An integrative review was conducted (protocol CRD42022299697 registered in PROSPERO platform)15 to assess the global evidence on the costs of long-term IMD sequelae, from a payer, patient and societal perspective. The Medline, Embase, Cochrane Library and Lilacs databases were searched on October 20th, 2021 (Supplementary Material available on the Cambridge Core website) (no date restrictions nor filters for country were applied), for studies in English, Portuguese or Spanish, combining search terms relating to meningococcal disease and economic costs. The Rayyan web tool was used for reference management and duplicate removal. Screening of titles and abstracts and full-text articles was conducted by two researchers independently, with any discordances discussed with a third researcher (NTSF or MG) to achieve consensus.

Cost-of-illness studies or economic evaluations in any country addressing the economic impact of long-term sequelae in IMD cases of any age were included. Costs of interest included direct medical costs (e.g., medical resource use and patients’ out-of-pocket expenses for them); direct non-medical costs (e.g., patients’ out-of-pocket expenses for transportation, accommodation and other non-medical resources); indirect costs (e.g., time, income and productivity losses); special education and social care costs; and costs relating to specific sequelae. Studies were excluded if they assessed preventive measures, outbreaks, or diagnosis and treatment without presenting sequelae cost data. Systematic reviews, expert opinion reviews, conference abstracts, editorials, letters, comments, and study protocols were also excluded. Systematic reviews were only considered as a source to identify additional primary studies.

Data were extracted, by two researchers (JM and MK) independently and using the Covidence web tool, on study characteristics (i.e., country, study design, data source, currency, time horizon, study perspective, sample size, age group, and type of sequelae) and outcomes of interest (i.e., direct medical, non-medical and indirect costs, education and social care costs, sequelae-specific costs, cost of medical resources, procedures, services, and length of stay).

The quality of included studies was analyzed using the revised Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist.16

The costs of IMD sequelae are presented by country, time horizon and cost category (e.g., healthcare, social care, education, indirect costs) with a breakdown by type of cost within each category. Costs relating to specific sequelae are presented separately and categorized by physical, neurological and psychological sequelae.

Cost estimates were converted to 2021 International dollars (I$) using the national gross domestic product deflators and the implied purchasing power parity conversion rates from the International Monetary Fund. Currency conversion rates and inflation adjustments were applied using consumer price indexes.17,18 Studies that did not indicate the year of cost analysis were assumed to have the same base year as the year of publication.

A Delphi survey, with two rounds, was conducted to estimate the use of medical and non-medical resources for treating long-term IMD sequelae in Brazil. This type of structured group communication process is used in health sciences to address data gaps, and can provide high levels of evidence when other approaches cannot be used.19

Participants (n = 33) from Brazil (including infectious disease experts from Brazil's public and/or private health system and parents of IMD patients) were invited to participate based on their experience with the treatment of IMD and familiarity with IMD sequelae.

A questionnaire was designed based on the integrative review findings to enquire about the use of medical resources for the seven most common types of sequelae identified from the review i.e., single limb amputation, multiple limb amputations, skin scarring, epilepsy/seizures, hearing loss/deafness, mental retardation/low IQ (Intelligence Quotient), and mental health disorder/anxiety/depression. The questionnaire was based on a cohort of Brazilian patients with a confirmed long-term IMD sequelae diagnosis and treated in the SUS and/or private health system. Participants were asked to provide information on medical resource use (e.g., medical visits, specialists, hospital days, rehabilitation, home adaptations) in the first Year (Y1) and in the Subsequent Year (SY) by sequela. In addition, participants were asked about indirect costs (e.g., need for paid caregiver, workdays lost) by sequela.

A week before the first round, a summary of the integrative review findings was emailed to all panel participants who agreed to be part of the study and provided informed consent. The questionnaire was then sent to all participants to start the first round. Participants were requested to complete and return the questionnaires to the research team within one week. Results (mean, minimum and maximum values for each question) from the first round were pooled and emailed to participants in the second round for their validation, in order to reach consensus on the final mean values to be reported.

