[back] Fever

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.
— Hypothesis—
According to epidemiological studies, autism, a neurodevelopmental disorder, is increasing in the pediatric population [1]. In 1966 the prevalence rate was 4-5/10,000 births [2], while two recent studies show prevalence rates of 14.9/10,000 [1] and 34/10,000 [3]. This apparent increase raises concerns about an autism epidemic.

In 1943, Kanner [4] 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 [5], and etiologies based on infectious [6], 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 [13] 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 [9]. 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 [23]. 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 [24].

Fever is metabolically expensive: every 1oC rise in temperature increases the metabolic rate approximately 10% [25]. 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 [36]. The use of antipyretics to suppress fever results in an increased mortality rate in bacterially infected rabbits [37] and an increase in influenza virus production in ferrets [38]. Brain hyperthermia markedly exacerbates neuronal injury [39]. 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. [40] 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 [41].

Ozato et al. [42] 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) [42]. 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 [44].

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 [45]. 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 [46].

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 [47]. It has recently been shown that AP added directly to splenocyte cultures inhibited the in vitro antibody response without affecting cell viability [48]. Other immune effects include an impairment of TNF-alpha release [49] and a 10-20-fold increase of monocyte chemoattractant protein (MCP-1) and chemokine receptor (CCR) from liver Kupffer cells (macrophages) [50]. 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 [51]. 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.

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Copyright © 2003, A. R. Torres, M.D., Utah State University, All rights reserved.