Long-Term Impacts of Invasive Meningococcal Disease on Survivors and Their Caregivers in the United States and Canada

Abstract

Introduction

Adolescents and young adults are among those most often impacted by invasive meningococcal disease (IMD), and survivors are often left with serious and permanent physical, neurological, psychological, or systemic complications. We conducted this targeted literature review with the primary goal of identifying evidence and evidence gaps relating to long-term health-related quality-of-life (HRQoL) and economic impacts for survivors who contracted IMD during adolescence or early adulthood and their caregivers.

Methods

We searched electronic databases and gray literature for studies assessing long-term clinical, HRQoL, and economic outcomes for patients who survived IMD in the US or Canada. Expert input provided by a survivor and patient advocate, as well as a pediatrician, was used to explore impacts and evidence gaps.

Results

Eleven studies met the prespecified inclusion criteria for this review. Seven studies from the US and four from Canada reported on long-term outcomes of interest, including ten studies reporting clinical sequelae experienced by IMD survivors, three reporting HRQoL/social impacts, five reporting healthcare resource utilization, and four reporting direct costs. Across seven studies, 10.6–41% of IMD survivors had ≥ 1 sequelae, with prominent examples including seizures, deafness or hearing loss, stroke, amputation, skin scarring, and renal dysfunction or failure. Qualitative interviews and questionnaires revealed that survivors face significant and persistent emotional distress and physical impairment that limit daily functioning and social activities. Healthcare resource use, including inpatient stays and specialist visits following IMD was high, leading to substantial healthcare costs, especially among survivors with sequelae. Expert input highlighted that much of the burden encountered by survivors is not included in the published literature, including the cumulative out-of-pocket and indirect costs of living with sequelae for decades and the extent of the physical, psychological, and social impacts.

Conclusion

While published evidence suggests that survivors with sequelae from IMD during adolescence or young adulthood have long-term and significant humanistic and economic impacts, considerable and important evidence gaps remain.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40121-025-01181-8.

Key Summary Points

Why carry out this study

Invasive meningococcal disease (IMD) inflicts severe and often irreversible complications with long-term health-related quality of life and economic impacts that survivors must manage throughout their lifetimes.

This review was conducted to illuminate the contemporary understanding of long-term IMD burden and incorporates the viewpoints of people directly affected to capture evidence gaps.

What was learned from the study?

IMD survivors face significant and persistent physical, neurological, psychological, and systemic complications that severely affect their daily functioning and social activities, and lead to substantial healthcare resource utilization and costs, especially among survivors with sequelae.

Based on expert opinion, much of the burden encountered by survivors is not included in scientific literature, including the extensive out-of-pocket and indirect costs of living with sequelae, as well as the full extent of the physical, psychological, and social impacts, underscoring the need for more holistic approaches to understanding and managing the long-term consequences of IMD.

Introduction

Neisseria meningitidis is a resident of the upper respiratory tract mucosa of around 10% of the population. Although usually harmless, when N. meningitidis enters the bloodstream or other normally sterile anatomical sites, it can cause invasive meningococcal disease (IMD) [1, 2]. N. meningitidis serogroups A, B, C, W, X, and Y account for the majority of such infections [3–5]. IMD cases are rare, with population-wide incidence rates of 0.09 per 100,000 people in the United States (US) as of 2022 and 0.28 per 100,000 persons in Canada from 2017 to 2021 [6–8]. Although IMD can occur at any age, particularly vulnerable populations include children, adolescents, and young adults because of their social behaviors [9–11]. Indeed, individuals who reside in crowded households or live in college dormitories or fraternities, smoke or are exposed to secondhand smoke, attend bars and large gatherings, are in intimate relationships, or have a recent history of respiratory tract infection are at elevated risk of developing IMD [12]. The elderly also have an increased risk of IMD, likely due to a combination of risk factors including medical comorbidities, social crowding, and immunosenescence [13].

Presenting primarily as meningitis, meningococcemia, or both, IMD causes severe clinical outcomes. Case-fatality rates (CFRs) are considerable for adolescents (10%), and young adults (15%), though they are highest for adults ≥ 80 years of age (33%) [14]. Approximately 20% of patients surviving IMD experience one or more potentially debilitating physical, neurological, psychological, or systemic sequelae after recovery that may persist throughout the patient’s lifetime (Table 1) [14–18].

Table 1.

Examples of sequelae experienced by IMD survivors

Physical sequelae	Neurological sequelae	Psychological sequelae	Systemic sequelae
Skin scarring Amputation(s) Chronic pain Fatigue Stunted growth	Learning difficulties Cerebral vascular events Sensory deficits (e.g., numbness, vision loss, and hearing loss) Motor deficits (e.g., weakness, loss of coordination, and paralysis) Seizures Radiculopathy	Depression Anxiety	Eczema Venous thrombosis Vasculitis Arthralgia Renal failure Anemia Autoimmune disease Increased susceptibility to infection

Sources: Wang et al., Olbrich et al., Shen et al., Stein-Zamir et al., and Voss et al. [14–18]

IMD invasive meningococcal disease

Literature reviews evaluating the long-term burden of IMD have described this phenomenon from a global perspective [15, 19–21]. However, to our knowledge, no reviews summarizing the contemporary understanding of the humanistic and economic burden of long-term sequelae on adolescent IMD survivors within the US and Canada have been conducted. This targeted literature review aims to comprehensively synthesize the existing literature on this topic, encompassing long-term physical, psychological, emotional, social, and economic impacts of IMD, and to identify any gaps. Two authors also provided expert input from their perspectives, one as a survivor and patient advocate (J.B.G.) and the other as a pediatrician (T.W.) with extensive experience with this patient group to provide context absent from published sources. In particular, several published articles that have examined economic impacts may focus on various data sources, such as claims databases, that, while valuable, may not capture the other economic impacts (e.g., out-of-pocket costs to patient/caregivers, etc.), that are especially burdensome. By capturing the various consequences experienced by survivors and their caregivers, as reported in the literature and by J.B.G. and T.W., this review attempts to provide a more holistic view of the long-term burden of IMD for patients in these countries and knowledge gaps that need to be filled. Addressing the gaps identified here will provide a greater understanding of this burden and inform more accurate economic evaluations in the future [16].

