The Economic Impact of Loss to Follow-Up in Eosinophilic Esophagitis: A Model-Based Analysis from the Perspective of Italian National Health Service

Abstract

Purpose

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease requiring long-term management. Loss to follow-up (LTFU) is a significant issue, leading to increased complications and higher healthcare costs. One key factor contributing to LTFU is the lack of structured transition models for patients moving from pediatric to adult care. This study provides the first model-based economic evaluation of LTFU in EoE within the Italian National Healthcare Service (NHS) and aims to quantify the economic impact of LTFU as well as evaluate the potential cost reduction associated with implementing a structured transition model.

Patients and Methods

A health economic model was developed to assess the financial burden of LTFU in EoE from the perspective of the Italian NHS. The model incorporated epidemiological, clinical, and economic inputs, estimating, within a time-horizon of one year, the economic burden of LTFU and the cost differential between patients with continuous care and those experiencing a care gap (≥2 years). The analysis included costs related to emergency department (ED) visits, hospitalizations, pharmacological treatments, and outpatient services. All costs were reported in 2024 euros. Additionally, a simulation was conducted to evaluate the potential economic benefits of a structured transition model.

Results

The total economic burden of LTFU in EoE was estimated at € 84.9 million, with an average cost per patient of € 15,468, nearly double the cost of patients receiving continuous care (€ 7,744). The primary cost drivers were hospitalizations (69%) and pharmacological treatments (30%). The introduction of a transition model reducing LTFU by 30% could result in a € 25.4 million cost reduction, primarily through decreased hospital admissions and optimized treatment strategies.

Conclusion

LTFU in EoE is associated with a significant economic burden. Implementing a structured transition model could improve patient retention, enhance adherence to treatment, and generate important cost savings.

Introduction

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease driven by type 2 immunity, characterized by esophageal dysfunction and eosinophilic infiltration of the esophageal tissue.^1,2 The prevalence of this condition, which affects both adults and children, has been increasing due to greater awareness, improved diagnostic sensitivity, and an actual rise in cases.²

In Italy, the prevalence of EoE among adults and adolescents is estimated at approximately 41 cases per 100,000 individuals, with a higher incidence in males.¹ Regarding the pediatric population, around 1,809 cases have been reported, though only half of these patients receive a correct diagnosis.³ These epidemiological data highlight the growing burden of EoE and the need for timely and accurate diagnosis to ensure appropriate disease management.

However, diagnosing EoE can be particularly challenging due to its highly variable clinical presentation across different age groups. In adults, the primary symptoms include dysphagia and food bolus impaction, whereas in children, symptoms tend to be non-specific and age-dependent, ranging from reflux-like manifestations and growth delay to dyspepsia, nausea, and vomiting. The non-specific nature of these symptoms, especially in pediatric patients, often contributes to delayed or missed diagnoses.^2,4–6

Further complicating the diagnostic process, individuals with EoE frequently adopt adaptive eating behaviors – such as chewing food thoroughly, avoiding solid foods, and drinking frequently during meals – to manage their symptoms. While these behaviors may temporarily alleviate discomfort, they can mask the severity of the disease and further delay appropriate medical intervention.⁷

Beyond its clinical challenges, EoE imposes a significant economic and social burden on both patients and healthcare services. A recent study by Fortunato et al (2024)⁸ assessed the impact of EoE in Italy from both the National Healthcare Service (NHS) and societal perspectives. The findings revealed a relevant economic impact, with an estimated annual cost of € 6,825 per patient, of which 60.73% was attributed to direct medical expenses and 29.68% to indirect costs. These data underscore the importance of efficient disease management strategies to mitigate the financial strain on healthcare resources and improve patient outcomes.

Given its chronic nature, EoE requires a structured and multidisciplinary approach to diagnosis and long-term management. Current clinical guidelines emphasize the importance of continuous treatment and systematic follow-up to monitor therapeutic efficacy and disease progression.^4,9 Indeed, it has been shown that EoE patients not achieving a period of histologic disease control have an increased risk of developing strictures.¹⁰ However, ensuring long-term care continuity can be particularly complex for patients diagnosed in childhood, as they must transition from a pediatric-centered to an adult-centered healthcare service.⁴

This transition represents a critical phase in disease management, during which gaps in care may arise. The lack of a well-structured transition process can lead to impaired communication between healthcare professionals, unnecessary repetition of costly diagnostic tests, and – most critically – loss to follow-up (LTFU), which can negatively impact on the disease control.¹¹ Latest guidelines from ESPGHAN emphasized this aspect by adding a recommendation to address transition of care in pediatric patients with EoE.⁴

LTFU is a well-documented issue in EoE, with a recent study by Chang et al (2022) estimating approximately 26% of patients having this condition.¹² Disruptions in follow-up care can lead to symptom worsening and disease progression, increasing the risk of severe complications such as esophageal food impaction (EFI), esophageal remodeling, and stenosis,¹² with each additional year of gap time increasing the odds of stricture by 26%.¹³ Despite these known clinical risks, the economic burden of LTFU remains unexplored.

