Herpes Zoster in Aging Patients: Risk Factors and Prevention Strategies.

Introduction

Herpes zoster (HZ), commonly referred to as shingles, is caused by varicella-zoster virus (VZV) reactivation; primary infection with VZV causes varicella (ie, chickenpox), after which VZV can remain dormant in dorsal root ganglia and reactivate later in life. 1 HZ typically presents as a rash with pain, itching, or tingling, and can result in complications such as postherpetic neuralgia (PHN), HZ ophthalmicus (HZO), hearing or vision loss, encephalitis, and pneumonia. 1 , 2 Observational studies also suggest an increased risk for certain severe outcomes (eg, cerebrovascular accidents [CVA; stroke] and myocardial infarction [MI]) in patients with HZ. 3 , 4 In the United States (US), about 99.5% of adults born prior to 1980 have been infected with VZV, and approximately 1 in 3 people will develop HZ in their lifetime. 1 Risk for HZ and related complications is greater in adults aged ≥50 years and increases with age, presence of certain medical conditions, and taking immunosuppressive medications. 1

The increased risk for HZ among older adults is of particular concern in the US, where recent projections predict a 61.1% increase in the US population aged ≥50 years from 137 million to 221 million between 2020 and 2050. 5 HZ-related burden of disease is also a concern among this population, with claims database studies reporting greater healthcare resource utilization and costs for patients with HZ compared with controls without HZ, and costs increasing with age and PHN diagnosis. 6 , 7 Along with the aging population, the number of US adults aged ≥50 years with at least one chronic disease is expected to increase significantly, from 72 million to 143 million between 2020 and 2050, representing a projected 99.5% increase. 5 Notably, further increased healthcare resource utilization has been reported among HZ patients with certain chronic conditions. 8 , 9 As a result, it is essential for healthcare providers to understand how chronic conditions increase HZ risk, and how prevention can be optimized in this patient population.

As the US population continues to age and experience a high chronic disease burden, prevention of HZ is increasingly important. The recombinant zoster vaccine (RZV) has been available in the US since 2017, and the US Advisory Committee on Immunization Practices (ACIP) recommends two doses of RZV for the prevention of HZ and related complications in adults aged ≥50 years and adults aged ≥19 years who are or will be immunodeficient or immunosuppressed because of disease or therapy. 10 The recommendations further state that adults aged ≥50 years should receive RZV if they have chronic medical conditions, such as chronic renal failure, diabetes mellitus, rheumatoid arthritis (RA), and chronic pulmonary disease. 11

This review seeks to consolidate the available information on risk factors for HZ among adults aged ≥50 years, including those with chronic underlying conditions, and highlight opportunities to address gaps in prevention in this population for the awareness of healthcare providers.

Search Methodology

A preliminary literature search of PubMed was performed for English-language clinical studies, comments, editorials, guidelines, and letters indexed since 2015. The search terms used can be found in Table S1 . Articles that presented results pertinent to risk factors for HZ or guidelines, recommendations, and best practices for HZ prevention in a population of US adults aged ≥50 years were included for review. These articles were supplemented with collated publications identified by the authors that were pertinent to the risk for and prevention of HZ among this population but not identified in the initial PubMed search. Additional searches were performed to identify publications for certain known risk categories for HZ which were not identified within the preliminary search parameters. Articles were included based on their relevance to the review, as assessed by authors, to support comprehensive coverage and inclusion of high-quality publications. A narrative synthesis of the included studies was conducted.

HZ Incidence and Risk

Fifty-six publications on incidence and risk factors for HZ and HZ outcomes ( Table 1 and Table 2 ) and 58 on HZ prevention were identified, for a total of 105 included publications. Several publications reported on both incidence and risk factors for HZ and HZ outcomes, as well as HZ prevention, and were thus included in both categories for review ( Table S2 ).

