A CoI model was used to calculate the total economic burden of MenB-related IMD in the Netherlands for a single annual cohort over a life-time horizon. The model included both short- and long-term sequelae and considered direct and indirect costs. Average costs incurred by one MenB IMD case over a lifetime horizon were also estimated. An existing model, previously used to estimate the economic burden of MenB-related IMD in Germany [14], was adapted to the Dutch setting. 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.

Cost data were retrieved from a literature search. When Dutch data were not available, studies from other countries were used and adapted using transferability methods (i.e., purchasing power parity) [9]. Moreover, experts validated and further completed the overview of medical costs for MenB-related IMD and sequelae. Costs were assessed from a third-party payer (TPP) perspective, which includes direct medical costs and a broader societal perspective including productivity losses. Costs were adjusted to the reference year 2021, using the harmonized Consumer Price Index (CPI) for the Netherlands published by Statistics Netherlands (see Appendix I, Table S1) [15]. As recommended for the Netherlands, future costs were discounted annually with 4% [16].

Population data for 2019 were collected from the Statistics Netherlands by age (0–100 years) [17]. MenB-related IMD incidence data were obtained from the Netherlands Reference Laboratory for Bacterial Meningitis for individuals 0–100 years of age (see Table 1) for the years 2015–2019. The number of MenB-related IMD cases was expressed as incidence per 100,000 inhabitants by age. The case-fatality rate for the MenB serogroup was extracted from a recent publication by Loenenbach et al. [18], and derived per age group. Sequelae probabilities in IMD survivors were obtained from the previously published model in Germany, in which the probabilities were derived from a systematic literature review [13, 14]. Costs and health impacts were calculated for the following age groups: “ < 1 year”, “1–4 years”, “5–9 years”, until the age group “90 years and older”.

Figure 1 shows the model structure. It includes costs of the IMD acute phase (i.e., costs for inpatient stay, productivity losses, and public health response), costs for the survivors with sequelae (i.e., costs for direct medical care, rehabilitation, special education, long-term care), and productivity losses. Co-payments of inpatient and outpatient visits were not included.

Schematic flowchart of the cost calculation for each case of invasive meningococcal disease. Abbreviation: IMD invasive meningococcal disease

Direct medical costs of the acute phase of MenB-related IMD are presented in the Appendix, Table S2 with the associated parameters in Appendix I, Table S3. Every patient with IMD was assumed to visit a general practitioner (GP) before being hospitalized. Direct medical costs related to GP visit and hospitalization were collected from the Dutch Costing Manual [16]. The median duration of hospitalization and admission to the intensive care unit (ICU) was derived from Stoof et al. [13]. It was assumed that 36.1% of the MenB-related IMD cases needed care in ICU [18]. The probability of developing sequelae after the acute IMD phase is reported in Table 1. For IMD survivors without sequelae, only one pediatrician/neurologist check-up visit was assumed.

Public health response costs following an IMD case were included as part of the direct costs of the acute phase and were based on Welte et al. [19]. They comprised costs for post-exposure prophylaxis treatment of close contacts (on average two children and three adults) with rifampicin or ceftriaxone, as well as pharmacy and GP visits and reports to other public parties [16]. No costs for local public health authorities were included.

Travel costs were only included in the costs of acute IMD. Travel costs to the GP and hospital were estimated using the travel distance and travel cost per kilometer following the Dutch Costing Manual [16].

Direct medical costs of the sequelae were estimated as the costs for the first year (i.e., the year of occurrence of the sequelae) plus the costs for the second year onwards (i.e., the following years after occurrence of the sequelae) of an IMD case (see Appendix, Table S3). Direct medical treatment costs were estimated for each sequelae using published cost estimates and costing approaches validated by Dutch clinical and medical experts. The direct medical cost estimates per sequela are described in the Appendix I, Table S4. As mentioned, travel costs were not considered for sequelae.

IMD survivors who develop long-term sequelae may also have special educational needs because of their physical and neurological conditions. Special education costs were taken into account at 50% for IMD survivors with severe hearing loss (i.e., with cochlear implant), severe neurological disorders, mental retardation/low intelligence quotient (IQ), motor deficits, limb amputation, blindness/severe visual impairment, and attention deficit hyperactivity disorder (ADHD) [12, 20].