To address this gap, this study aims to analyze the economic impact of care discontinuity in patients with EoE by assessing the additional healthcare costs incurred due to LTFU.

Materials and Methods

Model Framework

This study employs a health economic model, created in the environment of MS Excel, to estimate the financial impact of LTFU in patients with EoE from the NHS perspective.

The model follows patients experiencing a care gap and quantifies the resulting economic burden related to disease progression, increased complications, and higher healthcare resource utilization.

Secondary, the model compares the average economic burden differential between an EoE patient experiencing a gap in care and a patient without a gap in care, who receives regular follow-up and disease management.

Finally, it evaluates the opportunity to reduce the economic burden of LTFU through the implementation of a transition model.

A time horizon of one year was considered for the analysis.

Model Assumptions

The economic model is based on the following key assumptions.

• A care gap is defined as ≥2 years without specialist follow-up or active treatment, based on literature evidence.¹²

• Patients experiencing a care gap have an increased risk of disease progression, including stricture formation, food impaction, and symptom worsening.^12,14–18

• The estimate of the proportion of patients experiencing loss to follow-up was derived epidemiological studies,^12,14–18 and subsequently validated by Italian gastroenterologists with expertise in both pediatric and adult EoE care to ensure applicability to the Italian healthcare context.

• Healthcare resource utilization (eg, emergency department visits, hospitalizations, diagnostic tests, pharmacological treatments) is higher in LTFU patients compared to those receiving continuous care.¹² Importantly, the model does not assume that patients experiencing a care gap have higher continuous healthcare utilization. Instead, routine follow-up and maintenance treatment decrease during the gap period. However, when such patients re-enter the healthcare system, this typically occurs in the context of acute symptom exacerbation or complications, which require higher-intensity and higher-cost interventions (eg, emergency endoscopy, dilation procedures, treatment re-initiation). Therefore, the higher annual cost estimate reflects the episodic concentration of high-cost events, rather than ongoing utilization.

• Cost estimates are sourced from literature, national reimbursement tariffs, and expert panel evaluations, with adjustment for 2024 inflation.¹⁹

• To estimate the potential effect of the introduction of a transitional model, it was assumed that the proportion (rate) of patients lost to follow-up (LTFU) would be reduced by 30%. This assumption is based on evidence from chronic disease requiring long-term care continuity. Studies on conditions like inflammatory bowel disease and type 1 diabetes have shown that structured transition programs can reduce LTFU rates by 20–50%, improving adherence and lowering complication risks.^20–22 Additionally, improved continuity of care has been linked to fewer emergency visits and hospitalizations, key cost drivers in EoE management. Expert validation further supports this estimate as a reasonable assumption based on clinical experience and existing benchmarks.

• The effect of the transition model was parameterized on the causal reduction in the LTFU rate. Specifically, we applied the assumed relative reduction (30% in the base case) to the baseline LTFU prevalence to obtain a new number of patients classified as LTFU. All cost outcomes were then re-computed using the same per-patient cost estimates so that the estimated cost savings reflect the direct mechanical consequence of a lower number of patients experiencing a care gap. Sensitivity analysis explored alternative effectiveness values (15–50%).^20–22

Model Inputs

The model incorporates epidemiological, clinical, and economic inputs, sourced from national databases, peer-reviewed studies, and experts’ opinion.

Expert input was obtained through a structured consensus process involving two gastroenterologists (pediatric and adult) and one health economist. Each expert independently reviewed the preliminary model inputs derived from the literature, followed by two iterative consensus rounds to refine and validate the clinical and epidemiological parameters. No formal Delphi procedure was performed; however, agreement was reached through documented discussion and convergence of estimates across experts.

Epidemiological Inputs

Two main epidemiological inputs were considered: i. prevalence of EoE in the Italian population; ii. percentage of diagnosed and treated patients.

To estimate the patient population affected by EoE and its management, a patient-based model was implemented to estimate the number of individuals with EoE in Italy, as reported by Efthimiou O et al (2024).²³ This approach progressively narrows down the total population to identify subgroups of patients at different stages of the diagnostic and treatment pathway. The funnel model was built using epidemiological data from ISTAT (2024),²⁴ Fortunato et al (2024),⁸ and expert-based assumptions. This methodology allows for a structured and transparent representation of the EoE population, facilitating a better understanding of the disease burden and treatment landscape. It serves as a foundation for the subsequent economic modeling, ensuring that cost estimates are grounded in a realistic population framework.