Methods

Data Sources and Search Strategy

We performed a targeted literature review with the primary goal of identifying evidence on the long-term clinical, humanistic, and economic burden of IMD in adolescents and identifying any gaps in the literature. EMBASE, MEDLINE, and MEDLINE In-Process databases were searched from inception to the search date, February 18, 2025. Search strings were comprised of indexed and free-text terms to search for information related to meningococcal disease, meningitis, and long-term sequelae (Table S1 and Table S2). Additional grey literature and Google Scholar searches were conducted between February 13 and February 25, 2025. Grey literature sources included conference proceedings and relevant disease organization websites (Table S3). Additionally, reference lists of relevant systematic or narrative literature reviews and economic models were screened (Table S4).

Eligibility Criteria

Studies conducted in the US or Canada that assessed individuals who had a confirmed case of meningococcal disease at ≥ 10 years of age, or caregivers and family members of such individuals, and reported on any long-term clinical sequelae, economic impacts, social impacts, or health-related quality-of-life (HRQoL) burden were eligible for inclusion (Table 2). Studies that included patients who contracted IMD either before or after 10 years of age, or for which the age of onset was not reported, were included in this review if they included patients ≥ 18 years of age. Studies of patients < 18 years of age were only included if the data for patients ≥ 10 years were reported separately. There was no eligibility restriction on the date of publication for scientific articles and reports, but conference abstracts were only included if they were published in the three years prior to the search date.

Table 2.

Eligibility criteria for inclusion in the review

Component	Eligibility criteria for inclusion
Population	Individuals who had a confirmed case of meningococcal disease at ≥ 10 years of age Caregivers/family members of individuals who had a confirmed case of meningococcal disease at ≥ 10 years of age N.B.: Studies were also considered eligible if they included both patients < 10 and ≥ 10 years of age (or if the age of onset was not reported) and the study included patients ≥ 18 years of age (but not if the upper age of patients was < 18, unless data for those aged ≥ 10 were reported separately)
Intervention	No restriction
Comparators	No restriction
Outcomes	Including but not restricted to:  Long-term clinical sequelae:   Neurological impairments (e.g., epilepsy, obstructive hydrocephalus, cognitive deficits   Psychological impairments (e.g., anxiety, depression, post-traumatic stress disorder)   Functional disability (e.g., mobility issues, hearing impairment/loss, visual impairment/loss)   Amputations and limb deformities, skin scarring with/without grafting   Renal impairment (e.g., chronic kidney issues)   Respiratory issues  Long-term economic impact including costs and resource use:   Direct costs (direct medical and non-medical costs) including out-of-pocket expenses    Direct medical costs (e.g., hospitalizations, surgeries, rehabilitation, outpatient care visits for long-term management)    Direct non-medical costs (e.g., home modifications, adaptive devices, prosthesis, transportation, long-term caregiver expenses)   Rate of hospitalizations due to complications of meningococcal disease sequelae   Indirect costs (e.g., loss of productivity, caregiver burden)   Healthcare resource use (e.g., hospitalizations, surgeries, rehabilitation, outpatient care visits for long-term management)   Long-term social impact and quality of life burden: (e.g., changes in family dynamics, social isolation, impact on personal and professional relationships, patient reported outcomes)
Study types	Randomized controlled trials, observational cohort studies (retrospective or prospective), registry-based studies, cross-sectional studies, surveys, case series, and case reports
Language	English
Date of publication	No restriction
Geography	United States, Canada

Study Selection

Duplicate records obtained from electronic database searches were removed using Zotero (Corporation for Digital Scholarship). Titles and abstracts were screened against the pre-specified eligibility criteria by a single reviewer, and full texts of potentially relevant records were then retrieved and screened by that reviewer. A second independent reviewer performed a quality check to verify inclusion criteria were met.

Expert Review

Contributing authors (T.W. and J.B.G.) reviewed the literature review findings and wrote their expert insights to augment the publicly available information. T.W. provided perspective from his experience as a practicing pediatrician, whereas J.B.G., an IMD survivor, provided perspective from his experience since 2019 in patient advocacy for IMD, through which he has spoken with numerous IMD survivors. This allowed for verification of findings from published literature with respect to patient-centered and clinical experience. Additionally, they identified key evidence gaps that should be considered as the subject of future research.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

Study Selection and Characteristics

The electronic database search retrieved 397 records, from which 93 duplicates were excluded (Fig. 1). After eliminating a further 226 records during title and abstract screening against the pre-specified inclusion criteria, the full texts of 78 records were screened. Seven of these reports met the inclusion criteria. Of the additional 1353 records retrieved from grey material and supplementary sources and reviewed in full, 4 reports met the inclusion criteria. The 11 included reports presented data from separate studies (Table 3). Most of the included studies (n = 7) were conducted in the US and the remaining studies (n = 4) were conducted in Canada. Clinical sequelae of IMD were reported in 10 studies. Three studies reported on the HRQoL burden and six on the economic burden from healthcare resource utilization (HCRU) or direct costs.

Fig. 1.

Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) flow diagram

Table 3.

