A Causal Theory of Autism: Is fever suppression involved in the etiology of autism and neurodevelopmental disorders?
by Anthony R. Torres, M.D.
Copyrighted and submitted for publication 1/15/03
Is fever suppression involved in the etiology of autism and neurodevelopmental disorders?
— Abstract —
There appears to be a significant increase in the prevalence rate of autism. Reasons for the increase are unknown, however, there is a substantial body of evidence that suggests the etiology involves infections of the pregnant mother or of a young child. Most infections result in fever that is routinely controlled with antipyretics such as acetaminophen. The blocking of fever inhibits processes that evolved over millions of years to protect against microbial attack. Immune mechanisms in the central nervous system are part of this protective process.
The blockage of fever with antipyretics interferes with normal immunological development in the brain leading to neurodevelopmental disorders such as autism in certain genetically and immunologically disposed individuals.
Testing the hypothesis
Epidemiological studies to determine associations between the use of anti-pyretics and neurodevelopmental disorders should be undertaken. Biochemical tests will involve the examination of fluids/serum by mass spectrometry and the determination of cytokine/chemokine levels in serum and cell culture fluids after stimulation with fever inducing molecules from bacteria, viruses and yeast. Postmortem brain can be examined by immunohistochemistry to determine altered levels of chemokines/cytokines and other proteins.
Implications of the hypothesis
1) The use of antipyretics during pregnancy or in young children may be reserved for more severe fevers. 2) The perplexing genetic findings in autism may be better understood by categorizing genes along functional pathways. 3) New treatments based on immune, cell, pharmacological or even heat therapies may be developed.
According to epidemiological studies, autism, a neurodevelopmental disorder, is increasing in the pediatric population . In 1966 the prevalence rate was 4-5/10,000 births , while two recent studies show prevalence rates of 14.9/10,000  and 34/10,000 . This apparent increase raises concerns about an autism epidemic.
In 1943, Kanner  described autism as a neurodevelopmental disorder with impairments in social interactions, restricted stereotyped interests, and abnormalities in verbal and nonverbal behavior. Little is known about the etiology, and the diagnosis of autism is done by behavioral criteria as no biomarkers have yet been identified. There is a strong familial component to autism , and etiologies based on infectious , autoimmune [7,8,9,10], and cytokine factors [11,12] have been proposed.
About 40% of parents with autistic children report that their seemingly normal children experienced developmental regression after being vaccinated. However, the theory of vaccines or adjuvants being involved in the etiology  has little support as epidemiological studies have failed to show an association with the measles, mumps, and rubella (MMR) vaccine [14,15,16] and autism.
It has been reported that 43% of mothers with an autistic child experience upper respiratory tract, influenza-like, urinary, or vaginal infections during pregnancy compared to only 26% of control mothers . This suggests that certain cases of autism may be a sequela of pathogenic infections, especially those of a viral origin [17,18,19].
There is no overt pathological lesion in autism, however, subtle abnormalities in the cerebellum, hippocampal fields CA1-CA4, entorhinal cortex, amygdala, behavioral differences and imbalances in cytokines and brain growth factors suggest that abnormal brain development is important in the pathogenesis [20,21,22].
Pathological infections, including vaccinations, commonly result in fever. For example, 50-60% of young children develop fever after receiving the MMR vaccine . Fever is defined as an increase in the normal set point of body temperature. During the rising phase of fever, normal body temperature is below the new set point and the body, being hypothermic, uses several heat conserving and heat generating physiological reflexes, as well behavioral responses, to raise body temperature. The breaking of fever results in a variety of heat-losing reflexes and behavioral responses to lower body temperature.
There are two related fever pathways. The intraperitoneal injection of lipopolysaccharide (LPS), a potent pyrogen, results in the production of various cytokines from organs in the viscera. A signal from IL-1$ is thought to initiate afferent information traveling from the vagus nerve to the hypothalamus to increase hypothalamic IL-1$. This in turn causes an increase in hypothalamic IL-6, which raises the thermoregulatory set point. This pathway is mediated via prostaglandins that can be blocked by cyclooxygenase inhibitors (antipyretics). The second fever pathway, also initiated in the hypothalamus by afferent signals from the vagus nerve, is mediated by locally produced macrophage inflammatory protein-1 (MIP-1), a chemokine. MIP-1 appears to act directly on the anterior hypothalamus via a non-prostaglandin mechanism .