Epidemiological inputs according to the Patient Funnel methodology are reported in Table 1.

Table 1.

Patient Selection Funnel

Sections	Selection Criteria	Patients	Percentage	Notes	Source
A	General population	58,989,749		Includes population 16+ and 18+ (5% of total)	[24]
B	EoE estimated prevalence	58,990	0.10%	Based on epidemiological estimates	[8]
C	Diagnosed EoE patients	24,186	41%	Patients with confirmed diagnosis	[8]
D	EoE patients receiving treatment	23,460	97%	Percentage of diagnosed patients undergoing treatment	[8]

Abbreviations: EoE: Eosinophilic Esophagitis.

Clinical Inputs

To estimate the clinical impact of LTFU in patients with EoE, a targeted literature review was conducted, followed by validation from expert opinion. The objective was to identify the key complications associated with a prolonged gap in care and refine their estimated occurrence rates based on real-world clinical experience.

A care gap was defined as ≥2 years without medical contact for EoE, following the definition provided by scholars.^12,14–18 According to those studies, 26% of EoE patients experience LTFU, exposing them to a higher risk of disease progression and complications.

The main adverse events identified, along with their occurrence rates, are detailed in Table 2.

Table 2.

Adverse Events: Occurrence Rate from Literature and Expert Panel

Adverse Event	Occurrence Rate (Literature)	Validated Rate (Expert Panel)	Source
Esophageal food impaction	12%	12%	[12]
Esophageal remodeling (lumen narrowing)	48%	48%	[12]
Esophageal strictures	27%	30%	12(adjusted by experts)

EFI, esophageal remodeling, and esophageal strictures were identified as the main complications associated with prolonged LTFU. These events represent progressive disease manifestations and are associated with a higher need for emergency evaluation, endoscopic procedures, and treatment escalation. The corresponding occurrence rates were derived from literature and validated by clinical experts and were incorporated into the economic model to quantify the additional healthcare costs associated with LTFU.

Economic Inputs

The economic model quantifies the direct healthcare costs associated with LTFU in EoE patients. Three economic inputs were considered: i. costs for Emergency Department (ED) visits without hospitalization; ii. costs related to complications (EFI, Esophageal remodeling, Esophageal strictures); iii. costs of resuming treatment after a care gap, including diagnostic reassessments and therapy restart.

Costs for ED Admissions Without Hospitalization

Patients with EoE who experience a gap in care often face worsening symptoms and an increased risk of acute complications, leading to a greater reliance on emergency healthcare services. One of the most frequent consequences of inadequate disease management is EFI, which can cause severe dysphagia, retrosternal pain, and, in some cases, complete obstruction of the esophagus. These acute episodes often prompt patients to seek urgent medical attention in the ED. Although many EoE-related ED visits result in symptom relief through pharmacological intervention or spontaneous resolution, a significant proportion of patients require endoscopic intervention to remove impacted food. However, not all cases lead to hospitalization. To estimate the economic burden associated with these events, the model assumes that:

• 20% of patients experiencing a gap in care will require ED admissions due to uncontrolled symptoms or complications. This percentage was derived from scientific literature²⁵ and adjusted by experts for the Italian clinical practice.

• according to expert opinion, each affected patient will visit the ED on average three times per year for symptom management.

• for the unit cost of an ED admission, a proxy derived from “Progetto Mattoni SSN”²⁶ and applied by scientific literature²⁷ was considered and adjusted for 2024 inflation rate.

Costs Related to Complications (EFI, Esophageal Remodeling, Esophageal Strictures)

To estimate the economic burden of complications arising from LTFU, a micro-costing approach was employed.^28,29 This methodology involves breaking down the patient care pathway into distinct cost-driving phases, assessing healthcare resource utilization at each stage, and quantifying the consumption of medical services.

The patient journey for adverse event management was divided into five key phases.

1. Diagnosis – Specialist consultations, laboratory tests, and diagnostic procedures to confirm disease status and assess complications.

2. Pre-Treatment Evaluation – Further assessments to define the most appropriate treatment strategy.

3. Treatment Phase – Initiation or adjustment of therapy, including pharmacological treatment and interventional procedures where necessary.

4. Follow-Up – Periodic monitoring to assess treatment efficacy and disease progression.

5. Management of Treatment-Related Complications – Additional interventions required for side effects or treatment failure.

For each phase, the model quantified healthcare resource consumption in terms of: i. outpatient services (specialist visits, diagnostic exams, monitoring tests); ii. hospitalizations (for severe complications such as esophageal food impaction or strictures requiring endoscopic dilation); iii. pharmacological treatments (proton pump inhibitors, topical corticosteroids, biologics).

The estimated utilization of healthcare resources per phase was based on published literature and expert panel input, ensuring real-world applicability.

