Autism, or autism spectrum disorder (ASD), is a common and increasingly diagnosed entity among children in the United States (1). This complex neurodevelopmental disorder manifests with atypical social communication skills, and interactions consisting of restrictive, repetitive patterns of behavior. CDC’s MMWR data reports an ASD prevalence of 1 in 36 children in 2020 in the United States (2). Ratajczak proposed that this disorder is a consequence of genetic defects, with or without inflammation of the brain (3). Based upon the diverse and wide range of clinical histories in these children, he also postulated that inflammation could be the result of placental defects, blood–brain barrier immaturity, an abnormal maternal immune response in utero, prematurity, encephalitis, or toxic environmental exposures (3).

Considering the medical complexity associated with the wide array of clinical presentations, there is a substantial need for additional research into the causes of ASD neuropsychiatric conditions. A case published in 2019 reported significant improvement in a 14-year-old boy diagnosed with Pediatric Acute Onset Neuropsychiatric Symptoms (PANS), who was treated for infection with Bartonella henselae (4). Antimicrobial treatments directed at this bacterial pathogen resulted in a gradual return to baseline activities, resolution of his Bartonella-associated cutaneous lesions, and discontinuation of all psychiatric medications. We now describe a case involving a boy with developmental delays from an early age that was presumed to be associated with a congenital brain anomaly. Shifts in the constellation of his symptoms resulted in a high level of clinical suspicion for potential underlying infectious etiologies (5). In conjunction with the administration of antimicrobial therapy, the boy experienced a positive clinical response, including being moved from a long-term special education classroom setting to an age appropriate and grade level general classroom setting, based on standardized testing and school performance, in conjunction with dramatic improvement in cognitive functions, and ultimately acceptance to a 4-year college. In addition to these cognitive improvements, several other non-cognitive symptoms also significantly improved. This case report provides further support to the growing body of literature indicating that infectious triggers may contribute to neuropsychiatric disorders, including those in children who phenotypically present as academically challenged, or meet the criteria for autism spectrum disorder.

Autism spectrum disorders are increasing in prevalence and are negatively impactful on many families and individual communities throughout the United States. The CDC estimates that 1 in 36 children in the United States were diagnosed with an autism spectrum disorder in 2020 (2). The estimated annual cost for children’s autism spectrum disorder care is between $61 and $66 billion, while the annual adult services cost is estimated to be between $175 and $196 billion (21). A strategic therapeutic approach that significantly addresses the burdens placed on these families, their communities and society in general has been elusive. Despite substantial research efforts and an ever-increasing need to better understand the cause(s) of ASD, effective therapeutic interventions have focused on modifying or controlling abnormal behaviors. With the current medical philosophy that these disorders are largely caused by genetic abnormalities, the extent to which infectious agents might be contributory has been minimally explored on a clinical or research basis. It stands to reason that exposure to infectious agents or neurotoxins, either in utero or later during the early developmental years, might result in mutations or alternatively impact disease expression in genetically predisposed individuals. Agents that induce persistent, stealth intravascular or central nervous system infections would potentially negate the effectiveness of symptomatic therapies.

