Abstract
Introduction
Assessing vaccine serologic status presents opportunities to provide live vaccinations to kidney transplant candidates (KTC). This is especially important given the increased risk of infection while taking lifelong immunosuppression following transplant and the inability to routinely provide live vaccines to patients on immunosuppressive medications. In March 2019, the American Society of Transplantation Infectious Disease Community of Practice (AST‐IDCOP) released updated guidelines for vaccination of KTC, which emphasize pretransplant viral serology screening and live vaccine administration prior to transplant.
Primary Endpoint
The primary endpoint of this study was to determine adherence to AST‐IDCOP guidelines for live measles, mumps, and rubella (MMR) and VZV vaccination prior to transplant in KTC non‐immune by serology.
Methods
This retrospective, descriptive study examined serologic status and rates of live vaccination in 672 patients listed for kidney transplant at our center between July 2014 and July 2019. Secondary endpoints included subgroup analysis of adherence to full AST‐IDCOP vaccination recommendations and validation of CDC presumed immunity definitions for measles and VZV.
Results
Seventeen patients (2.7%) were nonimmune by serology for VZV, while 182 (27.1%) were nonimmune by serology to MMR. In a subgroup analysis of the seronegative KTC, none received VZV vaccination, and 6% received MMR vaccination prior to transplant or last follow‐up.
Conclusions
Overall, a large portion of KTC had immunity gaps that were not resolved before transplantation. These findings are limited due to the retrospective, single‐center nature of this study and should be confirmed with larger, prospective assessments of serologic status and vaccine administration.
Keywords: kidney transplant, live vaccines, pretransplant evaluation, serologies, vaccination rates
Abbreviations
- ACIP
Advisory Committee on Immunization Practices
- AST‐IDCOP
American Society of Transplantation Infectious Disease Community of Practice
- CDC
Centers for Disease Control
- EMR
electronic medical record
- ESRD
end‐stage renal disease
- KTC
kidney transplant candidates
- MMR
measles, mumps, and rubella
- SOT
solid organ transplant
- US
United States
- VZV
varicella zoster virus
1. INTRODUCTION
Vaccination prevents infectious diseases across all patient populations. Initial dosing regimens of some vaccines are believed to provide lifelong immunity. However, some patients may not demonstrate adequate serologic conversion after vaccination, or the initial immune response may deteriorate over time leading to inappropriate assumption of immunity. Serologic testing assesses immune response to vaccines and predicts whether a patient is vulnerable to a specific infection. In the case of kidney transplant candidates (KTC), assessment of serologic status prior to transplant allows an opportunity to provide vaccines to nonimmune patients. This is especially important given the increased risk of vaccine‐preventable infections while taking lifelong immunosuppression after transplant.
These immunosuppressive medications required posttransplant prohibit transplant recipients from receiving live vaccines due to risk of disseminated infection. This leaves a small window of opportunity for vaccination prior to transplant when compared to inactive vaccines, which can be administered before and after transplant. Additionally, vaccination during immunosuppression can result in decreased rates of seroconversion, lower antibody titers, and shortened duration of protective immunity. 1
Vulnerability to vaccine‐preventable infections can lead to increased morbidity and mortality in solid organ transplant (SOT) recipients. 1 , 2 , 3 , 4 , 5 , 6 For example, measles can lead to severe complications in immunocompromised hosts including pneumonitis and encephalitis. 7 Varicella is associated with acute rejection episodes in pediatric renal transplants, with fewer severe cases reported in vaccinated individuals. 8 Invasive pneumococcal and influenza infections may cause severe pulmonary and extrapulmonary complications, which may substantially increase morbidity and mortality in SOT recipients with or without comorbid lung, heart, or liver disease. 7
In March 2019, the American Society of Transplantation Infectious Disease Community of Practice (AST‐IDCOP) released updated guidelines for vaccination of SOT candidates and recipients. 2 These guidelines emphasize the importance of pretransplant screening and serologic testing to identify gaps in immune status, recommending that each patient's immunization records and titers be reviewed at the initial transplant visit. 2 The AST‐IDCOP recommends that any incomplete or unvaccinated transplant candidates receive live vaccines at least 4 weeks prior to transplant and inactivated vaccines at least 2 weeks before transplant. 2 Although inactivated vaccines, such as pneumococcal and influenza, can be given following transplantation, live vaccines, such as measles, mumps, and rubella virus (MMR) vaccine and varicella virus (VZV) vaccine, routinely cannot be given. Patients who are nonimmune to measles or VZV ideally must be vaccinated pretransplant to provide adequate protection once immunosuppressed. 2 These guidelines also recommend follow‐up assessment of serologies to assure seroconversion and immunity prior to transplant. 2 The Centers for Disease Control (CDC), Infectious Disease Society of America (IDSA), and Kidney Disease Improving Global Outcomes (KDIGO) groups have guidelines for vaccination in immunocompromised patients and end‐stage renal disease (ESRD) patients, which echo the recommendations of the AST‐IDCOP. 9 , 10
The aim of this study was to examine pretransplant serologic data to define baseline population seroprotection against vaccine‐preventable illnesses in KTC. In turn, subsequent vaccination rates for nonimmune KTC were assessed to examine whether vulnerable patients received optimal protection against vaccine‐preventable infections.
