Costs of Clinical Hepatitis E in Germany: A Cost-of-Illness Analysis

Abstract

Background: Hepatitis E virus (HEV) infection is endemic in Germany, where most notified cases are acquired domestically. Contemporary German cost-of-illness estimates are lacking. Sewer workers are an occupationally relevant group because HEV may occur in wastewater environments; German occupational-safety guidance classifies their infection risk as equal to or possibly slightly increased compared with the general population. We therefore additionally considered an employed-adult scenario, with sewer workers as an illustrative occupational example. Methods: A cost-of-illness model combined 2025 German HEV surveillance data, 2025 InEK hospital data valued with 2026 German hospital reimbursement parameters, 2026 statutory outpatient tariffs (EBM), and productivity losses valued by the human-capital approach. The base case used the RKI surveillance hospitalization proportion of 49.3%; deterministic scenarios included an alternative 32.9% proportion derived from 2025 InEK principal-diagnosis admissions, alternative outpatient resource use, and broader productivity assumptions. The base-case population comprised adults aged ≥18 years meeting the RKI reference definition for acute HEV disease. Results: In 2025, 5310 reference-defined HEV cases were notified, including 5215 in adults aged ≥18 years. The age-weighted outpatient pathway cost was €122.06 and inpatient reimbursement was €4245.96 per admission. Base-case expected direct medical expenditure was €2157.45 per adult case. Mean sickness absence of 28.10 days yielded €4494.35 in productivity loss per employed case assumed to incur sickness absence; after employment weighting, expected productivity loss was €2647.53 and modeled societal cost was €4804.98 per adult case. The employed-adult scenario yielded €6651.80. Applied to 5215 notified adult cases, the base case implied €25.06 million in annual modeled costs. Using the InEK principal-diagnosis admission ratio reduced direct expenditure to €1478.84 and modeled societal cost to €4126.37 per case. Varying sickness-absence duration from 14 to 42 days changed modeled societal cost from €3476.31 to €6114.03. Conclusions: Hospitalization is the principal driver of direct medical expenditure, while productivity loss is a major component of modeled societal cost. Notified acute HEV disease in adults is associated with substantial economic costs in Germany. The model provides an updated German benchmark for disease costs and illustrates the additional societal burden associated with productivity loss in employed adults. With respect to the probability of sickness absence, the base-case societal cost represents an upper-bound estimate, while the choice of hospitalization parameter is a key source of model variation.

1. Background

Hepatitis E is caused by the hepatitis E virus (HEV), a positive-sense single-stranded RNA virus transmitted enterically. The World Health Organization estimates that approximately 20 million HEV infections occur globally each year, of which about 3.3 million are symptomatic; approximately 4431 deaths were attributed to HEV in 2023 [1]. The highest disease burden occurs in sub-Saharan Africa and East and South Asia, where fecal–oral transmission through contaminated water is prominent [1]. In high-income countries, most infections are self-limiting, while chronic or persistent HEV infection is principally a concern in immunosuppressed patients [2]. Importantly, chronic infection appears to constitute a small subgroup even in risk-enriched immunosuppressed populations: in a recent prospective screening study of 740 solid-organ transplant recipients and patients with hematological disease, chronic HEV was identified in five patients (0.6%), all of whom were kidney-transplant recipients [3].

In Europe, HEV is now recognized as an endemic zoonotic infection rather than merely an imported travel-associated disease. Genotype 3 predominates in European Union/European Economic Area (EU/EEA) countries, with transmission linked particularly to infected pigs and wild boar and to consumption of raw or insufficiently cooked pork products [4,5]. The European Centre for Disease Prevention and Control (ECDC) recorded 21,081 confirmed hepatitis E cases in the EU/EEA during 2005–2015; reported cases increased from 514 in 2005 to 5617 in 2015, and infections were mainly locally acquired, with men and persons aged >50 years most affected [4]. Comparability between countries remains limited because HEV is not notifiable at the EU level and national surveillance systems, case definitions, and testing practices differ [4,5].

In Germany, the Robert Koch Institute (RKI), the national public health institute, recorded 4734 reference-defined HEV cases in 2024. Among cases with information on the probable country of infection, Germany was reported in 86%, supporting predominantly domestic acquisition; 74% of cases occurred among 40–79-year-olds, the highest incidence was observed among men aged 60–69 years, and 13 HEV-associated deaths were reported [6]. These epidemiological features are consistent with established endemic zoonotic HEV-3 circulation in Germany [7]. The RKI emphasizes substantial underascertainment because many HEV infections are mild or clinically inapparent [2,6].

