Acute Sickness Response Research Articles

Neurocognitive disturbances associated with acute infectious mononucleosis, Ross River fever and Q fever: A preliminary investigation of inflammatory and genetic correlates

Disturbances in neurocognitive performance are a core feature of the acute sickness response to infection; however the underlying mechanisms remain unclear. The current study used a computerised battery to assess neurocognitive functioning in subjects enrolled in the Dubbo Infection Outcomes Study (n=107) - a prospective cohort of subjects followed from documented acute infection with Epstein Barr virus, Ross River virus, or Coxiella burnetii until recovery. Subjects were assessed when ill, and a subset again after complete recovery. Associations between sickness-related cognitive disturbances and single nucleotide polymorphisms (SNPs) in cytokine (interleukin [IL]-6, IL-10, tumor necrosis factor-α and interferon-γ) and neurobehavioral genes (serotonin transporter and catechol-O-methyltransferase) were explored. During acute infection, subjects exhibited slower matching-to-sample responses (p=0.03), poorer working memory capacity (p=0.014), mental planning (p=0.045), and dual attention task performance (p=0.02), and required longer to complete discordant Stroop trials (p=0.01) compared to recovery. Objective impairments correlated significantly with self-reported symptoms (p<0.05) as well as levels of the inflammation marker, C-reactive protein (p=0.001). Linear regression analysis identified an association between neurocognitive disturbance during acute illness and functional polymorphisms in inflammatory cytokine genes. Specifically, the high cytokine producing G allele of the IL-6-174G/C SNP was associated with poorer neurocognitive performance when subjects were ill (p=0.027). These findings confirm that acute infection impacts on neurocognitive performance, manifesting as slowed responses and impaired performance on complex tasks requiring higher-order functioning which has important real-world implications. The data provide the first preliminary evidence for a role of a genetic predisposition to more intense inflammatory responses in objective neurocognitive disturbances during acute infections. These associations require replication in a larger sample size.

Mood disturbance after infection

An aetiological link between acute infection and major depression has long been hypothesized, and is increasingly gaining recognition within contemporary literature. This review aims to examine the evidence for such a link, specifically between acute, self-limiting infection and major depression, and to summarize the current understanding of pathophysiological mechanisms underlying this link. Relevant articles were sourced via an online search of published literature from Embase, MEDLINE, PsycINFO and PubMed using a variety of search terms including mood disorder, depression, infection and inflammation. Additionally, a search for articles from the bibliographies of retrieved papers was conducted. Findings from retrospective studies suggest an association between infection and subsequent mood disturbance, including major depression. This association has been confirmed by studies employing prospective observational or experimental challenge designs. The available evidence supports a multifactorial basis of vulnerability towards major depression in the context of acute infection. Genetic, neuroendocrine, autonomic and psychosocial factors may interact to potentiate the likelihood of a severe and prolonged depressive response to an immunological stressor in some individuals. Mood disturbance is likely to have a host-protective role in the context of an acute sickness response to infection. However, this usually adaptive and reversible response may progress in some vulnerable individuals into a more sustained and severe pattern of behavioural and physiological changes of major depression. Further research is needed to delineate the factors that predispose, precipitate and perpetuate depression in the context of acute infective illness. Such insights will inform effective prevention and treatment strategies.

26. Polymorphisms in both immune and behavioural genes affect mood as part of the acute sickness response to infection

The host response to infection triggers a distinct set of physiological and behavioural changes termed the acute sickness response. Although this response is universal, individuals differ considerably in terms of the overall severity and the specific manifestations of acute sickness symptoms – suggesting host determinants. We have previously reported a strong link between genetic variations in the intensity of the inflammatory response and the severity of the acute sickness across varied infections. Here we examined the impact of polymorphisms in cytokine [tumour necrosis factor (TNF)- α , interleukin (IL)-6, IL-10, interferon (IFN)- γ ; and the chemokine CCR5] and behavioural genes involved in the stress-response [neuropeptide Y (NPY) and monoamine oxidase A (MAOA)] on mood disturbance associated with infection in the Dubbo Infection Outcomes Study ( n = 296). Mood disturbance during infection was significantly increased by variants in cytokine genes that enhanced immune activity [IL-10-592A/C ( p = 0.04); IL-6-174 G/C ( p = 0.05); ‘wild type’ CCR5 ( p = 0.4)]; by several polymorphisms in the NPY gene linked to ‘low expression’ of NPY ( p s p = 0.03). In combination, immune and behavioural genes vulnerabilities acted synergistically to increase the likelihood of severe mood disturbance by up to 16-fold ( p = 0.004). These data provide novel insights into the complexity of genetic influences on the manifestations of the acute sickness response and shed light on the pathophysiology of post-infective depression.

