Infectious diseases and childhood disruptive behavior disorders: a reappraisal

Disruptive behavior disorders (DBDs) of childhood include conduct disorder (CD) and oppositional defiant disorder (ODD). These conditions are characterized by recurrent defiant, disruptive, or aggressive behaviors that go against accepted social norms ( Robles et al., 2021). ODD is characterized by defiance towards authority figures, often accompanied by chronic irritability or anger outbursts. CD is a more severe disorder characterized by prominent rule-breaking, disregard for the rights or feelings of others, and prominent aggression or violence (Fairchild et al., 2019). ODD may represent a milder form of CD, or a distinct condition that overlaps clinically and etiologically with it (Blair et al., 2014).DBDs are considered to arise from complex gene-environment interactions. Genes implicated in DBDs include those related to the monoamine neurotransmitters serotonin and dopamine, the hormones testosterone and cortisol, and the neuropeptide oxytocin (Holz et al., 2018;Moore et al., 2019). These interact with environmental factors such as prenatal exposure to alcohol, tobacco or viral infections, peri-or neonatal complications, early childhood adversity, parental exposure to stress, and parenting style (Latimer et al., 2012). This results in alterations in the structure and functioning of brain circuits connecting the frontal, anterior cingulate and temporal cortices to the amygdala, caudate nucleus, and thalamus. These circuits are involved in psychological processes such as decision-making, responsiveness to threats, empathy, emotional regulation, and social behavior. Dysfunction of these circuits leads to traits of irritability, callousness and aggression. These manifest as symptoms of ODD or CD at home, in school, and in various social settings (Jansen 2022;Gao et al., 2024).DBDs are associated with significant individual and social costs across the life-span. In childhood, these include conflicts with parents, teachers, and the juvenile justice system, low educational attainment, and substance misuse. Adult consequences of untreated DBDs include substance use disorders, unemployment, criminality, intimate partner violence, child abuse, and suicide (Blair et al., 2014;Fairchild et al., 2019;Goulter et al., 2023). Individual and family therapies have the best evidence of efficacy in the management of DBDs. These treatment approaches are not always available, particularly in low-or middle-income settings, and response to treatment is often incomplete (Perlstein et al., 2023). Pharmacological agents, particularly antipsychotics, have modest effects on symptoms of aggression and irritability. The long-term efficacy and safety of these drugs is unknown (Loy et al., 2017). For these reasons, the identification of novel approaches for the prevention and treatment of DBDs is a priority area in child and adolescent mental health (Waddell et al., 2007;Hofvander et al., 2017).A preliminary literature search revealed that the available research on this topic was heterogeneous and did not lend itself to a formal systematic review. Therefore, a narrative synthesis and conceptual analysis of available results was undertaken, in keeping with standard recommendations (Gregory and Denniss 2018;Sukhera 2022). The PubMed, ScienceDirect and Scopus databases were searched using the keywords "infection", "infectious", "infective", or "infectious disease", both alone or in conjunction with "respiratory", "gastrointestinal", or "childhood", along with the keywords "oppositional defiant disorder", "conduct disorder", or "disruptive behavior disorder." Papers were selected for discussion only if they examined the association between infectious diseases and childhood DBDs from either a theoretical or a clinical perspective. Out of 276 initial citations screened, a total of 53 relevant articles were selected.The key findings and hypotheses outlined in these papers were summarized under three headings:• General associations between infectious diseases and DBDs in childhood • Associations between specific infections or pathogens and DBDs in childhood • Possible mechanisms linking infection to the onset of pediatric DBDs or DBD symptoms Following this, the available evidence was critically appraised and synthesized to address any possible confounding effects, or limitations of the existing literature.A risk factor that merits further investigation in this context is exposure to infectious pathogens early in life. Prenatal viral infection has been considered a possible risk factor for childhood DBDs (Latimer et al., 2012). Maternal systemic inflammation, as indexed by elevated serum C-reactive protein (CRP), is not directly associated with DBDs (Chudal et al., 2020). On the other hand, specific histological evidence of chorionic vasculitis and umbilical cord inflammation, known as the fetal inflammatory syndrome (FIRS), is associated with an approximately 1.5-fold increase in the risk of CD. The FIRS can be induced by several factors, including viral infection (Gibson et al., 2023).These findings naturally lead to the question of whether post-natal infections, particularly in early childhood, are also associated with DBDs. A study of pre-term infants diagnosed with neonatal infections, followed up till the age of 9 years, found evidence of an association with attention-deficit / hyperactivity disorder (ADHD), but not DBDs (Rand et al., 2016). In contrast, exposure to infection later in childhood may be associated with CD or ODD. In a study which examined over 1,000,000 Danish children until a mean age of 9.8 years, infections requiring either hospitalization or treatment with antibiotics were associated with a 1.5-to 3-fold increase in subsequent CD or ODD (Köhler-Forsberg et al., 2019). A similar study of 1,285 youth from the United States found that infections requiring antibiotic therapy during the first year of life, as reported by parents or caregivers, was associated with a 3.7-fold increase in ODD at ages 9 to 17; the number