HZ Incidence Among Adults Aged ≥50 Years

An increased incidence of HZ was reported with increasing age in the US, as were increases in HZ incidence over time. 12 , 13 A study of US claims data which stratified by age up to age ≥80 years reported an HZ incidence rate (IR) of 8.46 (95% confidence interval [CI] 8.39–8.52) per 1000 person-years (PYs) among adults aged ≥50 years, an IR of 10.46 (95% CI 10.35–10.56) per 1000 PYs among adults aged ≥60 years, and an IR of 12.78 (95% CI 12.49–13.07) per 1000 PYs among adults aged ≥80 years. 12 Although the highest IR was reported among adults aged ≥80 years, the highest number of HZ cases (29,266/113,861 HZ cases; 26%) occurred among adults aged 50–59 years. 12 Similar trends in incidence increasing with age were seen for the incidence of HZO. 43

Risk of HZ in Patients with Chronic Conditions

In a 2020 meta-analysis, an increased risk for HZ was associated with a number of chronic conditions, including cardiovascular conditions, diabetes, chronic obstructive pulmonary disease (COPD), asthma, and chronic kidney disease (CKD). 14

Cardiovascular disease has been associated with an increased risk of HZ in several studies; 14 , 22 , 27 , 28 heart failure has also been associated with a higher risk of HZ 22 , 29 and HZ episodes requiring hospitalization. 28

Diabetes was identified as a risk factor for HZ in multiple studies, 9 , 14 , 22 , 30–33 and a meta-analysis of cohort studies on diabetes and risk of HZ found that patients with diabetes mellitus had a significantly higher risk of developing HZ compared with patients without diabetes mellitus (incidence rate ratio: 1.60 [95% CI 1.33–1.93]). 32 Additionally, in a US claims analysis, HZ infection increased healthcare resource utilization for diabetes patients in the year following HZ infection. 9

Multiple chronic respiratory conditions have been identified as risk factors for HZ. Across studies spanning diverse geographies, asthma 8 , 14 , 22 , 34–37 and COPD 14 , 22 , 34 , 36 were found to increase the risk of HZ. One review found that certain asthma medications also increased HZ risk, including systemic corticosteroids, as well as long-acting beta-agonists combined with the use of inhaled corticosteroids. 35 Inhaled corticosteroid therapy was also associated with an increased risk of HZ among COPD patients. 38

CKD has also been identified as a risk factor, 14 with HZ in patients with CKD found to be associated with higher risk of progression to end-stage kidney disease (ESKD)/CKD stage V. 44 , 45 This risk was further inflated by the presence of other chronic conditions, such as hypertension and diabetes. 44 One case-control study found that most (72.3%) HZ cases identified among CKD patients were among patients with stage IV to stage V CKD. 39

Other identified risk factors for HZ in older adults included frailty 41 and multimorbidity (the presence of more than one underlying condition). 42 One retrospective study utilizing a US claims database evaluated IRs for HZ in patients with an increasing number of comorbidities, analyzing this risk among adults of different age groups and with select comorbidities (diabetes, asthma, COPD, CKD, depression, stress, and/or trauma). 42 This study found that IRs increased with an increasing number of comorbidities (1 comorbidity: 6.87 [aged 50–59 years], 7.88 [aged 60–69 years], 9.34 [aged 70–79 years], 9.78 [aged ≥80 years]; 2 comorbidities: 8.59 [aged 50–59 years], 9.17 [aged 60–69 years], 10.73 [aged 70–79 years], 11.18 [aged ≥80 years]; ≥3 comorbidities: 9.22 [aged 50–59 years], 10.30 [aged 60–69 years], 12.04 [aged 70–79 years], 12.92 [aged ≥80 years]). 42

Risk of HZ in Patients with Immunocompromising Conditions or on Immunosuppressive Therapies

