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 studiesClinical Sequelae

Clinical sequelae of IMD were reported in ten studies [22,23,24,25,26,27,28,29,30, 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 [22,23,24,25, 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.

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 . 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 [24,25,26]. 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 USCosts 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, 26,27,28]. 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

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.