A microcosting analysis based on the Delphi survey estimates was performed to evaluate the costs associated with treatment of long-term IMD sequelae from the public health system (Sistema Único de Saúde, SUS) SUS perspective. The codes for the procedures and their unit costs were sourced from the Table of Procedures, Drugs, Orthotics, Prosthetics and Special Materials (SIGTAP) from SUS. Cost data were sourced from public Brazilian databases including SIGTAP.20 Hospitals accredited by the SUS are paid by the Ministry of Health budget through reimbursement, and only procedures listed in SIGTAP are reimbursed, using a reference price list to calculate a minimum transfer of values from the Ministry of Health budget to hospitals. Although the reference price list was used for the cost estimates, there may still have been an underestimation of the actual hospital expenditure for long-term IMD sequelae. Considering SIGTAP unit costs only represent federal costs, they were adjusted by a correction factor of 2.8 to obtain the total cost. This correction factor was suggested by the Ministry of Health,21 and was also applied by the Comissão Nacional de Incorporação de Tecnologias (Brazil's National Commission for the Incorporation of Technologies ‒ CONITEC) in a cost-effectiveness analysis of COVID-19 (Coronavirus Disease 2019) vaccines.22,23 All costs were recorded in Brazilian Reals (R$) and then converted to US dollars (US$) based upon the official exchange rate for Jan‒June 2024 (US $1.00 equals R$5.04).

The search strategy retrieved 2,838 unique records of which eight studies, published from 2011 to 2021, presented costs of IMD sequelae and were included (Fig. 1). All studies reported costs for IMD patients with a range of physical, neurological and psychological sequelae, except one study in the US (United States)24 which did not include psychological sequelae. Study designs included cost of illness (n = 1)25 and cohort studies (n = 2),24,26 economic models (n = 1),27 and studies estimating the costs of hypothetical severe IMD cases presenting with meningitis or septicemia (n = 4).28-31 IMD patients of all ages were included. All studies were conducted in high-income countries and there were no studies identified in Latin America. Costs were provided from the payer perspective, patient and/or societal perspectives.

Fig. 1.

PRISMA flow chart. IMD, Invasive Meningococcal Disease; n, number; PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses.

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There were two studies in France,25,30 one in Germany,31 one in Spain,29 one in the United Kingdom,28 two in Australia,26,27 and one in the US24 (see Table S2 for study details).

Studies in the UK (United Kingdom),28 Spain,29 and France30 estimated the costs associated with the lifetime management of a hypothetical severe case of IMD with sequelae in a young child, presenting either as septicemia or as meningitis. The cases were based on expert and family interviews. In the UK, the lifetime costs of IMD sequelae were assessed from the healthcare payer perspective, including medical, social services, education, and other government costs (e.g., for disability services, lost tax revenue, financial aid).28 In Spain, lifetime sequelae costs were estimated from the payer perspective, including medical, education and social care costs.29 The French study estimated lifetime costs of IMD sequelae from a payer, societal, and patient and health insurance perspective, including medical costs, education costs and revenue loss for parents.30

A cost of illness study in France assessed long-term sequelae costs, up to six years after IMD, using the national claims database (French National Healthcare Data System, [Système National des Données de Santé, SNDS]), in patients of all ages. Costs, from a payer perspective, included medical costs and sick leave and disability compensation.25

There were two modelling studies. A model-based costing study in Germany, in a cohort of hypothetical IMD patients of all ages, estimated sequelae costs over 14-years from a societal perspective, including medical and public health response costs, education costs and parental lost productivity costs.31 An economic model in Australia estimated the lifetime costs of sequelae in adults with IMD aged 20 or 30 years, from a payer and societal perspective, including medical costs, non-healthcare government subsidies, informal caregiver costs, education costs, home/vehicle modification costs, out-of-pocket costs, and productivity loss and premature death costs.27

There were two cohort studies assessing medical costs of IMD sequelae, from a payer perspective, over one year; a cohort study in Australian infants and children included acute hospitalization and readmission costs,26 and a US cohort study in IMD patients of all ages included medical costs based on a claims database analysis.24

Table 1 presents the breakdown of costs by country, time horizon and cost category, including direct medical costs (e.g., hospital, outpatient), costs for special education needs, social care costs, and indirect lost productivity costs for patients and/or their parent(s). The total costs by country are also presented, which include the costs of treating specific sequelae (presented separately in Table 2 where applicable).