Associations between immunocompromising conditions and HZ are well established. Solid organ transplant patients have been found to be at increased risk for HZ compared with immunocompetent older adults, with the highest risk for heart and lung transplants, followed by kidney and liver transplants. 25 Two studies identified hematopoietic cell transplant (HCT) as a risk factor for HZ, 17 , 18 with increased risk among older patients. 17 One study identified a notable proportion of HZ diagnoses among patients with cancer, 15 and several studies identified certain cancer treatments as risk factors for HZ. 16–18 Among patients with cancer, adjusted analyses indicated a higher likelihood of developing HZ during periods of immunosuppressive treatment versus periods without. 16 In a cohort of patients with hematological malignancies, HZ incidence rates were highest in those with non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma; in a cohort of patients with solid tumors, HZ incidence rates were highest in those with lung cancer, non-melanoma skin cancer, and endometrial cancer. 16 Lastly, one study also found an association between lung cancer and HZ risk, with risk increased in older adults and those with comorbidities. 34

Other conditions which involve treatment with immunosuppressive therapies have also been associated with an increased HZ risk, including RA, 14 , 21 psoriasis, 23 lupus nephritis, 24 and inflammatory bowel disease (IBD). 19 , 46 , 47 Janus kinase inhibitors, in addition to increasing HZ risk in RA patients and psoriatic arthritis patients, were found to increase risk of HZ among ulcerative colitis patients, with further increased rates among patients aged ≥65 years. 20

HZ Outcomes and Complications

In several studies, HZ was associated with functional decline (ie, a decrease in the ability to perform activities of daily living) during and after HZ and PHN episodes, as well as negative impacts on quality of life among older adults, 48–51 which may be amplified by underlying conditions such as cardiovascular disease, diabetes, and respiratory diseases 51 ( Table 2 ). Per a post-hoc analysis of one prospective cohort study, patients with these underlying conditions experienced more intense pain and lower quality of life scores one to three months after HZ onset. 51 A Mendelian randomization study of genetic samples (of European ancestry) found that HZ is associated with an increased risk of depressive symptoms and an increased number of episodes with depressed mood. 52

Two studies identified older age, in addition to severe immunosuppression, diabetes, asthma, COPD, smoking, and being underweight or obese, as risk factors for PHN; 53 , 54 odds of developing PHN went up by 19%, 21%, and 53% for HZ patients with diabetes, asthma, and COPD, respectively. 53 Among patients with PHN, one retrospective cohort study found high rates of anxiety and depression; these conditions were associated with the magnitude of pain intensity and the spread of the HZ rash. 65 Among populations with diabetes, a higher likelihood of PHN, 55 as well as a higher incidence of hospitalization, stroke, and MI following an HZ episode, were identified. 30

Numerous studies identified increased risk of CVAs and MI in patients with HZ. 26 , 27 , 56–64 Risk of these CVA events was acute and time-dependent, with the highest risk in the weeks and months after HZ; 26 , 27 , 56 , 58–63 risk of CVA was highest within the first month following HZ (relative risk: 1.78 [95% CI 1.70–1.88]) and remaining elevated for up to one year. 59 Limited data also suggest that risk of CVA may remain higher over longer periods, beyond one year. 64 While the mechanism is not established and thought to be multifactorial, 27 it has been hypothesized that VZV traverses along nerves and can infect arterial walls, leading to VZV vasculopathy; this is the likely mechanism for reported ischemia and stroke events following HZ. 26 , 56 , 62

Prevalence of Co-Morbid Conditions

Chronic conditions associated with HZ risk have varying prevalences among the US population aged ≥50 years. Centers for Disease Control and Prevention (CDC) reports estimate 12.3% of US adults aged 45–64 years and 33.7% aged ≥65 years have CKD, 66 and 4.9% of US adults aged 50–64 years and 14.6% of US adults aged ≥65 years had coronary heart disease in 2023, 67 underscoring a large population segment that is vulnerable to HZ due to underlying comorbidities. CDC reports estimate 29.2% of adults aged ≥65 years have diagnosed or undiagnosed diabetes. 68 Respiratory conditions associated with HZ risk are also prevalent in this population, with the CDC reporting an 8.0% prevalence of asthma among adults aged ≥65 years 69 and a 6.1% and 9.6% prevalence of COPD among adults aged 50–64 years and ≥65 years, respectively, in 2023. 70

