INFECTIOUS AGENTS ASSOCIATED WITH AUTISM

In the early 1970s, research began to emerge linking autism to persistent infections. First study published pointing to a possible role for congenital rubella in the cause of autism[i]. As of today, a quantity of publications showing an association of autism with chronic infections has grown dramatically[ii] [iii]. Attempts to find the possible involvement of these infectious agents in ASD began many years ago and continue up to present time. The first publication on the association of autism with infection was published by S. Chase in 1971[iv]. In the study, out of 243 children with congenital rubella, 18 were subsequently diagnosed with autism (10 with syndrome and 8 with partial syndrome); while at that period 4.5 children out of 10,000 were reported to be autistic. This study showed that children with congenital rubella were 200 times more likely to have a consequent autism diagnosis. Increasing evidence of an association between chronic viral infections and neurological disorders began emerging about three decades ago. In 1989[v] it was shown that herpes simplex virus type 1 (HSV 1) was found to tend to localize in temporal and orbitofrontal lobes of the brain resulting in damages to those lobes leading to herpes encephalitis with the following symptoms, aggression, language impairments, and memory deficit. In a later case study[vi]  an 11-year-old patient was described as developing symptoms of autism following an episode of herpes encephalitis. A study in Japan[vii] (3,257 participants including 27 autistic children) by Sakamoto et al. The Japanese study showed that there was a high prevalence of congenital CMV infection among newborns who were later diagnosed with ASD. Congenital CMV among ASD children was about 25 times higher than among healthy control.  The study indicated that both inflammation and herpes infection are possible causes of autistic symptoms. Moreover, a relatively recent publication showed strong evidence that the Herpes simplex virus type 2 (HSV-2 or HHV-2) was connected to a higher risk of ASD in male offspring[viii]. The association between ASD, TORCH, and some other infectious agents, including herpesviruses, measles, rubella, Toxoplasma gondii, Chlamydia spp., Mycoplasma spp. continuous to be extensively described in the literature[ix] [x] [xi] [xii] [xiii] [xiv] [xv]. For example, TORCH congenital pathogens possess the capacity to cause damage to CNS and induce neurodevelopmental disorders[xvi]. The clinical presentations of TORCH infections at birth are described with such symptoms as meningoencephalitis, cerebral palsy, thrombocytopenia, anemia, sensorineural deafness, visual deficit, seizures, intracranial calcifications, growth retardation, and substantial delay in attaining developmental milestones[xvii]. In the cases of maternal infection, microorganisms present in the mother's bloodstream enter and infect the placenta. Subsequently, these microorganisms can have the potential to break the placenta, infiltrate the fetus's circulation, and spread throughout the fetal organism[xviii]. TORCH complex, or TORCH infections, refers to congenital infections caused by Toxoplasma gondii, syphilis, Treponema pallidum, hepatitis B virus, rubella virus, cytomegalovirus (CMV), herpes simplex virus (HSV-1/2), varicella zoster virus (VZV), human immunodeficiency virus (HIV), parvovirus, and some others[xix] [xx]. In our two studies performed several years ago[xxi] [xxii] (57 and 30 ASD children), we detected the high presence of CMV (up to 80%), rubella virus (60 to 80%), HSV-1/2 (25-30%), and low frequency of Toxoplasma and VZV, all belonging to TORCH complex. Also, we detected a high presence of Epstein-Barr virus (EBV) (up to 80%) and infrequent presence of intracellular bacteria Mycoplasma (up to 20%), Chlamydia (3.5%) and non-invasive Helicobacter pylori (15-20%), all of which are not considered TORCH infectious agents yet. In the recent study (142 children)[xxiii], (Fig. 1) we present the expanded panel of antibodies to persistent (latent and chronic) infections found in the blood tests of children with ASD.

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[i] Chess, S. (1971). Chess S. Autism in children with congenital rubella. J Autism Child Schizophr. 1971 Jan-Mar; 1(1):33-47. PMID: 5172438. doi:10.1007/bf01537741

[ii] Al-Beltagi M, Saeed NK, Elbeltagi R, Bediwy AS, Aftab SAS, Alhawamdeh R. Viruses and autism: A Bi-mutual cause and effect. World J Virol. 2023 Jun 25; 12(3):172-192. doi: 10.5501/wjv.v12.i3.172. PMID: 37396705; PMCID: PMC10311578.

[iii] Shuid AN, Jayusman PA, Shuid N, Ismail J, Kamal Nor N, Mohamed IN. Association between Viral Infections and Risk of Autistic Disorder: An Overview. Int J Environ Res Public Health. 2021 Mar 10; 18(6):2817. doi: 10.3390/ijerph18062817. PMID: 33802042; PMCID: PMC7999368.