Characteristics of included studies

References	Country	Population (n)	Study design	Age of IMD onset (years)	Follow-up period	Outcomes of interest
Bettinger et al. [22]	Canada	Patients hospitalized with IMD (n = 769)	Prospective chart review	Overall Median: 11.9 Children (< 20 years) Median: 2.5 Adults (≥ 20 years) Median: 41.3	Until discharge	HCRU, sequelae
Davis et al. [23]	United States	Patients hospitalized with IMD with ≥ 12 months of continuous health plan enrollment (n = 173)	Retrospective cohort study using administrative claims data	Overall Mean: 33.2 (SD: 24.7) With sequelae Mean: 40.0 (SD: 26.3) Without sequelae Mean: 28.5 (SD: 22.6)	12 months	Costs, HCRU, sequelae
Erickson and De Wals [24]	Canada	Patients hospitalized with serogroup B or serogroup C IMD (n = 471)	Retrospective chart review with cross-sectional surveys and interviews	Serogroup B Mean: 13.5 Median: 2 Serogroup C Mean: 17.6 Median: 14	Mean: 38 months (range: 9–72)	HRQoL, sequelae
Erickson et al. [25]	United States	Patients with IMD while enrolled in college or university (n = 28)	Retrospective chart review and cross-sectional interviews	NR	NR	HRQoL, sequelae
Herrera-Restrepo et al. [26]	United States	Adolescent or adult IMD survivors and their caregivers (n = 14)	Cross-sectional surveys and interviews	Survivors Median: 36 (range: 14–51) Caregivers Median: 58 (range: 30–60)	> 12 months	Costs, HRQoL, sequelae
Herrera-Restrepo et al. [27]	United States	Individuals presenting to an emergency department or hospitalized with IMD and with ≥ 12 months of continuous health plan enrollment (n = 618)	Retrospective cohort study using administrative claims data	Median: 66 (range: 48–76)	Mean: 844 days or 1373.28 patient-years	Costs, HCRU, sequelae
Karve et al. [28]	United States	Patients hospitalized with IMD with ≥ 12 months continuous health plan enrollment (n = 343)	Retrospective cohort study using administrative claims data	Overall Mean: 34.2 (SD: 22.6) With sequelae Mean: 41.4 (SD: 24.6) Without sequelae Mean: 30.4 (SD: 20.6)	12 months	Costs, HCRU, sequelae
Le Saux et al. [29]	Canada	Patients hospitalized with serogroup C or serogroup Y IMD (n = 227)	Prospective chart review	Median: 18.5 (range: 0–95)	Until discharge	Sequelae
Marshall et al. [30]	United States	Patients with IMD	Commentary	NR	NR	Sequelae
O’Brien et al. [31]	United States	Patients hospitalized with meningococcal disease (n = 1654)	Retrospective cohort study using administrative claims data	Range: 0– ≥ 50	Until discharge	HCRU
Sadarangani et al. [32]	Canada	Patients hospitalized with IMD (n = 868)	Prospective chart review	Proportion ≥ 18 years: 52%	Until discharge	Sequelae

HCRU healthcare resource utilization, HRQoL health-related quality-of-life, IMD invasive meningococcal disease, NR not reported

Clinical Sequelae

Clinical sequelae of IMD were reported in ten studies [22–30, 32]. These studies were from the US (n = 6) and Canada (n = 4) and varied in study design, follow-up duration, and the IMD-related clinical sequelae that were reported. In an expert commentary, clinicians validated 16 neurological (anoxic brain damage, blindness or severe visual impairment, communication disorders, motor deficits, obstructive hydrocephalus, seizures, intellectual disabilities, bilateral hearing loss, unilateral hearing loss, and stroke), psychological (depression and general anxiety), and physical (amputation, skin scarring with or without grafting, and renal conditions) IMD-related sequelae that sometimes or always persist for several years to an entire lifetime [30].

Two studies by Herrera-Restrepo and colleagues reported on sequelae in IMD survivors a year or more after disease resolution [26, 27]. In interviews with 11 survivors who had IMD during adolescence (11–17 years) or adulthood (≥ 18 years) that were conducted more than 12 months following IMD resolution, survivors stated that following IMD they experienced complications such as clinical depression, grief, multisystem dysfunction, and inability to engage in formerly normal daily activities [26]. All the survivors had difficulty walking and most experienced other potentially irreversible complications, including balance issues (10/11), fatigue (9/11), repeated secondary infections (9/11), scarring (7/11), and amputation (6/11), among others. Several survivors also reported kidney issues (5/11) and neurological complications such as numbness (6/11), confusion (4/11), and nerve pain (3/11). In a retrospective analysis of claims data for 618 IMD survivors (median age at admission: 66 years) with at least 12 months of follow-up (mean: 844 days), Herrera-Restrepo and colleagues found that the post-acute phase (> 30 days after discharge) categories of sequelae with the highest incidence rates were ‘other physical conditions’, including anemia, pulmonary conditions, and autoimmune diseases, among others (300,719 per 1000 patient-years), renal conditions (222,432 per 1000 patient-years), abnormal brain activity (107,109 per 1000 patient-years), intellectual, behavioral, emotional, neurological, and psychological disorders (90,372 per 1000 patient-years), and motor deficits (70,891 per 1000 patient-years) [27].

Seven studies reporting on the proportions of IMD survivors who experienced potentially irreversible sequelae from IMD are summarized in Table 4 [22–25, 28, 29, 32]. In a retrospective analysis of insurance claims (1997–2009) by Karve et al. [28], 34.1% of 343 IMD survivors had at least one IMD-related sequela during the 12-month follow-up period. The most common sequelae or complications were stroke (14.3%), seizures (11.7%), hearing loss (10.5%), and epilepsy (7.0%) [28]. These proportions are consistent with those reported by Davis et al. for a similarly designed study using a different claims database (1998–2009), in which 41.0% of 173 survivors experienced at least one IMD-related complication during the 12-month follow-up period, with seizure (13.9%), stroke (12.1%), hearing loss (9.3%), and chronic renal failure (8.7%) frequently observed [23].

Table 4.

Commonly occurring complications or sequelae among IMD survivors.

Color intensity increases linearly with proportion of survivors experiencing the sequela. Where ‘discharge’ was noted for the follow-up period, the sequelae considered were those that are life-long