Fever is metabolically expensive: every 1oC rise in temperature increases the metabolic rate approximately 10% . It stands to reason that a defense mechanism that evolved over millions of years and is so costly in terms of energy must be important. Numerous studies have shown that fever enhances the immune response by increasing mobility and activity of white cells, stimulating the production of interferon, causing the activation of T-lymphocytes, and indirectly reducing plasma iron concentrations [24,25,27,28]. Antiviral and antibacterial properties of interferon are also increased at febrile temperatures [29,30]. A decreased morbidity and mortality rate has been associated with fever in a variety of infections [31,32,33,34,35]. Newborn animals infected with a variety of viruses have a higher survival rate when febrile . The use of antipyretics to suppress fever results in an increased mortality rate in bacterially infected rabbits  and an increase in influenza virus production in ferrets . Brain hyperthermia markedly exacerbates neuronal injury . There is anecdotal evidence that children with autism show behavioral improvement when febrile (D. Odell, personal communications, 2003).
Sequestering fever during pregnancy may have effects on the fetus. Goetzl et al.  have shown that the treatment of epidural fever with acetaminophen significantly decreased maternal and fetal serum IL-6 levels at the time of birth. This may be significant, as it appears that the fetus is incapable of producing IL-6 at the time of birth and is dependent on maternal IL-6 .
Ozato et al.  described the response of cell-surface toll-like receptors (TLRs) upon binding to microbial pathogens. There are at least 10 TLRs that recognize ligands from bacteria, viruses, yeast, and nucleic acids from viruses. There is a high binding specificity of the different TLRs for each microbial structure referred to as pathogen-associated molecular patterns (PAMPs) . The best studied is TLR4 that binds LPS from gram-negative bacteria. The ligation of LPS to cell surface TLR4 initiates a signal cascade that results in the activation of intracellular nuclear factor kappa beta (NF6B) and the transcription of numerous genes involved in immune responses. This signaling pathway appears to be common to all the TLRs whether the PAMPs originate from bacteria, virus, or yeast. TLR are mainly expressed myeloid lineage cells including macrophages, granulocytes and dendritic cells.
The central nervous system exhibits a similar immune reaction to pathogenic infection. The binding of LPS to TLR on microglia cells (brain macrophage) leads to the expression of cytokines, chemokines, extracellular matrix proteins, proteolytic enzymes, and complement proteins in the brain parenchyma [43,44]. The release of the many different cytokines and chemokines produced by microglia cells exert a diversity of actions in neurodevelopment as well as neurodegeneration .
Fever is generally considered harmful by physicians and is treated with antipyretics as it may lead to febrile seizures, stupor, dehydration, increased breathing, discomfort, and tachycardia . Home use of antipyretics upon the first signs of a fever is also common. This approach has lead to the ubiquitous use of aspirin, acetaminophen, nimesulide, and ibuprofen, which control temperature by inhibiting prostaglandin synthesis in the hypothalamus. Aspirin it is not currently used in the pediatric population due to an association with Reye’s syndrome .
Acetaminophen (AP), the most widely used medication, is considered safe when used at pharmacological doses. High doses of AP can lead to liver failure and death without proper emergency treatment. Although the hepatotoxic actions of AP have been extensively researched, there is evidence that it is also an immunosuppressive agent. Suppression of the delayed hypersensitivity response and mixed lymphocyte reaction occur in mice fed AP . It has recently been shown that AP added directly to splenocyte cultures inhibited the in vitro antibody response without affecting cell viability . Other immune effects include an impairment of TNF-alpha release  and a 10-20-fold increase of monocyte chemoattractant protein (MCP-1) and chemokine receptor (CCR) from liver Kupffer cells (macrophages) . These studies suggest that the AP directly effects immune cells and is not a secondary response to AP-hepatitis.
Presentation of the hypothesis
The premise of this theory is that the blockage of fever with antipyretics interferes with normal immunological development in the brain, leading to neurodevelopmental disorders in certain genetically and immunologically disposed individuals. The effects may occur in utero or at a very young age when the immune system is rapidly developing.
Testing the hypothesis
The experimental avenues below can be used to test the theory:
1) Epidemiological studies to determine any association between the use antipyretics and neurodevelopment disorders.
2) Peripheral blood cells from subjects with neurodevelopmental disorders and controls can be examined in culture for chemokine/cytokine production after stimulation with bacterial, viral, or yeast PAMPs.
3) An example of infection postulated to progress to neurological abnormalities goes by the acronym PANDAS for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections . This disorder could be examined as a model for understanding the immune system in autistic subjects.
4) Postmortem brain can be examined by immunohistochemistry to determine altered expression of chemokine/cytokine, complement, extracellular matrix, and HLA proteins.
5) Serum samples can be evaluated by analytical methods in an attempt to detect biomarkers.
6) Animal models can be tested in vivo to determine the neurodevelopmental effects of fever.
Implications of the hypothesis
Several important changes may result from studies designed to test the theory:
1) The use of antipyretics during pregnancy or in young children may be reserved for more severe fevers.
2) Many of the perplexing genetic findings in autism may be better understood by categorizing genes along functional pathways.
