ABSTRACT
Alterations in the immune system are often found in children with Autism Spectrum Disorders [ASD], leading to an aberrant
immune response which compromises host defense. Fewer regulatory T-cells, elevation in inflammatory cells and proinflammatory
cytokines have been highly reported in this population and it has been recently seen as a chronic neuroinflammatory disorder.
Cytokines are often dysregulated in ASD especially IL-6, which is one of the biggest concerns during the current COVID-19
pandemic, as well as other immune dysregulations. We strongly believe that this proinflammatory environment in ASD could
increase the vulnerability of a poor clinical outcome for COVID-19 infection.
Keywords: ASD, COVID-19, immune system.
RESUMEN
Las alteraciones en el sistema inmunitario se encuentran a menudo en niños con trastornos del espectro autista [TEA], lo que
conduce a una respuesta inmune aberrante que compromete la defensa del huésped. Menos células T reguladoras, elevación
en las células inflamatorias y citoquinas proinflamatorias han sido muy reportados en esta población y se ha visto reciente-
mente como un trastorno neuroinflamatorio crónico. Las citocinas a menudo están desreguladas en el TEA, especialmente la
IL-6, que es una de las mayores preocupaciones durante la pandemia actual del COVID-19, así como otras desregulaciones
inmunes. Creemos firmemente que este entorno proinflamatorio en TEA podría aumentar la vulnerabilidad de un resultado
clínico pobre para la infección por COVID-19.
Palabras clave: TEA, COVID-19, sistema inmunitario.
INTRODUCTION
Up to now, scientists are uncertain about repercussions of the new coronavirus SARS-CoV-2 in populations with different
immunological backgrounds. Alterations in the immune system are often found in children with Autism Spectrum Disorders
[ASD], leading to an aberrant immune response which compromises host defense (Masi et al., 2017). In addition, sub-populations
of ASD suffer from different autoimmune and metabolic disorders (Hughes et al., 2018; Mora et al., 2009); as a consequence,
the outcome of COVID-19 patients with ASD as a concomitant, is so far, hard to predict.
COVID-19 infection and Autism Spectrum Disorders
Evidence has shown that the course of the COVID-19 can be influenced by existing comorbidities with an inflammatory
component as seen in diabetes, obesity, and cardiovascular affected populations (Guo et al., 2020; Bravo-Acosta, 2020).
Patients with severe COVID-19 have shown an influential decrease in CD8+ T-cells, NK cells (seen as exhaustion markers),
and monocytes (Cao, 2020). On the other hand, Autism Spectrum Disorder has a multifactorial and heterogeneous etiology.
Fewer regulatory T-cells, elevation in inflammatory cells, and proinflammatory cytokines have been highly reported (Hughes
et al., 2018) and it has been recently seen as a chronic neuroinflammatory disorder (Kern et al., 2016). In addition, autoimmuni-
ty, immunodeficiency, and allergies have been observed in children with ASD (Enstrom et al., 2009; Heuer et al., 2008), and the
latter has been recently linked with the central nervous system, suggesting a “brain allergy” phenomenon (Theoharides, 2013).
ISSN: 1390 - 5546
ARTÍCULO RECIBIDO: 31/08/2020
ARTÍCULO ACEPTADO: 26/10/2020
ARTÍCULO PUBLICADO: 30/11/2020
THE UNKNOWN CONSEQUENCES OF COVID-19
IN PEOPLE WITH AUTISM SPECTRUM DISORDERS
Maria Andrea Castillo , Kendy Eduardo Urdaneta , Nola Montiel , Dilia Martínez-Mendez , Neomar Semprún-Hernández
1 1 1 11, 2
Research Division, Immunology Unit “Nola Montiel” (UINM), Venezuela.
International Master in Innovative Medicine. Uppsala University. Sweden.
1
2
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CONSECUENCIAS DESCONOCIDAS DEL COVID-19
EN PERSONAS CON TRASTORNOS DEL ESPECTRO AUTISTA
It is known that the viral-induced hyper inflammation expressed in COVID-19 patients can have severe outcomes leading to
respiratory failure with multiple organ involvement (Huang et al., 2020). The innate response to environmentally relevant
pathogens of the ASD population is described as dysfunctional, with elevated cytokine production in comparison with
neurotypical individuals. Moreover, alterations in circulating monocytes, dendritic cells, and NK cells are frequently observed
(Hughes et al., 2018; Bennabi et al., 2019). This immune dysfunction and dysregulation present in the vast majority of the
ASD population is a worrying scenario for the current COVID-19 pandemic.