Significant differences were observed for costs of education (range: I$8,118–I$1,249,674) and social care (range: I$4,175–I$843,744), which can vary according to the type and number of sequelae and the type or availability of services. For education, services may include special education needs, learning support assistance, school adaptations and equipment, transport from and to school, and specific services such as speech and language therapy and physiotherapy. For social care, costs may include day-care centers for activities, social care assessments, home visits and reviews.28-30

Costs associated with specific physical, neurological or psychological sequelae were reported in all countries except the US (Table 2). Costs of managing each sequela differed by study, with the highest costs observed for amputations, prosthesis, and chronic renal failure, among physical sequelae; hearing loss requiring cochlear implant and epilepsy among neurological sequelae; and psychological problems and depression, among psychological sequelae (Table 2). From the payer perspective, mean costs varied substantially by type of sequelae (e.g., I$14,511 for hearing loss versus I$144,087 for amputation), by type of care (e.g., I$28,498 for outpatient care versus I$67,038 for inpatient care), and by medical procedure (e.g., I$22,794 for shunt revision versus I$508,735 for prosthesis).

Mean costs were calculated across studies adopting the provider perspective and applying a lifetime horizon (Fig. 2). The unweighted mean lifetime costs were: I$67,038 (range: I$58,314–75,763)30 for inpatient care; I$28,498 (range: I$12,059–56,936) for outpatient care27-30; and for sequelae, they were I$19,291 for mental disorders (range I$11,038 for anxiety to I$36,283 for general psychological problems)27-29; I$37,201 (range: I$6,532–99,610) for epilepsy/seizures27-29; I$14,511 for hearing loss (range: I$6,435 for hearing loss requiring adaptation strategies to I$21,179 for cochlear implant)27 ; I$144,087 for amputation (range: I$36,805 for single amputation to I$252,519 for multiple amputations).27 The unweighted mean lifetime costs of medical procedures27-30 were I$508,735 (range: I$420,975–653,255) for prosthesis; I$106,455 (range I$14,349–306,564) for cochlear implant; I$24,117 (range I$8,969–38,072) for stump revision and skin grafting; and I$22,794 (range: I$12,689–35,511) for shunt revision. The mean discounted lifetime cost of education was I$248,161 (range: I$8,118–1,249,674) and of social care, I$223,043 (range: I$4,175–843,744).28-30

Fig. 2.

Mean discounted lifetime costs and range (I$) of long-term IMD sequelae. I$, International Dollars; IMD, Invasive Meningococcal Disease.

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The previously described evidence was used to support the development of a Delphi questionnaire aimed to estimate medical Resource Use (RU) and caregiver productivity loss during the First Year (Y1) and the Subsequent Year (SY) for the most frequently reported sequelae in the literature (e.g., amputation, skin scars, hearing loss, epilepsy, mental retardation and mental health disorders, Fig. S1). Of the 33 participants invited to participate in the Delphi survey, five confirmed participation and provided informed consent, including three infectious disease doctors and two mothers of IMD patients. The survey group included individuals with diverse backgrounds and perspectives i.e., healthcare providers versus patients’ parents, public versus private sector, from different regions of Brazil (i.e., São Paulo in the Southeast, Pernambuco in the Northeast, Paraná in the South, Minas Gerais in the Southeast, and Rio de Janeiro in the Southeast).

All participants completed and returned the questionnaire in Round 1 and provided validation of the pooled results in Round 2. The Delphi survey reached a consensus on the mean, minimum and maximum values for most resources used. However, one participant did not answer all the questions and disagreed with the values reported for the number of physiotherapy sessions (i.e., participant reported 8 vs. 6 from the other participants) and the average number of working days lost (i.e., participant reported no value for SY vs. 28 days from the other participants). Both questions related to multiple limb amputations after the first year.

