Vaccination of adolescents with chronic medical conditions: Special considerations and strategies for enhancing uptake

Abstract

Adolescents with chronic medical conditions (CMCs), a growing population worldwide, possess a wide array of preventive health care needs. Vaccination is strongly recommended for the vast majority of these adolescents given their increased risk of vaccine preventable infection and associated complications. Not only should they receive routine vaccines, but some also require additional vaccines. Despite these guidelines, evidence suggests that adolescents with CMCs often fail to receive needed vaccines. Many factors contribute to this under-immunization, including lack of knowledge among parents and providers and suboptimal coordination of primary and subspecialty care. This review describes current vaccination recommendations for these adolescents as well as recent data related to infection risk, vaccine efficacy and safety, vaccination coverage, and the unique multilevel factors impacting uptake in this population. It also discusses strategies for improving coverage levels and reducing missed vaccination opportunities, with a particular focus on technology-based interventions.

Keywords:

• adolescent
• chronic medical condition
• vaccination

Abbreviations

ACIP	=	Advisory Committee on Immunization Practices
AE	=	adverse event
CDC	=	Centers for Disease Control and Prevention
CMC	=	chronic medical condition
EHR	=	electronic health record
HIV	=	human immunodeficiency virus
GMT	=	geometric mean titers
HPV	=	human papillomavirus
IIS	=	immunization information systems
PCV	=	pneumococcal conjugate vaccine
PPSV	=	pneumococcal polysaccharide vaccine
SLE	=	systemic lupus erythematosus
Td	=	tetanus-diphtheria
Tdap	=	tetanus-diphtheria-acellular pertussis
WHO	=	World Health Organization

Introduction

A growing number of adolescents worldwide have one or more chronic medical conditions (CMCs). Many adolescents with CMCs are at increased risk of vaccine-preventable infections. Vaccination is one of the most effective strategies for reducing disease burden, including for these high-risk adolescents, and thus is strongly recommended. Nonetheless, coverage levels remain suboptimal, and missed vaccination opportunities are common. In this review, we describe current vaccination recommendations for adolescents with CMCs and present evidence related to infection risk and vaccine efficacy and safety among select groups. We also examine coverage levels and missed opportunities and assess unique individual, parent, provider, and systems-based determinants of vaccination in this high-risk population. Lastly, we discuss strategies for improving coverage and reducing missed opportunities for vaccination of these vulnerable adolescents.

Chronic medical conditions: epidemiology and definitions

It is estimated that one in every 6 to 10 adolescents has a CMC or disability limiting daily activities.^1-7 The prevalence appears to be increasing, likely as a reflection of medical advances reducing mortality and a rise in conditions such as human immunodeficiency virus (HIV) infection, diabetes mellitus, and mental health disorders.⁸ Challenges with interpreting epidemiological studies exist, primarily as a result of using different age cutoffs for defining adolescence and variable classification of CMCs.^8-10 With respect to vaccination, a narrow definition focused on medical diagnoses may be most relevant when considering infection risk, associated complications, and a vaccine's efficacy and safety profile. A more comprehensive definition addressing functional status, limitations in socially defined roles, services needed, and resource utilization could be valuable when assessing risk of under-immunization and strategies for improving outcomes. Future investigations may consider using a standardized approach to adolescents with CMCs as well as including a healthy control population in order to facilitate comparison both within and across studies. Given the current data available, we opted to present a range of studies describing either disease-specific populations or CMCs more broadly. Although this is not a systematic review, we attempted to be as inclusive as possible in order to illustrate both general principles and special considerations with respect to vaccination of this heterogeneous population.

Vaccination overview

Many countries rely on vaccination recommendations from the World Health Organization (WHO), while others convene a committee of experts who establish national recommendations such as the Advisory Committee on Immunization Practices (ACIP) in the United States. This review focuses on 5 vaccines currently recommended for adolescents with CMCs by the WHO and/or ACIP (Table 1): human papillomavirus (HPV), tetanus-diphtheria-pertussis, meningococcal, pneumococcal, and influenza.^11,12 Evidence underlying these recommendations as well as vaccination coverage estimates across a range of CMCs, ages, and settings are presented below.

