Chronic Inflammatory Response Syndrome: Exploring Neuroimmune Pathology and Multisystem Framework for Differential Diagnosis in Pediatrics- Part 1
Main Article Content
Abstract
This paper is the first in a series of three case-controlled reviews of neurological disorders in pediatric medicine. It examines the pathophysiology, diagnostic markers, and clinical features of Chronic Inflammatory Response Syndrome (CIRS) through molecular immunology, functional transcriptomics, neuroimaging, and biomarker integration, with a focus on children with special needs. Clinical observations by the lead author highlight recurring similarities that warrant closer investigation of the neuroimmune inflammatory mechanisms underlying overlapping symptoms in autism spectrum disorder (ASD). Identifying and treating CIRS may be a critical step toward improved prognosis, with sustained gains and symptom alleviation in treatment-resistant populations. This review underscores the concept that ASD, and CIRS represent subsets within a shared paradigm of neuroinflammatory and immune-mediated disorders affecting human health worldwide. These conditions may be considered indistinguishable across populations due to overlapping neurological, immunological, and biochemical features.
Article Details
How to Cite
DASHORE, Jodie A. et al.
Chronic Inflammatory Response Syndrome: Exploring Neuroimmune Pathology and Multisystem Framework for Differential Diagnosis in Pediatrics- Part 1.
Medical Research Archives, [S.l.], v. 13, n. 10, oct. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6952>. Date accessed: 15 nov. 2025.
doi: https://doi.org/10.18103/mra.v13i10.6952.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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7. Shoemaker RC, Hudnell HK, House DE, van Kempen A, Pakes GE; COL40155 Study Team. Atovaquone plus cholestyramine in patients coinfected with Babesia microti and Borrelia burgdorferi refractory to other treatment: a double-blind, placebo-controlled crossover clinical trial. Adv Ther. 2006;23(1):1-11. doi:10.1007/BF02850341. PMID:16644602.
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17. Ryan JC, Wu Q, Shoemaker RC. Transcriptomic signatures in whole blood of patients who acquire a chronic inflammatory response syndrome (CIRS) following an exposure to the marine toxin ciguatoxin. BMC Med Genomics. 2015; 8:15. PMID: 25889530.
18. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67-81. PMID: 15622539.
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20. McMahon S. Longitudinal imaging and biomarker trends in pediatric CIRS patients. Biotoxin Med Res J. 2021;3(2):55-68.
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26. Mah TF, O’Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001;9(1):34-39. PMID: 11166241.
27. Parsek MR, Singh PK. Bacterial biofilms: an emerging link to disease pathogenesis. Annu Rev Microbiol. 2003;57:677-701. PMID: 14527295.
28. Ramos S, Barros L, Teixeira A. The role of melanocortins in inflammation and neuroimmune communication. Pharmacol Res. 2021;163:105267. PMID: 33127553.
29. Baraniuk JN, Zheng S, Broderick JE. Cytokines in chronic fatigue syndrome, fibromyalgia, and other overlapping syndromes. Curr Rheumatol Rep. 2005;7(5):387-394. PMID: 16174492.
30. Shoemaker RC, Hudnell HK. HLA genotyping in pediatric mold illness: predictive value and clinical correlation. Neurotoxicol Teratol. 2006;28(5):639-650. PMID: 16982140.
31. Hudnell HK. Visual contrast sensitivity testing in CIRS. Neurotoxicology. 2005;26(4):565-578. PMID: 16112317.
32. James SJ, Melnyk S, Jernigan S, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2009;147B(8):1327-1334. PMID: 19288560.
33. Parks T. Pediatric regression in biotoxin illness: clinical observations and treatment outcomes. J Pediatr Environ Health. 2022;4(1):12-25.
34. Swedo SE, Leckman JF, Rose NR. From PANDAS to PANS: expanding the clinical spectrum of post-infectious autoimmune encephalopathy. J Child Psychol Psychiatry. 2012;53(10):1047-1055. PMID: 22924 360.
35. Fallon BA, Levin ES, Schweitzer PJ, Hardesty D. Inflammation and central nervous system Lyme disease. Neurobiol Dis. 2010;37(3):534-541. PMID: 19944760.
36. Shoemaker RC, House DE. A time-series study of sick building syndrome: chronic, biotoxin-associated illness from exposure to water-damaged buildings. Neurotoxicol Teratol. 2005;27(1):29-46. PMID: 1568 1119.
37. Napoli E, Wong S, Giulivi C. Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Biochim Biophys Acta. 2013;1832(10):1620-1630. PMID: 23706623.
38. McMahon SW, Smith J. Pediatric Quirks of CIRS and PANS. Paper presented at: Surviving Mold Annual Conference; May 4th, 2018; Salisbury, MD.
