**Background**
Neglected tropical diseases (NTDs) are a diverse group of infections that disproportionately affect the world's poorest populations, causing both reversible and irreversible health outcomes. For many NTDs, morbidity arises not from a single infection but from cumulative exposure over years or decades, drawing parallels with non-communicable diseases like smoking and lung cancer. This temporal disconnect between infection and severe sequelae, combined with heterogeneities in host exposure and response, presents significant challenges for mathematical models that aim to project future morbidity burden. As global efforts push toward WHO 2030 elimination targets, understanding how morbidity risk changes after interventions is critical for policy and resource allocation.
**Methods**
The authors present a perspective that reviews existing modelling frameworks and proposes a simplified epidemiological framework for macroparasites. The framework tracks mean worm burden M(a,t) as a function of host age a and time t, incorporating a force of infection Λ(a,t) and worm mortality μ. Heterogeneity in exposure is introduced via a gamma-distributed individual susceptibility term s_i with shape parameter k, leading to a negative binomial distribution of worm burden. Cumulative worm burden w_i(a) is integrated over age, and morbidity probability is modeled as a logistic function of cumulative damage D_i(a), which may either resolve at rate γ or persist. The authors also discuss ecological dose-response curves that relate community-level infection prevalence to morbidity prevalence, using a modified logistic expression. Case studies of trachoma, schistosomiasis, and foodborne trematodes (Opisthorchis viverrini and Clonorchis sinensis) are used to illustrate data needs and modelling gaps.
**Key Results**
- For trachoma, age-specific prevalence of trachomatous scarring (TS), trichiasis (TT), and corneal opacity (CO) increases with age, supporting a cumulative exposure model. The WHO elimination threshold for active trachoma is <5% TF in children aged 1–9 years, but TT can persist for decades after this target is met. The authors note that the number of lifetime infections required for TS (100) and TT (150) has been assumed in prior models, but individual heterogeneity in immune response and genetic factors is poorly characterized.
- For schistosomiasis, WHO defines morbidity control as <5% prevalence of heavy-intensity infections (PHI) and elimination as a public health problem (EPHP) as <1% PHI. However, recent analyses show that light infections also cause significant morbidity, and post-intervention, morbidities associated with lower-intensity infections may become proportionally more important. The authors highlight that thresholds do not correspond to interruption of transmission, and there may be no safe level of exposure.
- For foodborne trematodes, O. viverrini and C. sinensis are classified as Group 1 carcinogens by IARC. A cohort study in Thailand found that of 3359 egg-positive individuals, 785 (23%) had severe periductal fibrosis and 4 (0.1%) had a biliary mass at baseline; over 5 years, 5 additional individuals developed a liver mass, giving an incidence of approximately 1 case per 420 person-years. For C. sinensis in Guangdong, China, 92 of 259 egg-positive individuals (36%) had at least one sequela. The authors note that elevated mortality from cholangiocarcinoma in heavily infected individuals likely contributes to lower mean worm burdens in older age groups.
- The authors present a general agent-based model output showing that 20 years after interruption of transmission, cumulative exposure is shifted to older age groups, and incident cases of morbidity may continue for years due to historical exposure. The time to achieve control (e.g., 5 vs. 7 years of MDA) directly affects cumulative burden, as illustrated by a resurgence model.
**Clinical Implications**
The paper underscores that for NTDs with long-term morbidity, reaching infection-based elimination targets does not guarantee the end of disease burden. Post-control, incident cases of chronic pathology (e.g., TT, periportal fibrosis, cholangiocarcinoma) may continue for decades, concentrated in older populations with high historical exposure. Mathematical models that track cumulative exposure and individual heterogeneity can help identify which communities will need ongoing morbidity management (e.g., surgery for TT, screening for cholangiocarcinoma) and for how long. The authors call for better characterization of dose-response relationships, incorporation of host-specific factors (immune response, genetics, co-morbidities), and use of DALYs or QALYs to weight different sequelae. They also highlight the need for cohort studies and genomic data to parameterize models, particularly for trachoma and foodborne trematodes, where data gaps are largest.