Table 1. WHO and ACIP vaccination recommendations

Vaccine	Population	Dosing
WHO^12
HPV	Female adolescents (target group: 9–13 year-olds)	<15 yr: 2 doses (≥6 mo interval between doses); 3 doses if immunocompromised; ≥15 yr: 3 doses
Td	Adolescents (e.g., 12–15 years)	1 dose
Meningococcal	Countries with intermediate/high endemic rates and outbreak frequency (e.g.,, African meningitis belt) High-risk CMCs: immunodeficiency (e.g., asplenia, complement component deficiency, advanced HIV)	MenA conjugate: 1 dose (9–18 mo) MenC conjugate: 2 doses (2–11 mo) + 1 booster dose at 1 y after 1^st dose (≥12 mo) MenACWY-D, MenACWY-CRM: 2 doses (9–23 mo) or 1 dose (≥2 yr)
Influenza	Countries with influenza vaccination programs: high-risk populations (e.g.,, patients with certain CMCs)	1 dose annually (children ≤8 yr require 1–2 doses, depending on prior receipt)
Pneumococcal	Infants	PCV: 2 primary doses (<6 mo) + 1 booster dose (9–15 mo) OR PCV: 3 primary doses • Plus 1 booster dose if HIV or preterm infant and primary doses received <12 mo
ACIP^11
HPV	11–12 y Catch-up vaccination through 26 y for females, immunocompromised males, men who have sex with men or through 21 y for all other males	3 doses
Tdap	11–12 y Consider earlier administration (<5 years since prior dose) for those with high-risk CMCs	1 dose
Meningococcal	Adolescents High-risk CMCs: asplenia, complement component deficiency, HIV	MenACWY-D, MenACWY-CRM: 1 primary dose (11–12 yr) + 1 booster dose (16 yr) • 2 primary doses if adolescent with HIV 2 primary doses (≥2 yr) + booster doses every 5 y thereafter (if ≥7 yr of age) if asplenia or complement component deficiency
Influenza	Universal (6 mo and older) Priority groups based on CMCs: chronic pulmonary, cardiovascular, neurologic, hematologic, hepatic, renal, or metabolic disorders, immunosuppression	1 dose annually (children ≤8 yr require 1–2 doses, depending on prior receipt)
Pneumococcal	Infants High-risk CMCs: CSF leak, cochlear implant, chronic heart, lung, or liver disease, diabetes mellitus, asplenia, immunocompromising conditions	PCV13: 3 primary doses (2, 4, 6 mo)+ 1 booster dose (12–15 mo) • Catch-up vaccination if CSF leak, cochlear implant, asplenia, immunocompromised (6–18 yr) PPSV23: 1 dose if high-risk CMCs (≥2 yr) • Revaccination at 5 y after 1^st dose if asplenia or immunocompromised

^a Vaccine of choice depends on locally prevalent serogroup(s) or serosubtype. Recommended formulation/schedule may vary by country.

^b Other high-risk populations (e.g., laboratory workers for meningococcal vaccination; pregnant women for influenza vaccination) were not included given the scope of this review.

^c Meningococcal vaccine may also be given between 2 mo-23 mo to children with certain high-risk conditions. Formulation and schedule vary and are beyond the scope of this review.

Human papillomavirus (HPV)

HPV vaccination recommendations for adolescents with CMCs resemble those of the general population with a few notable exceptions: 1) extended duration of catch-up vaccination for immunocompromised males (ACIP); 2) increased dosing requirements for immunocompromised females <15 y (WHO) (Table 1).^13,14 These discrepancies primarily reflect disease epidemiology and vaccine efficacy data.

Cancer survivors, transplant recipients, patients with HIV, and those with Fanconi's anemia have been shown to be at increased risk of HPV infection and related complications.^15-19 There is also evidence that patients with systemic lupus erythematosus (SLE) have a high frequency of persistent HPV infection^20,21 and greater odds of developing high grade squamous intraepithelial lesions compared to healthy controls, possibly due to decreased clearance of HPV-infected cells secondary to disease- or treatment-specific immunosuppression.^17,22,23 Thus, sustained vaccination efforts through 26 years, i.e., the upper age limit for which the HPV vaccines are currently licensed, may be beneficial for patients with such conditions.

