Specific immune system proteins may help forecast mental health symptoms in children living with chronic physical illnesses, according to new research published in Brain and Behavior. The study found that certain inflammation-related biomarkers were linked to increased or decreased risk of emotional and behavioral difficulties. While the findings do not confirm a direct causal link, they suggest that immune system activity may play an important role in shaping mental health outcomes for children managing long-term medical conditions.
The rationale for the study stems from growing recognition that children with chronic physical illnesses are more likely to experience mental health challenges than their healthy peers. Past research has repeatedly found elevated rates of depression, anxiety, and behavioral disorders among children diagnosed with conditions such as asthma, diabetes, and juvenile arthritis. Despite this, scientists still do not fully understand why physical and mental health tend to intersect so frequently during childhood.
One hypothesis that has gained attention points to inflammation—a biological process where the immune system activates in response to illness or injury. In recent years, researchers have begun exploring how persistent inflammation might not only contribute to physical symptoms but also affect mood, behavior, and cognition. While this line of inquiry is expanding in adult populations, there has been little longitudinal research on how immune system changes relate to mental health over time in children, especially those already coping with chronic physical illness.
“Evidence shows that children with chronic physical illnesses such as asthma, diabetes, and epilepsy are at increased risk for developing co-occurring mental illness, but the mechanisms that link childhood physical and mental illness remain unconfirmed,” said study author Mark Ferro, Canada Research Chair in Youth Mental Health and associate professor at the University of Waterloo.
“While some work has shown that physical and mental illnesses share immunological or inflammatory responses, no studies have examined longitudinal associations between inflammatory biomarkers and symptoms of mental illness in children with physical illness over a four-year period.”
To address this gap, the research team analyzed data from the MY LIFE study, a long-term project tracking children with various chronic illnesses in Ontario, Canada. The MY LIFE cohort includes children between the ages of 2 and 16 who have been diagnosed by healthcare professionals with a chronic physical condition. For this particular investigation, the researchers focused on a subset of 128 children who provided dried blood samples at the start of the study and completed psychological assessments over a 48-month period.
The average age of participants at enrollment was 11 years, and the sample was evenly split between boys and girls. These children were living with a variety of physical illnesses, including respiratory, neurological, endocrine, and rheumatological conditions.
To measure mental health symptoms, both parents and children completed the Emotional Behavioural Scales, a standardized tool that assesses internalizing problems (such as anxiety or sadness), externalizing problems (such as aggression or rule-breaking), and total psychological symptoms. These assessments were repeated at five time points: baseline, 6 months, 12 months, 24 months, and 48 months.
At the start of the study, blood samples were analyzed for a range of immune-related proteins called cytokines and growth factors, which are known to influence inflammation. The researchers used a panel capable of detecting 17 different biomarkers, although not all were present in large enough quantities for analysis. Three biomarkers emerged as especially relevant to mental health outcomes over time: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-6 (IL-6).
Higher levels of G-CSF were linked to more internalizing symptoms, as reported by parents. In other words, children with elevated G-CSF at baseline were more likely to exhibit anxiety-like behaviors or emotional distress during follow-ups. GM-CSF was associated with an even broader range of difficulties.
Children with higher GM-CSF levels had elevated total symptom scores on both child- and parent-reported measures, as well as higher internalizing and externalizing symptom ratings. These associations suggest that greater GM-CSF levels may reflect a more general vulnerability to emotional and behavioral problems in this population.
By contrast, IL-6 showed an inverse pattern. Children with higher IL-6 levels at baseline tended to report fewer total psychological symptoms over time. Parents also reported fewer externalizing symptoms in children with elevated IL-6. This finding runs counter to some earlier studies linking IL-6 with worse mental health, raising the possibility that this cytokine’s role may be more complex—or may depend on age, illness context, or other individual factors.
The researchers also explored whether the type of physical illness a child had affected either their mental health scores or biomarker levels. Psychological symptom scores did not differ across illness types, such as respiratory versus neurological conditions. Most biomarkers also showed no variation between these diagnostic groups, except for one: IL-1β was found to be lower among children in the neurological subgroup compared to other categories.
Overall, the findings suggest that the immune system may be involved in shaping long-term mental health trajectories for children with chronic physical conditions. While not definitive proof of a biological cause, the associations observed between immune markers and psychological symptoms point to potential early warning signs. If validated in larger studies, these biomarkers could be used to identify children who may be at elevated risk for mental health problems and prioritize them for early support or monitoring.
But the study, like all research, has some limitations. First, only 128 children in the MY LIFE cohort provided blood samples, which limits statistical power. This small sample size also prevented the researchers from analyzing specific psychiatric diagnoses or breaking down results by age or sex. Several biomarkers also could not be analyzed due to low detection rates, including some that have been linked to mood and behavior in other studies.
Despite these limitations, the research adds to a growing body of evidence suggesting that immune activity and mental health are closely connected, even in children. The authors propose that when physicians order blood work for children with chronic illness, including a broader panel of inflammatory biomarkers might offer insight into future psychological risk. Identifying children at risk earlier could shorten the time to mental health referral and improve outcomes through integrated care.
The research team plans to continue following the MY LIFE cohort to see whether the predictive value of these biomarkers holds up over longer time periods. They are also interested in exploring how these biological indicators interact with social and environmental factors.
“Whether these inflammatory biomarkers continue having predictive power over the longer-term, or new biomarkers emerge over time will be investigated in this cohort,” Ferro said. “The extent to which inflammatory biomarkers interact with psychosocial processes in the development of physical-mental comorbidity will be studied to better understand opportunities for early detection and targets for intervention to reduce the incidence of physical-mental comorbidity in children.”
The study, “Inflammatory Biomarkers Predictive of Psychopathology in Children With Physical Illness,” was authored by Mark A. Ferro, Christy K. Y. Chan, Fasih A. Rahman, Joe Quadrilatero, and Brian W. Timmons.