The estimation of direct healthcare costs relied on the utilization of Italian national tariffs as detailed below.

Drugs: We referenced the transparency lists of the Italian Drug Agency (AIFA) and the Summaries of Product Characteristics (SmPC), respectively, to identify an average posology.^30,31 Ex-factory prices were considered.

Outpatient services (blood tests, outpatient consultations, specialist visits): we referred to the national outpatients’ tariffs (“Tariffario delle prestazioni di assistenza specialistica ambulatoriale”).³²

Hospitalizations: The national Diagnosis Related Group (DRG) tariffs were considered (“Tariffario delle prestazioni di assistenza ospedaliera per acuti – Sistema Diagnosis Related Group (DRG)”).³³

By applying micro-costing approach, a unit cost was assigned to each resource component based on national reimbursement tariffs and literature data. This method allows for a granular and precise assessment of the financial impact of adverse event management in LTFU patients, distinguishing between avoidable costs (due to lack of follow-up) and necessary expenditures in structured disease management. For a detailed economic analysis of the considered healthcare resources, see Supplementary Table 1.

Costs of Resuming Treatment After a Care Gap

For patients who have experienced a gap in care, the diagnostic re-evaluation pathway includes the procedures identified in Fortunato et al (2024).⁸ The analysis compared healthcare resource utilization between patients with uncontrolled EoE (after a period of LTFU) and those with controlled disease under regular follow-up.

Two macro cost items were considered: (i) visits and outpatients services (a detail is reported in Table 3) and (ii) pharmacological treatments. Esophageal manometry is not intended as part of routine follow-up, but is included exclusively within the diagnostic reassessment phase, as it may be performed in selected cases when patients return to care after ≥2 years with persistent or atypical symptoms and when differential diagnosis with esophageal motility disorders must be reconsidered. Its inclusion therefore reflects clinical re-evaluation needs, not standard monitoring practice.

Table 3.

Visits and Outpatients Services for Resuming Treatment After a Care Gap

Visits and Outpatient Services		Uncontrolled EoE (Annual Frequency)	Controlled EoE (Annual Frequency)	Unit Cost
Visits	General practitioner visits	2	2	€ 22.00
	Gastroenterologist visits (excluding visits for complications)	4	2	€ 16.20
	Dietitian visits	3	2	€ 22.00
	Total Annual Cost (Visits)	€ 174.80	€ 120.40
Laboratory	Blood tests (complete blood count, eosinophilic cationic protein)	5	2	€ 16.70
	Allergy testing	3	1	€ 71.18
	Total Annual Cost (Tests)	€ 297.04	€ 104.58
Imaging & Endoscopic Diagnostics	Endoscopy with biopsy	1	1	€ 14.10
	Manometry	2	1	€ 67.14
	Fibroscopy with swallowing test	2	1	€ 27.11
	Total Annual Cost (Imaging)	€ 202.60	€ 108.35

Abbreviation: EoE, Eosinophilic Esophagitis.

For patients resuming pharmacological treatment after a care gap, two treatment duration scenarios were considered (Table 4). Based on clinical expert validation, it was assumed that:

• 25% of patients require a full 12-month treatment course, as they restart long-term maintenance therapy after re-engagement.

• 75% of patients receive 10 months of treatment, since part of their therapeutic exposure is already included within the timeframe of adverse event management (eg, treatment administered during the management of EFI or strictures) and subsequent clinical reassessment.

Table 4.

Pharmacological Treatments for Resuming Treatment After a Care Gap

Therapy	Unit Cost (Annual)	Percentage	Uncontrolled EoE (12 Months, 25% of Patients)	Uncontrolled EoE (10 Months, 75% of Patients)	Controlled EoE (12 Months, 100% of Patients)
PPI monotherapy	€ 164.42	25%	€ 41.14	€ 34.28	€ 41.14
TCs monotherapy	€ 1,514.38	30%	€ 448.41	€ 373.68	€ 448.41
PPI + TCs combination therapy	€ 1,678.80	19%	€ 325.21	€ 271.01	€ 325.21
Biologic therapy	€ 33,280.00	26%	€ 8,652.80	€ 7,210.67	€ 8,652.80
Weighed Total			€ 2,366.89	€ 5,917.22	€ 9,467.56

Abbreviations: PPI, Proton Pump Inhibitors; TCs, Topical corticosteroids; EoE, Eosinophilic Esophagitis.

This distinction reflects real-world clinical practice, where treatment resumption does not always coincide with the beginning of the observation period, and where therapy duration may vary depending on the timing of re-entry into care and the clinical severity at presentation.

Model Structure and Analysis

Figure 1 returns a graphical representation of the model.

Figure 1.

Graphical representation of the model.