Studies of HPV vaccine immunogenicity and safety have been conducted in certain high-risk populations.^24-27 High seroconversion rates (>92%) were exhibited by HIV-positive females after completion of the 3-dose series,^24,25 although geometric mean titers (GMTs) were lower than for historic controls²⁴ and among those not taking vs. taking antiretroviral therapy.²⁵ Female patients with SLE also demonstrated high seroconversion rates (>94%) after receiving the third dose,²⁶ although one study observed lower rates (74–92%), possibly reflecting a slightly older study population and the use of immunosuppressive agents.²⁷ These findings lend support to the WHO recommendation that young adolescents with immunocompromising conditions complete the 3-dose series rather than the 2-dose regimen otherwise recommended by the WHO for young adolescents based upon promising immunogenicity data.^28,29 Clinical trial and post-licensure studies have not raised safety concerns for high-risk patients; thus, there are no contraindications to HPV vaccination based upon underlying medical conditions.^13,14

Studies describing HPV vaccination coverage among adolescents with CMCs are limited. Two studies of US adolescent cancer survivors demonstrated that only one-third had received one or more doses.^30,31 Although no difference in uptake was observed between adolescents with and without a history of cancer in one of those studies, this remains worrisome since cancer survivors are at increased risk of HPV-related complications.³¹

Tetanus/diphtheria/pertussis

Recommendations for Td (WHO) and Tdap (ACIP) are similar between adolescents with and without CMCs, although the ACIP notes that providers could consider a shorter dosing interval for Tdap vaccination for adolescents with severe CMCs (Table 1).³² This stems in part from evidence that they are at increased risk of death following pertussis infection. Between 1990 and 2004, for example, there were 2 pertussis-related deaths among adolescents aged 11–18 years, both with a CMC (malignancy and severe neurologic impairment).³² Waning immunity following acellular pertussis vaccination—although unclear whether it disproportionately affects individuals with CMCs—and high rates of pertussis infection among adolescents may also lend support to using a shorter dosing interval.^33,34 With respect to safety, the WHO reports no contraindications to these vaccines, while the ACIP states that Tdap vaccination is contraindicated among individuals with encephalopathy of unknown etiology that occurred within 7 d of any prior diphtheria-tetanus-pertussis-containing vaccination.^32,35,36

As with HPV, there are few studies describing tetanus/diphtheria/pertussis coverage levels specifically among adolescents with CMCs. One study from Brazil found that 72% of 4–17 year-old patients with a history of renal transplantation were up-to-date with tetanus/diphtheria/pertussis vaccination.³⁷ Conversely, a study from Italy demonstrated that only 4% of 14 year-olds with CMCs were up-to-date with tetanus/diphtheria/pertussis vaccination.³⁸ In that study, patients with diabetes mellitus were the most likely to have delayed tetanus/diphtheria/pertussis vaccination. Given that the Brazilian study included a small sample (n = 46) and both studies lack a comparison group, further investigation is needed. Nonetheless, it remains apparent that improvements could be made.

Meningococcal

Both the WHO and ACIP recommend meningococcal vaccination of individuals with high-risk conditions beginning in early childhood (Table 1).^39-41 These guidelines are based upon epidemiological evidence that individuals with complement component deficiencies and functional or anatomic asplenia are particularly susceptible to meningococcal infection.³⁹ For example, the former have a 7,000–10,000-fold increased risk for meningococcal infection, and a recurrence rate 100–150 times greater than the general population.⁴²

Several meningococcal vaccine formulations are available. Conjugate vaccines are preferred over polysaccharide vaccines for children given their potential for herd protection and increased immunogenicity, and specific vaccine selection should be determined by local serogroup/serosubtype prevalence.^40,41 The ACIP recommends use of the quadrivalent meningococcal conjugate vaccine, although it also recently approved the newly licensed serogroup B meningococcal vaccine for high-risk individuals aged 10 and older.^39,43

The recommended dosing schedule is shaped by evidence that certain individuals exhibit a less robust immune response to meningococcal vaccination. For example, one study demonstrated that those with asplenia had lower serum bactericidal antibody (SBA) GMTs in response to meningococcal serogroup C conjugate vaccine compared to matched controls, although most (80%) still exhibited protective GMTs, particularly after 2 doses (93%).⁴⁴ Another study found response rates to 4 vaccine serogroups between 52–73% in HIV-infected adolescents.⁴⁵ Consequently, these individuals require 2 primary doses. Similarly, SBA GMTs against the 4 serogroups have been shown to decline after quadrivalent meningococcal conjugate vaccination,^46,47 lending support to booster dose recommendations. One study found that, among breakthrough meningococcal cases, individuals with CMCs exhibited fewer days since meningococcal vaccination than observed among those without CMCs.⁴⁸ This suggests that booster doses may be particularly important for high-risk individuals, although further investigation is needed.