of children diagnosed with CD was too small for a meaningful comparison (Goodwin 2011). A longitudinal study of children with fever of unknown origin did not report significant associations with DBDs, but this study included several children with non-infectious causes of fever, and did not include a control group (Weakley et al., 2020).The next question that arises is whether the association between infections and DBDs is non-specific, or whether certain pathogens are associated a particular increase in risk. Infections that directly affect the brain have been associated with the emergence of CD-or ODD-like symptoms in previously healthy children: in these cases, the symptoms are probably the consequence of direct brain damage caused by the pathogen, and are often accompanied by prominent cognitive impairment. Such presentations were first documented during the encephalitis lethargica outbreak of the 1920s, in which some affected children were reported to exhibit irritability and aggressive behavior similar to that seen in CD, and which represented a radical change from their premorbid selves (Cheyette and Cummings 1995;Ruiz 2015). Similar presentations have been reported more recently in children with acute viral encephalitis (Deka et al., 2006;Lin et al., 2022;Bergman et al., 2024), cerebral malaria (Sveinbjornsdottir et al., 2025), and chronic encephalitis caused by the Epstein-Barr virus (EBV) (Caruso et al., 2000). Though these cases cannot be considered "true" DBDs, they may provide valuable clues about the functional neuroanatomy and neurophysiology of DBDs, as discussed in a subsequent section. Leaving these aside, the following associations between specific infections and DBDs in childhood have been documented in the literature:Perinatal infection with HIV has been associated with subsequent CD or ODD in youth in several studies from the United States. In a sample of youth with perinatal HIV infection, currently aged 9-16 years, 13% were diagnosed with CD and 11% with ODD. The majority of this sample were receiving antiretroviral treatment (ART) and more than 90% had CD4+ counts higher than 200 cells/mm3, indicating relatively well-preserved immune function (Mellins et al., 2006). Markers of HIV disease severity, such as CD4+ counts less than 660 cells/mm3 or low CD4+ counts at baseline, were associated with more severe symptoms of CD (Nozyce et al., 2006;Nachman et al., 2012). However, some researchers failed to find an association between perinatal HIV and DBDs (Gadow et al., 2010), while others found that variations in CD in children with AIDS were more significantly correlated with measures of parent-child attachment and consistency of parental discipline (Osigwe et al., 2020;Drabick et al., 2025). These associations are not mutually exclusive: it is highly likely that both disease activity and social factors play a role in the pathogenesis of DBDs in HIV-positive youth.Results from other countries yield a slightly different picture. Among children and adolescents from India and Uganda, 5-9% were diagnosed to have either CD or ODD, and these conditions were more common in younger children. Overall, 45-55% of psychiatric diagnoses made in these children were DBDs (Pilania et al., 2020;Taylor Salisbury et al., 2020). These studies did not include a healthy control group or examine the association between HIV disease activity and symptoms of ODD or CD. A study of adolescents living with HIV from South Africa found that self-reported health was negatively associated with symptoms of CD. The same study found that these symptoms were significantly associated with psychosocial variables, including HIV-related stigma, experiences of abuse or bullying, the availability of social support, and the parent-adolescent relationship (Boyes et al., 2019).A longitudinal study of children from England, followed up until adolescents, found that episodes of gastroenteritis in the first three years of life were associated with symptoms of CD in both the fourth and seventh years of life. There was an apparent "dose-response" relationship, in that the number of such episodes was correlated with the severity of CD symptoms. At 15 years of age, gastroenteritis was associated with an increased likelihood of being formally diagnosed with either CD or ODD. Though this association was small in magnitude, it was significant even after adjusting for potential confounders. Peripheral levels of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6) at ages 9 or 15 did not appear to mediate this association (Parent et al., 2019).Though this result awaits replication, a recent Mendelian randomization study found evidence that the composition of the gut microbiome is associated with CD. More specifically, the bacterial genus Coprococcus and class Coriobacteriia were associated with a two-fold increase in CD risk, while the genera Adlercreutzia and Ruminococcaceae, the class Negativicutes and the order Selenomonadales reduced the risk of CD by approximately one-half (Fatoba and Simpson 2025). This result is relevant given that both intestinal infections, and the antibiotics, used to treat them can alter the composition of the gut microbiome in childhood (He et al., 2025).Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) refer to new-onset behavioral and movement disorders occurring after infections with group A βhemolytic streptococci. More recently, the concept of PANDAS has been extended to neuropsychiatric symptoms occurring after other infections. This has been referred to as pediatric acute-onset neuropsychiatric syndrome (PANS) (La Bella et al., 2023;Lojek and Rzeszutek 2025). ODD has been specifically associated with PANDAS and not with other movement disorders of childhood and adolescence (Ben-Pazi et al., 2011), while 27.5% of children with movement disorders following streptococcal pharyngitis have been reported to develop CD (Dale et al., 2004). A more recent study using a data mining approach found that ODD symptoms were one of the "core" features of PANS, occurring in 89% of affected children. However, this study did not find any associations between ODD and immune parameters, such as elevated antistreptolysin O (ASO) titer or altered natural killer (NK) cell count. 