High-Dose versus Standard-Dose Influenza Vaccine in Patients on Hemodialysis

Patients with end-stage renal disease (ESRD) are at increased risk of morbidity and mortality associated with influenza compared with individuals in the general population. Patients with ESRD have an impaired innate and adaptive immune system, including defects in complement activation and B- and T-cell function, adding to the increased risks for complications from influenza, mortality, and increased healthcare costs. The recommendation from the Centers for Disease Control and Prevention (CDC) strongly recommend annual influenza vaccinations for patients with ESRD.

At present, there are several types of influenza vaccines in the United States, including the standard-dose vaccine (SDV) and the high-dose vaccine (HDV). Standard practice in dialysis clinics is administration of the trivalent, and more recently quadrivalent, inactivated seasonal SDVs. In 2009, a trivalent HDV was licensed by the US FDA for use among adults ≥65 years of age; the HDV contains the same three strains as the SDV, but has more antigen than standard vaccines (60 vs 15 mg per strain). Over time, use of the HDV among patients receiving maintenance dialysis has increased.

A small observational study conducted among the dialysis population demonstrated that the HDV was more effective in preventing all-cause hospitalization during the 2016 to 2017 influenza season. However, the results were limited by the small sample size, adjustment for a small set of confounders, and the lack of outcomes related to influenza. Anne M. Butler, PhD, and colleagues recently conducted a cohort study to examine the effectiveness of standard-dose versus high dose influenza vaccine among patients on dialysis. Results were reported in the American Journal of Kidney Diseases [2020;75(1):72-83].

Patients with chronic kidney disease receiving in-center maintenance dialysis during 2009 to 2015 were identified using data from the US Renal Data System. The researchers constructed yearly cohorts for five individual influenza seasons: 2010 to 2011, 2011 to 2012, 2012 to 2013, 2013 to 2014, and 2014 to 2015. Eligible patients were ≥18 years of age with ESRD who had initiated hemodialysis at least 9 months prior to the index date. Additional inclusion criteria were receipt of continuous hemodialysis for 3 months immediately prior to vaccination and Medicare as a primary insurance payer.

There were three primary clinical outcomes of interest: (1) all-cause mortality; (2) the first occurrence of hospitalization for influenza or pneumonia; and (3) the first occurrence of influenza-like illness (ILI).

Patients were eligible for inclusion in multiple yearly cohorts. The unit of analysis was the influenza patient-season. Propensity score weighting of Kaplan-Meier functions were used to estimate risk differences and risk ratios. A wide range of covariates were identified during the 6-month baseline period, including demographic characteristics (age, sex, race, dual-eligible for Medicaid, region, and year), clinical characteristics (cause of ESRD and duration of dialysis), dialysis facility characteristics (affiliation, type, profit status, and size), and comorbid conditions and procedures. Other covariates included preventive health services (other vaccinations and health screenings), health care utilization, and frailty. Timing of administration of the influenza vaccine was categorized as August or September versus October through the start of the influenza season.

Following application of inclusion and exclusion criteria, the researchers identified 255,281 eligible adults who contributed 507,552 unique influenza patient-seasons. The primary analysis included 225,215 adults ≥65 years of age; of those, 97.4% (n=219,439) of eligible vaccinations were SDV, and the remaining 2.6% (n=5776) received HDV. All HDV were trivalent; 76.7% of SDV were trivalent  and 23.3% were quadrivalent.

Mean age was slightly older among those who received the HDV compared with those who received SDV (75.8 years vs 74.6 years). HDV administration was less common among patients who were black or other race, were dual-eligible for Medicaid, were on dialysis for >3 years, or resided outside of the Midwest. The prevalence of comorbid conditions was higher in recipients of HDV; frailty indicators were similar between those who received SDV and those who received HDV. Recipients of HDV were more likely to receive preventive healthcare such as diabetic eye examinations, lipid testing, and cancer screenings.

After accounting for the competing risk of death for nonmortality outcomes, for each outcome of interest the weighted risks for HDV and SDV were similar. In the weighted analyses, there were similar associations between vaccine dose and risk for mortality (risk difference, –0.08%; 95% confidence interval [CI], –0.85% to 0.80%), hospitalization due to influenza or pneumonia (risk difference, 0.15%; 95% CI, –0.69% to 0.93%), and ILI (risk difference, 0.00%; 95% CI, –1.50% to 1.08%).

Risks for mortality, hospitalization for influenza or pneumonia, and ILI within subgroups defined by influenza season, age group, dialysis vintage, month of influenza vaccination, and vaccine valence were generally similar between HDV and SDV recipients throughout the influenza season, with a few exceptions. In the 2010 to 2011 season, there was a higher risk for hospitalization among patients who received the HDV compared with patients who received the SDV (risk difference, 2.85%; 95% CI, 0.59% to 5.86%). There were no differences in risk in any of the other four seasons.

For both hospitalization and ILI outcomes, the risk among HDV versus SDV recipients ≥65 years of age was higher; the risk was lower among HDV versus SDV recipients 75 to 84 years of age. There was no difference in risk among those <65 years of age or ≥85 years of age.

There were some limitations to the findings cited by the authors, including the observational design of the study that did not involve randomization of the exposure, only accounting for baseline characteristics measured prior to vaccination, the requirement of survival until 9 months following initiation of dialysis, and basing the study primarily on administrative billing claims data.

In summary, the researchers said, “Our large comparative study failed to demonstrate that HDV has superior effectiveness compared to SDV for preventing all-cause mortality and influenza-related outcomes among patients receiving maintenance hemodialysis. Given the findings of our population-level study, along with the substantially higher cost and side-effect profile of HDV compared to SDV, it appears that HDV should not conclusively be considered the standard of care at the present time for influenza immunization of patients treated by maintenance hemodialysis. The findings of our population-level study should not be interpreted to discourage influenza vaccination in the dialysis population. Rather, dialysis patients should continue to receive annual influenza immunization per CDC guidelines. In addition, future studies of alternative strategies (eg, booster doses) and alternative vaccine production technologies (eg, adjuvanted or cell-based vaccines) are warranted because there remains a need for improved influenza prevention efforts in this population.”

Takeaway Points

  1. Researchers conducted a cohort study to compare the effectiveness of standard-dose influenza vaccine (SDV) with high-dose influenza vaccine (HDV) in patients on maintenance hemodialysis.
  2. Outcomes of interest were all-cause mortality, hospitalization for influenza or pneumonia, and influenza-like illness during the influenza season.
  3. The findings suggested that the HDV does not provide additional protection beyond that of the SDV for adults on maintenance hemodialysis.