There are few published studies to date describing meningococcal coverage among high-risk patients. One small study in Spain found that 81% of HIV-positive children and adolescents had received meningococcal vaccine,⁴⁹ below routine coverage levels reported in their general pediatric population (90–95%).⁵⁰ Studies in other vulnerable populations as well as comparison studies with the general population, when recommended, would be valuable.

Influenza

Although their recommendations differ with respect to universal influenza vaccination, the WHO and ACIP both suggest targeting high-risk populations (Table 1).^51,52 Certain CMCs place children and adolescents at increased risk of influenza-related complications, hospitalizations, and deaths.^52-58 For example, one study of children hospitalized with community-acquired laboratory-confirmed influenza found that chronic pulmonary, cardiac, and neurological/neuromuscular diseases were associated with respiratory failure.⁵⁷ Being in the older adolescent/young adult age group (18–21 years) increased the risk of those with cardiac and neurological/neuromuscular disease, likely reflecting the medical fragility of these patients surviving into later adolescence and early adulthood.

The optimal number of doses and timing of revaccination among patients with CMCs is unclear. Immunogenicity data indicate that children and adolescents with certain CMCs have a suboptimal immune response to vaccination, although this may vary depending on the underlying condition.^59-62 With the pandemic 2009 H1N1 influenza vaccine, one study found that a lower proportion of immunocompromised children achieved adequate seroprotective antibody titers than immunocompetent children, even after 2 doses.⁶¹ Another study found that the boosting effect of prior seasonal influenza vaccine doses may be attenuated in immuncompromised hosts.⁶⁰ Although there may be issues with obtaining adequate protection, there are no known contraindications to inactivated influenza vaccination based upon underlying medical conditions. For live attenuated influenza vaccination, immunosuppression and asthma are considered contraindications by the WHO and/or ACIP.^51,63

Numerous studies indicate that adolescents with CMCs frequently fail to receive influenza vaccine,^38,64-77 although coverage levels vary across conditions, seasons, and settings. In the US, for example, a study conducted before the universal influenza vaccination recommendation found high coverage (91%) among 5–17 year-olds with cystic fibrosis,⁷¹ whereas national data revealed that only one-third of those with any high-risk condition were vaccinated during the same seasons.⁶⁶ More recent US data showed that 50% of 6 month-17 year-olds with neurologic or neurodevelopmental conditions received influenza vaccine in the 2011–2012 season, comparable to the general pediatric population (52%).⁶⁸

There are limited data demonstrating missed opportunities for influenza vaccination. In one study, approximately half of all unvaccinated adolescents with CMCs in a large health maintenance organization had at least one missed opportunity.⁶⁴ Another study found that approximately one-quarter of children with comorbidities who were hospitalized with influenza had a prior hospitalization in the influenza season,⁷⁸ suggestive of a missed opportunity.

Pneumococcal

In addition to recommending routine pneumococcal conjugate vaccination (PCV), the WHO and ACIP offer guidance with respect to high-risk populations (Table 1).^79,80 The WHO suggests an additional booster dose for select preterm infants and infants with HIV. The ACIP expanded its target population for 13-valent PCV (PCV13) to include 6–18 year-olds with certain underlying conditions. The latter is supported by data showing that PCV13-type invasive pneumococcal disease incidence is markedly elevated among 6–18 year-olds with hematologic malignancy, HIV/AIDS, and sickle cell disease compared to those without those conditions (rate ratios of 822, 122, and 27, respectively).⁸⁰ In addition, a recent investigation found that one PCV13 dose induced an immune response to all vaccine serotypes and caused no unexpected reactions or AEs among children aged 6–17 y with sickle cell disease,⁸¹ although studies in other high-risk populations are needed.