82% of the children in this study had a history of recurrent respiratory or skin infections (Gagliano et al., 2020).Evidence for a link between other types of infection and childhood DBDs is largely anecdotal. In a study of 375 children and adolescents from Iran who were hospitalized with COVID-19, found that nine children (2.4%) developed new-onset ODD, out of a total of 58 with new-onset psychiatric diagnoses; in other words, ODD accounted for 15.5% of new psychiatric diagnoses following COVID-19. The mean age of children receiving this diagnosis was 8.5 years, and it was not significantly associated with either demographic variables or the presence of neurological disorders secondary to COVID-19 (Zahed et al., 2023). In a series of seven individuals who had concurrent infection with two zoonotic infections -the protozoan Babesia odocoilei and the bacterium Bartonella henselae -one patient was diagnosed with ODD at the age of 9, and subsequently developed depression in adult life (Maggi et al., 2024). On the other hand, a serological study found no association between antibodies to herpes simplex virus (HSV) and conduct disorder in childhood (Sylvester Jorgensen et al., 1982).The above data suggests that certain infections may play a role in triggering DBDs in childhood. In the case of HIV / AIDS, it could be argued that these symptoms result from the stigma and psychosocial adversities associated with the disease. However, this does not explain the occurrence of CD or ODD symptomatology in relation to other common infections of childhood. Based on the available evidence, there are at least three plausible mechanisms that may link specific infections to DBDs in the pediatric population.The association between DBDs and PANDAS / PANS suggests that it is the immune response triggered by pathogens, and not the pathogens themselves, that is responsible for the emergence of symptoms of irritability, oppositional behavior, and aggression in these children. There is a relative paucity on studies of inflammatory markers in children and adolescents with DBDs, particularly in comparison to assays of neuroendocrine parameters (Goulter et al., 2025). Early research on immunological alterations in youth with DBDs yielded negative results: youth with these conditions did not exhibit significant differences in total leukocyte count, B-or T-cell distribution, or natural killer (NK) cell activity from those with depression or from healthy controls (Targum et al., 1990;Birmaher et al., 1994). Subsequent research found evidence of subtle immune dysfunction, including an increased plasma IgG3:IgG4 ratio (Pajer et al., 2002) and IgG autoantibodies that reacted against adrenocorticotrophic hormone (ACTH) (Schaefer et al., 2013). Studies of children with ADHD and comorbid DBDs have found that levels of high-sensitivity CRP (hsCRP) were correlated with symptoms of ODD, while levels of myelin-associated glycoprotein (MAG) were correlated with symptoms of CD (Tezcan et al., 2025). The cytokine IL-13 was also positively correlated with CD / ODD symptoms in this population (Gonzalez-Villen et al., 2024).Despite several findings suggestive of subtle immune dysfunction in children with DBDs, it is not yet possible to link these to the effects of a given infection. However, it is worth noting that certain viral respiratory infections can, in principle, induce the formation of anti-ACTH antibodies, as have been reported in children with CD symptoms (Wheatland 2004). In addition, animal models of PANDAS / PANS have found evidence of IgG antibody deposition in the corpus striatum associated with behavioral and motor changes; this may be related to the alterations in IgG ratios seen in some children with DBDs (Wald 2019). How such changes may relate to possible infection-induced CD or ODD is unknown.Altered functioning of basal ganglia circuitry, particularly of connections between the frontal cortex and the caudate nucleus and striatum, has been implicated in the pathogenesis of childhood DBDs (Zhang et al., 2015;Pu et al., 2017). It has been suggested that complex psychiatric presentations in children, who exhibit symptoms of DBDs in association with obsessive-compulsive or ADHD symptoms, may be the result of basal ganglia dysfunction triggered by bacterial or viral infection (Yaryura-Tobias et al., 2003). This hypothesis aligns with some of the data from patients with CD or ODD occurring in relation to PANS, as discussed above. Some of the viruses associated with symptoms of DBD are known to cause basal ganglia lesions (Azab and Azzam 2021;Hu and Cheng 2024), but such lesions have not yet been demonstrated in children experiencing CD or ODD symptoms following infection.A third line of evidence suggests that certain infections may trigger conduct symptoms through alterations in the gut microbiome, which in turn leads to altered signaling in the gut-brain axis. Research in young children has found that specific alterations in the gut microbiome are associated with poor social skills (van de Wouw et al., 2024) and symptoms of DBDs (Nieto-Ruiz et al., 2023). Prenatal exposure to chemical toxins has also been associated with symptoms of CD, which appear to be correlated with altered gut microbial diversity (Zhou et al., 2024). In animal models of Parkinson's disease, alterations in gut microbiota composition have been linked to changes in serotonergic and dopaminergic transmission in the striatum, suggesting that the microbiota-gut-brain axis can modulate the functioning of basal ganglia circuity (Ni et al., 2025). However, the relevance of such changes to the very different clinical scenario of childhood DBDs is debatable.The evidence summarized above suggests that an association between certain kinds of infection and DBDs is both biologically and epidemiologically plausible. 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