IMD invasive meningococcal disease, NR not reported

In several cohort studies using data from patient health records, various irreversible sequelae were present at hospital discharge. Bettinger et al. reported that 74 of 391 IMD survivors (18.9%) had one or more infection-related complications or sequelae at the time of discharge, including 10 of 94 survivors (10.6%) 5–19 years of age [22]. In this age group, 4 survivors (4.3%) experienced scarring from skin necrosis, 3 (3.2%) experienced unilateral or bilateral deafness, and 2 (2.1%) experienced other neurological sequelae (1 with a brain stem and cerebellar infarct and the other with decreased mobility affecting activities of daily living). Similarly, in the prospective analysis by Sadarangani et al., at hospital discharge 157 of 868 patients with IMD (18.4%) had complications from their infection, such as 95 (11.2%) with neurological complications, including 46 (5.4%) with hearing loss, and a further 87 (10.2%) with non-neurological complications, including 46 (5.4%) with skin scarring [32]. Notably, complications were more frequent for infections from serogroup C (n = 38/164; 23.2%) than serogroup B (n = 91/478; 19.0%), serogroup W (n = 6/46; 13.0%), or serogroup Y (n = 21/148; 14.2%). Le Saux et al. noted that 37 of 227 patients (16.3%) of any age (median: 18.5 years) with serogroup A, C, W, or Y IMD had at least one infection-related sequela at discharge [29]. Children in the 2–19 years age group were more likely to have sequelae than adult patients {odds ratio: 2.0 [95% confidence interval (CI) 0.87–4.4]}. Of the 57 patients aged 2–19 years who survived, 13 (22.8%) had sequelae from serogroup C or Y IMD, including 6 (10.5%) with an amputation, 6 (10.5%) with skin scarring, 3 (5.3%) with renal dysfunction, 2 (3.5%) with deafness, and 2 (3.5%) with other neurological sequelae. Erikson and De Wals reported that, among 420 IMD survivors with cases catalogued in a Quebec registry, 45 (10.7%) had sequelae at discharge [24]. In total, 32 (7.6%) of these survivors had skin scarring, 13 (3.1%) had amputations, 8 (1.9%) had sensorineural hearing loss, 3 (0.7%) had renal failure, and 13 (3.1%) had other sequelae. Notably, serogroup C infection resulted in sequelae in a significantly greater proportion (15%; n = 40/262) of cases than serogroup B (3%; n = 5/158). Finally, in a second study, Erikson et al., 5 (20.0%) of 25 people who survived IMD when they were college students in Pennsylvania between 1990 and 1999 had potentially permanent sequelae at discharge, including three with amputation, one with extensive skin scarring, and one with both hearing loss and decreased knee mobility [25].

HRQoL and Social Impact of Sequelae on IMD Survivors

The long-term impacts of IMD on survivors and their caregivers in terms of social function and HRQoL have been discussed in three studies [24–26]. Herrera-Restrepo et al. used qualitative interviews to assess the consequences of long-term sequelae on IMD survivors (n = 11) and their caregivers (n = 3) [26]. A year or more after IMD, survivors reported experiencing lasting physical problems due to sequelae, such as mobility challenges, cognitive deficits, and chronic pain, which led to substantial limitations in daily functioning (n = 10/11) and physical activities (n = 7/11), as well as overall detriments to HRQoL (n = 7/11). Survivors reported negative impacts on social activities (n = 9/11), recreational activities (n = 10/11), and relationships (n = 10/11). Emotional trauma, including feelings of worry (n = 9/11), and post-traumatic stress disorder as a result of their hospitalization or near-death experience (n = 7/11), were prevalent among survivors. Likewise, caregivers faced emotional trauma (3/3), problems sleeping (2/3), and challenges with normal daily activities (2/3), among other difficulties. In addition, survivors and their caregivers reported experiencing significant worries about insurance coverage, copays, and out-of-pocket expenditures, including medical devices and home adaptations, as a result of IMD.

Erickson et al. assessed the HRQoL of five IMD survivors who had been infected between 1990 and 1999 while enrolled in college or university [25]. The Annotated Scale of Bodily Injuries Regulation from the Quebec Occupational Health and Safety Commission was used to assess physical impairment for five IMD survivors with sequelae [33]. Possible scores span 0%, indicating no impairment, to 100%, indicating a complete inability to work. Survivor scores ranged from 0% for a survivor with extensive skin scarring to 87% for a survivor with amputation of fingers from both hands and both forefeet. The EuroQol EQ-5D questionnaire, with scores that can range from 0.0 for the worst possible health state to 1.0 for the best possible health state, was also used to assess four of the same survivors. EQ-5D scores were as low as 0.69 for the survivor with finger and forefeet amputation to as high as 0.80 for the survivor with finger amputations on both hands. During interviews, survivors elaborated on their persistent psychological and emotional turmoil following IMD until the time of the interviews, which were held up to four years or more after the infection.

Erickson and De Wals developed a self-administered questionnaire to assess the HRQoL among survivors of serogroup B and C IMD in Quebec [24]. The questionnaire was designed as twelve statements related to HRQoL for which patients were asked to rate their level of impairment on a 5-point scale. Responses were then summed and reported as a percentage of the total (i.e., 60) to determine an overall HRQoL score, with 100% corresponding to maximum impairment. Almost one-quarter (23%) of the respondents (n = 231) reported a reduction in their HRQoL due to IMD-related sequelae. The most common complaints among those reporting a reduction in HRQoL included reduced energy, increased anxiety, reduction of leisure activities, and reduced ability to work. Among survivors of serogroup C disease who reported a reduction in their HRQoL, 63% also had physical sequelae, compared to only 16% of survivors of serogroup B disease. Of the survivors without physical sequelae, 19.3% still mentioned experiencing adverse psychosocial consequences.

Healthcare Resource Use for Complications and Sequelae after IMD

HCRU following recovery from IMD was reported in five studies [22, 23, 27, 28, 31]. In a 2010–2022 retrospective claims database study by Herrera-Restrepo et al., post-acute-phase (> 30 days post discharge; mean follow-up: 844 days) HCRU ranged from 3.6 (95% CI: 1.18–8.50) ICU stays per 1000 patient-years to 7808.3 (95% CI: 7661.22–7957.54) specialist visits per 1000 patient-years [27]. The mean number of hospitalizations in the post-acute phase was 8.7 (95% CI 4.5–15.3) per 1000 patient-years (Table 5) [27]. Based on analyses of claims data collected from 1997 to 2009 by Davis et al. and Karve et al., in the 12 months following IMD, survivors had an average 40.2 (standard deviation [SD]: 44.2)–56.8 (SD: 66.7) interactions with healthcare services [23, 28]. Across these studies, patients averaged 1.5 (SD: 1.3)–1.7 (SD: 1.3) hospital stays in this period, with a mean total time in hospital of 14.0 (SD: 27.6)–17.8 (SD: 26.8) days [23, 28], and Davis et al. noted that patients with IMD-related sequelae such as seizures, stroke, and chronic renal failure had even higher utilization, with 2.1 (SD: 1.7) unique admissions and mean 26.7 (SD: 31.7) total days in hospital during the follow-up period [23]. O'Brien et al. reported that during 1999–2001 in California, Florida, Massachusetts, and Washington, 10% of adolescent IMD survivors aged 11–17 years needed home healthcare services after discharge and 5% were discharged to sub-acute care facilities, such as skilled nursing facilities and long-term care facilities [31]. Adolescents (11–17 years) and adults (≥ 18 years) more frequently needed post-acute care and home healthcare than infants (< 1 year) and children (1–10 years). Similarly, in a Canadian prospective study using 2002–2011 surveillance data by Bettinger et al., 17 (23.3%) of 74 IMD survivors with at least one complication or sequela were discharged to an inpatient facility for rehabilitation after IMD [22].