The WHO does not recommend 23-valent pneumococcal polysaccharide vaccination (PPSV23) of high-risk individuals in resource-poor settings with competing priorities. ⁷⁹ The ACIP, however, does recommend PPSV23 for those with conditions placing them at increased risk of pneumococcal disease from a broader array of serotypes.^80,82,83 The limited studies examining PPSV23 efficacy and effectiveness among high-risk children and adolescents suggest benefit.^84-86 One observational study found 63% effectiveness of PPSV among children with eligible CMCs.⁸⁴ Another study revealed that 76–96% of children with HIV on highly active antiretroviral therapy achieved sufficient antibody levels following receipt of PCV, followed by a dose of PPSV.⁸⁷ Immunity following pneumococcal vaccination wanes over time, and PPSV may interfere with the response to subsequent PCV and PPSV doses.⁸⁶ The optimal timing, frequency, and clinical effectiveness of additional doses remain unclear.⁸⁸

Pneumococcal vaccination coverage among high-risk populations is variable. One study found that 73% of US children with sickle cell disease were up-to-date with pneumococcal vaccination by 59 months, higher than observed among control patients (35%), but lower than national data in the general population (80%).^89,90 Another study from the US revealed that 54% of adolescent and young adult patients with cochlear implants had received PPSV.⁹¹ An Italian study demonstrated that <25% of high-risk children had received PPSV.⁷⁶ In England and Wales, the proportion of PPSV-vaccinated 15–19 year-olds ranged between <5% and approximately 65%, depending on the underlying medical condition and patient gender.⁹²

Unique factors impacting vaccination

In order to improve the suboptimal vaccination coverage of adolescents with CMCs, it is important to understand the patient, family, provider, and systems-based factors impacting vaccination of this population. Although some play a role in adolescent vaccination in general, others may disproportionately or uniquely affect adolescents with CMCs, as illustrated below.

Patient

Demographic characteristics such as age, gender, race/ethnicity, and insurance status have been associated with vaccination of patients with CMCs.^{30,31,64,70,71,92} For example, a study of cancer survivors demonstrated a particularly wide age-based discrepancy in HPV vaccination (5% of 11–12 year-olds, 39% of 13–17 year-olds, and 78% of 18 year-olds).³⁰ Another study demonstrated that Hispanic ethnicity was associated with lower influenza vaccination coverage among 5–17 year-olds with cystic fibrosis.⁷¹

Risk behaviors (actual or perceived) could affect vaccination patterns among adolescents with CMCs. Although historically it was believed that these adolescents were protected from engaging in drug/alcohol use, sexual intercourse, and violence, more recent data indicate that many are equally, if not more, likely to engage in such activities.^4,7,8,93-95 Misconceptions about this risk could have implications for preventive care services. For example, despite data showing that adolescents with sickle cell disease and cystic fibrosis may engage in sexual activity before 15 years,⁹⁵ many providers delay sexual health counseling (≥15 years).⁹⁶ Similarly, another study found that mothers of cancer survivors were less likely to predict that their daughters would be sexually active by high school graduation than mothers of healthy adolescents,³¹ likely contributing to the aforementioned delays in HPV vaccination. These findings are concerning since the adverse health outcomes of such behaviors may be more significant due to their underlying conditions and treatment regimens.⁸

The adolescent's unique experiences with their CMCs, including psychosocial burdens, could also shape their priorities and, consequently, their acceptance of vaccination. For example, one study found that adolescents with select CMCs placed high importance on pain management.⁹⁷ Thus, one could hypothesize that injection site pain, i.e., as reported by many recipients of HPV vaccine,⁹⁸ could be a particular deterrent to vaccine uptake.