Acute mountain sickness, chemosensitivity, and cardiorespiratory responses in humans exposed to hypobaric and normobaric hypoxia

We examined the control of breathing, cardiorespiratory effects, and the incidence of acute mountain sickness (AMS) in humans exposed to hypobaric hypoxia (HH) and normobaric hypoxia (NH), and under two control conditions [hypobaric normoxia (HN) and normobaric normoxia (NN)]. Exposures were 6 h in duration, and separated by 2 wk between hypoxic exposures and 1 wk between normoxic exposures. Before and after exposures, subjects (n = 11) underwent hyperoxic and hypoxic Duffin CO2 rebreathing tests and a hypoxic ventilatory response test (HVR). Inside the environmental chamber, minute ventilation (V(E)), tidal volume (V(T)), frequency of breathing (fB), blood oxygenation, heart rate, and blood pressure were measured at 5 and 30 min and hourly until exit. Symptoms of AMS were evaluated using the Lake Louise score (LLS). Both the hyperoxic and hypoxic CO2 thresholds were lower after HH and NH, whereas CO2 sensitivity was increased after HH and NH in the hypoxic test and after NH in the hyperoxic test. Values for HVR were similar across the four exposures. No major differences were observed for Ve or any other cardiorespiratory variables between NH and HH. The LLS was greater in AMS-susceptible than in AMS-resistant subjects; however, LLS was alike between HH and NH. In AMS-susceptible subjects, fB correlated positively and Vt negatively with the LLS. We conclude that 6 h of hypoxic exposure is sufficient to lower the peripheral and central CO2 threshold but does not induce differences in cardiorespiratory variables or AMS incidence between HH and NH.

Aging leads to prolonged duration of inflammation-induced depression-like behavior caused by Bacillus Calmette-Guérin.

Geriatric depression is a costly health issue, but little is known about its physiological underpinnings. Systemic inflammation sensitizes the innate immune system of aged animals and humans, but it is unknown if chronic, low-grade infections affect the duration of depressive-like behaviors. In this report, we infected adult (4-6 months) and aged (20-24 months) Balb/c mice with an attenuated strain of Mycobacterium bovis, Bacillus Calmette-Guérin (BCG), to induce a chronic infection. We then measured depression-like behaviors that have construct, face and predictive validity for human inflammation-associated clinical depression. Exposure to BCG caused acute sickness responses in both adult and aged mice. However, sickness behavior was prolonged in aged mice, as assessed by both locomotor and rearing activity. Two measures of depression-like behavior, which were tests involving sucrose preference and tail suspension, both showed that adult mice displayed depression-like behaviors at one day and seven days after exposure to BCG. However, aged mice continued to express both of these depression-like behaviors at three weeks following infection. Infection with BCG caused an increase in tryptophan catabolism, as evidenced by a significant rise in the plasma kynurenine/tryptophan ratio that peaked at 7 days post-infection. In aged mice, greater tryptophan catabolism persisted longer and remained elevated at 21 days post-infection. This finding is consistent with the prolonged duration of depression-like behaviors in aged mice. These are the first data using a chronic infection model to establish that recovery from inflammation-induced depression-like behavior and tryptophan catabolism are prolonged in aged animals.