For the present study, we additionally queried SurvStat@RKI 2.0, the RKI’s interactive database for notified infectious diseases. The 2025 query identified 5310 reference-defined HEV cases, of which 5215 (98.2%) occurred in adults aged ≥18 years [8]. Importantly, the RKI reference definition for hepatitis E comprises clinically–epidemiologically confirmed and clinically–laboratory-confirmed disease (categories B and C) and therefore requires a clinical picture of acute hepatitis E; laboratory-only detections without the required clinical picture, including asymptomatic infections, are excluded from the reference definition [9]. We therefore use the term ‘clinically manifest’ for reference-defined notified disease throughout the model.

To our knowledge, no HEV-specific cost-of-illness analysis has previously been conducted for Germany, and European economic evidence remains limited. Mangen et al. estimated €4224 per HEV case in the Netherlands in 2011 [10]; subsequent RIVM assessments reported approximately €4900 per case and €4 million in annual HEV cost of illness for 2021 [11], and approximately 990 incident cases and €5 million in total HEV cost of illness for 2023 [12]. These Netherlands analyses are national incidence-based disease-burden models that estimate population incidence, including corrections for incomplete ascertainment, within a broader food-related pathogen framework. The present study instead values German reimbursement and productivity consequences conditional on a notified, reference-defined adult HEV case. The approaches are therefore complementary but estimate different constructs.

As an illustrative application to employed populations, we also considered sewer workers. TRBA 220 classifies HEV infection risk in wastewater facilities as equal to or possibly slightly increased compared with the general population [13], and German case–control evidence has identified wastewater contact as a possible risk factor [14]. However, occupation was not assumed to alter clinical management, disease severity, or the probability that an HEV infection was occupationally acquired. The occupational example therefore serves only to illustrate the cost consequences of applying the full productivity loss to an employed adult.

Against this background, the aim of our study was to estimate reimbursement-based direct medical expenditure and productivity losses associated with clinically manifest acute HEV in German adults, to quantify the model-implied costs among notified adult cases, and to examine an employed-adult scenario with sewer workers as an illustrative occupational example.

2. Methods

2.1. Study Design and Population

A model-based cost-of-illness analysis was conducted for clinically manifest acute HEV in Germany. Direct medical expenditure was valued from the German statutory health insurance (Gesetzliche Krankenversicherung, GKV) reimbursement perspective; these amounts represent payments rather than economic opportunity costs of resources. Productivity loss was added to obtain a partial societal perspective. Informal care, patient travel costs, out-of-pocket expenditure, and unpaid work were not included. The base-case population comprised adults aged ≥18 years, who accounted for 5215 of 5310 reference-defined HEV cases in the 2025 SurvStat query [8]. Under the RKI case definition, reference-defined hepatitis E requires the clinical picture of acute hepatitis E and either epidemiological or laboratory confirmation; laboratory-only detections without the required clinical picture are excluded [9]. Only 95 reference-defined cases occurred below age 18. Robust HEV-specific pediatric utilization data were not identified, and all 40 intensive-care admissions identified in the InEK analysis were adults. Chronic or persistent HEV was excluded because it represents a distinct management pathway concentrated in immunosuppressed patients [3].

The 2025 SurvStat age distribution was used to weight age-dependent outpatient reimbursement and employment rates [8]. The base-case hospitalization parameter came from the 2024 RKI yearbook and referred to all age groups: hospitalization status was known for 4279 of 4734 reference-defined HEV cases (90.4%), of whom 2111 were hospitalized (49.3%) [6]. The RKI table records hospitalization among notified disease cases but does not establish that HEV was the principal hospital diagnosis. The observed proportion (2111/4279) was used without rounding in the base case. Because hospitalization status was missing for 455 cases, selection bias is possible if completeness differed by disease severity. In addition, transferring the 2024 proportion to the 2025 case population assumes short-term stability. The Wilson 95% confidence interval (47.8–50.8%) was retained as a sampling-error analysis. As an alternative structural scenario, we calculated the ratio of 1715 InEK admissions with principal diagnosis B17.2 to the 5215 reference-defined adult HEV cases notified in 2025 (32.9%). This scenario has the advantage of using hospitalization data from the same calendar year as the notification volume and from the same administrative system that underlies the inpatient cost calculation. Because InEK captures only admissions with B17.2 as the principal diagnosis and counts admissions rather than unique notified persons, the 32.9% value was interpreted as a more restrictive structural scenario rather than as an empirical hospitalization probability.