In addition, vaccination coverage varies by high-risk condition.^38,64,76,96 In one study, for example, patients with diabetes mellitus had significantly lower pneumococcal and influenza vaccination coverage compared to those with HIV, cystic fibrosis, and a history of liver transplantation.⁷⁶ Further, the number of underlying conditions faced by the adolescent could impact vaccine uptake. One study found that patients with more than 2 conditions were 22–35% more likely to receive influenza vaccine.⁷⁵ The severity of underlying disease could play an important role as well. For example, “concurrent disease” was a commonly identified reason for missing/delayed vaccination among children with CMCs, particularly for certain recommended vaccines compared to others (i.e., tetanus/diphtheria/pertussis vs. meningococcal vaccines).³⁸ Whether these missing/delayed vaccinations were warranted based upon actual contraindications remains unclear, although another study found that most visits when influenza vaccine was not administered to adolescents with CMCs were actual missed opportunities rather than reflective of contraindications.⁶⁴

Family

Parents of patients with CMCs are asked to make vaccination decisions in the face of great complexity. Infection risk, vaccine efficacy and safety, and vaccination recommendations for their adolescent may differ or be perceived as differing from those of an otherwise healthy adolescent, resulting in greater educational needs than for the general parent. Data suggest that many parents of these high-risk patients lack requisite vaccine-related knowledge.^38,65,99-102 An Australian study found that few parents of immunosuppressed adolescents were knowledgeable about HPV infection, and some had limited understanding of their adolescent's risk of HPV infection.⁹⁹ A previous study in the US reported that only half of parents believed their child with asthma should be vaccinated against influenza.⁶⁵ Similarly, another study found that one-quarter of parents did not feel that influenza vaccine was needed for their child with CMCs.¹⁰¹ A study from the United Kingdom, conducted when the national vaccination program only recommended influenza vaccination of at-risk children (<16 years), showed that over half of parents of these children were not aware of this recommendation.¹⁰² These findings are concerning, especially since parents of children with CMCs often cite lack of information as a reason underlying delayed or non-receipt of recommended vaccines.³⁸ For certain parents, such as those with less formal education, special attention to their educational needs may be warranted. This is exemplified by a study showing that parents without a high school education were less likely to have their child with asthma vaccinated against influenza compared to college-educated parents.⁶⁹

For parents of adolescents with CMCs, beliefs about vaccination are likely complicated by the unique relationship between their adolescent's underlying conditions, treatment regimen, and the vaccine's efficacy and safety profile. One study found that some parents of immunosuppressed adolescents were concerned about adverse events following HPV vaccination, especially the vaccine's effect on immunity and its interaction with medications.⁹⁹ Parents may be particularly worried about “newer” vaccines, including influenza vaccine with its variable efficacy and potentially different safety profile with each formulation and season. In support of this, one study found that 19% of parents of children with CMCs feared influenza vaccine and 15% feared pneumococcal vaccine, whereas 1% feared polio and tetanus/diphtheria/pertussis vaccines.³⁸

Providers

Numerous studies have demonstrated that provider recommendation plays a key role in vaccine acceptability and uptake among patients with CMCs.^{30,31,65,99-101,103,104} Providers also have an opportunity to educate patients and families and clarify vaccine misconceptions. For patients with CMCs, this is arguably more crucial given the complexity of underlying conditions, their management, vaccine efficacy and safety data, and special vaccination schedule considerations. Yet, despite its importance, many providers fail to recommend or discuss vaccines to these high-risk patients.^{30,31,65,76,103,104} Perhaps consequently, missed vaccination opportunities are common.^64,101

There may be several reasons why some providers do not communicate with these patients and families about vaccination. First, provider attributes such as age or medical specialty could play a role.^76,104-106 Second, they may have limited understanding of and comfort with adolescents and their unique health issues,¹⁰⁷ especially for those with CMCs.^8,96,108 For example, one study found that pediatricians and subspecialists frequently fail to provide needed preventive health services like risk behavior counseling to adolescents with cystic fibrosis and sickle cell disease.⁹⁶ Similarly, another study revealed that subspecialists often lacked insight into what adolescents with CMCs felt were important components of physician-patient communication,¹⁰⁸ which could affect their ability to effectively deliver key information about vaccination to them. Third, providers may be misinformed about infection risk as well as vaccine efficacy and safety (including contraindications) for high-risk patients.^{100,101,104,109} They may also lack awareness of vaccination recommendations, which are undoubtedly more complicated for this high-risk population. One study found that most primary care pediatricians were unable to list all of the high-risk conditions for which influenza vaccination is recommended.¹⁰⁰ An Italian study found that the impact of an intervention on influenza vaccination of pediatric cancer survivors differed depending on the time since completion of chemotherapy, which may have resulted in part from varying provider interpretations of existing recommendations.¹¹⁰ Another study showed that providers frequently adapted their influenza vaccination practices based upon the severity of the underlying illness.¹⁰⁶