3) The discovery of specific immune defects may suggest new therapies for neurodevelopment disorders. These treatments may be based on immune, cell, pharmacological or even heat therapies that alter the CNS immune system.
List of abbreviations: Defined in text.
Competing interests: None declared.
David Ward at Yale University, Dennis Odell and Virgil Caldwell at Utah State University for thoughtful comments on the manuscript and Melanie Fillmore for proofreading.
1) Croen LA, Grether JK, Hoogstrate J, Selvin S: The Changing Prevalence of Autism in California. J of Autism and Dev Disorders 2002, 32#3: 207-215
2) Lotter V: Epidemiology of autistic conditions in young children. I. Prevalence. Social Psychiatry 1966, 1: 163-173
3) Yeargin-Allsopp M, Rice C, Karapurkar T, Doerberg N, Boyle C, Murphy C: Prevalence of Autism in a US Metropolitan Area. JAMA 2003, 289(1): 49-55
4) Kanner L: Autistic disturbances of affective contact. Nervous Child 1943, 2: 217-250
5) Turner M, Barnby G, Bailey A: Genetic clues to the biological basis of autism. Mol Med Today 2000, 6: 238- 244
6) Binstock T: Intra-monocyte pathogens delineate autism subgroups. Med Hypotheses 2001, 56: 523-531
7) Money J, Bobrow NA, Clark FC: Autism and autoimmune disease: a family study. J Autism Child Schizophr 1971, 1: 146-160
8) Burger RA, Warren RP: Possible immunogenetic basis for autism. Ment Retard Dev Disabil Res Rev 1998, 4: 137-141
9) Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN: Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol 1999, 14(6): 388-394
10) Torres AR, Maciulis A, Stubbs EG, Cutler A, Odell D: The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum disorder. Human Immunol 2002, 63: 311-316
11) Jyonouchi H, Sun S, Le H: Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J of Neuroimmunol 2001, 120: 170-179
12) Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M: Activation of the inflammatory response in autism. Neuropsychobiol 2002, 45(1): 1-6
13) Wakefield AJ, Puleston JM, Montgomery SM, Anthony A, O’Leary JJ, Murch SH: Review article: the concept of cntero-colonic encephalopathy, autism and opioid receptor ligands. Aliment Pharmacol Ther 2002, Apr;16(4): 636-674
14) Halsey NA, Hyman SL; Conference Writing Panel. Measles-mumps-rubella vaccine and autistic spectrum disorder: report from the New Challenges in Childhood Immunizations Conference convened in Oak Brook, Illinois. June 12-13, 2000. Pediatrics 2001, May;107(5): E84
15) Madsen KM, Hviid, Vestergaard M, et al: A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 2002, 347: 1477-1482
16) Taylor B, Miller E, Lingam R, Andrews N, Simmons A, Stowe J: Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study. BMJ 2002, 324: 393-396
17) Ciaranello AL, Ciaranello RD: The neurobiology of infantile autism. Annu Rev Neurosci 1995, 18: 101-128
18) Hornig M, Weissenbock H, Horscroft N, Lipkin WI: An infection-based model of neurodevelopmental damage. Proc Natl Acad Science 1999, 96(21): 12102-12107
19) Patterson PH: Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness. Curr Opin Neurobiol 2002, 12: 115-118
20) Kemper TL, Bauman M: Neuropathology of infantile autism. J. Neuropathol Exp Neurol 1998, 57: 645-652
21) Sweeten TL, Posey DJ, Shekhar A, McDougle CJ: The amygdala and related structures in the pathophysiology of autism. Pharmacol Biochem Behavior 2002, 71: 449-455
22) Nelson KB, Grether JK, Croen LA, Dambrosia JM, Dickens BF, Jelliffe LL, Hansen RL, Phillips TM: Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol 2001, 49: 597-606
23) Stuck B, Stehr K, Bock HL: Concomitant administration of varicella vaccine with combined measles, mumps and rubella vaccine in healthy children aged 12 to 24 months of age. Asian Pac J Allergy Immunol 2002, Jun;20(2): 113-120
24) Kluger MJ, Leon LR, Kozak W, Soszynski D, Conn CA: Cytokine Actions On Fever. In: Cytokines in the Nervous System (Edited by Rothwell NJ) Pub. RG Landes Company 1996, 5: 73-92
25) Kluger MJ: Fever: Role of Pyrogens and Cryogens. Physiological Reviews 1991, 71(1): 93-127
26) Hanson DG, Murphy PA, Silican R, Shin H.S: The effect of temperature on the activation of thymocytes by interleukin I and II. J Immunol 1983, 130: 216-221