2.2. Ambulatory Costs

Outpatient services were valued using the Einheitlicher Bewertungsmaßstab (EBM), the German fee schedule for statutory outpatient care [15,16,17]. The diagnostic pathway is a costing construct and not a prescriptive clinical algorithm. At first presentation, acute hepatitis was treated as etiologically undifferentiated, with initial viral differential serology including markers for HAV, HBV, HCV, and HEV. In the HEV pathway, a positive anti-HEV IgM result was followed by HEV RNA testing for costing purposes; this does not imply that RNA testing must await serology, as the DGVS recommends quantitative HEV RNA when HEV is clinically suspected [18]. Beyond the virological work-up, the base case included a general laboratory panel, one abdominal ultrasound, and one follow-up laboratory assessment. Because no HEV-specific recommendation mandates ultrasonography in every case, its inclusion was based on its use in the initial evaluation of acute hepatitis of initially uncertain etiology, by analogy with the German S3 hepatitis B guideline [19]; complete omission of ultrasound and the associated commissioned specialist consultation was tested in sensitivity analysis. Full GOPs, resources, and age weights are provided in Supplementary Methods and Supplementary Tables S1 and S2.

The resulting age-weighted outpatient cost for adults aged ≥18 years was €122.06, comprising €36.53 for age-weighted primary-care and commissioned specialist fees, €44.59 for the initial viral serological differential, €18.31 for HEV RNA, €2.58 for general laboratory tests, €18.22 for abdominal ultrasonography, and €1.83 for follow-up laboratory testing.

2.3. Inpatient Costs

Hospital data were obtained from the 2025 InEK Data Browser using ICD-10-GM B17.2 (acute hepatitis E) as the principal diagnosis and age ≥ 18 years [20]. The query identified 1715 admissions. Seven DRGs were individually reportable and covered 1695 admissions (98.8%); 20 admissions (1.2%) were distributed across 12 suppressed DRGs and could not be individually costed because InEK does not report cell-specific weights or lengths of stay for counts below four. The weighted reimbursement estimate therefore used the 1695 reportable admissions as its denominator. The 20 suppressed admissions represented only 1.2% of all admissions; however, because their DRG-specific resource use is unknown, the direction and magnitude of any resulting bias in the weighted mean cannot be determined. H63C accounted for 78.4% and H41F for 13.8% of reportable admissions [20,21].

For each reportable DRG, the non-nursing payment was calculated as DRG cost weight × the 2026 federal base rate (€4570.64), while nursing reimbursement was calculated as HEV-specific mean length of stay × DRG-specific daily nursing weight × the 2026 nursing reference value (€246.01) [21,22,23]. Frequency weighting across the 1695 reportable admissions yielded €2938.42 for the aG-DRG component and approximately €1012.19 for nursing, or €3950.61 before case-level surcharges. Four standard system and quality surcharges added €5.75 per admission: external quality assurance €0.84, DRG-system surcharge €1.59, G-BA system surcharge €3.12, and the inter-institutional incident-reporting surcharge €0.20 [24]. For vocational training, the revised model uses the latest available national mean billing amount of €289.60 per fully inpatient admission (billing code A6200011; data year 2025), provided in writing by the German Hospital Federation (Deutsche Krankenhausgesellschaft, DKG) on 5 November 2026 [25]. Together, case-level surcharges amounted to €295.35, yielding total inpatient reimbursement of €4245.96 per admission. Complete omission of the vocational training surcharge was retained as a deterministic sensitivity scenario. Details are provided in Supplementary Tables S3 and S4.

A separate InEK intensive-care query identified 40 of 1715 adult admissions (2.33%) that received intensive care; the mean total hospital stay in these cases was 17.2 days, with hepatic, renal, and respiratory complications documented [20]. No generic ICU add-on was applied because ICU resource intensity contributes to DRG assignment, case mix, and length of stay, and adding an external per-day ICU cost would risk double counting. However, aggregate InEK data do not permit identification of all case-specific additional payments that may occur in highly complex ICU treatment; omission of such payments could lead to some underestimation in this small subgroup.