39. Shoemaker RC, Maizel MS. Exposure to interior environments of water-damaged buildings causes a CFS-like illness in pediatric patients: a case/control study. Bull IACFS ME. 2009;17(2):69-81.
40. Tang N, Zhang X, Zhang Y, et al. Inhibition of VEGF signaling exacerbates mitochondrial dysfunction and cognitive impairment in a model of neuroinflammation. J Neuroinflammation. 2019;16(1):214. doi:10.1186/ s12974-019-1601-7.
41. Lee RJ, Saban R, Saban M. VEGF and epithelial repair in inflammatory diseases: implications for lung and gut pathology. Am J Physiol Lung Cell Mol Physiol. 2015;308(6):L539-L548.
42. Harmar AJ, Marston HM, Fone KC, et al. The VPAC1 receptor: structure and function in immune modulation and neuroprotection. Br J Pharmacol. 2012;166(2): 447-461.
43. Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune and physiological functions. Nat Rev Neurosci. 2004;5(5):393-406.
44. Shoemaker RC, House DE. Metabolism, molecular hypometabolism and inflammation: Complications of proliferative physiology include metabolic acidosis, pulmonary hypertension, T reg cell deficiency, insulin resistance and neuronal injury. Trends Diabetes Metab. 2020;3(2):1–15
45. Shoemaker RC, House DE, Ryan JC. Defining the neurotoxic signature of chronic inflammatory response syndrome: A case/control study of patients with chronic fatigue syndrome and healthy controls using NeuroQuant. Neurotoxicol Teratol. 2014;45:18-26.
46. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013
2. McMahon S. Mold illness made simple 2.0. Surviving Mold; 2021.
3. Shoemaker RC, Ryan JC. NeuroQuant and CIRS: brain imaging in the biotoxin pathway. Surviving Mold Case Series Report; 2016.
4. Shoemaker RC, McMahon S. NeuroQuant MRI: a tool for tracking brain recovery in chronic inflammatory conditions. Intern Med Rev. 2019;5(7):1-13.
5. Ryan J, Shoemaker R. RNA-Seq on patients with chronic inflammatory response syndrome (CIRS) treated with vasoactive intestinal peptide (VIP) shows a shift in metabolic state and innate immune functions that coincide with healing. Med Res Arch. 2016;4(7):1-11.
6. Shoemaker RC, House DE. Sick building syndrome (SBS) and exposure to water-damaged buildings: time series study, clinical trial, and mechanisms. Neurotoxicol Teratol. 2006;28(5):573-588. PMID: 17010568.
7. Shoemaker RC, Hudnell HK, House DE, van Kempen A, Pakes GE; COL40155 Study Team. Atovaquone plus cholestyramine in patients coinfected with Babesia microti and Borrelia burgdorferi refractory to other treatment: a double-blind, placebo-controlled crossover clinical trial. Adv Ther. 2006;23(1):1-11. doi:10.1007/BF02850341. PMID:16644602.
8. Shoemaker RC,. Surviving Mold: Life in the Era of Dangerous Buildings. Otter Bay Books; 2019
9. McMahon SW, Shoemaker RC, Ryan JC. Reduction in forebrain parenchymal and cortical grey matter swelling across treatment groups in patients with inflammatory illness acquired following exposure to water-damaged buildings. J Neurosci Clin Res. 2016;1(1):1-4.
10. Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM. Elevated immune response in the brain of autistic patients. J Neuroimmunol. 2009;207(1-2):111-116. PMID: 19157572.
11. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011;25(1):40-45. PMID: 20705131.
12. Ryan JC, Wu Q, Shoemaker RC. Transcriptomic signatures in whole blood of patients with chronic inflammatory response syndrome after exposure to water-damaged buildings. BMC Med Genomics. 2015; 8:15.
13. Rose DR, Yang H, Serena G, et al. Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. Brain Behav Immun. 2018; 70:354-368. PMID: 29572185
14. Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015;16(8):469-486. PMID: 26189694.
15. Zilbovicius M, Boddaert N, Belin P, et al. Temporal lobe dysfunction in childhood autism: a PET study. I am J Psychiatry. 2000;157(12):1988-1993. PMID: 11097964
16. Rossignol DA, Frye RE. A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry. 2012;17(4):389-401. PMID: 22158305.
17. Ryan JC, Wu Q, Shoemaker RC. Transcriptomic signatures in whole blood of patients who acquire a chronic inflammatory response syndrome (CIRS) following an exposure to the marine toxin ciguatoxin. BMC Med Genomics. 2015; 8:15. PMID: 25889530.
18. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67-81. PMID: 15622539.
19. Shoemaker RC, House DE, Ryan JC. Structural brain abnormalities in patients with inflammatory illness acquired following exposure to water-damaged buildings: a volumetric MRI study using NeuroQuant®. Neurotoxicol Teratol. 2014; 45:18-26. PMID: 24946038.