[iv] Chess, S. (1971). Chess S. Autism in children with congenital rubella. J Autism Child Schizophr. 1971 Jan-Mar; 1(1):33-47. PMID: 5172438. doi:10.1007/bf01537741

[v] Greer MK, Lyons-Crews M, Mauldin LB. A case study of the cognitive and behavioral deficits of temporal lobe damage in herpes simplex encephalitis. Autism Dev Disord. 1989; 19(2):317–326. Available from: https://doi.org/10.1007/BF0221184

[vi] Ghaziuddin M, Al-Khouri I, Ghaziuddin N. Autistic symptoms following herpes encephalitis. European Child & Adolescent Psychiatry. 2002; 11(3):142–146.

[vii] Sakamoto, A., Moriuchi, H., Matsuzaki, J., Motoyama, K., & Moriuchi, M. (2015). Retrospective diagnosis of congenital cytomegalovirus infection in children with autism spectrum disorder but no other major neurologic deficit. Brain and Development, 37(2), 200– 205.doi:10.1016/j.braindev.2014.03.016

[viii] Magaret AS, Wald A. Autism Link to Herpes Simplex Virus 2 Antibody in Pregnancy Likely To Be Spurious. mSphere. 2017 Mar 29; 2(2):e00106-17. doi: 10.1128/mSphere.00106-17. PMID: 28405628; PMCID: PMC5371694.

[ix] Chess, S. (1977). Follow-up report on autism in congenital rubella. J Autism Child Schizophr, 7:69–74

[x] Valayi S, Eftekharian MM, Taheri M, Alikhani MY. Evaluation of antibodies to cytomegalovirus and Epstein-Barr virus in patients with autism spectrum disorder. Hum Antibodies. 2018; 26(3):165-169. doi:10.3233/HAB-180335

[xi] Slawinski BL, Talge N, Ingersoll B, et al. Maternal cytomegalovirus sero-positivity and autism symptoms in children. Am J Reprod Immunol. 2018; 79(5):e12840. doi:10.1111/aji.12840

[xii] Mahic M, Mjaaland S, Bøvelstad HM, et al. Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. 2017; 2(1):10.

[xiii] Al Malki JS, Hussien NA, Al Malki F. Maternal toxoplasmosis and the risk of childhood autism: serological and molecular small-scale studies. BMC Pediatr. 2021 Mar 17; 21(1):133. doi: 10.1186/s12887-021-02604-4. PMID: 33731054; PMCID: PMC7968291

[xiv] Hutton J. Does Rubella Cause Autism: A 2015 Reappraisal? Front Hum Neurosci. 2016;10. doi:10.3389/fnhum.2016.00025

[xv] Nicolson GL, Gan R, Nicolson NL, Haier J. Evidence for Mycoplasma ssp., Chlamydia pneumoniae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders. Journal of Neuroscience research. 2007; 85:1143–1148.

[xvi] Jash S, Sharma S. Pathogenic Infections during Pregnancy and the Consequences for Fetal Brain Development. Pathogens. 2022; 11(2). doi:10.3390/pathogens11020193

[xvii] Hon KL, Leung KKY, Leung AKC, Man E, Ip P. Congenital infections in hong kong: Beyond torch. Hong Kong Med J. 2020; 26(4):323-330. doi:10.12809/hkmj208398

[xviii] Zeichner SL, Plotkin SA. Mechanisms and pathways of congenital infections. Clin Perinatol. 1988 Jun;15(2):163-88. PMID: 3288420.

[xix] Morsy TA, Hussein HE MA. TORCH infections, pathogenicity & mortality assessments. J Egypt Soc Parasitol. 2022;52(1):53-70. doi:10.21608/jesp.2022.235777

[xx] Jaan A, Rajnik M. TORCH Complex. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560528/

[xxi] Alibek K, Tskhay A, Farmer S, Moldakozhayev A, Isakov T. Case Series of 57 Autism Spectrum Disorder Children from Central Asia and Eastern Europe. J of Neurology and Psychiatric Diseases. 2019;1(1):1-11.

[xxii] Alibek, K., Farmer, S., Tskhay, A., Moldakozhayev, A., Isakov, T. (2019). Treatment of Chronic and Latent Infections Combined with Nutritional Supplementation Positively Affects Quality of Life of ASD Children: Series of 30 Cases. J Nutr & Diet Suppl 3(1): 102

[xxiii] Alibek K and Alibek R. (2024). Diagnostic Biomarkers of Autism Comorbidities: Case Series of 142 Children from Seven Eurasian Countries. Manuscript in preparation.