Post-discharge follow-up was treated as an outpatient resource and was not included in hospital reimbursement. Following discharge, one outpatient biochemical follow-up was assumed. The base case added only the laboratory component (€1.83) to the hospitalized disease pathway; this €1.83 is therefore an ambulatory post-discharge cost, not a hospital cost. Because HEV-specific data on separately billable post-discharge primary-care contacts are unavailable, no additional primary-care fee was assigned in the base case. German acute-hepatitis guidance recommends repeat transaminases and prothrombin time according to the clinical course until normalization, although the cited recommendation is HBV-specific [19]. A sensitivity analysis assumed a separately remunerated outpatient follow-up in a new treatment quarter and added the corresponding primary-care remuneration [15,16].

2.4. Productivity Loss

Productivity loss was valued using the human-capital approach recommended by the Hannover Consensus [26]. Employee compensation in 2025 was €58,370 per employee, equivalent to €159.92 per calendar day [27]. Diagnosis-specific sickness-absence data are not available for ICD-10-GM B17.2; the closest official proxy is ICD-10 B17. In the 2020 BMG statistics, 951 B17 sickness-absence episodes generated 26,727 days, corresponding to 28.10 days per episode [28]. The base case assumes that each employed reference-defined HEV case incurs one sickness-absence episode of this mean duration. This is a structural assumption because the BMG source describes sickness-absence episodes rather than the probability that an employed HEV patient requires absence from work, and it may overestimate productivity loss if a substantial proportion of employed notified cases do not take sickness absence. Because B17 includes acute viral hepatitis diagnoses other than HEV and the available data refer to 2020, the direction and magnitude of any additional bias from the diagnostic proxy and reference year cannot be determined from the available data. Using unrounded values yielded €4494.35 per employed case assumed to incur sickness absence.

For the general adult population, 2025 age-specific employment rates from the German Federal Statistical Office (Destatis) were weighted by the 2025 HEV age distribution, yielding an employment rate of 58.91% [8,29,30]. Expected productivity loss was therefore €2647.53 per adult case in the base case. The employed-adult scenario set employment to 100% and applied the full €4494.35 productivity loss; a sewer worker is one illustrative example, but the same estimate applies to any employed adult under the same assumptions. The human-capital approach uses average employee compensation and does not capture individual working hours, occupation-specific earnings, or heterogeneity in actual wages. Detailed calculations are provided in Supplementary Methods and Supplementary Table S5.

2.5. Cost Aggregation and Sensitivity Analysis

Expected direct expenditure was calculated by weighting the hospitalized and outpatient pathways by the base-case RKI hospitalization proportion (49.3%) and its complement. In the hospitalized disease pathway, €4245.96 represented inpatient reimbursement and €1.83 the incremental outpatient laboratory component after discharge. Modeled societal cost added employment-weighted productivity loss. Deterministic sensitivity and scenario analyses addressed: a separately remunerated post-discharge primary-care follow-up; complete omission of the vocational training surcharge; the Wilson limits of the RKI hospitalization proportion; the alternative 32.9% InEK principal-diagnosis admission ratio; omission of outpatient ultrasonography and its commissioned specialist fee; sickness-absence durations of 14 and 42 days; sickness-absence probabilities of 50%, 75%, and 100% among employed cases; employment rates 10 percentage points below and above the base-case value; and employee compensation at 80% and 120% of the base value. In the absence of an empirical HEV-specific confidence interval or an alternative diagnosis-specific German estimate, sickness-absence duration was varied by approximately ±50% around the observed B17 mean of 28.10 days, corresponding to 14.05 and 42.15 days and rounded to 14 and 42 days. These deliberately broad deterministic stress tests were intended to explore substantial uncertainty in this parameter and should not be interpreted as empirically derived bounds or confidence limits. An additional illustrative scenario assigned 14 days of sickness absence to ambulatory cases and the observed 28.10-day B17 mean to hospitalized cases to explore treatment-setting heterogeneity; these values likewise represent a structural stress test rather than empirical setting-specific HEV estimates. The employment and compensation ranges are also deterministic stress tests, not statistical intervals. A probabilistic sensitivity analysis was not performed because empirical probability distributions are unavailable for several structural assumptions. Monetary values are displayed to the cent to allow reconciliation with tariff inputs and calculations; this should not be interpreted as statistical precision.