Fatigue after infection: aetiology and pathophysiology

Individuals suffering from acute infections typically experience systemic symptoms, including fever and musculoskeletal pain, as well as fatigue. Acute infections are also accompanied by increased slow wave sleep and stereotyped behavioural responses, including reduced motor activity, social withdrawal and anorexia. These manifestations are collectively termed the ‘acute sickness response’. The action of pro-inflammatory cytokines, such as interleukin (IL)-1 and IL-6 on the central nervous system mediate the key features of the response. In the great majority of cases, these constitutional symptoms, including fatigue, resolve in parallel with the fever. However, in a minority, a disabling fatigue statemay persist forweeks,months or (rarely) years. Many of the features of the acute sickness response remain evident in the prolonged fatigue state.

Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut–brain axis

The gut–brain axis refers to the bidirectional communication between the gut and the brain. Four information carriers (vagal and spinal afferent neurons, immune mediators such as cytokines, gut hormones and gut microbiota-derived signalling molecules) transmit information from the gut to the brain, while autonomic neurons and neuroendocrine factors carry outputs from the brain to the gut. The members of the neuropeptide Y (NPY) family of biologically active peptides, NPY, peptide YY (PYY) and pancreatic polypeptide (PP), are expressed by cell systems at distinct levels of the gut–brain axis. PYY and PP are exclusively expressed by endocrine cells of the digestive system, whereas NPY is found at all levels of the gut–brain and brain–gut axis. The major systems expressing NPY comprise enteric neurons, primary afferent neurons, several neuronal pathways throughout the brain and sympathetic neurons. In the digestive tract, NPY and PYY inhibit gastrointestinal motility and electrolyte secretion and in this way modify the input to the brain. PYY is also influenced by the intestinal microbiota, and NPY exerts, via stimulation of Y1 receptors, a proinflammatory action. Furthermore, the NPY system protects against distinct behavioural disturbances caused by peripheral immune challenge, ameliorating the acute sickness response and preventing long-term depression. At the level of the afferent system, NPY inhibits nociceptive input from the periphery to the spinal cord and brainstem. In the brain, NPY and its receptors (Y1, Y2, Y4, Y5) play important roles in regulating food intake, energy homeostasis, anxiety, mood and stress resilience. In addition, PP and PYY signal to the brain to attenuate food intake, anxiety and depression-related behaviour. These findings underscore the important role of the NPY-Y receptor system at several levels of the gut–brain axis in which NPY, PYY and PP operate both as neural and endocrine messengers.

Point: Counterpoint: Hypobaric hypoxia induces/does not induce different responses from normobaric hypoxia

Point: Counterpoint: Hypobaric hypoxia induces/does not induce different responses from normobaric hypoxia

Dipyrone attenuates acute sickness response to lipopolysaccharide in mice

Sickness behavior appears to be the expression of a central motivational state that reorganizes the organism's priorities to cope with infectious pathogens. To evaluate the effect of dipyrone in lipopolysaccharide (LPS)-induced sickness behavior, mice were subjected to the forced swim test (FST), tail suspension test (TST), dark–light box test, open field test, sucrose preference intake test and food intake test. LPS administration increased the immobility time in the TST, increased the time spent floating in the FST, and depressed locomotor activity in the open field test. Treatment with LPS decreased the total number of transitions made between the dark and light compartments of the apparatus and induced anhedonia and anorexia. Pre-treatment with dipyrone (10, 50, or 200mg/kg) attenuated behavioral changes induced by LPS in the FST, TST, open field and light–dark box tests. In addition, dipyrone prevented anhedonia and anorexia in mice challenged with LPS. Considering that dipyrone attenuates LPS-induced behavioral changes, it is proposed that LPS-induced sickness behavior is dependent on the COX pathway.

Genetic associations of fatigue and other symptom domains of the acute sickness response to infection

