Rethinking early-life pathogen exposure: Lessons from a natural experiment controlling hookworms

While technology and improved medical care have rapidly improved outcomes for many types of diseases, there has been an increase in a variety of chronic inflammatory disorders such as asthma, inflammatory bowel disease, and even multiple sclerosis. One frequently mentioned explanation for this rising incidence of inflammatory diseases is the “hygiene hypothesis” or “old friends hypothesis.” These hypotheses suggest that early-life pathogen exposure may have beneficial health impacts later in life, as exposure from these pathogens may challenge the developing immune system and help it function optimally (1). One class of organisms central to this hypothesis is parasitic intestinal worms that live in human digestive tracts (2).

In this issue, Lawton leverages variation in the timing of hookworm eradication efforts across different regions and birth cohorts in the United States to provide compelling causal evidence against this commonly accepted hypothesis (3). In addition to finding immune benefits to deworming campaigns—reduced biomarkers for inflammation and skin-tested allergies—, Lawton also finds notable gains in lifespan as a result of deworming, with the average dewormed individual living 2.5 additional months. Lawton’s work provides compelling evidence that one of the potential major tradeoffs in deworming campaigns may not be as strong a tradeoff as originally thought: Deworming children may improve health not only in the short term but also in the long term on a number of important measures.

What makes this study particularly compelling is its sophisticated approach to identifying the causal relationship between deworming and long-term health at scale despite the fact that the treatment was not formally randomized. Natural experiments are notoriously challenging because the “treatment” assignment—in this case, exposure to hookworm eradication programs—is rarely truly random. The primary concern is that the deworming program rollout might correlate with other unobserved factors that independently affect health outcomes, such as improvements in sanitation, nutrition, or healthcare access. In other words, in natural experiments, it can be difficult to determine whether the observed differences between those who are treated and those who are not are driven by the treatment or some other unobserved confounder.

Lawton alleviates these concerns by combining two “as good as random” sources of variation within a campaign to eradicate hookworm across 11 states in the southeastern United States in the early 20th century, making the children studied as similar as possible except for whether they were rid of hookworms. The first source of variation is location: While a large area was all treated for hookworm, the initial prevalence of the disease varied markedly across fairly small distances, both within and across states, due to differences such as soil type. Put another way, he can compare kids who were likely to be infected to those who were not likely to be infected, but were born at the same time and geographically close to each other. Because treatment was widespread, the infected children were cured while the uninfected children serve as a “control group.” Second, he uses variation in the timing of the rollout. For example, imagine two children in a family born 5 y apart. The campaign arrives just as the second child is born. The two children are very similar, with one key difference: The younger child has five fewer years of exposure to hookworm. Lawton combines this time and place based variation into a single analysis in which the treatment is baseline prevalence of hookworm multiplied by years of exposure, allowing him to isolate the effect of the eradication campaign by leveraging small—likely random—differences in place and time while controlling for other factors that could influence hookworm exposure (i.e., the year and geographic area within a state in which a child was born). Consistent with the causal interpretation and the fact that worms primarily infect children (4), the positive effects of deworming increase with each additional year of exposure up to about 10 y.

Beyond this compelling initial approach, Lawton uses placebo tests and extensive robustness checks to further strengthen the evidence. The placebo tests are particularly valuable—if the observed effects were driven by confounding factors rather than deworming per se, we would expect to see similar patterns for other health outcomes unrelated to the hygiene hypothesis such as cholesterol levels. Yet, these outcomes show no changes for those who benefited from the deworming.

These findings represent a notable challenge to the hygiene hypothesis, at least as it applies to helminth infections and impacts on inflammation and allergies. The large-scale evidence on this relationship is particularly valuable as the biological rationale for this hypothesis is quite plausible: helminths like hookworm have coevolved with humans over millennia, developing sophisticated mechanisms to modulate host immune responses. Immunological models suggested that moderate early-life exposure might help train the immune system to maintain appropriate regulatory responses, protecting against excessive inflammation throughout life (5). These models are supported by a large number of animal studies and short-term associations in humans (6–8).

Nonetheless, Lawton’s empirical evidence over the long term tells a different story. Rather than finding that early deworming leads to increased inflammatory diseases—as the hygiene hypothesis would predict—the study demonstrates clear benefits in inflammation markers and allergies from pathogen elimination as well as gains in lifespan.

Lawton’s work provides compelling evidence that one of the potential major tradeoffs in deworming campaigns may not be as strong tradeoff as originally thought: deworming children may improve health not only in the short term but also in the long term on a number of important measures.

Though they require careful interpretation, these findings have implications for global health policy. Worms are incredibly common in the global south—nearly 2 billion people, most of whom are children, are infected globally (9). The immediate benefits of treating heavy helminth infections—improved nutrition, reduced anemia, and higher school attendance—with corresponding improved labor market outcomes later in life—are well established and substantial (10–13). This research suggests that any potential tradeoffs around negative long-term health effects driven by inflammation are less serious than previously thought: in fact, there may be both short and long-term health benefits. The study also highlights the importance of taking a life-course perspective on infectious disease interventions. Many cost-effectiveness analyses focus primarily on short-term outcomes, potentially missing crucial long-term benefits. Incorporating these longer-term effects could substantially strengthen the case for preventive interventions that appear marginally cost-effective based on immediate outcomes alone.

However, caution is warranted in overgeneralizing from these findings as there may be other outcomes unstudied by Lawton such as diabetes or multiple sclerosis where the hygiene hypothesis is borne out. Similarly, results may be pathogen specific such that other types of early-life infections could have long-term benefits. In addition, the study examines a specific historical context—hookworm eradication in early 20th century populations. Extrapolating these findings to contemporary settings requires caution as nutritional status, healthcare access, coinfection patterns, and other relevant factors have changed substantially.

The findings also open several important avenues for future research. First, investigating which specific aspects of hookworm infection drive the long-term health costs could help identify mechanisms and potential interventions. Is it chronic anemia, nutritional malabsorption, inflammatory response, or some combination of factors?

Second, exploring whether similar patterns hold for other helminth species or other types of infections would help determine the generalizability of these findings. Different infections have varying effects on host physiology, and some may indeed provide net benefits despite their costs.

Third, examining heterogeneity in responses across different populations and nutritional contexts could reveal important moderating factors. The costs of helminth infection may be particularly severe in populations that are already nutritionally stressed, while potentially being more tolerable in well-nourished populations.

In short, this study provides compelling evidence that challenges a key prediction of the hygiene hypothesis, at least as applied to hookworm infections and outcomes such as allergies. Rather than finding that early-life deworming leads to adverse long-term health consequences, Lawton demonstrates clear and substantial benefits from hookworm elimination during childhood, adding further evidence in favor of global deworming programs.

Beyond the specific findings of this work, the research demonstrates the power of quasi-experimental approaches for addressing questions that cannot be tackled through randomized trials. The combination of natural variation in policy implementation with sophisticated econometric techniques provides a template for examining other difficult-to-study public health questions where randomization would be impractical (e.g., very long time horizons) or unethical.