Notes: The model combines epidemiological inputs (number of diagnosed EoE patients and those experiencing a gap in care), clinical inputs (rate and type of complications associated with LTFU), and economic inputs (costs of emergency care, complication management, and treatment resumption). These inputs are used to quantify healthcare resource consumption across hospitalizations, pharmacological treatments, diagnostic procedures, and outpatient services. The model outputs include the total economic impact of LTFU in EoE, the cost difference between patients with and without a care gap, and the estimated cost reduction achievable through the implementation of a structured transition model.

A cohort-based static cost model with a one-year time horizon was developed. The total annual cost for patients experiencing LTFU was calculated as follows:

where:

• Incidence(i) represents the occurrence of each adverse event (EFI, esophageal remodeling, esophageal strictures),

• Cost(i) corresponds to the management cost per adverse event,

• Cost_ED represents the annual cost of ED visits not followed by hospitalization,

• Cost_Treatment Resumption captures the costs required to re-establish disease control and restart therapy.

The cost for patients receiving continuous care was defined as:

The incremental economic burden associated with a care gap was estimated as:

The total annual burden attributable to LTFU was then calculated as:

The economic impact of introducing a structured pediatric-to-adult transitional care model was estimated by applying a 30% reduction in the number of LTFU patients:

This approach allows estimation of the potential decrease in total costs if care continuity is improved.

Model Validation

The model underwent internal validation through expert review (three experts) to assess structural and face validity. Model outputs were compared with published economic estimates to verify plausibility. External validation against longitudinal real-world datasets was not feasible due to limited availability of Italian LTFU data.

Sensitivity Analysis

To assess the robustness of the model results, a one-way sensitivity analysis was conducted on the main input variables that influence the total economic burden associated with LTFU in EoE patients. This analysis tested the impact of variations in key assumptions on the model’s outputs, particularly the total cost burden and the estimated savings from implementing a structured transitional care model.

The following variables were examined:

• Prevalence of LTFU: varied from 20% to 35%, based on published data¹³ and clinical expert validation;

• Incidence of complications among LTFU patients: sensitivity ranges were applied to the rates of esophageal food impaction (10–15%), esophageal remodeling (40–55%), and esophageal strictures (25–35%);

• Unit cost of hospitalizations: adjusted by ±20% to reflect inter-regional and institutional cost variability.

• Annual average cost per patient with controlled EoE: varied from € 6,500 to € 9,000 to account for the use of ex-factory prices and potential pricing variability due to regional purchasing agreements. The lower bound (€ 6,500) reflects potential regional discounts and real-world prescribing variability, while the upper bound (€ 9,000) accounts for patients requiring more intensive follow-up or combination therapies, including biologics. According to the expert opinion, this range ±15% from base case, is consistent with the ±30% variation commonly observed in annual management costs for chronic conditions.

• Effectiveness of the transitional care model: the assumed reduction in LTFU was tested across a range from 15% to 50%,^20–22 based on data from structured transition programs in other chronic conditions.

All key model assumptions were included in the sensitivity analysis to ensure that the uncertainty surrounding epidemiological, clinical, cost, and transition-effectiveness parameters was reflected in the robustness testing.

Results

Economic Impact of LTFU in EoE Patients

The analysis quantifies the annual economic burden associated with LTFU in EoE patients, considering the costs of emergency care, complications, and treatment resumption. The total cost estimated for the 6,100 patients experiencing LTFU, calculated on the basis of the clinical and epidemiological inputs of the model, is € 84,915,324, corresponding to an average cost of € 15,468 per patient (Table 5).

Table 5.

Economic Burden Associated with LTFU in EoE Patients

	EFI (732 Patients)	Esophageal Remodeling (2928 Patients)	Esophageal Strictures (1830 Patients)	Total Costs (6100 Patients)	Cost per Patient	%
ED admissions	€ 107,431	€ 429,724	€ 268,578	€ 805,733	€ 147	1%
LTFU complications	€ 3,850,713	€ 39,931,083	€ 15,012,841	€ 58,794,637	€ 10,710	69%
Resuming EoE treatment	€ 3,375,327	€ 13,501,308	€ 8,438,318	€ 25,314,953	€ 4,611	30%
Total Costs	€ 7,333,471	€ 53,862,116	€ 23,719,736	€ 84,915,324	€ 15,468	100%

Abbreviations: ED, emergency department; LTFU, Loss To Follow-up; EoE, Eosinophilic Esophagitis; EFI, esophageal food impaction.

Emergency department visits represent the smallest portion of the total economic burden, amounting to € 805,733, which corresponds to 1% of the overall costs. These visits are largely attributable to acute episodes, where patients present with severe dysphagia, chest pain, and, in some cases, complete obstruction of the esophagus. Although many of these cases do not require hospitalization, the recurring need for emergency care reflects the impact of uncontrolled disease. On a per-patient basis, the cost of ED utilization is estimated at € 147, highlighting an avoidable expense that could be significantly reduced through structured disease management and timely intervention.

