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Infectious diseases have been linked with the development of attention deficit hyperactivity disorder (ADHD), the most common neurobiological disorder in childhood. While most kids recover from fever without ever experiencing adverse neurodevelopmental effects, the long-term impact of common infectious processes during infancy and early childhood has yet to be explored.¹

With this in mind, investigators based in New York and Israel asked whether febrile episodes in the first 4 years of life鈥攐ne of the most frequent reasons for visits to a pediatrician鈥攁re connected to ADHD, examining the association between the severity and frequency of fever and a subsequent ADHD diagnosis.¹

This observational, population-based, case-control study drew information from the database of a large Israeli health maintenance organization (HMO), Leumit Health Services (LHS), with regard to patients ages 5 to 18 who were enrolled with LHS between 2002 and 2022.¹ The authors identified a total of 204,871 children. In a 1:2 ratio, 18,558 pediatric patients with ADHD were matched with a control group of 37,116 children who were not diagnosed with ADHD.

Are febrile episodes linked to ADHD?

The authors identified a robust independent association between the number and magnitude of febrile episodes during early childhood and the probability of developing ADHD.¹ In general, the ADHD group experienced many more fevers than controls (P<.001 for each of the thresholds: 37.5 掳C, 38 掳C, 38.5 掳C, and 39 掳C). In particular, fever >39.5 掳C鈥攚hich is equivalent to 103.1 掳F鈥攆or 鈮�3 days was linked with a more than 2 times risk of future ADHD (odds ratio [OR] 2.135, 95% confidence interval [CI] 1.256 to 3.639; P=.0029).

Conversely, children who never had a temperature of >37.5 掳C (99.5 掳F) were much less likely to be diagnosed with ADHD in later years (OR 0.834, 95% CI 0.802 to 0.866; P<.0001), and those with no fever at all developed ADHD at a much lower rate (all ORs <1). Considering this significant dose-response relationship, the authors theorized that elevated body temperature and frequency of fever during early childhood has the potential to interfere with brain development and lead to ADHD. 

Despite several interesting findings, many questions remain

The authors note that since the phase of life at the center of this study鈥攆rom birth through age 4鈥攊s marked by postnatal brain development, stress on the central nervous system during this critical period may lead to adverse neurobehavioral outcomes. Whether this disruption in brain maturation is the result of the infectious agent itself, or an indirect result of systemic inflammation, requires more prospective study.

Fever, the authors point out, is a proxy for the inflammatory processes mounted against infection. They also note that, while febrile episodes in children usually have infectious causes, immune dysregulation and allergies may be the culprit of inflammation in some cases. Considering that ADHD is highly heritable, it鈥檚 plausible that immune predispositions may spark an interaction between the nervous and immune systems to cause such disorders.

Limitations and conclusions

There were a few limitations to this study, among them its observational nature, which doesn鈥檛 allow it to establish causality, only possible associations. Also, because patients were from a single HMO in Israel, the findings may not be generalizable to pediatric populations in other countries. And, as the authors stated, concerned parents may have taken their child鈥檚 temperature numerous times on their own. 鈥淭here is a possibility,鈥� they wrote, 鈥渢hat the fever was measured outside of the clinic and was not recorded in the electronic medical file, which would have impacted the number of recorded febrile episodes.鈥�¹

However, the results of this study align with prior research, which has highlighted theories of a direct connection between neuroinflammation and disorders like ADHD. In fact, the authors completed a prior study in which children who developed shigellosis during the first 3 years of life went on to have ADHD at significantly higher rates, possibly caused by prostaglandins.² They also cited a nationwide study of the pediatric population in Denmark which revealed a link between both bacterial and viral infections and an increased risk for numerous neurodevelopmental disorders.³

鈥淧hysicians should be aware of these associations,鈥� the authors concluded. 鈥淎lthough speculative, repeated exposures to febrile episodes may contribute, in a dose-dependent manner, to a disruption in neurodevelopmental pathways implicated in the emergence of ADHD.鈥�¹

Published: May 01, 2024