2. MATERIALS AND METHODS
2.1. Setting and purpose
This retrospective, single‐center, descriptive study was conducted to determine prevalence of seronegativity against MMR and VZV illnesses in KTC. This information will help to identify the prevalence of at‐risk patients within our kidney transplant program and provide baseline information for pretransplant vaccination rates. Data collection and data evaluation were conducted from June 2019 through March 2020 as part of a quality‐improvement initiative. The institutional review board at the University of Utah approved this project with exemption from informed consent.
2.2. Primary and secondary endpoints
The primary endpoint for this study was to determine the percentage of patients that were nonimmune by serology to MMR and VZV and determine rates of live vaccine administration in non‐immune patients prior to transplant. Secondary endpoints were to determine if CDC presumed immunity definitions for measles and varicella apply to KTC born in the United States (US). These definitions state that patients born in the US prior to 1957 are assumed immune to measles, 11 and those born prior to 1980 are assumed immune to varicella. 12 Additionally, pretransplant vaccination rates for AST‐IDCOP recommended vaccines were collected to assess adherence to AST‐IDCOP guideline recommendations.
2.3. Patients
Patients eligible for inclusion were aged 18 years and older and listed for kidney transplant at our center between July 1, 2015 and June 30, 2019. Patients were excluded for the following reasons: listed for multiorgan transplant (e.g., simultaneous pancreas‐kidney), previous organ transplant, and/or pretransplant serologic data and vaccination records not available in the electronic medical record (EMR).
2.4. Data collection
Eligible patients were identified from the United Network for Organ Sharing database by our transplant quality group. Laboratory data including serology values for measles, mumps, rubella, and varicella, as well as country of birth, and ICD.10 codes for pertinent exclusion criteria were collected on identified patients from the EMR via the electronic data warehouse. Finally, immunization history, contraindications to vaccination, and any information not retrievable from the electronic data warehouse were collected via manual chart review. The subgroup evaluations for the primary endpoint of live virus vaccination and the secondary endpoint of adherence to AST‐IDCOP vaccination recommendations included up to 100 patients in each group. Vaccination records until the time of transplant or until November 2019 if not yet transplanted were reviewed. Patients were evaluated in reverse chronological order starting from addition to the waitlist in June 2019 in order to provide the most accurate reflection of current vaccination practices at our center. For the secondary endpoint of CDC presumed immunity, all patients identified as eligible were evaluated for birth year, country of birth, and measles, and varicella serology values. For measles presumed immunity, serologic values of patients born in the US prior to 1957 were assessed. For varicella presumed immunity, serologic values of patients born in the US prior to 1980 were assessed.
2.5. Statistical analysis
For rates of seronegativity and vaccination, simple descriptive statistics were performed and reported as percentages.
3. RESULTS
In total, 945 patients were listed for transplant from July 1, 2015 and June 30, 2019. Of these patients, 273 were excluded, leaving 672 patients eligible for inclusion in our study. Patients were most commonly excluded for having screening laboratory workup performed at an outside hospital. Baseline characteristics of the included patients are listed in Table 1.
TABLE 1.
Baseline characteristics
| Characteristic | n (%) |
|---|---|
| Male (%) | 416/672 (62%) |
| Age range, years (median) | 18‐73 (53) |
| Renal replacement therapy (%) | 428/672 (64%) |
| ‐Hemodialysis (%) | 349/428 (82%) |
| ‐Peritoneal dialysis (%) | 79/428 (18%) |
| Time on renal replacement therapy, years (median) | 1.92 |
| Time on waitlist prior to transplant, years (median) | 0.47 |
| Cause of ESRD | |
| ‐Diabetes mellitus | 206/672 (31%) |
| ‐Hypertensive nephropathy | 78/672 (12%) |
| ‐IgA nephropathy | 41/672 (6%) |
| ‐Polycystic Kidney Disease (PKD) | 56/672 (8%) |
| ‐Focal glomerular sclerosis (FGS) | 34/672 (5%) |
| ‐Chronic Glomerulonephritis | 22/672 (3%) |
| ‐Unknown | 24/672 (4%) |
| ‐Other | 211/672 (31%) |
3.1. Primary objective
3.1.1. Measles, mumps, and rubella
Of the 672 patients included, 182 patients (27.1%) were nonimmune by serology to one or more components of the MMR vaccine. Patients were most commonly nonimmune to mumps (109/182, 59.9%), followed by measles (89/182, 48.9%), and rubella (56/182, 30.8%). As defined by study protocol, 100 of these 182 patients were evaluated for MMR vaccination prior to transplant or by completion of data collection in November 2019 if not yet transplanted. In this subgroup, six of 100 (6%) received vaccination (see Figure 1). Fifteen patients (15%) of the 100 subgroup patients had contraindications to live vaccination due to immunosuppressive medications (14/15, 93%) and immunosuppressive conditions (1/15, 7%).