The acute sickness response to infection is a conserved set of changes in physiology and behaviour, featuring fever, fatigue, musculo-skeletal pain, disturbed mood, and cognitive difficulties. The manifestations differ somewhat between individuals, including those infected with pathogens which do not have genetic variability--suggesting host determinants. Principal components analysis (PCA) was applied to acute phase, self-report symptom data from subjects in the Dubbo Infection Outcomes Study (n=296) to empirically derive indices of fatigue, pain, neurocognitive difficulties, and mood disturbance, as well as overall illness severity. Associations were sought with functional single nucleotide polymorphisms (SNPs) in the cytokine genes, interleukin (IL)-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-10. The summed individual symptom indices correlated with overall severity and also with functional status. The relative contribution of individual symptom domains to the overall illness was stable over time within subjects, but varied between subjects with the same infection. The T allele of the IFN-γ +874 T/A SNP was associated with increased fatigue (p=0.0003; OR: 3.3). The C allele of the IL-10 -592 C/A SNP exerted a protective effect on neurocognitive difficulties (p=0.017; OR: 0.52); while the A allele for the IL-10 -592 SNP was associated with increased mood disturbance (p=0.044; OR: 1.83), as was the G allele of the IL-6 -174 G/C SNP (p=0.051; OR: 1.83). The acute sickness response has discrete symptom domains including fatigue, which have unique genetic associations. These data provide novel insights into the pathophysiology of fatigue states.

Sickness Response Symptoms among Healthy Volunteers after Controlled Exposures to Diesel Exhaust and Psychological Stress

Background: Interactions between acute exposures to environmental chemical contaminants and psychological stress may be important in situations where they are likely to co-occur, ranging in intensity from daily urban living to participation in war. Modification of symptomatic responses by stress may play a role in medically unexplained symptoms attributed to low-level chemical exposures.Objectives: We hypothesized that the combination of exposure to diesel exhaust (DE) and acute psychological stress would cause sickness responses in healthy volunteers. Moreover, these responses would be greater in individuals with self-reported prior chemical odor intolerance.Methods: One hundred adult subjects underwent 1-hr exposures to diluted DE and clean air control. Half of the subjects performed a public-speaking stressor task during the exposures. Subjects completed questionnaires to determine their Chemical Odor Intolerance Index score. Plasma cortisol, end-tidal carbon dioxide, and the severity of 35 symptoms were measured at time points before and after the exposures.Results: Subjects exposed to DE demonstrated small but statistically significant increases in severity for several symptom categories, including sickness response and upper respiratory, central nervous system, and total symptoms. The psychological stressor did not increase symptom severity independently or via interaction with DE. Subjects with prior self-reported chemical intolerance had more severe sickness response symptoms from DE.Conclusions: These results suggest that exposure to DE can cause acute sickness response symptoms and that these symptoms are also associated with increased levels of self-reported chemical intolerance. The results did not confirm our hypothesis that an acute stressor would increase sickness response symptom severity during the exposure.

The Lack of Associations Between Alleles at the Hypoxia-Inducible Factor 1A C1772T Loci and Responses to Acute Hypoxia

The aim of this study was to investigate the associations between alleles of the hypoxia-inducible factor 1A (HIF1A) C1772T polymorphism and several physiological responses to hypoxia, including the hypoxic ventilatory response (HVR), and serum erythropoietin (EPO), arterial oxygen saturation (Sao2), and acute mountain sickness (AMS) responses during 8 hours of exposure to normobaric hypoxia. A total of 76 males participated in the study; 52 participants completed an 8-hour exposure to 12.7% oxygen, during which time Sao2, EPO concentrations, and AMS scores were measured, while 62 individuals took part in an HVR trial (in total 38 individuals completed both protocols). DNA was obtained from leukocytes, and a 346-bp fragment of the HIF1A gene containing the C1772T polymorphism was amplified using polymerase chain reaction. Fragments were sequenced to reveal individual genotypes, and the associations between HIF1A genotype and EPO, Sao2, AMS responses to hypoxia and HVR were examined. The magnitude of the hypoxic responses was highly variable between individuals. The increase in participants' EPO responses ranged from 89% to 388% of baseline values following hypoxia, while Sao2 values during the exposure ranged from 71% to 89%. The HVR ranged from -0.04 to +2.18 L x min(-1) x Sao2 %(-1) among participants. No significant differences in EPO, Sao2, AMS, or HVR results were observed between the HIF1A CC genotype and the combined CT/TT genotype group. In this study, the HIF1A C1772T polymorphism does not appear to influence EPO, Sao2, or AMS responses during acute hypoxic exposure, or the magnitude of the HVR.