27) Jampel HD, Duff GW, Gershon RK, Atkins E, Durum SK: Fever and immunoregulation. III. Hyperthermia augments the primary in vitro humoral immune response. J Exp Med 1983, 157: 1229-1238
28) Roberts NJ, Jr, Steigbigel RT: Hyperthermia and human leukocyte functions: effects of response of lymphocytes to mitogens and antigens and bacterial capacity of monocytes and neutrophils. Infect Immun 1977, 18: 673-679
29) Heron I, Berg K: The actions of interferon are potentiated at elevated temperature. Nature Lond. 1978. 274: 508-510
30) Yerushalmi A, Tovey M, Gresser I: Antitumor effect of combined interferon and hyperthermia in mice. Proc Soc Exp Biol Med 1982, 169: 413-415
31) Bryant TE, Hood AF, Hood CE, Loenig MG: Factors affecting mortality of gram-negative rod bacteremia. Arch Intern Med 1971, 127: 120-128
32) Hoefs J, Sapico FL, Canawati HN, Montgomerie JZ: The relationship of white blood cells (WBC) and pyrogenic response to survival in spontaneous bacterial peritonitis (SBP). Gastroenterology 1980, 78: 1308
33) Mackowiak PA, Browne RG, Southern PM, Jr, Smith JW: Polymicrobial sepsis: an analysis of 184 cases using log linear models. Am J Med Sci 1980, 280: 73-80
34) Weinstein MP, Iannini PB, Stratton CW, Eickhoff TC: Spontaneous bacterial peritonitis. A review of 28 cases with emphasis on improved survival and factors influencing prognosis. Am J Med 1978, 64: 592-598
35) Yerushalmi A, Wolff A: Traitement du coryza et des rhinites persistantes allergizues par la thermotherapie. C.R. Hebd Seances Acad Sci Ser D Sci Nat 1980, 291: 119-124
36) Haahr S, Mogensen S: Function of fever. Lancet 1977 2: 613
37) Vaughn LK, Veale WL, Cooper KE: Antipyresis effect on mortality rate of bacterially infected rabbits. Brain Res Bull 1980, 5: 69-73
38) Husseini RH, Sweet C, Collie MH, Smith H: Elevation of nasal viral levels by suppression of fever in ferrets infected with influenza viruses of differing virulence. J Infect Dis 1982, 145: 520-524
39) Busto R, Dietrich WD, Globus MY, Valdes I, Scheinberg P, Ginsberg MD: Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987, 7: 729-738
40) Goetzl L, Evans T, Rivers J, Suresh MS, Lieberman E: Elevated maternal and fetal serum interleukin-6 levels are associated with epidural fever. Am J Obstet Gynecol 2002, Oct;187(4): 834-8.
41) De Jongh RF, Puylaert M, Bosman E, Ombelet W, Maes M, Heylen R: The fetomaternal dependency of cord blood interleukin-6. J of Perinatol 1999, 16(3): 121-128
42) Ozato K, Tsujimura H, Tamura T: Toll-like Receptor Signaling and Regulation of Cytokine Gene Expression in the Immune System. BioTechniques 2002, October;33:(suppl): S66-S75
43) Aloisi F: Immune Function of Microglia. Glia 2001, 36: 165-179
44) Nguyen MD, Julien JP, Rivest S: Innate Immunity: The missing link in neuroprotection and neurodegeneration? Nature Reviews/ Neuroscience 2002, Vol.3;March: 2216-227
45) Chandra J, Bhatnagar SK: Antipyretics in children. Indian J Pediatr 2002, Jan;69(1): 69-74
46) Hurwitz ES, Barrett MJ, Bregman D, Gunn WJ, Pinsky P, Schonberger LB, Drage JS, Kaslow RA, Burlington DB, Quinnan GV, et al: Public Health Services study of Reye’s syndrome and medications. Report of the main study. JAMA 1987, Apr 10;257(14): 1905-1911
47) Ueno K, Yamaura K, Nakamura T, Satoh T, Yano S. Acetaminophen-induced immunosuppression associated with hepatotoxicity in mice. Res Commun Mol Pathol Pharmacol 2000, 108(3-4): 237-51
48) Yamaura K, Ogawa K, Yonekawa T, Nakamura T, Yano, Ueno K: Inhibition of antibody production by acetaminophen independent of liver injury in mice. Biol Pharm Bull 2002, Feb;25(2): 201-205
49) Nastevska C, Gerber E, Horbach M, Rohrdanz E, Kahl R: Impairment of TNF-alpha expression and secretion in primary rat liver cell cultures by acetaminophen treatment. Toxicology 1999, April15;133(2-3): 85-92
50) Dambach DM, Watson LM, Gray KR, Durham SK, Laskin DL: Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse. Hepatology 2002, May;35(5): 1093-1103
51) Swedo SE, Garvey M, Snider L, Hamilton C, Leonard H: The PANDAS Subgroup: Recognition and Treatment. CNS Spectrum 2001, May 6(5): 419-42
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