Special education costs were assumed annually until the end of schooling age (i.e., 18 years) (detailed in Appendix I, Table S5). Education costs were dependent on age (primary or secondary education) and category of special education needs (i.e., children with a physical or intellectual disability, or serious learning difficulties) [21, 22]. Costs for deafness were assumed to be the same as costs for blindness [23]. Educational costs for ADHD were derived from Van der Kolk et al. [24]. Costs for issuing and review of the special education needs assessment statement were not considered in this analysis.

An overview and description of the long-term sequelae are presented in Table S4. Long-term care costs were only considered for IMD survivors with severe long-term sequelae (i.e., hearing loss with a cochlear implant, severe neurological disorders, motor deficits, mental retardation/low IQ, limb amputation with severe disability, and blindness/severe visual impairment). Based on previous studies, it was assumed that 25% of patients with severe sequelae need lifetime care in institutes for mentally and physically disabled [20, 25].

Productivity losses due to the IMD acute phase were calculated for (i) the patient or his/her parents during hospitalization, (ii) premature patient mortality, and (iii) survivors with sequelae.

Productivity losses were calculated using the friction-costs approach (FCA) and the human-capital approach (HCA) [26,27,28]. FCA assumes that a person will be replaced by another member of the active workforce, limiting productivity loss to the time required to hire and train his/her replacement, i.e., the friction period. On the other hand, HCA values the entire productivity loss incurred by an individual’s premature death or morbidity due to long-term sequelae. The average yearly income was age-dependent and derived from Statistics Netherlands [29]. The friction period was derived from the Dutch Costing Manual and amounted to 85 days [16].

For hospitalized patients under 15 years of age, productivity losses were calculated for one of the parents. Costs were estimated by multiplying the age-dependent length of stay in the hospital with the age-specific employment wage per day [13, 29]. The average age of mothers at the birth of their first child (i.e., 29.9 years) was used to estimate the age-specific wage per day of the parent(s) [30]. There was no difference in costs using the HCA or the FCA as the duration of the acute phase was below the friction period.

Costs related to premature mortality were calculated using friction period, duration of job, age-specific wage per day, and life expectancy at the time of death. The numbers of days of productivity lost are presented in Appendix I, Table S6 [16, 29]. No productivity losses have been included for children who die under the age of 15 years.

Costs for reduced productivity among patients and their parents were estimated for each survivor with sequelae. Productivity losses due to epilepsy and separation anxiety were not included, as separation anxiety is seen up to 12 years of age and epilepsy recovery was assumed after 2 years of treatment. For patients under 18 years of age with severe sequelae, one of the parents was assumed to stay at home to take care of their disabled child [14, 31], for the other sequelae, a productivity loss of 10% for one of the parents was assumed. Patients were assumed to have reduced labor participation throughout life, because of their severe disability (detailed in Appendix I, Table S7). The degree of work impairment (absenteeism) was used to calculate the indirect costs. Productivity losses for mental disorders, hearing, vision, and mobility disabilities were obtained from Dutch specific public health data [32]. Due to the lack of data, productivity losses for the other sequelae were taken from a previous German study [14]. For FCA, the percentage of productivity loss was multiplied with the age-specific wage per day [29, 31].

A probabilistic sensitivity analysis was conducted to assess the impact of uncertainty in the input parameters of the total costs from a TPP perspective. The distribution was dependent on the relevant parameters (see Table 1, and Appendix I, Tables S2 and S8) and the availability of underlying data. The analysis was performed using 1000 Monte Carlo simulations, independently and randomly varying all input variables over their range at the same time.

A deterministic analysis to test the robustness of the model and identify major drivers of the outcomes was performed, and included the following parameters: IMD cases, case-fatality rate, age at first child, percentage long-term care, and the percentage special education need (see Appendix I, Table S8).

To further explore the variation in the base case, nine scenario analyses were performed: (1) Direct medical costs of the sequelae from Scholz et al. [14], (2) direct medical costs of the sequelae from Beck et al. [31]; (3) public health response and outbreak management costs from Scholz et al. [14], (4) productivity losses during hospitalization of the acute phase based on Welte et al. [19], (5) patients with severe sequelae requiring long-term informal care (changing 25% institutional care to 10% informal care), (6) all patients requiring long-term informal care instead of only patients with severe sequelae needing institutional care, (7) exclusion of psychological impairments, (8) no discounting applied, and (9) discounting costs with 1.5%. Detailed scenario analyses are shown in the Appendix I, Tables S9 and S10.