3. Results

3.1. Direct and Societal Costs

The age-weighted outpatient pathway cost was €122.06. The hospitalized disease pathway cost was €4247.79, comprising €4245.96 in inpatient reimbursement and €1.83 for the outpatient laboratory component of post-discharge follow-up. Weighting these mutually exclusive pathways by the base-case RKI hospitalization proportion yielded expected reimbursement-based direct medical expenditure of €2157.45 per reference-defined adult HEV case. The hospitalized branch accounted for 97.1% of expected direct expenditure under this base-case weighting.

Productivity loss was €4494.35 per employed case assumed to incur sickness absence and €2647.53 after applying the HEV-case-weighted employment rate of 58.91%. The modeled societal cost, defined here as direct medical reimbursement plus productivity loss, was €4804.98 per reference-defined adult case; productivity loss represented 55.1% of this amount.

The main cost components are summarized in Table 1.

Table 1. Summary of pathway-specific and expected costs per reference-defined adult HEV case.

Cost Component	€ Per Reference-Defined Adult HEV Case
Ambulatory pathway	122.06
Hospitalized disease pathway incl. post-discharge outpatient follow-up	4247.79
Expected direct medical expenditure	2157.45
Expected productivity loss	2647.53
Modeled societal cost	4804.98

Note: Ambulatory and hospitalized pathway costs are alternative pathways and should not be added. Expected direct medical expenditure weights these pathways using the base-case RKI hospitalization proportion (2111/4279; 49.3%) and its complement. The hospitalized disease pathway comprises €4245.96 in inpatient reimbursement plus €1.83 for outpatient laboratory follow-up after discharge. Inpatient reimbursement includes €295.35 in system, quality, and vocational training surcharges (Supplementary Table S4).

3.2. Employed-Adult Scenario

Applying the same medical pathway to an employed adult and setting employment to 100% yielded a modeled societal cost of €6651.80 per reference-defined HEV case. This is an employment scenario rather than an occupation-specific cost estimate; a sewer worker is an illustrative example. Pathway-specific costs are shown in Table 2.

Table 2. Cost of a reference-defined HEV case in an employed adult.

Clinical Pathway	Direct Medical Cost (€)	Productivity Loss (€)	Modeled Societal Cost (€)
Ambulatory symptomatic patient	122.06	4494.35	4616.41
Hospitalized symptomatic patient incl. post-discharge outpatient follow-up	4247.79	4494.35	8742.14
Expected employed adult (50.7% ambulatory; 49.3% hospitalized)	2157.45	4494.35	6651.80

Note: The hospitalized disease pathway includes €4245.96 in inpatient reimbursement plus €1.83 for outpatient laboratory follow-up after discharge. The base case applies the same 28.10-day sickness-absence duration to ambulatory and hospitalized employed cases because BMG B17 data are not stratified by treatment setting [26]. The employed-adult scenario also applies to a sewer worker but is not occupation-specific.

3.3. Model-Implied Annual Costs Among Notified Adult Cases

Applying the base-case per-case estimates to the 5215 reference-defined adult HEV cases notified in 2025 yielded €11.25 million in reimbursement-based direct medical expenditure and €13.81 million in productivity loss, for €25.06 million in model-implied annual costs. This figure pertains only to notified adult disease meeting the RKI reference definition. It is not an estimate of the total national economic burden of all HEV infections: the 95 notified pediatric cases, chronic HEV, unrecognized infections, and cost components outside the model perspective are excluded. Valuation at GKV reimbursement rates does not imply that every notified case was GKV-insured.

3.4. Sensitivity Analyses

The broader deterministic analyses identified hospitalization and productivity assumptions as the main sources of model variation (Table 3). Using the InEK 32.9% principal-diagnosis admission ratio as an alternative structural scenario reduced the expected direct expenditure to €1478.84 and the modeled societal cost to €4126.37 per case, approximately 14.1% below the base-case societal estimate. Omitting the vocational training surcharge reduced the expected direct expenditure to €2014.57; omitting ultrasonography and its commissioned specialist fee reduced it only to €2147.05. Varying sickness-absence duration from 14 to 42 days changed the modeled societal cost from €3476.31 to €6114.03. Assuming sickness absence in only 50% or 75% of employed cases reduced the modeled societal cost to €3481.21 or €4143.09, respectively. In the illustrative treatment-setting scenario, assigning 14 sickness-absence days to ambulatory cases and 28.10 days to hospitalized cases reduced the modeled societal cost to €4131.79 per case. Employment and compensation stress tests produced intermediate changes. These deterministic scenarios are not confidence intervals and do not capture all model uncertainty.