20. McMahon S. Longitudinal imaging and biomarker trends in pediatric CIRS patients. Biotoxin Med Res J. 2021;3(2):55-68.
21. Proctor RA, von Eiff C, Kahl BC, et al. Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol. 2006;4(4):295-305. PMID: 16541137.
22. Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science. 1999;284(5418):1318-1322. PMID: 10334980.
23. Donlan RM. Biofilms: microbial life on surfaces. Emerg Infect Dis. 2002;8(9):881-890. PMID: 12194761.
24. Romani L. Immunity to fungal infections. Nat Rev Immunol. 2011;11(4):275-288. PMID: 21394104.
25. Tan NC, Foreman A, Jardeleza C, Wormald PJ. The role of bacterial biofilms in chronic rhinosinusitis and implications for therapy. Am J Rhinol Allergy. 2014;28(1):3-7. PMID: 24717869.
26. Mah TF, O’Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001;9(1):34-39. PMID: 11166241.
27. Parsek MR, Singh PK. Bacterial biofilms: an emerging link to disease pathogenesis. Annu Rev Microbiol. 2003;57:677-701. PMID: 14527295.
28. Ramos S, Barros L, Teixeira A. The role of melanocortins in inflammation and neuroimmune communication. Pharmacol Res. 2021;163:105267. PMID: 33127553.
29. Baraniuk JN, Zheng S, Broderick JE. Cytokines in chronic fatigue syndrome, fibromyalgia, and other overlapping syndromes. Curr Rheumatol Rep. 2005;7(5):387-394. PMID: 16174492.
30. Shoemaker RC, Hudnell HK. HLA genotyping in pediatric mold illness: predictive value and clinical correlation. Neurotoxicol Teratol. 2006;28(5):639-650. PMID: 16982140.
31. Hudnell HK. Visual contrast sensitivity testing in CIRS. Neurotoxicology. 2005;26(4):565-578. PMID: 16112317.
32. James SJ, Melnyk S, Jernigan S, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2009;147B(8):1327-1334. PMID: 19288560.
33. Parks T. Pediatric regression in biotoxin illness: clinical observations and treatment outcomes. J Pediatr Environ Health. 2022;4(1):12-25.
34. Swedo SE, Leckman JF, Rose NR. From PANDAS to PANS: expanding the clinical spectrum of post-infectious autoimmune encephalopathy. J Child Psychol Psychiatry. 2012;53(10):1047-1055. PMID: 22924 360.
35. Fallon BA, Levin ES, Schweitzer PJ, Hardesty D. Inflammation and central nervous system Lyme disease. Neurobiol Dis. 2010;37(3):534-541. PMID: 19944760.
36. Shoemaker RC, House DE. A time-series study of sick building syndrome: chronic, biotoxin-associated illness from exposure to water-damaged buildings. Neurotoxicol Teratol. 2005;27(1):29-46. PMID: 1568 1119.
37. Napoli E, Wong S, Giulivi C. Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Biochim Biophys Acta. 2013;1832(10):1620-1630. PMID: 23706623.
38. McMahon SW, Smith J. Pediatric Quirks of CIRS and PANS. Paper presented at: Surviving Mold Annual Conference; May 4th, 2018; Salisbury, MD.
39. Shoemaker RC, Maizel MS. Exposure to interior environments of water-damaged buildings causes a CFS-like illness in pediatric patients: a case/control study. Bull IACFS ME. 2009;17(2):69-81.
40. Tang N, Zhang X, Zhang Y, et al. Inhibition of VEGF signaling exacerbates mitochondrial dysfunction and cognitive impairment in a model of neuroinflammation. J Neuroinflammation. 2019;16(1):214. doi:10.1186/ s12974-019-1601-7.
41. Lee RJ, Saban R, Saban M. VEGF and epithelial repair in inflammatory diseases: implications for lung and gut pathology. Am J Physiol Lung Cell Mol Physiol. 2015;308(6):L539-L548.
42. Harmar AJ, Marston HM, Fone KC, et al. The VPAC1 receptor: structure and function in immune modulation and neuroprotection. Br J Pharmacol. 2012;166(2): 447-461.
43. Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune and physiological functions. Nat Rev Neurosci. 2004;5(5):393-406.
44. Shoemaker RC, House DE. Metabolism, molecular hypometabolism and inflammation: Complications of proliferative physiology include metabolic acidosis, pulmonary hypertension, T reg cell deficiency, insulin resistance and neuronal injury. Trends Diabetes Metab. 2020;3(2):1–15
45. Shoemaker RC, House DE, Ryan JC. Defining the neurotoxic signature of chronic inflammatory response syndrome: A case/control study of patients with chronic fatigue syndrome and healthy controls using NeuroQuant. Neurotoxicol Teratol. 2014;45:18-26.
46. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013