FIGURE 1.
Primary outcome results of seroprotection and vaccination rates for live vaccines
3.1.2. Varicella zoster
Seventeen (2.7%) of the 672 patients were nonimmune by serology to VZV. Of these 17 patients, none (0%) received VZV vaccination prior to transplant or by November 2019 if not yet transplanted (see Figure 1). Two patients (12%) of the 17 eligible subgroup patients had contraindications to live vaccination due to immunosuppressive medications.
3.2. CDC Presumed immunity
Out of all 672 patients included in this study, 161 patients were born in the US prior to the year 1957. Based on laboratory data, 159 of 161 (98.8%) were immune by serology to measles. There were 372 patients born in the US prior to the year 1980. Of these patients, 365 of 372 (98.1%) were immune by serology to varicella.
3.3. AST‐IDCOP vaccination adherence
Findings from this evaluation are listed in Table 2. Of the 100 patients evaluated, eight received all AST‐IDCOP and ACIP recommended vaccines prior to transplant.
TABLE 2.
American Society of Transplantation Infectious Disease Community of Practice (AST‐IDCOP) inactive vaccination adherence*
| Vaccine name | n (%) |
|---|---|
| Pneumococcal conjugate 13‐valent | 59/100 (59%) |
| Pneumococcal polysaccharide 23‐valent | 57/100 (57%) |
| Influenza | 97/100 (97%) |
| Tetanus, diphtheria, and acellular pertussis | 52/100 (52%) |
| Hepatitis B a | 61/100 (61%) |
| Human papilloma virus b | 2/21 (9.5%) |
| Herpes zoster virus c | 10/54 (18.5%) |
| Meningococcal A d | 1/1 (100%) |
| Meningococcal B d | 1/1 (100%) |
| Haemophilus influenza B d | 1/1 (100%) |
As defined by study protocol, 100 patients were evaluated for AST‐IDCOP pretransplant recommended vaccine administration.
Including patients proven immune by serology demonstrating prior vaccination and with documented hepatitis B vaccines.
Per updated Advisory Committee on Immunization Practices (ACIP) age recommendations, 13 15 of these 21 patients were between aged 27 and 45 and were designated as “recommended intervention based on shared decision making.”
Either zoster vaccine recombinant, adjuvanted (Shingrix) or zoster vaccine, live (Zostavax).
Patient with documented splenectomy.
4. DISCUSSION
To our knowledge, this is first formal evaluation of baseline serologic status for MMR and VZV and vaccination rates in the KTC population. Ramakrishna and colleagues 5 examined the ability to specifically optimize MMR screening and vaccination in KTC. Seckin and colleagues 6 examined serologies and vaccine administration in heart, lung and liver candidates and highlighted an increased need for serologic evaluation and vaccination. As highlighted by the AST‐IDCOP guideline recommendations, assessment of baseline immunity prior to transplant is paramount to identify immune gaps and necessary vaccination interventions. Based on our findings, approximately 1 in 4 KTC are nonimmune by serology to at least one component of the MMR vaccine, while a smaller, although relevant, portion of KTC are nonimmune by serology to VZV. Although these findings may not represent the worldwide KTC population, they highlight the importance of live vaccine administration to resolve immunity gaps in pretransplant candidates, as these are difficult to address following transplant. With nationwide vaccination rates declining and the recent resurgence of measles cases, 14 vulnerable kidney transplant recipients may experience higher rates of infections. Though there are publications on safe and effective posttransplant live vaccine administration, most of these experiences come from the pediatric population with low immunosuppressive regimens, 15 , 16 which does not apply to this selected patient population currently.
Our assessment of vaccine administration rates for both live and inactivated vaccines showed that a large portion of KTC undergo transplantation without receiving AST‐IDCOP recommended vaccines. Although inactive vaccines can be given following transplant, the concern for diminished immune response compared to an immunocompetent patient's response may leave the transplant recipient at a higher risk for vaccine non‐response or shortened duration of antibody protection. These findings highlight possible gaps in pretransplant evaluation and need for thorough assessment of vaccination history. Although several barriers to vaccine optimization exist, such as vaccine hesitancy or lack of perceived vaccine benefit, educating patients and providers on the importance of assuring immunity prior to immunosuppression is critical. Other barriers observed included nonstandardized pretransplant vaccine history assessment, inaction despite negative vaccine serology results, and lack of transplant team understanding of vaccination recommendations in KTC.