The management of complications resulting from LTFU represents a much more substantial financial burden, accounting for € 58,794,637 (69%) of total costs. Among these complications, esophageal remodeling emerges as the most significant cost driver, with a total expenditure of € 39,931,083. This is primarily due to the high prevalence of esophageal remodeling (2,928 patients), which necessitates long-term management and repeated medical interventions. Esophageal strictures, which develop in more advanced cases of disease progression, contribute an additional € 15,012,841 to the total economic burden, while EFI management alone results in € 3,850,713 in direct medical costs. These findings highlight the long-term economic consequences of untreated EoE, as fibrotic complications require repeated endoscopic interventions, pharmacological escalation, and, in severe cases, surgical procedures.

Finally, resuming EoE treatment after a period of LTFU represents 30% of the total burden, with a total of € 25,314,953. This category includes diagnostic reassessments, therapeutic interventions, and long-term disease monitoring required once patients return to medical care.

Cost Comparison Between Patients with and without a Gap in Care

The economic impact of LTFU in EoE patients was further assessed by comparing the annual per-patient costs between those who experienced a gap in care and those who remained under continuous management. The results highlight a relevant cost increase for patients with LTFU, with an average total cost per patient of € 15,448, compared to € 7,744 for patients who maintained continuous care. This represents an additional financial burden of € 7,724 per patient due to disease progression, increased resource utilization, and complications associated with the lack of timely treatment.

The most significant contributor to the increased costs in patients with a gap in care is hospitalizations, which amount to € 9,128 per patient and are entirely absent in continuously managed patients. Pharmacological treatment remains the largest cost driver in both patient groups, but with notable differences. Patients with LTFU incur an annual drug cost of € 4,168, compared to € 7,411 in those without a gap. This difference can be attributed to the fact that the model assumes that a 10-month time horizon for resumption of drug therapy was considered for 75% of patients assuming that the remaining two months are for complication management, short-term follow-up drug treatment and identification of the best drug treatment in terms of drug choice and dosage. Costs related to outpatient services and diagnostic procedures (including laboratory tests, imaging, endoscopic diagnostics and other outpatient services) are also significantly higher in patients with LTFU (€ 1,774 vs € 213). Other outpatient services refers to outpatient management of any complications such as EFI, esophageal remodeling and stenosis. Visits and ED admissions also contribute to the overall cost increase. Patients with LTFU incur € 251 in visit-related expenses compared to € 120 in continuously managed patients, reflecting a greater number of consultations needed after disease reactivation. Moreover, ED admissions account for € 147 per LTFU patient, whereas no such costs are observed in the continuously treated cohort (Figure 2).

Figure 2.

Cost comparison between patients with and without a gap in care.

Impact of a Transitional Model on Healthcare Costs

To evaluate the potential economic benefits of implementing a transitional care model for patients with EoE, a simulation was conducted assuming that such a model could reduce the proportion of patients LTFU by 30%. The results demonstrate that introducing a structured transition of care could lead to a substantial cost reduction, lowering the total healthcare expenditure from € 84,915,324 to € 59,440,727, resulting in overall reduced costs of € 25,474,597.

The primary cost reduction driver is the decrease in hospitalizations, which drop from € 50,109,484 in the standard care scenario to € 35,076,639 with a transitional model. This corresponds to a reduction of approximately € 15 million, emphasizing that improved continuity of care may prevent disease progression and complications requiring inpatient treatment. Another key area of cost reduction is pharmacological treatment, which drops from approximately € 23 million to € 16 million, generating a reduction in costs of over € 6.8 million. This likely reflects the avoidance of aggressive re-initiation therapies and high-cost treatments needed for patients who experience prolonged gaps in management. Spending on outpatient services, diagnostic procedures, and laboratory tests also declines, reflecting a more efficient use of healthcare resources through early intervention and optimized disease monitoring. Other outpatient service costs decrease from € 4,054,109 to € 2,837,876, representing an approximate € 1.2 million reduction. Furthermore, ED admissions decrease from € 805,733 to € 564,013, reinforcing the potential role of a transitional model in reducing acute exacerbations that require urgent medical attention (Figure 3).

Figure 3.

Economic impact after the introduction of a transition model.

Sensitivity Analysis

Table 6 summarizes the results of the one-way sensitivity analysis performed to test the robustness of the model against key input variations. Results showed that total economic burden estimates were most sensitive to changes in LTFU prevalence and hospitalization costs, with potential deviations ranging from approximately € 67.9 million to € 101.9 million. Variation in the effectiveness of the transition model and assumptions around esophageal complication rates also significantly influenced the outputs. Notably, adjusting the average cost of a controlled EoE patient within a plausible range (€6,500–9,000/year) produced only moderate changes in the overall burden, supporting the stability of the base case estimate.