Table 3. Deterministic sensitivity and scenario analyses.

Sensitivity Parameter	Scenario	Expected Direct Expenditure (€)	Modeled Societal Cost (€)
Post-discharge follow-up	Separate new-quarter primary-care remuneration	2174.34	4821.87
Vocational training surcharge	Omitted from reimbursement calculation (€0)	2014.57	4662.10
Hospitalization probability	47.8–50.8% (Wilson limits)	2094.16–2217.93	4741.69–4865.46
Principal-diagnosis admission ratio	32.9% (InEK alternative structural scenario)	1478.84	4126.37
Abdominal ultrasonography and commissioned specialist fee	Both omitted (€0)	2147.05	4794.58
Sickness-absence duration	14–42 days	2157.45	3476.31–6114.03
Setting-specific sickness-absence duration	14 d ambulatory; 28.10 d hospitalized (illustrative)	2157.45	4131.79
Probability of sickness absence among employed cases	50–100%	2157.45	3481.21–4804.98
Employment rate	48.9–68.9%	2157.45	4355.54–5254.41
Employee compensation	80–120% of base value	2157.45	4275.47–5334.48

4. Discussion

This analysis provides a German estimate of reimbursement-based direct medical expenditure and productivity losses associated with notified, reference-defined acute HEV disease in adults. Under the base case, the hospitalized branch accounted for 97.1% of expected direct medical expenditure because inpatient reimbursement (€4245.96 per admission) was much higher than the outpatient pathway (€122.06), and the RKI surveillance proportion classified 49.3% of cases with known status as hospitalized. Productivity loss was the largest single component of the modeled societal cost. Applying the base-case estimates to 5215 notified adult cases yielded €25.06 million in model-implied annual costs.

The expanded sensitivity analyses show that the earlier narrow sampling-error range around the RKI hospitalization proportion understated overall model uncertainty. The alternative InEK structural scenario reduced the modeled societal cost by approximately 14.1%, while productivity assumptions had an even larger influence: varying sickness-absence duration from 14 to 42 days changed the estimate from €3476.31 to €6114.03 per case. The base case should therefore be interpreted as a transparent reference estimate rather than a robust point estimate. The deterministic scenarios identify influential assumptions but do not substitute for probabilistic uncertainty analysis, which was not feasible because empirical distributions were unavailable for several structural parameters.

The difference between the RKI and InEK hospitalization measures is conceptually important. The RKI proportion is based on hospitalization status among notified reference-defined disease cases across all ages, whereas the InEK numerator consists of adult hospital admissions for which B17.2 was the principal diagnosis. HEV may be documented as a secondary diagnosis in some hospitalized patients, and InEK counts admissions rather than unique notified persons. Conversely, hospitalization status was missing for 9.6% of 2024 RKI cases, and more complete reporting among severe cases could bias the RKI proportion upward. We therefore retained the surveillance proportion as the base case and used the InEK 32.9% principal-diagnosis admission ratio as a more restrictive alternative structural scenario. The latter has the advantage of using 2025 hospitalization data from the same calendar year as the notification volume and from the same administrative system that underlies the inpatient cost calculation, but it should not be interpreted as an empirical hospitalization probability because it includes only principal-diagnosis admissions. The inpatient reimbursement estimate itself includes the frequency-weighted aG-DRG payment, separately reimbursed nursing, and system, quality, and vocational training surcharges. Complete omission of the vocational training surcharge reduced the expected direct expenditure by €142.87 per case.

The outpatient pathway should likewise be interpreted as a costing construct rather than a clinical algorithm. At first presentation, the etiology of acute hepatitis may be uncertain, so the model includes differential viral testing and, for costing purposes, places HEV RNA after a positive anti-HEV IgM result. Abdominal ultrasonography was assumed once in the base case but is not necessarily required in every HEV patient. Its complete omission together with the commissioned specialist fee changed the expected direct expenditure by only €10.40 per case, indicating that this assumption has little influence on the overall estimate.