Table 5.

Healthcare resource utilization by patients with IMD in the US

References	Number of IMD patients (n) Country	Follow-up period	Mean number of medical encounters (SD)	Mean number of hospital admissions (SD)	Length of stay, days (SD)
Herrera-Restrepo et al. [27]	n = 618 US	30 days	NR	254.42 (95% CI: 139.09–426.87) per 1000 patient-years	NR
		Mean: 844 days	NR	8.7 (95% CI: 4.5–15.2) per 1000 patient-years	NR
Karve et al. [28]	n = 343 US	12 months	40.2 (44.2)	1.5 (1.3)	14.0 (27.6)
Davis et al. [23]	n = 173 US	12 months	56.8 (66.7)	1.7 (1.3)	17.8 (26.8)

CI confidence interval, IMD invasive meningococcal disease, NR not reported, SD standard deviation

Costs of Complications and Sequelae after IMD

Four studies discussed the direct healthcare costs following IMD and consistently reported substantial total costs for IMD survivors after discharge [23, 26–28]. Herrera-Restrepo et al. reported that patients with IMD incurred average total healthcare costs (2022 USD) of US$145,883.65 (SD: 362,929.29) during the post-acute phase (mean: 844 days), defined as from 30 days after discharge to death, disenrollment, or study end (Table 6) [27]. Types of healthcare expenditures included in the cost calculations were hospitalizations, emergency department visits, physician visits, surgical procedures, and rehabilitation.

Table 6.

Direct healthcare costs for patients with IMD in the US

References	Number of IMD patients Country	Currency (reference year)	Follow-up period	Mean total hospital costs (SD)	Mean total healthcare costs (SD)
Herrera-Restrepo et al. [27]	n = 618 US	USD (2022)	30 days	$24,399.71 (19,960.72)	$60,866.23 (110,605.92)
			Mean: 844 days	$125,168.46 (149,721.07)	$145,883.65 (362,929.29)
Karve et al. [28]	n = 343 US	USD (2009)	12 months	Overall: $41,552.30 (96,517.64) With sequelae: $74,879.40 (155,443.30) Without sequelae: $24,298.90 (28,741.20)	Overall: $55,001.96 (108,858.35) With sequelae: $99,742.57 (172,815.09) Without sequelae: $31,839.78 (32,176.91)
Davis et al. [23]	n = 173 US	USD (2009)	12 months	Overall: $46,736.50 (109,924.40) With sequelae: $65,012.70 (122,510.20) Without sequelae: $34,014 (98,880.20)	Overall: $55,701.80 (121,740.10) With sequelae: $77,216.0 (134,322.9) Without sequelae: $40,726.3 (110,374.2)

CI confidence interval, IMD invasive meningococcal disease, NR not reported, SD standard deviation, USD United States dollars

In retrospective analyses of claims data, mean total healthcare costs (2009 USD) in the 12 months following the index encounter were $55,001.96 (SD: 108,858.35)–$55,701.80 (SD: 121,740.10), with most of the costs attributable to mean total hospitalization costs, $41,552.30 (SD: 96,517.60)–$46,736.50 (SD: 109,924.40) [23, 28]. Overall healthcare costs also included emergency department visits, physician visits, prescriptions, outpatient visits, home health and durable medical equipment, laboratory services, and ancillary care.

The economic burden was higher for patients with IMD-related sequelae in the year after hospital discharge compared to survivors without sequelae. Davis et al. reported unadjusted mean total costs (2009 USD) of $77,216.0 (SD: $134,322.9) for patients with sequelae from IMD in the 12 months following infection, almost double the $40,726.3 (SD: $110,374.2) for cases without complications [23]. Similarly, Karve et al. found mean total costs (2009 USD) for IMD survivors with sequelae to be $99,742.57 (SD: $172,815.09), significantly higher than the $31,839.78 (SD: $32,176.91) for patients without sequelae from IMD [28]. In both cases, with or without sequelae, the inpatient costs during the 12-month follow-up were the main drivers of total healthcare costs, $65,012.70 (SD: 122,510.20) and $34,014 (SD: 98,880.20), respectively.

While detailed indirect costs were not identified in any included studies, Herrera-Restrepo et al. reported that survivors stated they experience significant productivity losses, career limitations, and high out-of-pocket medical costs [26].

Patient and Physician Perspectives

John B. Grimes, a survivor of IMD, provides a poignant and deeply personal account of the long-term sequelae he has endured following his infection. His story, detailed in his personal narrative (www.johnsstory.com), underscores the profound and multifaceted impact of IMD on survivors, which is often inadequately captured in clinical studies and economic evaluations.

John contracted IMD as a college student at the age of 19, and despite receiving prompt medical intervention, he experienced severe neurological complications, including bilateral vision loss and persistent neurogenic bladder. Though he was up-to-date with respect to his childhood vaccines, there was no meningococcal vaccine approved for use at the time and thus he was not protected against this debilitating infection. John’s care team had a significant struggle to save his life, but as John said, “Surviving meningitis was the easy part— so easy that I did it in my sleep. The seemingly impossible part was living after surviving meningitis.” In the immediate aftermath, John had to retrain his body and learn to walk and eat again, like many survivors of bacterial meningitis [34]. However, for John and many other IMD survivors, the journey did not end there, as many of the long-term sequelae are permanent and lifelong. He describes his experience as “a mental battlefield—processing what had happened, accepting what had changed, and figuring out how to move forward when nothing felt the same.”