Immunocompromising conditions which are risk factors for HZ become more common with advancing age. In recent years, over half of cancer diagnoses in the US have been among adults aged ≥65 years. 71 Additionally, older adults in the US are at greater risk for certain conditions such as RA. 72

HZ Prevention

RZV as HZ Prevention in Older Adults

In two Phase 3 clinical trials assessing the efficacy and safety of RZV in immunocompetent adults aged ≥50 years (ZOE-50) and adults aged ≥70 years (ZOE-70), RZV significantly reduced the risk of HZ and PHN, with a vaccine efficacy against HZ of 97.2% (95% CI 93.7–99.0%) in adults aged ≥50 years and a pooled efficacy of 91.3% (95% CI 86.8–94.5%) in adults aged ≥70 years, over approximately 3–4 years of follow-up. 73 , 74 In a long-term follow-up study of ZOE-50 and ZOE-70 (ZOE-LTFU), RZV efficacy against HZ remained high (82.0%) and the safety profile remained clinically acceptable at 11 years after vaccination; an HZ efficacy of 79.8% was demonstrated during the long-term follow-up period (5.6–11.4 years after vaccination) among adults vaccinated at age ≥50 years. 75

Identified studies also assessed the safety of RZV in a population aged ≥50 years. 76–80 In a pooled analysis of clinical trials among immunocompromised populations, unsolicited adverse events and serious adverse events were comparable with placebo. 80 The most commonly reported symptoms following vaccination in clinical trial populations of adults aged ≥50 years were pain, redness, and swelling at the injection site, and fatigue, headache, and myalgia. 77–79 Two of these studies found that the reactogenicity of either dose of RZV in adults aged ≥50 years did not significantly impact quality of life. 77 , 78 In the post-licensure setting, two observational studies in Medicare populations (individuals aged ≥65 years) reported approximately 3.1–6.6 excess Guillain-Barré syndrome (GBS) cases per million vaccinations during the 42-day period following vaccination. 76 , 81

Additional analyses in ZOE-50/70 participants assessed RZV efficacy and safety based on frailty status (defined using an index accounting for medical history and questionnaire responses) and presence of common comorbid conditions. 82 , 83 Efficacy and safety did not vary based on frailty status or common comorbid conditions. 82 , 83 In the pooled results of the two clinical study cohorts, with subjects aged ≥50 years and ≥70 years, RZV significantly reduced the risk of HZ in frail participants compared with those in the placebo group. 82 Pre-licensure studies were also conducted in immunocompromised patient populations. In patients aged ≥18 years who had undergone autologous hematopoietic stem cell transplantation, efficacy was 68.2%, 84 while a post-hoc analysis of another study assessing efficacy in patients with hematological malignancies reported an efficacy of 87.2%. 85

In a real-world evidence study assessing HZ prevention in both immunocompetent and immunocompromised patients aged ≥50 years, RZV demonstrated a vaccine effectiveness of 76% that waned minimally over four years of follow-up (73% during the third and fourth years). 86 A cohort study of Medicare beneficiaries aged >65 years found a vaccine effectiveness of 70.1% (95% CI 68.6–71.5%), which was not substantially lower for individuals with autoimmune conditions. 83 Vaccine effectiveness also remained high in populations with comorbidities at baseline, ranging from 62.7% (95% CI 50.4–72.0%) among patients with liver disease to 74.5% (95% CI 70.2–78.3%) among patients with diabetes. 87