Systems

Adolescents with CMCs typically require care from multiple providers in a variety of clinical settings, which presents unique challenges to vaccination. Thus, a primary medical home is recommended for comprehensive, coordinated care and optimizing vaccine delivery.^111-113 Nonetheless, many of these adolescents identify a subspecialist as their main physician, and few discuss general health care needs with them.^96,114,115 As a result of this fragmented care, it may be unclear who should assume responsibility for vaccination and where vaccination should occur. In support of this, one study found that the most significant deterrent to a provider vaccinating a high-risk patient against influenza was the involvement of another physician in that patient's care.¹⁰⁶ Further, given the complex health care needs of these patients, there are likely many competing priorities during primary and subspecialty care visits, which could result in missed vaccination opportunities. Time constraints during a medical encounter could serve as a particular deterrent to discussing and offering vaccines to these high-risk adolescents. Providers have expressed that they need more time to establish a trusting relationship with these patients and families in order to convince them that the HPV vaccine was necessary.¹¹⁶

Roughly one-third of adolescents with CMCs, including a disproportionately high number of racial and ethnic minorities from urban settings, have no medical home or a usual source of primary care.^{1,114,115,117-119} Infrequent preventive care visits have been associated with lower influenza vaccination coverage in patients with CMCs.^64,70 Logistical problems are frequently identified by parents of children with CMCs as a reason for delayed/missing vaccinations.³⁸ Conversely, easy access to the provider's office has been associated with a greater odds of influenza vaccination of patients with CMCs.⁶⁵ Other systems-based barriers, including vaccine availability, vaccine cost, and staffing limitations, could also contribute to under-vaccination of these adolescents.

Strategies to improve vaccination

Innovative strategies targeting identified patient, family, provider, and systems-based barriers to vaccination are needed in order to improve coverage levels and reduce missed vaccination opportunities for adolescents with CMCs. Vaccine interventions targeting these high-risk adolescents should build upon earlier successes in the general adolescent population, yet should be tailored to address their unique barriers and circumstances. Likely, a combination of approaches will be required, and the use of health information technology holds particular promise.

Patient and family

Vaccine reminder/recall systems are strongly recommended given evidence of their effectiveness in improving vaccination coverage.^120,121 Recent studies have demonstrated their positive impact on routine vaccination of adolescents in general through traditional approaches such as letter or telephone,^122,123 novel strategies like text messaging,^124-126 and in combination with immunization tracking, patient outreach, and clinician decision support.^127,128 They may be particularly useful for completion of vaccine series, such as for HPV vaccination.^124,126,128

Traditional reminder/recall interventions have focused on patients with CMCs, primarily for influenza vaccination of children with asthma. One study found that most pediatricians and family medicine providers were interested in using a centralized reminder system to target patients with asthma in need of influenza vaccination.¹²⁹ Two interventions demonstrated that centralized reminders improved influenza vaccination coverage among young children with CMCs.^130,131 Additional studies in adolescents with CMCs are needed.

Tailoring of the reminder/recall system may be necessary for patients with CMCs. One study found that telephone reminders for parents of children with asthma were most effective in increasing influenza vaccination coverage when the call and vaccine administration were performed by the pediatricians and clinic involved in the child's asthma care,¹³² although another study of pediatric cancer survivors did not observe this differential impact.¹¹⁰ A customized approach depending on the underlying disease and treatment history could incorporate educational information that may facilitate adolescent and parent decision-making, including current materials about infection risk, vaccine efficacy and safety, vaccination recommendations, and common misconceptions.