John has now been a member of the disabled community for over 28 years, and, although his disabilities are mostly invisible, they have substantially impacted his daily life, like his neurogenic bladder which requires him to catheterize himself four to six times a day. His disabilities have limited his opportunities to engage in activities he once enjoyed and have required that he seek ongoing medical care. This is in addition to the psychological toll of experiencing a traumatic event and adjusting to his new reality. As John shared, “My disabilities, though mostly invisible to others, consumed me and impeded my ability to perform to my potential. Eventually it dawned on me that a world that can’t really see my disabilities is not going to wait for me to catch up. That responsibility belonged to me—I would never truly succeed until my desire to do so was greater than my disabilities.”

John’s experience highlights several key gaps in the literature. While studies document the prevalence of physical and neurological sequelae among IMD survivors, they often fail to capture the full extent of the psychological, social, and economic impacts. Moreover, many studies focus on the post-acute period (30 days to 12 months) and do not fully capture the impact of life-long sequelae, which can touch all aspects of life. For example, no data on work productivity related to the long-term sequelae of IMD was identified in this review; however, John Grimes noted that IMD-related disabilities can limit survivors’ career choices and whether one is selected for certain roles, both due to physical limitations and discrimination. Dr. Todd Wolynn, a pediatrician who has cared for patients with IMD, echoed this sentiment and noted that interruption of the survivor’s educational path and need for adaptations required to function with the ongoing sequelae are additional impacts, especially for those affected as adolescents. Moreover, illness-related absences from work or school for both patients and caregivers can impact productivity and reduce potential earnings.

In addition, both John Grimes and Dr. Todd Wolynn identified out-of-pocket costs as being significant for IMD survivors. These may include out-of-pocket costs for purchasing special medical devices, making living space adaptations and performing ongoing maintenance of medical or other necessary equipment, transportation costs that can be higher than those of the general population (due to the need to use taxis or adapted vehicles), as well as the time cost of dealing with insurance companies for submission and appeals processes.

Personal financial burdens related to securing adequate health care are seldom reported in the literature, but given that they are required for lengthy periods, spanning adolescence through the remainder of the survivors’ lives, they are substantial and limiting. Of note, John Grimes acknowledges that while he did have adequate health insurance and family financial support to cover needed medical care and rehabilitation, others without this may have further financial pressures to be able to secure the care needed. This may be especially true for particular types of healthcare commonly needed by survivors of IMD, such as long-term psychological and/or physical and rehabilitation therapy, for which access and insurance coverage can be limited and may prevent survivors from receiving the full range of care needed.

The impact of IMD-related long-term sequelae on HRQoL is multi-faceted and unique to each survivor’s circumstance. Traditional HRQoL questionnaires often fail to capture the circumstances around the scores and may not be validated in this population. As John Grimes shared, a survivor’s ability to adapt to their given situation can influence their life’s trajectory, and this may influence HRQoL scores assessed at a given timepoint. Moreover, Dr. Todd Wolynn highlighted that long-term residual pain, disfigurement, and mental health (for both survivors and caregivers) issues have very real impacts, but are difficult to capture quantitatively. Connecting patients and their family members with appropriate counseling and support groups can substantially help survivors to rebuild their lives, a more holistic healthcare need that is rarely captured by traditional metrics.

Lastly, there are often unseen social implications of surviving IMD, which can compound the effects of long-term sequelae on HRQoL. Both John Grimes and Dr. Todd Wolynn point to social exclusion, isolation, activity limitations, and additional disability accommodations as potential challenges faced by IMD survivors. John Grimes highlighted that his vision impairment can be socially isolating because, for example, he cannot see friends in passing or watch sports events. People with visible disabilities or physical differences can face comments from strangers and discrimination that can have substantial psychological impacts as well. Moreover, there is a significant impact on family members that persists long-term. John Grimes noted a continued burden on his wife, despite meeting her several years after contracting IMD.

The insights provided by John Grimes are invaluable for understanding the true burden of IMD. His story may reflect the experiences of many survivors and serves as a compelling reminder that the long-term consequences of IMD extend far beyond the acute phase of the disease, affecting every aspect of a survivor’s life for decades.

Discussion

The evidence from this review demonstrates that survivors of IMD experience heterogeneous long-term sequelae, many of which can extensively affect their daily activities and HRQoL. Frequently reported sequelae have been verified by clinical experts as IMD-related complications and include seizures, hearing loss, stroke, amputation, scarring, and renal dysfunction, among others. Other sequelae, such as vision loss, are less common but are accompanied by a significant burden. Moreover, there are challenges in attributing specific sequelae to a case of IMD or another complication or comorbidity. As one patient interviewed by Herrera-Restrepo et al. noted, doctors were unsure if their patient’s epilepsy was a result of the IMD itself, brain surgery to address the IMD, or if the epilepsy had preceded IMD [26]. In addition, there can be long-term consequences resulting from the tests, treatments or scans performed during hospitalization, for which it can be challenging to determine possible attribution to IMD or to another cause. These are also infrequently evaluated in studies reported in the published literature.

Many IMD survivors report experiencing emotional distress, psychological disorders, and, notably, lower HRQoL due to consequences of IMD [24–26]. Although Erickson and De Wals designed a questionnaire to assess HRQoL in IMD survivors [24], details of this questionnaire have not been published with respect to possible validation in IMD, and no additional fully-validated questionnaires for IMD survivors were identified in this review. The EQ-5D, used by one study identified through this review, has been evaluated for both survivors with permanent sequelae after meningitis [35]; however, while it yielded reliable weights for health states, it lacked sensitivity in several areas that are highly relevant to the long-term sequelae of IMD including hearing and cognitive impairments. The lack of questionnaires with adequate sensitivity for key measures related to long-term sequelae of IMD potentially limits the comprehensiveness of the data collected.

