejection after vaccination are minimal. Some studies have described problems in children with nephrotic syndrome due to MC and HB vaccination. However, disease prevention appears to be more important than the risk for disease relapse; therefore, vaccination should still be recommended. Finally, the risks for disease due to live attenuated vaccines are not significant enough to not recommend their use. Given these premises, we recommend that all children with CKD be vaccinated according to normal immunization schedules. In addition, these children should receive the influenza and pneumococcal vaccines due to the risks for influenza or pneumococcal-related complications. In children with ESKD on dialysis, antibody titers (against at least measles, varicella, and HB) should be monitored regularly to evaluate protection. Transplant candidates should receive age-appropriate vaccinations at least 1 month before RT and also be monitored periodically after RT and

Post-vaccination testing is recommended 1–2 months after the primary series is completed, with up to three additional doses if protective antibody levels (>10 mIU/mL) are not achieved.Antibody levels should be monitored annually and booster doses provided when levels fall below protective. Live attenuated vaccine is not recommended. Once corticosteroids are discontinued, MMR vaccination has to be delayed for at least 1 month.Repeated vaccination should be given to patients with negative titers.

Antibody titers should be measured before transplant in any patient without a history of wild-type infection. In all the subjects without positive antibody titers a dose of vaccine has to be administered. A 2nd dose is required if IgG negative after 1st vaccination. In younger patients: 13-valent conjugate vaccine as in healthy children. A dose of polysaccharide 23-valent vaccine over the age of 2 years and 5 years later. A third dose is recommended after further 5 years.In children aged 6–18 years who have not received either 7-valent or 13-valent conjugate vaccine, administer one dose of 13-valent conjugate vaccine, followed by a dose of 23-valent polysaccharide vaccine and 5 years later by a second dose. Annual administration. Live attenuated vaccine is not recommended.

Available data are conflicting. Studies are currently underway.

administered vaccine booster doses when needed. Table 1 summarizes the vaccination schedule suggested by the authors for children with CKD on the basis of the available literature. 6. Conclusive remarks Children with CKD are at an increased risk of infections, many of which can be prevented by currently available vaccines. Health authorities worldwide consider vaccination among these children an absolute priority. Moreover, vaccination with some vaccines, as the influenza vaccine, is recommended for children with CKD even in countries that do not consider influenza vaccine essential for healthy individuals. However, specific vaccination recommendations among children with CKD are not clear. For instance, immune responses to the HB vaccine can be poor and protection against HB wanes quickly following vaccination in both healthy adults and children. To ensure adequate protection, higher vaccine dosages or more vaccine doses or use of adjuvanted vaccines are recommended for adults. In contrast, standard doses are suggested for children despite the same vaccination issues [71], and adjuvanted HB vaccines are not licensed for use in children younger than 15 years of age. Moreover, when antibody titers should be monitored to verify the persistence of an antibody level >10 mIU/mL is not precisely defined and remains unclear. Periodic monitoring with administration of a booster dose if needed is also recommended for other vaccinations. However, there are no clear recommendations for how to monitor and administer booster vaccine doses when putative protective antibody levels are not established. Only adequate controlled studies can address this issue, but such studies are difficult to perform due to the large number of patients needed.

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Live attenuated vaccines remain another unknown variable for children with CKD. Live attenuated vaccines are usually contraindicated after RT and in children who are severely immunocompromised due to the risks of inducing life-threatening infections. However, some clinical studies have demonstrated that the MMR and varicella vaccines can be administered without real risks. In this case, controlled studies cannot be conducted due to ethical concerns. In conclusion, vaccines are useful in children with CKD because they have acceptable immunogenicity, efficacy, and safety profiles. However, there are currently no definitive rules for the administration of vaccines (especially live attenuated vaccines) in these cases. Vaccination among several groups of children with CKD must be individually managed; protective antibody levels against vaccinespreventable diseases in these children must be evaluated and taken into account when assessing the benefit to risk ratio of administering a booster vaccine dose. Furthermore, close contacts and household members of children with CKD should complete ageappropriate vaccination schedules to increase the child’s indirect protection [13,71].

7. Future perspectives Several new vaccines have been developed for some of the infectious diseases that are relatively common in children with CKD but cannot currently be adequately prevented. It is unlikely that these vaccines will be marketed in the next 5 years, but their safety, tolerability, and efficacy may be tested in these patients. Cytomegalovirus (CMV) infection is the most common viral infection in children with CKD, particularly those who undergo RT [72]. Prevention of CMV infection in these patients is critical because this virus can directly cause a very severe disease and can be associated with a range of indirect effects, including increased risks for other infections and a higher incidence of rejection, graft loss, and death [73]. Current methods of preventing CMV are limited. Immunoglobulin, interferon, and currently proposed live attenuated vaccines have not been associated with benefits [74]. Pharmacologic prophylaxis has been shown to be effective but requires long-term administration of drugs, which have potential adverse effects [75]. New vaccines could significantly improve protection against CMV infection. Unfortunately, no effective vaccine presently exists because the current CMV vaccine candidates are not able to elicit both cellular and humoral immune responses essential for complete prevention of CMV infection In addition, no data regarding their safety and tolerability in children are available [76]. Further studies are needed to identify an adequate CMV vaccine; therefore, CMV will remain a problem for children undergoing RT for the foreseeable future. Several vaccines against other infections, such as respiratory syncytial virus (RSV), that negatively impact children with chronic renal failure are in more advanced stages of development. Infants and younger children frequently suffer from RSV and children with CKD experience many RSV-related complications [77]. RSV vaccines offer the possibility of protecting all children with chronic diseases, including those with CKD, who are at risk for RSV and RSV-related complications.

Acknowledgments SE received research grants from GSK, Novartis, and Pfizer as well as honoraria from AstraZeneca, Bayern, GSK, Johnson & Johnson, Pfizer, Takeda and Vifor Pharma. No other authors have any commercial or other relationships that might pose a conflict of interest.

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This review was supported by a grant from the Italian Ministry of Health (GR-2009-1596786) (Bando Giovani Ricercatori 2009).

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