Results from this evaluation were shared with members of the transplant department, and a small workgroup was formed that included representatives from transplant infectious disease, transplant nurse coordinators, and transplant pharmacists. This workgroup secured authorization from the institution's EMR informational technology committee to build out specific programming to better highlight care gaps, in an attempt to improve vaccination rates both pre‐ and posttransplant. The aim of the build is to consider a transplant patient's phase within transplant (i.e., evaluation, waitlist, and posttransplant), and cross‐reference serologies and key findings from the problem list, as well as immunizations within the EMR, to formulate patient‐specific vaccination recommendations. These recommendations will be consistent with AST‐IDCOP and CDC vaccination recommendations, and regular updates are planned as the vaccine schedule is modified. Unfortunately, due to the COVID‐19 pandemic, resources and implementation of this programming have been delayed. We are optimistic for a go‐live date in late spring 2022.
An interesting and encouraging finding from this study is that CDC presumed immunity for measles and varicella in US‐born patients appears to hold true. We wanted to assess this outcome specifically due to the concern that patients with ESRD lose antibody protection over time, which could indicate that we may be wrongly assuming immunity in KTC populations. Our data suggest that over 98% of US‐born KTC were confirmed immune by serology and that protective immunity appears to persist regardless of ESRD status.
Strengths of this study include the large population of KTC evaluated over 5 years at our center. Additionally, published data to define baseline seroprotection against vaccine‐preventable illnesses in transplant patients are scarce. This study provides some preliminary insight into prevalence of immunity gaps and vaccination needs in pretransplant populations. Limitations of this study include the retrospective nature and inability to control possible confounding variables with vaccine administration, such as vaccine availability in clinic or patient refusal. The reliance on chart review and data entry within the EMR was challenging, as many patients did not have up‐to‐date vaccine records entered in the statewide immunization database or EMR records. Additionally, lack of national online access to immunization databases presented a barrier for interstate validation of vaccination records across a wide geographic region. Our protocol specified that up to 100 patients in each seronegative group were reviewed for vaccine administration due to the limited timeline of this project. As such, only 55% of total MMR nonimmune patients were evaluated for vaccination. The patients assessed were those most recently listed for transplant to best reflect current vaccination practices at our center, but this may not accurately represent vaccination status of the entire MMR nonimmune cohort. Additionally, due to the timeframe of this study, pretransplant human papilloma virus vaccination screening may have occurred prior to the ACIP June 2019 update, or vaccination practices may not have changed to include patients within the “shared decision making” age group. Finally, this was a single‐center assessment of baseline serologic status focusing primarily on patients listed for kidney transplant in the western US. Serologic status of this population may not reflect KTC in other geographic locations or nonkidney transplant candidates.
4.1. Conclusions
Based on our findings, a large portion of KTC had immunity gaps to vaccine‐preventable illnesses that were not resolved prior to transplant. Over one in four KTC may require MMR vaccination prior to transplant, and one in 33 may require VZV vaccination based on our serologic laboratory assessment. Our findings suggest that CDC presumed immunity definitions can be considered true for KTC. Limitations of this study include the retrospective design, limited information within the EMR, and lack of generalizability to other geographic regions or nonkidney transplant populations. At this time, improvement in vaccination rates has been slow, despite strategies to call awareness to seronegativity, although we are hopeful that implementation of a patient‐specific tool in the EMR to highlight immunity gaps will improve overall vaccination rates in our population. A prospective, multicenter assessment of baseline serologic data, vaccine history assessment, and subsequent vaccination rates prior to transplant is necessary to confirm findings presented here.
AUTHOR CONTRIBUTIONS
Design of work, data collection and analysis, manuscript drafting and revision, and final approval for publication: SS. Design of work, manuscript drafting and revision: AC. Design of work, manuscript drafting, and revision: BS. Design of work, manuscript drafting, and revision: BC. Design of work, data collection and analysis, manuscript drafting and revision, and final approval: CT.
CONFLICT OF INTEREST
The authors of this manuscript declare no conflict of interest.
FUNDING INFORMATION
This study did not receive any financial support from external or internal sources.
Supporting information
Graphical Abstract
ACKNOWLEDGMENTS
The authors acknowledge the dedication of pharmacists, physicians, and nurses to improving pretransplant vaccination by the Transplant Department at University of Utah Health.
Schneider S, Carlson A, Sirandas B, Clark B, Truax C. Serologic evaluation of vaccine preventable infections and vaccination rates in kidney transplant candidates. Transpl Infect Dis. 2022;24:e13973. 10.1111/tid.13973
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Graphical Abstract
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.