Table 6.

One-Way Sensitivity Analysis

Variable	Base Case (€)	Lower Estimate (€)	Upper Estimate (€)
LTFU prevalence (20–35%)	84,915,324	67,932,259	96,652,487
Esophageal remodeling rate (40–55%)	84,915,324	79,669,558	90,161,150
Esophageal strictures rate (25–35%)	84,915,324	81,169,558	88,661,090
Hospitalization cost (±20%)	84,915,324	67,932,259	101,898,389
Controlled EoE patient cost (€6,500–9,000/year)	84,915,324	80,000,000	89,000,000
Transition model effectiveness (15–50%)	84,915,324	74,000,000	95,000,000

Abbreviations: LTFU, Loss to Follow-up; EoE, Eosinophilic Esophagitis.

Discussion

The results of this analysis highlight the significant impact of LTFU in patients with EoE, both in clinical and economic terms. Discontinuity of care is associated with an increased incidence of severe adverse events, including food impaction (12%), esophageal remodeling (48%), and esophageal strictures (30%), leading to substantial healthcare costs. The economic analysis demonstrated that patients with a treatment gap of ≥2 years generate almost double the costs compared to those who remain under regular monitoring (€ 15,468 vs € 7,744 per patient), with pharmacological treatment and hospitalizations being the primary cost drivers.

It should be noted that the primary estimate of LTFU prevalence used in this model originates from a U.S.-based study, conducted in a healthcare system structurally different from the Italian NHS. For this reason, the prevalence value was not adopted directly; instead, it was validated by Italian clinical experts to ensure alignment with local patterns of care discontinuity, particularly during the pediatric-to-adult care transition. Future access to European registry or claims data would further strengthen the robustness of these estimates.

Moreover, the selection of a one-year cohort-based static economic model aligns with the primary objective of the study, which was to estimate the annual incremental burden of LTFU and evaluate the potential benefit of introducing a transition model. While multi-year state-transition (Markov) models are conceptually suitable for chronic conditions, their implementation requires longitudinal evidence on disease progression and adherence trajectories that is currently limited in EoE. Developing such a model would introduce additional structural uncertainty. The chosen approach therefore ensures methodological transparency and reproducibility, while remaining expandable should longitudinal data become available.

The findings of this study align with and expand upon the estimates provided by Fortunato et al (2024)⁸ who reported substantial healthcare costs associated with EoE management. Our results specifically differentiate costs by care continuity status, showing that patients experiencing LTFU incur markedly higher healthcare utilization, including hospitalizations, emergency department visits, and pharmacological expenditures. In particular, the average per-patient cost of LTFU (€ 15,468) observed in this study is higher than the estimated annual cost of a well-managed EoE patient in Fortunato et al’s model (€ 6,852 which does not include cost of biological therapies),⁸ reinforcing the economic burden associated with treatment gaps. Notably, increased costs among LTFU patients are driven not by greater routine care use, which generally decreases, but rather by infrequent and high-cost complications such as emergency management of food impaction or endoscopic dilation for strictures, and from the resource-intensive process of re-establishing disease control. This pattern mirrors observations in other chronic inflammatory diseases in which interruption of therapy leads to delayed, complication-driven healthcare utilization.

The transition from pediatric to adult services is a particularly vulnerable stage, during which the risk of LTFU is high and disease progression more likely. Structured transition pathways involving multidisciplinary coordination may therefore play a decisive role in improving long-term disease control and reducing preventable complications. This is consistent with evidence from other chronic diseases in which transition models improve adherence and reduce healthcare costs.^34,35

The implementation of a structured transition model emerges as a potential strategy to mitigate this impact. The simulation, assuming a 30% reduction in LTFU patients, revealed total cost reduction of over € 25 million, lowering the total expenses from € 84.9 million to € 59.4 million. This effect is primarily attributable to a reduction in costly hospital-based interventions, highlighting the value of maintaining continuous clinical oversight. While supported by evidence from comparable chronic disease contexts,^34,35 the assumption that a structured transition model could lead to a 30% reduction in LTFU, implies a linear reduction in both patient numbers and cost burden. In practice, re-engaged patients will continue to generate ongoing care costs, likely approximating those of well-managed EoE patients. Therefore, the projected savings should be interpreted as directional estimates.

These findings may be generalizable beyond Italy, as the drivers of LTFU burden are common across healthcare systems where EoE management relies on long-term care continuity. The results also highlight an ethical concern, as patients lost to follow-up face disproportionate risk of preventable complications. Real-world implementation of transition models, however, may vary depending on local care organization and resource availability, which should be considered when interpreting the potential impact.