RZV co-administration with other vaccines among older adults has been assessed in clinical studies. Two clinical trials were identified which demonstrated the safety and immunogenicity of co-administration of RZV with influenza vaccines. 88 , 89 Clinical trials have also shown the safety and immunogenicity of RZV co-administration with the 13-valent pneumococcal conjugate vaccine, 90 the 23-valent pneumococcal polysaccharide vaccine, 91 the reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine, 92 the coronavirus disease 2019 mRNA-1273 booster vaccine, 93 and the adjuvanted respiratory syncytial virus (RSV) prefusion F protein vaccine. 94 Based in part on these data, the CDC recommends that recombinant and adjuvanted vaccines, such as RZV, can be co-administered with other adult vaccines. 95

Gaps in HZ Prevention

Multiple studies identified gaps in HZ vaccine coverage and adherence, with opportunities to increase RZV uptake among adults aged ≥50 years. 96–98 Comparing patterns of RZV initiation among immunocompetent and immunocompromised US adults aged 50–64 years, one cohort study found 30% higher initiation (1.30 [95% CI 1.27–1.32]) among immunocompromised patients compared with immunocompetent patients, though series completion was similar. 99 In patients with chronic conditions, burden of disease may play a role in missed opportunities for vaccination; one claims analysis found that, among patients who had received one RZV dose, most chronic conditions, including both COPD and type 2 diabetes, were associated with lower completion. 100 Further research is needed to elucidate trends of RZV initiation and series completion in risk groups to inform opportunities to improve HZ prevention in these populations. Other studies assessing vaccination practices have shown lower uptake associated with certain social determinants of health, including poverty, lack of internet access, African American race, male gender, healthcare access, and health insurance status. 97 , 100–102

Regarding addressing gaps in HZ prevention, identified studies reported the impacts of immunization check-ups at employee health screenings and the expansion of vaccination into more medical practices, in order to reach more patients. 103 , 104 Strategies for patient populations with specific comorbidities have also been explored; one study in a population of hospitalized diabetes patients found that hospitalization and multidisciplinary care management may be key opportunities to increase vaccination coverage. 105

Guidelines and Recommendations for the Prevention of HZ

The CDC recommends two doses of RZV for adults aged ≥50 years and adults aged ≥19 years who are or will be immunodeficient or immunosuppressed because of disease or therapy. 10 In order to increase adult vaccination rates, the National Vaccine Advisory Committee has published Standards for Adult Immunization Practice that include, but are not limited to, RZV. 106 As a provider recommendation is the strongest predictor of patient vaccination, the CDC encourages providers to implement these standards into their practice using the following guidelines: 1) Assess patients’ immunization status at each clinical encounter; 2) Make clear and tailored recommendations for the vaccines that patients need; 3) Administer vaccines or refer patients to a vaccine provider at the same visit as the recommendation; and 4) Document vaccines received by patients. 107 A number of medical societies have reinforced these recommendations in their society guidelines or consensus reports ( Table 3 ).

Several medical organizations recommend RZV for patients with chronic medical conditions, including the National Kidney Foundation, for adults with advanced CKD, who have kidney failure or ESKD, or on dialysis, 115 and the American Association of Clinical Endocrinology and the American Diabetes Association, for patients with diabetes. 113 , 114 The Global Initiative for Chronic Obstructive Lung Disease 2025 Report recommends routine vaccination against HZ for adults with COPD, 111 and the American Lung Association recommends that patients with asthma or COPD stay up to date on vaccinations, including those for HZ. 112 The American Heart Association and the American College of Cardiology also recommend that all adults aged ≥50 years receive RZV. 4 , 110 Some medical organizations, including the American College of Cardiology, have also adopted the CDC standards for adult immunization practice, and have made a commitment to advancing adult immunization. 120

Several identified studies and guidelines also highlight the importance of HZ prevention through vaccination in populations with certain immune-related conditions, such as IBD, 19 , 46 , 47 rheumatic diseases, 109 myeloma, 121 HCT treatment, 18 , 84 , 85 and solid organ transplant. 122 Candidates for and recipients of solid organ transplant are recommended to receive a two-dose series of RZV. 122 For adult patients with cancer, the American Society of Clinical Oncology guidelines also recommend the RZV series. 117