Other educational interventions targeting families of patients with CMCs have also shown benefit. A Turkish study demonstrated higher influenza vaccination coverage of diabetic patients aged 2–21 y following a summer educational session compared to prior seasons.⁷⁷ The session included discussion of the need for and benefits of vaccination, vaccine AEs, and other vaccine information as well as a recommendation from the child's endocrinologist–all of which may be particularly important for patients with CMCs. Innovative outreach strategies such as peer support groups or social media campaigns specifically targeting adolescents and families dealing with chronic disease also may be beneficial, especially for those with rare conditions.^8,133,134 Novel delivery models for vaccine-related information such as personal health records could be useful as well, but have yet to be studied. Supporting this possibility, one study found that parents of children with CMCs thought patient portals would be beneficial for management of their child's care,¹³⁵ and another study found that parents in general were interested in using portals for vaccine information.¹³⁶

Given the growing population of adolescents with CMCs, it is important for all vaccine-related interventions, public health initiatives, and awareness campaigns targeting the general population to consider the needs of these high-risk patients and their families.

Provider

Interventions targeting providers may also improve vaccination uptake and reduce missed vaccination opportunities for adolescents with CMCs. In the general adolescent population, clinician decision support in the electronic health record (EHR) has been shown to increase HPV vaccination initiation¹²⁸ and reduce missed opportunities for receipt of the first and third HPV vaccine doses.¹³⁷ Similarly, a recent study found that a registry-linked reminder in the EHR increased influenza vaccine uptake in a general pediatric population.¹³⁸ Among patients with CMCs, the impact of clinician decision support has been variable. For example, in a study of 5–18 year-olds with asthma, an EHR alert had a modest effect on influenza vaccination coverage (3.4% greater improvement among intervention vs. control sites).¹³⁹ One before/after study observed significant improvement in influenza vaccination coverage among pediatric rheumatology patients following introduction of an EHR alert.¹⁴⁰

Other educational strategies, such as continuous medical education workshops or webinars, could enhance provider awareness of the need for vaccination among adolescents with CMCs and promote more accurate and effective communication with these adolescents and their families. Additional key issues to address include who should discuss vaccination with patients and families and who should be responsible for vaccinating these patients. Subspecialists need to be engaged given their vital role in caring for these patients. Consultation with adolescent health subspecialists would also be valuable given the complex developmental issues faced by being an adolescent with a CMC.

Systems

A variety of systems-based approaches can be implemented in order to improve vaccine uptake and reduce missed opportunities. First, because patients with CMCs see multiple providers in diverse settings, there is a tremendous need for a centralized immunization record. Immunization information systems (IIS), now present in 50 states, 5 cities, and the District of Columbia in the US as well as numerous countries worldwide, could merge immunization records scattered across clinical settings and facilitate care coordination.¹¹²

Interventions that reduce time constraints and increase access such as standing vaccination orders, flagging charts for patients in need of vaccination, vaccine-only visits, and expanded evening/weekend clinic hours for vaccination would also be helpful for these adolescents with many competing priorities given their complex care needs.¹⁴¹ Further, if we are to achieve optimal coverage levels, vaccination should be offered in diverse settings.¹⁴² For adolescents with CMCs without a medical home or usual source of primary care or who identify their subspecialist as their main provider, the subspecialty clinic may be optimal for vaccination. One study found that 74% of parents in a pediatric cardiology clinic would be open to having their child receive needed vaccines in that clinic.¹⁴³ Vaccine delivery in other settings such as schools or pharmacies is another possibility, but could be more challenging depending on the vaccine administrator's level of understanding of and comfort with the adolescent's underlying conditions and treatment regimen. Entry of vaccine administrations into an IIS could also be more problematic in those settings. Lastly, it is worth noting that school mandates have substantially increased vaccination coverage of adolescents in general;¹⁴⁴ however, they may be less effective for this population if parents or providers request unnecessary medical exemptions.

Conclusions

This review highlights the problem of under-immunization for routinely recommended and specially indicated vaccines among the growing population of adolescents with complex health care needs. Ongoing investigation of vaccine efficacy and safety concerns as well as factors impacting vaccine uptake in this population is crucial. Interventions need to be tailored to address the unique barriers to vaccination of these high-risk patients, including strategies to enhance provider-family communication and promote greater collaboration between primary care providers and subspecialists.

Disclosure of Potential Conflicts of Interest

Dr. Hofstetter receives research support for an investigator-initiated study funded by the Pfizer Medical Education Group. Dr. Rosenthal is an unfunded investigator on that study. Dr. LaRussa has no conflicts of interest or financial relationships to disclose.