This analysis has some limitations that should be considered. First, the estimation of adverse event incidence is based on literature data and clinical validation, but it could benefit from prospective studies analyzing in greater detail the consequences of LTFU. Additionally, a systematic review of the literature was not conducted, which could have influenced the selection of sources and data representativeness.

From an economic standpoint, the micro-costing methodology enabled a detailed assessment of the resources consumed in EoE management, but some cost variables may vary based on specific healthcare settings or future tariff updates. Moreover, the cost analysis was based on ex-factory prices, which do not account for potential discounts, reimbursement agreements, or real-world pricing variations across different healthcare settings.

An additional key limitation lies in the assumption that the introduction of a transitional care model could lead to a 30% reduction in loss to follow-up (LTFU). While this figure is supported by evidence from other chronic diseases and appears clinically plausible, the model assumes a linear reduction in both the number of patients lost and their associated costs. In reality, patients who are retained in care through a transitional model do not eliminate their economic impact on the healthcare system. Rather, their burden is expected to shift toward the average annual cost associated with controlled EoE, estimated at €7,744 per patient. This simplification may underestimate the complexity of individual patient trajectories and healthcare resource utilization, warranting cautious interpretation of the projected minor costs.

Finally, the validation of the study was conducted with only three experts, which, although providing relevant insights, represents a relatively small sample size for consensus validation.

A sensitivity analysis was conducted to partially address these uncertainties. A probabilistic sensitivity analysis was not performed because several parameters relied on expert validation, and empirical distributional data were not available to support the assignment of probability distributions. Future research using real-world longitudinal or registry data could enable a probabilistic analysis to quantify overall joint parameter uncertainty.

Despite these limitations, the findings provide strong indications of the importance of continuous therapeutic management in EoE and the need for structured interventions to prevent patient LTFU. Future research could explore innovative organizational models, such as the implementation of structured transitional models to further optimize disease management, especially in the critical phase of transition from pediatric to adult care.

Conclusions

This analysis highlights the significant economic impact of LTFU in EoE and underscores the value of implementing a structured transitional care model. By addressing discontinuity of care, such models may reduce preventable complications and associated high-cost healthcare utilization.

The findings may be generalizable beyond Italy, as the drivers of LTFU burden are common across healthcare systems where EoE management relies on long-term care continuity. However, variations in organizational structures and resource allocation across settings should be acknowledged when considering broader implementation. The results also highlight an ethical concern, as patients lost to follow-up face an elevated and avoidable risk of disease progression and complication-related morbidity.

Ensuring continuity of care can prevent disease progression, reduce the need for costly interventions, and ultimately alleviate the burden on healthcare services. Structured transitional pathways, integrated care coordination, and proactive monitoring interventions represent promising strategies to support long-term disease control and reduce healthcare resource use, reinforcing the importance of sustained engagement throughout the care pathway.

Funding Statement

The authors declare that financial support for the research and publication of this article was provided by Sanofi & Regeneron. Medical writing support was provided by PharmaLex Italy S.p.A. (Marzia Bonfanti) and was funded by Sanofi & Regeneron.

Ethics Approval and Consent to Participate

This study did not involve the collection, analysis, or use of individual-level patient data. All clinical and epidemiological inputs were derived from published literature and validated through consultation with clinical experts. No identifiable human data, biological materials, or interventions involving human participants were used. This is not an interventional study. As such, ethical approval and informed consent were not required, in accordance with the principles outlined in the Declaration of Helsinki.

Disclosure

The experts received no payment related to the authorship of this manuscript. Sanofi reviewed the manuscript and provided non-binding editorial suggestions. The authors retained full editorial control and made the final decision to submit the manuscript. MB is a consultant of PharmaLex Italy S.p.A. and has no conflicts of interest in this research. MF is a consultant of PharmaLex Italy S.p.A. and has no conflicts of interest in this research. MM is a consultant of PharmaLex Italy S.p.A. and has no conflicts of interest in this research. SO received consulting fees from Sanofi, Alfasigma, Medtronic, and Bristol Myers Squibb. Received consulting fees for analysis, conduction, and/or participation in Advisory Boards and/or Conferences from Sanofi. EVS has served as speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, Mayoly Biohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, Unifarco; has served as consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Takeda, Unifarco; he received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, Zeta Farmaceutici. JPS is Sanofi employee and may hold shares and/or stock options in the company. EC received PhD grant co-funded by Sanofi. AT is Sanofi employee and may hold shares and/or stock options in the company. UR received fees for advisory board participation by PharmaLex Italy S.p.A. The authors report no other conflicts of interest in this work.