Specialists play a growing role in the care of US older adults, and therefore in the prevention of HZ, as reflected by a 20% increase in mean specialist visits from 4.05 in 2000 to 4.87 in 2019 among Medicare beneficiaries (for adults aged ≥65 years). 123 Additionally, in 2019, 30.1% of Medicare beneficiaries saw ≥5 physicians annually. 123 Among healthcare providers, knowledge and vaccine confidence can influence the recommendations made to their patients, 124 making knowledge and endorsement of RZV recommendations and HZ prevention practices increasingly pertinent to specialists, particularly those working with older adults or specializing in conditions which may place their patients at an increased risk for HZ. To prevent HZ and its outcomes in an aging, increasingly comorbid US population, specialists play a crucial role in routinely assessing immunization status and providing strong recommendations for RZV as part of comprehensive prevention efforts, rather than relying solely on primary care providers.

Limitations

This review is subject to those limitations which are typical of literature searches and narrative reviews, such as reviewer bias and potential for noncomprehensive study identification. Additionally, all syntheses were descriptive and did not include quantitative analyses; however, this approach is inherent to narrative reviews, for which the aim is to summarize available evidence and distill insights to inform directions for future research and ongoing conversations in relevant clinical and policy settings. Due to the inclusion of studies conducted outside of the US, the generalizability of findings of these studies to a population of US adults may be limited and should be interpreted with the study geography in mind. The included studies report outcomes, such as increases in HZ risk, using different measures and study designs, which may influence the comparability of the results.

Conclusions

Due to the increasing proportion of US older adults living with chronic conditions and increased HZ risk and burden among those with comorbid conditions, understanding the risk factors for HZ in adults aged ≥50 years in the US, including those beyond age-related immunosenescence, will continue to grow in importance. The improvement of HZ prevention, particularly the vaccination of those aged ≥50 years with underlying conditions, is crucial, with opportunities for wider endorsement of vaccination by medical societies and healthcare providers of patients with comorbid disease.

Specialists and primary care providers are central to reducing HZ burden in adults aged ≥50 years, particularly those with chronic conditions. By embedding risk assessment into routine care, recommending vaccination without hesitation, and working together across disciplines, clinicians can protect patients from serious complications and drive a unified approach to prevention.

Acknowledgments

The authors acknowledge David Singer and Nikita Stempniewicz, GSK, Philadelphia, US, for contributions to study support, and Seongbin Shin, GSK, Philadelphia, US for publication management. The authors also thank Costello Medical for editorial assistance and publication coordination, on behalf of GSK, and acknowledge Madeline Block, Costello Medical, US for medical writing and editorial assistance based on authors’ input and direction.

Funding Statement

This study was sponsored by GSK. Support for third-party writing assistance for this article, provided by Madeline Block, Costello Medical, US was funded by GSK in accordance with Good Publication Practice (GPP 2022) guidelines ( https://www.ismpp.org/gpp-2022 ).

Data Sharing Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

CO has no disclosures to declare. BA has no disclosures to declare. RC is employed by GSK and holds financial equities in GSK, has received consulting fees and support for attending meetings from Neurelis Inc., and was formerly employed by and held financial equities in UCB Inc. CH has received consulting fees from Polarean Inc and payment for GSK Educational Videos, Boehringer Ingelheim Speakers Bureau, and GSK Advisory Board, and has stock options in Polarean Inc. HH has no disclosures to declare. JG has received grants from Merck & Co, AstraZeneca, and GSK; has received consulting fees from Genentech and Janssen; has received payment from Janssen and Merck & Co; has received support for attending meetings from the Hematology/Oncology Pharmacy Association; and is employed by GSK and holds financial equities in GSK. RP is employed by GSK and holds financial equities in GSK. The authors report no other conflicts of interest in this work.

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Associated Data

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.