Recurrent themes among survivors in published literature and from John Grimes’ and Dr. Todd Wolynn’s experiences included the long-term social impact, financial burden, and limitations for education and employment resulting from IMD and its complications for both survivors and caregivers. Survivors reported that they had persistent challenges with physical impairment, which limited their ability to work, mobility limitations, cognitive deficits, and chronic pain [24–26]. According to one study, caregivers are also impacted, faced with both lingering anxiety and stress stemming from the IMD episode and the burden of caring for an individual with often complex health needs [26]. John Grimes also underscored the burden of IMD sequelae on social interactions as well as on family members helping manage survivors’ health conditions. Only one study identified in this review assessed the impact of IMD long-term sequelae on caregivers, highlighting a significant gap in the literature.

From a healthcare perspective, long-term sequelae of IMD are costly [23, 27, 28], and IMD survivors with sequelae have significantly higher costs than survivors without sequelae. According to two studies, costs at 12 months post-infection are between two to three times higher for patients with sequelae than those without [23, 28]. High HCRU contributes to the elevated costs associated with IMD sequelae and includes ICU stays, specialist visits, hospital stays, and use of care facilities [23, 27, 28, 31]. Patients with IMD-related sequelae, such as seizures, stroke, and chronic renal failure, had higher utilization than those without [23]. It is important to note that most studies assessed costs in the acute and post-acute period, with the longest follow-up period in the included studies being a mean of 844 days. Longer-term costs associated with persistent sequelae were not identified, representing an important gap in the literature, given that survivors with sequelae from IMD contracted during adolescence or early adulthood may accrue costs over their entire remaining lifetimes.

Though data were not always stratified by serogroup of the invading pathogen, a few studies reported that complications were more frequent and severe, and HRQoL was lower, for survivors of infections from serogroup C N. meningitidis compared to serogroup B [24, 32] or Y [29, 32]. The increased severity of serogroup C is reflected in the higher CFR for serogroup C (19.2%) in the US in 2022 compared to B (6.7%) or W (9.1%). The CFR for serogroup Y is almost as high as serogroup C (17.2%), indicating that this serogroup causes particularly severe disease. This is especially relevant as serogroup Y infections have been increasing in the US in recent years [6, 36], underscoring the importance of protection against all pathogenic N. meningitidis serogroups and understanding the associated long-term impacts.

Incidence of IMD is highest in infants, and though it declines in older children, it peaks again in adolescence and young adulthood [6, 7], due in part to environmental and behavioral factors such as crowded living arrangements, sharing food or drink, visiting bars, and close intimate relationships [37, 38]. IMD is, fortunately, rare in modern times, attributable in large part to the introduction of highly effective vaccines against the most prevalent serogroups [39–42]. In the US, the quadrivalent meningococcal conjugate vaccine (MenACWY) is routinely administered at age 11 or 12 years with a booster dose at 16 years [42, 43]. The meningococcal B vaccine (MenB) is recommended for those aged 16–23 years based on shared clinical decision-making [44]. Canadian authorities recommend the MenC or MenACWY vaccine for children at 12 years of age [45]. In the US in 2023, 88.4% of adolescents aged 13–17 years had received ≥ 1 dose of MenACWY. Among those aged 17 years, coverage with ≥ 2 MenACWY doses was 59.7%. A recent study estimated that in the absence of vaccination, the cumulative incidence of IMD in adolescents and young adults in the US would have been 59% higher between 2005 and 2021 [46]. For those aged 11–15 years, it is estimated that the incidence of IMD without vaccination would have been 110% higher (an increase of 172 cases, 95% credible interval: 85–345), highlighting the importance of vaccination in this age group [46]. The CDC reported that among adolescents aged 11–15 years in the US, the incidence of serogroup CWY IMD decreased by 27.8% after a primary vaccination dose [41].

Often, the long-term consequences of IMD are overlooked, and more emphasis is placed on the acute phase of the disease. However, the studies identified in this review demonstrate that, although it is rare, IMD can have wide-ranging long-term impacts with substantial individual and societal costs. John Grimes’ commentary based on his own experiences as a survivor and, as a patient advocate for over 5 years, offers more insight into the long-term sequelae of IMD, highlighting the extensive physical, psychological, and social impacts that are often overlooked in clinical studies and economic evaluations. Neurological and other deficits that arise in pediatric and young adult IMD survivors can affect their entire developmental trajectory, potentially affecting all aspects of their lives, as highlighted by John Grimes and Dr. Todd Wolynn, including educational outcomes and career prospects, limiting future earnings. Despite surviving IMD with prompt medical intervention, John experienced severe neurological complications, including bilateral vision loss and a persistent neurogenic bladder, which have significantly affected his daily life and career opportunities for the last 28 years. Thus, there is a continued need to prioritize IMD prevention.

Strengths and Limitations

This review offers several strengths. This is a comprehensive review to identify information on the long-term sequelae of IMD in the US and Canada. The search was not restricted by outcome terms or timeframe to capture all studies on a wide range of potential long-term impacts of IMD. Moreover, contributing authors have provided their expert perspectives to supplement published literature. The available data suggest a substantial multi-faceted long-term burden of IMD resulting from clinical sequelae as well as permanent alterations from the acute phase, such as vision loss, deafness, or amputation. These sequelae have a profound impact on HRQoL, in addition to emotional trauma related to the IMD event itself. IMD survivors noted a lack of societal support to manage the consequences, and face challenges in accessing adequate insurance coverage, leading to further financial stress [26]. John Grimes’ narrative and Dr. Todd Wolynn’s experiences in clinical practice further illuminate the persistent emotional trauma and social isolation that many IMD survivors face, emphasizing the need for holistic support systems that address both physical and mental health. Additionally, their account of the financial strain caused by out-of-pocket medical expenses and the need for adaptive devices underscores the economic burden that is frequently under-represented in existing studies.

This review also had some limitations. Despite aiming to focus on IMD contracted over the age of 10, due to reporting limitations in the available literature, this review was restricted in its ability to differentiate between the impact of IMD contracted at different ages. Moreover, analyses of insurance claims databases, such as those performed in four identified studies [23, 27, 28, 31], may under-represent IMD cases in adolescents and young adults since they may be less likely to have private insurance, as discussed by Herrera-Restrepo et al. [27]. Many studies did not report the age of onset of IMD or included a mixed population of individuals who contracted IMD either as infants, as children, as adolescents, or as adults. To maximize the inclusion of relevant information, studies on mixed-age populations were included in this review. However, studies that included only pediatric patients (≤ 18 years of age) were only included if they reported data separately for the subgroup of adolescent patients aged ≥ 10 years. Studies that included patients who contracted IMD before 10 years of age, or for whom the age of onset was not reported, were only included if they also included individuals over the age of 18. This was to ensure that the studies did not entirely focus on cases contracted by infants or children.