Cytokine Polymorphisms Have a Synergistic Effect on Severity of the Acute Sickness Response to Infection

Functional polymorphisms in immune response genes are increasingly recognized as important contributors to the marked individual differences in susceptibility to and outcomes of infectious disease. The acute sickness response is a stereotypical set of illness manifestations mediated by the proinflammatory cytokines induced by many different pathogens. The genetic determinants of severity of the acute sickness response have not previously been explored. We examined the impact of functional polymorphisms in cytokine genes with critical roles in the early immune response (tumor necrosis factor-alpha, interleukin-6, interleukin-10, and interferon-gamma) on the severity and duration of illness following acute infection with Epstein-Barr virus, Coxiella burnetii (the causative agent of Q fever), or Ross River virus. We found that the interferon-gamma +874T/A and the interleukin-10 -592C/A polymorphisms significantly affected illness severity, cytokine protein levels, and the duration of illness. These cytokine genotypes acted in synergy to potentiate their influence on disease outcomes. These findings suggest that genetically determined variations in the intensity of the inflammatory response underpin the severity of the acute sickness response and predict the recovery time across varied infections.

Psychoneuroimmunology - mind-brain-immune interactions : mind and body : SAMJ forum

Psychoneuroimmunology (PNI) is the study of interactions between psychological, neuroendocrine and immune processes under basal, disease and therapeutic conditions. It expands the understanding of disease, recognising that psychological phenomena and social context can influence the aetiology and progression of and recovery from illness. While debate continues regarding the way in which intangible mental processes and identifiable physiological ones interact, there can be little argument that these psychological processes require an evolved nervous system, with certain neural networks — identified through imaging studies and neurological disease affecting the mind — related to mental and emotional functions. 1 The extension of the mind/brain relationship to include the immune system is predicated on the presence of multiple neuropeptides and their receptors in cells of the immune system, where they are produced and expressed de novo with high sequence homology to their neuroendocrine relatives, as well as structural links between lymphoid organs and noradrenergic and peptidergic nerve fibres. 2 Furthermore many immunopeptides and their receptors are produced de novo in discrete regions of the brain, most specifically the limbichypothalamic axis, where they may exert a neuromodulatory effect. 2 The functionality of the immune-brain-behavioural pathway has been well described during the acute phase or sickness response. The acute behavioural and physiological changes that regularly accompany infectious illness include, for example, fever, depression, social withdrawal, increased desire for sleep, decreased interest in food and perceptual changes. As part of the immune response to infection, interleukin-1 (IL-1) acts on IL-1 receptors in the vagus nerve and in the brain to mediate such sickness behaviours. 3

Acute Mountain Sickness in Tourists with Children at Lake Chungará (4400 m) in Northern Chile

To evaluate the presence of acute mountain sickness (AMS) and cardiorespiratory responses in adult and pediatric tourists exposed to high altitude (Putre and Chungará). The study was performed during a tourist expedition to Lake Chungará (4400 m) with an overnight stay in the town of Putre (3500 m). The study group included 15 adults (21-44 years), 10 teenagers (13-18 years), and 6 children (6-48 months). We evaluated AMS symptoms in adults with the Lake Louise questionnaire and in children with the modified Children's Lake Louise Score for preverbal subjects. Cardiorespiratory measurements included heart rate and oxygen saturation on arrival at Putre and Chungará. Values were expressed as mean +/- SD; significance was tested by analysis of variance, followed by the Newman-Keuls test (P < .05). Significantly lower hemoglobin saturation was found among the children in Putre (74.8% +/- 5.2%) and Chungará (65.3%+/-1.3%) than among the teenagers (82.2%+/-3.2% and 78.6% 2.5%) and adults (83.9%+/-3.3% and 79.7%+/-5.5%) at a similar altitude. A higher incidence of AMS was observed in children (100%) in Putre than in teenagers (50%) and adults (27%). Our results indicate that children are extremely sensitive to hypoxia, as expressed by symptoms of AMS and significant desaturation. Our findings add to the available information regarding the problems encountered when ascending to high altitude with children and support the importance of close monitoring of young children during ascent to high altitude.