European economic evidence on HEV remains limited. The Dutch analyses provide useful context but should not be interpreted as validation of the German estimates because they use population-based foodborne-disease models, incorporate corrections for incomplete ascertainment, and reflect a different healthcare and labor-market setting [10,11,12]. The present model is conditional on notified reference-defined disease and uses German reimbursement rules and labor-market inputs. Consequently, the monetary estimates are not directly transferable to other countries without adapting the clinical pathways, tariffs, hospital payment system, employment structure, and productivity valuation.

The employed-adult scenario is not an occupation-specific economic assessment. Its higher cost compared with the age-weighted general adult population arises solely because employment is set to 100%, so the full productivity loss is applied. It does not estimate the probability of occupational acquisition, the attributable fraction of HEV due to wastewater exposure, or occupation-specific treatment intensity. Sewer workers are retained only as an illustrative occupational example because TRBA 220 considers their HEV risk equal to or possibly slightly increased relative to the general population [13]. This occupational context should be distinguished from the broader zoonotic transmission of HEV in Germany, which is predominantly linked to animal reservoirs and foodborne exposure [7].

No HEV vaccine is currently licensed in the European Union [1,13], and prevention therefore relies on exposure reduction. The present analysis, however, does not estimate the effectiveness, costs, or cost-effectiveness of preventive interventions. Its contribution is limited to quantifying disease-related reimbursement and productivity consequences under the stated assumptions; any prevention implications should be interpreted in that context.

Our analysis has several strengths. It integrates contemporary German data sources selected specifically for the respective cost components: SurvStat for the age distribution of notified disease, national RKI surveillance for hospitalization probability, InEK for the HEV-specific inpatient case mix and length of stay, current EBM and aG-DRG parameters for monetary valuation, BMG data for sickness absence, and Destatis VGR (German National Accounts) data for productivity valuation together with Destatis employment data [6,8,15,16,17,18,19,20,21,22,23,26,27,28,29,30]. In addition, the model explicitly incorporates hospital financing components beyond the DRG and nursing amounts and now tests key structural alternatives, including the InEK-derived hospitalization ratio and broader productivity assumptions.

Some limitations should nevertheless be considered. First, the base-case hospitalization proportion was derived from 2024 surveillance across all age groups and transferred to the 2025 adult case population; missing hospitalization status may cause selection bias, while the alternative InEK measure is narrower because it is admission-based and restricted to B17.2 as the principal diagnosis. Second, sickness absence relies on 2020 data for the broader ICD-10 category B17. The base case assumes one 28.10-day sickness-absence episode for each employed reference-defined HEV case, even though the source does not provide the probability of sickness absence or setting-specific durations. Because B17 includes acute viral hepatitis diagnoses other than HEV and the data refer to 2020, the direction and magnitude of potential bias from these features cannot be determined. The same duration is applied structurally to hospitalized and non-hospitalized employed cases. If hospitalized cases require longer absence than ambulatory cases, this common-duration assumption may underestimate productivity loss in the hospitalized subgroup while potentially overestimating it in ambulatory cases; the net effect cannot be determined without setting-specific HEV data. Third, the human-capital approach uses average employee compensation and does not account for individual working hours, occupation-specific wage distributions, or actual earnings. Fourth, the direct medical component values GKV reimbursement rather than the underlying economic resource costs, and case-specific additional hospital payments may not be fully captured in the aggregate InEK data.

The model was intentionally restricted to notified, reference-defined acute HEV disease in adults. Chronic or persistent infection follows a distinct management pathway and, although rare, may be costly in immunosuppressed patients [3]. Pediatric cases, unrecognized infections, informal care, patient travel costs, out-of-pocket expenditure, and unpaid work were not included. These omissions tend to lower the modeled total, whereas the base-case hospitalization assumption may increase it relative to the InEK structural scenario; the net direction of overall bias is therefore uncertain. The €25.06 million estimate should accordingly be interpreted as the model-implied cost associated with the 5215 notified adult reference-defined cases under the 2026 reimbursement levels, not as the total economic burden of HEV in Germany.

5. Conclusions

Notified, reference-defined acute hepatitis E in German adults is associated with substantial reimbursement-based healthcare expenditure and productivity loss. Under the base case, the modeled societal cost was €4804.98 per adult case and €6651.80 in the employed-adult scenario; applying the base case to 5215 notified adult cases yielded €25.06 million in model-implied annual costs. Hospitalization is the principal driver of direct medical expenditure, while productivity loss is a major component of the modeled societal cost.