This patient had a well-defined embryonic abnormality diagnosed in utero, clearly complicating the developmental assessment of his physical and mental capabilities. Based upon symptomatology he was diagnosed and treated medically for over a decade as an “impaired” child, up to the time of our initial evaluation. Test results in this patient supported exposure to one or more vector borne pathogens, a serological diagnosis of bartonellosis and borreliosis, and the borderline presence of anti-neuronal antibodies, which can occur in association with vector borne and other non-vector borne infections (22). Therefore, a decision was made to treat with antimicrobial agents targeting a potential infectious etiology, with secondary auto-antibody formation. His response to this therapeutic approach included improvement or elimination of a substantial number of neuropsychiatric symptoms and significant improvement in his academic status, placing him at grade level without accommodations and eligible for more advanced educational planning. Lacking the benefit of clinical trials or previously defined treatment protocols, antibiotics targeting two vector borne genera were administered for an extended period, while carefully monitoring various symptomatic responses and safety parameters. Despite having stable or progressive symptoms for potentially his entire life, the response to treatment suggested that neither the cerebellar hypoplasia, inherited genetic defects, or autoimmunity were singularly causative. Strikingly, normalization of some symptoms supported the possibility that there had been no permanent CNS damage, although the onset and duration of the putative infections remains unknown. Although very much incompletely studied, perinatal transmission of both Bartonella and Borrelia species have been suspected (23, 24). Ongoing antimicrobial coverage was required at the time of writing this case report due to recurrence of all symptoms to one degree or another with the exception of oppositional behavior and anger with discontinuation, potentially related to ongoing infection with Borrelia and Bartonella quintana. Treatments with single or combinations of several antimicrobial drugs were accompanied by substantial improvements in neurological symptoms; however, research testing in August, 2022, documented the presence of B. quintana and potentially Borrelia spp. DNA in blood and enrichment blood cultures by ddPCR and qPCR/DNA sequencing testing in the patient and his mother. Our interpretation is that the treatments utilized suppressed, but did not eliminate these infections in the patient, indicating the need for future studies that use sequential testing with advanced direct detection modalities to assess treatment response. Nonetheless, until further documented efficacious therapeutic options are available, and with close monitoring for safety and tolerability, benefits from improved quality of life outweigh the risks of long-term antibiotic administration.

We propose that a risk/benefit analysis in most patients diagnosed with autism spectrum disorder would warrant evaluation and treatment for potential chronic infectious triggers. Incorporation of diagnostic modalities that detect pathogen antigens or DNA will allow for increased support for a causative role for specific organisms in association with patient symptoms. More research is obviously needed, but if this type of clinical and microbiological approach were to be further explored, the result could dramatically impact future clinical practice. Documenting the presence of an infectious etiology in blood or cerebrospinal fluid could provide an even more meaningful, positive impact in the lives of so many who are suffering with limited therapeutic options. The fact that this patient was treated as a teen also indicates that these infections may persist, well beyond any acute exposures, or occurring in utero, or during the perinatal period. Therefore, treating earlier in life may result in improvements in academic performance, improved social development, and a better chance at full adult independence, which would represent a significantly altered outcome for many people. Currently, borreliosis and bartonellosis are infections that are rarely considered in the evaluation and treatment of patients with neuropsychiatric presentations, but this case and others point to the possibility that chronic persistent infections may contribute to the presence and severity of symptoms in children and young adults with neuropsychiatric symptoms. Although an autoimmune or immunomodulatory component is suspected, more research is clearly needed to further delineate if it is the infection itself or the secondary immune consequences of the infection that may contribute to this phenotypic presentation of neuropsychiatric disease.

This teenage boy had a drastic improvement in his neuropsychiatric symptoms and in his academic standing, moving from special education services with accommodations to grade level academic standing without accommodations, to college acceptance. Progressive symptomatic improvement occurred only following targeted administration of antimicrobial agents directed at suspected, underlying, chronic infectious pathogens, namely the causative agents of bartonellosis and borreliosis. Further research is clearly needed to define if or the extent to which occult infections can contribute to neuropsychiatric illness, such as ASD.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The patient and his parents provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Research testing at North Carolina State University was conducted as a component of a study entitled: Detection of Bartonella Species in the Blood of Healthy and Sick People (NCSU Institutional Review Board approval, IRB 1960).

AO was the primary physician providing medical care, was in charge of the diagnostic testing, therapy plan, patient follow-up, and drafted the manuscript. EB conducted further microbial diagnostic testing on the patient and co-wrote the manuscript. All authors contributed to the article and approved the submitted version.

Research testing was supported through a grant from the Steven and Alexandra Cohen Foundation and donations to the Bartonella/Vector Borne Diseases Research Fund at the North Carolina State University College of Veterinary Medicine and by the state of North Carolina.

AO was employed by Heart and Soul Integrative Health.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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