One of the cornerstones to understanding these severe consequences are the cytokines often dysregulated in ASD, especially
IL-6, being one of the biggest concerns. Levels of IL-6 tend to be elevated in ASD individuals, as shown by Ashwood (2011)
study where this cytokine was two-fold higher in plasma collected from ASD children than compared with neurotypical
children. This cytokine has multiple functions including inflammation, autoimmunity, and acute phase response; simulta-
neously modulates the host immune response by enhancing monocytes differentiation into macrophages as well as other cell
differentiation with further impairment of NK cell function (Wu et al., 2019). In fact, elevated levels of IL-6 have been reported
to have a strong correlation with an upcoming respiratory failure for COVID-19 patients (Chen et al., 2020). In addition,
elevated IL-6 has been discussed by different researchers to be a useful tool to predict the course of the infection or identify
patients with a high risk of respiratory failure, therefore the possible need for mechanical ventilation (Herold et al., 2020).
Another concern that has arisen regarding this topic is the effect on the fetus of COVID-19 infected pregnant women
(Steinman, 2020). This is based on the higher risk of postpartum autism after an infection accompanied by fever during the
second trimester of pregnancy, related to the proinflammatory environment produced by the host in response to the infection
(Croen et al., 2019). The combination of the immunological dysfunction and dysregulation could contribute to impair the
virus clearance and exacerbate the severity of the clinical outcome by enhancing the proinflammatory “cytokine storm”.
There is a reason to believe that this proinflammatory environment in ASD could increase the vulnerability of a poor clinical
outcome for COVID-19 infection, but also expected to be highly variable within patients based on the heterogeneity of the
disorder, mainly influenced by the type of existing immune or metabolic alteration.
CONCLUSIONS
The heterogenous immune background withing ASD population is a grey area that leads to the remarked queries within this
article regarding COVID-19 prognostics. Decrease in a subpopulation of immune cells, autoimmunity, immunodeficiencies,
and cytokine dysregulation often present in this population could lead to an impairment of a proper immune response for viral
clearance. However, we are in the need to clarify that these are assumptions based on what is known for ASD, thus
COVID-19 research within ASD population must be performed to get trustworthy conclusions. We encourage the caretakers
of people with ASD to take all possible and extra measures against COVID-19. The remaining question in the near future or
soon is not only the consequences of the COVID-19 infection in people with ASD, but how effective immune response will
be against the virus infection and if compensatory mechanisms of their dysregulated immune system are enough for viral
clearance. For the time being, prevention is still the most important tool to avoid the severe consequences of the COVID-19
infection, and crucial for people with ASD.
REFERENCES
Ashwood, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Pessah, I., & Van de Water, J. (2011). Elevated plasma cytokines
in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral
outcome. Brain, Behavior, and Immunity, 25(1), 40–45. https://doi.org/10.1016/j.bbi.2010.08.003
Bennabi, M., Tarantino, N., Gaman, A., Scheid, I., Krishnamoorthy, R., Debré, P., Bouleau, A., Caralp, M., Gueguen, S.,
Le-Moal, M. L., Bouvard, M., Amestoy, A., Delorme, R., Leboyer, M., Tamouza, R., & Vieillard, V. (2019). Persis
tence of dysfunctional natural killer cells in adults with high-functioning autism spectrum disorders: Stigma/conse-
quence of unresolved early infectious events? Molecular Autism, 10(1). https://doi.org/10.1186/s13229-019-0269-1
• María Andrea Castillo
• Kendy Eduardo Urdaneta
• Nola Montiel
• Dilia Martínez Mendez
• Neomar Semprún Hernández
REVISTA INVESTIGACIÓN Y DESARROLLO I+D • VOLUMEN 12 • JULIO - DICIEMBRE 2020 • P. 85 - 87 • UNIVERSIDAD TÉCNICA DE AMBATO - DIDE • AMBATO - ECUADOR
86
Bravo-Acosta, M., Vélez-Solorzano, P., & Martínez- Méndez, D. (2020). Clinical characteristics of Covid-19 cases in Gua-
yaquil, Ecuador. Journal of Human Virology & Retrovirology, 8(2). https://doi.org/10.15406/jhvrv.2020.08.00221
Cao, X. (2020). COVID-19: immunopathology and its implications for therapy. Nature Reviews Immunology
20(5):269–270. https://doi.org/10.1038/s41577-020-0308-3
Chen, X., Zhao, B., Qu, Y., Chen, Y., Xiong, J., Feng, Y., Men, D., Huang, Q., Liu, Y., Yang, B., Ding, J., & Li, F. (2020).
Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6
(IL-6) level in critically ill COVID-19 patients. Clinical Infectious Diseases, ciaa449. https://doi.org/10.1093/cid/
ciaa449
Chomarat, P., Banchereau, J., Davoust, J., & Palucka, A. K. (2000). IL-6 switches the differentiation of monocytes from
dendritic cells to macrophages. Nature Immunology, 1(6), 510–514. https://doi.org/10.1038/82763
Croen, L. A., Qian, Y., Ashwood, P., Zerbo, O., Schendel, D., Pinto‐Martin, J., Daniele Fallin, M., Levy, S., Schieve, L. A.,
Yeargin‐Allsopp, M., Sabourin, K. R., & Ames, J. L. (2019). Infection and Fever in Pregnancy and Autism Spectrum
Disorders: Findings from the Study to Explore Early Development. Autism Research, 12(10), 1551–1561. https://doi.org
/10.1002/aur.2175
Enstrom, A. M., Lit, L., Onore, C. E., Gregg, J. P., Hansen, R. L., Pessah, I. N., Hertz-Picciotto, I., Van de Water, J. A., Sharp,
F. R., & Ashwood, P. (2009). Altered gene expression and function of peripheral blood natural killer cells in children
with autism. Brain, Behavior, and Immunity, 23(1), 124–133. https://doi.org/10.1016/j.bbi.2008.08.001
Guo, W., Li, M., Dong, Y., Zhou, H., Zhang, Z., Tian, C., Qin, R., Wang, H., Shen, Y., Du, K., Zhao, L., Fan, H., Luo, S., &
Hu, D. (2020). Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes/Metabolism
Research and Reviews, e3319. https://doi.org/10.1002/dmrr.3319
Herold, T., Jurinovic, V., Arnreich, C., Lipworth, B. J., Hellmuth, J. C., von Bergwelt-Baildon, M., Klein, M., & Weinberger,
T. (2020). Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. Journal of
Allergy and Clinical Immunology, 146(1), 128-136. https://doi.org/10.1016/j.jaci.2020.05.008
Heuer, L., Ashwood, P., Schauer, J., Goines, P., Krakowiak, P., Hertz-Picciotto, I., Hansen, R., Croen, L. A., Pessah, I. N., &
Van De Water, J. (2005). Reduced levels of immunoglobulin in children with autism correlates with behavioral
symptoms. Autism Research, 1(5), 275–283. https://doi.org/10.1002/aur.42
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y.,
Wu, W., Xie, X., Yin, W., Li, H., Liu, M., & Cao, B. (2020). Clinical features of patients infected with 2019 novel
coronavirus in Wuhan, China. The Lancet, 395(10223), 497–506. https://doi.org/10.1016/S0140-6736(20)30183-5
Hughes, H. K., Mills Ko, E., Rose, D., & Ashwood, P. (2018). Immune Dysfunction and Autoimmunity as Pathological
Mechanisms in Autism Spectrum Disorders. Frontiers in Cellular Neuroscience, 12, 405. Frontiers Media S.A.
https://doi.org/10.3389/fncel.2018.00405
Jones, B. E., Maerz, M. D., & Buckner, J. H. (2018). IL-6: a cytokine at the crossroads of autoimmunity. Current Opinion in
Immunology, 55, 9–14. https://doi.org/10.1016/j.coi.2018.09.002
Kern, J. K., Geier, D. A., Sykes, L. K., & Geier, M. R. (2016). Relevance of neuroinflammation and encephalitis in autism.
Frontiers in Cellular Neuroscience, 9, 519. https://doi.org/10.3389/fncel.2015.00519
Masi, A., Glozier, N., Dale, R., & Guastella, A. J. (2017). The Immune System, Cytokines, and Biomarkers in Autism Spec-
trum Disorder. Neuroscience Bulletin, 33(2): 194–204. https://doi.org/10.1007/s12264-017-0103-8
Mora, M., Quintero, L., Cardenas, R., Suárez-Roca, H., Zavala, M., & Montiel M. (2009) Infecciones por HSV-2 y su relación
con anticuerpos antiencéfalo de rata en suero de pacientes con autismo. Investigaciones clínicas, 50(3).
Steinman, G. (2020). COVID-19 and autism. Medical Hypotheses, 142, 109797. https://doi.org/10.1016/j.mehy.2020.109797
Theoharides, T. C. (2013). Is a subtype of autism an allergy of the brain? Clinical Therapeutics, 35(5):584–591.
https://doi.org/10.1016/j.clinthera.2013.04.009
Wu, J., Gao, F. X., Wang, C., Qin, M., Han, F., Xu, T., Hu, Z., Long, Y., He, X. M., Deng, X., Ren, D. L., & Dai, T. Y. (2019).
IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal
squamous cell carcinoma. Journal of Experimental and Clinical Cancer Research, 38(1), 321. https://doi.org
/10.1186/s13046-019-1310-0
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