Additional comments provided by the participants highlighted that severity can have an important impact on the burden of IMD sequelae, including the need for rehabilitation or consultations; and the presence of multiple sequelae can affect burden and costs significantly. A case story by one participant highlighted the nature of long-term healthcare resource use and indirect costs (e.g., four months in the intensive care unit, various procedures and treatments including tracheostomy for seven months, need for home oxygen, prosthesis and use of orthoses due to amputations which required changes with growth, the need for a caregiver, and the need for parental caregiving as home care was only provided for eight months).

From the results of the Delphi survey, Fig. 3 presents the mean medical resource use needed to treat the seven sequelae, in the first Year (Y1) and the Subsequent Year (SY) of IMD (see Supplementary File for Delphi results by round).

Fig. 3.

Mean medical resource use (days or visits) by IMD sequela in (A) Year 1 (Y1) and Y1 + Subsequent Year (SY) and (B) subsequent year ‒ results from the Delphi survey for Brazil. IMD, Invasive Meningococcal Disease; IQ, Intelligence Quotient.

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The use of medical resources was significantly higher during Y1 compared with SY for all sequelae. Patients with single limb and multiple limb amputations had the highest overall medical resource use. All cases with a sequela required medical doctor visits (18‒40 in Y1 vs. 10‒20 SY), emergency department visits (13‒36 in Y1 vs. 5‒13 SY) and psychologist visits (48‒116 in Y1 vs. 24‒56 SY). Patients with amputations and skin scarring also required many inpatient hospital days (24‒28 in Y1 vs. 6‒8 SY). Patients with single or multiple limb amputations required physiotherapy visits (132‒149 in Y1 vs. 56‒70 SY) and orthotist visits (2 SY), and those with multiple limb amputation required 12 prosthetist visits (in Y1 and SY). There were 96 occupational therapist visits (in Y1 and SY) for patients with multiple limb amputations, and also for patients with mental retardation (36 in Y1 vs. 12 SY). Patients with skin scarring required outpatient visits for dressing (32 in Y1 vs. 14 SY). Patients with hearing loss or deafness required speech therapy visits (72 in Y1 vs. 36 SY) (Fig. 3).

The estimated per-patient costs of medical resource use to treat long-term IMD sequelae in the first and subsequent years of IMD are presented in Fig. 4. For amputation of a single limb, we estimated a cost of $2,803.24 and $902.73 for Y1 and SY, respectively. These costs were almost doubled ($4,139.70 in Y1 and $1,874.39 in SY) for multiple limb amputation. Costs for treatment of skin scarring sequelae were $2,307.69 in Y1 and $816.19 in SY. For IMD-associated seizures, we estimated that the per-patient cost was $369.11 in Y1 and $150.67 for SY, excluding the anticonvulsant therapy (which are mainly out of pocket expenses and reported by one of the respondents in the Delphi panel). For hearing loss, Y1 and SY costs were estimated at $728.11 and $355.11, respectively. It is noteworthy that hearing aid costs are not included in these estimates. Medical resource use costs were also estimated for mental retardation ($911.33 in Y1 and $317.44 for SY) and IMD-associated mental health disorders ($533.22 in Y1 and $240.22 for SY).

Fig. 4.

Total cost per patient (USD) by IMD sequela in (A) Year 1 (Y1) and (B) Subsequent Year (SY) ‒ results from the microcosting approach for Brazil. IMD, Invasive Meningococcal Disease; USD, US Dollar.

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Fig. 5 presents the mean number of working days lost for the treatment of the seven long-term IMD sequelae, in Y1 and Y1 + SY.

Fig. 5.

Mean number of working days lost by sequela, in (A) Year 1 (Y1) and Y1 + Subsequent Year (SY) and (B) subsequent year ‒ results from the Delphi survey for Brazil. IMD, Invasive Meningococcal Disease; IQ, Intelligence Quotient; Y, Year.

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The Delphi survey shows that all sequelae were associated with multiple working days lost, ranging from 33 for skin scarring to 85 for multiple limb amputations in Y1, and from 9 for skin scarring to 28 for multiple limb amputations SY. The mean number of working days lost was considerably higher in Y1 versus SY for all sequelae, representing an important indirect cost driver (Fig. 5). In addition, participants reported needing a paid caregiver for most of the sequelae in Y1 and SY.