The identified evidence suggests that the impact of long-term sequelae on individuals who contract IMD as adolescents may be particularly notable. O’Brien et al. noted that adolescents (11–17 years) and adults (≥ 18 years) more frequently needed post-acute care and home healthcare than infants (< 1 year) and children (1–10 years) [31]. Moreover, Le Saux et al. found that children in the 2–19 years age group were more likely to have sequelae than adult patients (odds ratio: 2.0 [95% CI: 0.87–4.4]) [29]. These findings highlight the importance of considering the unique burden of IMD on adolescents and underscore the need for further research in this population.

Economic modeling studies were not included in the PICO criteria for this targeted review. As such, indirect costs (such as those resulting from lost productivity) from economic models were not captured. Sources referenced in any identified economic evaluations were assessed for any epidemiological, HCRU, or economic inputs that would meet the inclusion criteria of the targeted review; however, these source publications did not report on patients with IMD or meet one or more other predefined study selection criteria, so further indirect or non-medical costs were not identified.

Moreover, there was limited evidence on direct non-medical costs, including expenses such as assistive devices and home adaptations, leading to an incomplete understanding of the true economic burden of IMD. Although specific studies estimating out-of-pocket costs were not identified in this review, Herrera-Restrepo et al. interviewed survivors and their caregivers in the US and found that many experience significant worries about insurance coverage, copays, and other out-of-pocket expenditures, including for items such as medical devices and home adaptations [26]. John Grimes and Dr. Todd Wolynn provided further insight into this evidence gap, noting that out-of-pocket costs are significant and life-long, ranging from the needs for specialized equipment to daily transportation costs. This demonstrates that financial burden is an important consequence of IMD and should be considered when describing the long-term impact of this disease. Of note, given differences in health care structures, out-of-pocket costs may differ between the US and Canada and also according to a patient’s insurance coverage.

Conclusion

This literature review has demonstrated that there is a paucity of published studies reporting on the long-term sequelae and burden of IMD contracted by adolescents in the US and Canada. The additional inputs provided by the patient advocate and the clinical expert collaborator further highlight the need to consider the long-term psychological, social, and economic impacts of IMD in healthcare decision-making. Addressing these evidence gaps through well-designed observational studies would assist in promoting a more holistic understanding of the impact of IMD on survivors, caregivers, and society overall, and in optimizing the prevention and care of IMD, especially among those at increased risk for the disease, such as adolescents. Additionally, the development, full validation, and implementation of patient assessment tools for HRQoL and functional status in IMD would be important to support research to quantify patient-relevant endpoints and burden.

Addressing the long-term consequences of IMD requires a comprehensive approach, focusing on both prevention and improvement of support to manage sequelae. Incorporating patient perspectives into future research and healthcare decision-making is crucial for developing more holistic approaches to IMD prevention and management, ensuring that survivors receive the comprehensive care and support that they need to rebuild their lives. While IMD is a rare condition, the life-long impact of IMD sequelae on adolescent and young adult survivors and their caregivers is substantial, and continued and enhanced efforts to prevent IMD with vaccination are critical.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Maureen P. Neary, Sayali Nerurkar, and Liga Bennetts conceived the review. Sayali Nerurkar and Liga Bennetts designed the study. Formal analysis, and investigation were performed by Sayali Nerurkar, Evan Jones Mann, and Liga Bennetts. Interpretation was performed by Todd Wolynn, John B. Grimes, Sayali Nerurkar, Rachel Dawson, Katherine Galarza, Helay Hassas, Angie Upegui, David P. Greenberg, Corwin A. Robertson, Heather Entenmann, Evan Jones Mann, Liga Bennetts, and Maureen P. Neary. Todd Wolynn, John B. Grimes, Evan Jones Mann, and Liga Bennetts prepared the manuscript. Todd Wolynn, John B. Grimes, Sayali Nerurkar, Rachel Dawson, Katherine Galarza, Helay Hassas, Angie Upegui, David P. Greenberg, Corwin A. Robertson, Heather Entenmann, and Maureen P. Neary reviewed the manuscript for critical intellectual content. Todd Wolynn, John B. Grimes, Sayali Nerurkar, Rachel Dawson, Katherine Galarza, Helay Hassas, Angie Upegui, David P. Greenberg, Corwin A. Robertson, Heather Entenmann, Evan Jones Mann, Liga Bennetts, and Maureen P. Neary edited the manuscript and approved the final version.

Funding

This review, medical writing assistance, and manuscript submission fees (including the journal’s Rapid Service Fee) were fully funded by Sanofi.

Data Availability

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

Declarations

Conflict of Interest

Rachel Dawson,, David P. Greenberg, Helay Hassas, Heather Entenmann, and Maureen P. Neary are employees of Sanofi Vaccines US and Angie Upegui, and Corwin A. Robertson are employees of Sanofi Vaccines Global and may hold shares and/or stock options in the company. Katherine Galarza is a former employee of Sanofi Vaccines US. Sayali Nerurkar, Evan Jones Mann, and Liga Bennetts are employees of Amaris Consulting, which received professional fees from Sanofi for the study. Todd Wolynn has received consulting fees from Moderna, Pfizer, Merck, and Seqirus, payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Moderna, and support for attending meetings and/or travel from Moderna, Sanofi, and Seqirus. John B. Grimes or his corporation Cemblem, LLC have received grants or contracts and consulting fees from GSK and Convatec, payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Sanofi and IQVIA, and support for attending meetings and/or travel from GSK. He has participated in an advisory board for GSK and has a leadership or fiduciary role in the Confederation of Meningitis Organizations (Board Member) and Shots 4 Meningitis (Executive Director). Neither Todd Wolynn or John B. Grimes received compensation from Sanofi for this manuscript.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.