Regulation of the Acute Sickness Response by the P2RX7 Receptor.

BACKGROUND: The acute sickness response to infection is a stereotyped set of illness manifestations initiated by proinflammatory signals in the periphery but mediated centrally. P2RX7 is a highly polymorphic gene encoding an ATP-gated cationic pore, widely expressed on immune cells and the brain, and regulating the NLRP3 inflammasome, as well as diverse neural functions. METHODS: Associations between P2RX7 genotype, pore activity, and illness manifestations were examined in a cohort with acute viral and bacterial infections (n = 484). Genotyping of 12 P2RX7 function-modifying single-nucleotide polymorphisms (SNPs) was used to identify haplotypes and diplotypes. Leucocyte pore activity was measured by uptake of the fluorescent dye, YO-PRO-1, and by ATP-induced interleukin-1ß (IL-1ß) release. Associations were sought with scores describing the symptom domains, or endophenotypes, derived from principal components analysis. RESULTS: Among the 12 SNPs, a 4-SNP haplotype block with 5 variants was found in 99.5% of the subjects. These haplotypes and diplotypes were closely associated with variations in pore activity and IL-1ß production. Homozygous diplotypes were associated with overall illness severity as well as fatigue, pain, and mood disturbances. CONCLUSIONS: P2RX7 signaling plays a significant role in the acute sickness response to infection, likely acting in both the immune system and the brain.

The severity of the pathogen-induced acute sickness response is affected by polymorphisms in genes of the NLRP3 inflammasome pathway.

The acute sickness response (ASR) is a stereotyped set of symptoms including fatigue, pain, and disturbed mood, which are present in most acute infections. The immunological mechanisms of the ASR are conserved, with variations in severity determined partly by the pathogen, but also by polymorphisms in host genes. The ASR was characterised in three different serologically-confirmed acute infections in Caucasians (n = 484) across four symptom domains or endophenotypes (termed 'Fatigue', 'Musculoskeletal pain', 'Mood disturbance', and 'Acute sickness'). Correlations were sought with functional single nucleotide polymorphisms in the NLRP3 inflammasone pathway and severity of the endophenotypes. Individuals with severe Fatigue, Musculoskeletal pain, or Mood endophenotypes were more likely to have prior episodes of significant fatigue (11.4 vs. 3.8%, p = 0.07), pain (14.3 vs. 1.2%, p = 0.001), or Mood disturbance (13 vs 1%, p=0.001), suggesting trait characteristics. The high functioning allele of the rs35829419 SNP in NLRP3 was more common in those with severe Fatigue (OR = 13.3, 95% CI: 1.7-104), particularly in a dominant inheritance pattern (OR = 13.4, 95% CI: 1.8-586.3). In a multivariable analysis assuming dominant inheritance, both rs35829419 and the rs4848306 SNP in Interleukin(IL)-1ß, were independently associated with severe Fatigue (OR = 29.6, 95% CI: 2.6-330.9 and OR = 13, 95% CI: 2.7-61.8, respectively). The severity of fatigue in acute infection is influenced by genetic polymorphisms in NLRP3 and IL-1ß.

The impact of childhood trauma on psychosocial functioning and physical health in a non-clinical community sample of young adults.

OBJECTIVE: Given the fundamental emotional, social and physical development that occurs during the early years of life, childhood experiences are formative in shaping a person's life trajectory. Childhood trauma is a prevalent, multifaceted issue with well-documented long-term adverse health effects in clinical populations however; the impact of childhood trauma in the community is less clear. To address this, this study investigated how childhood trauma may impact physical and psychological health, sleep quality and autonomic function in a non-clinical community sample of adults. METHOD: Participants completed questionnaires, an in-laboratory autonomic assessment (including stress reactivity to mental and physical stressors) and overnight autonomic and sleep monitoring. Overall childhood trauma and its subtypes (e.g. physical abuse, emotional neglect) were defined using the Childhood Trauma Questionnaire. RESULTS: We identified 22 childhood trauma cases (total score > 36) and, of the 89 non-childhood trauma cases, some individuals also experienced significant levels of trauma in one or more of the childhood trauma subtypes. Childhood trauma and some trauma subtypes were significantly correlated with a myriad of negative physiological and physical health outcomes including elevated psychological distress, increased sleep disturbances, reduced emotional wellbeing and lower perceived social support. Autonomic dysregulation was found in those with high levels of childhood trauma, which was reflected in an increased stress response to laboratory tasks. Notably, the experience of physical abuse in childhood was significantly associated with alterations in nocturnal heart rate and heart rate variability. CONCLUSION: Together, these results highlight that childhood trauma can have lasting detrimental consequences on an individual's emotional and physical health, sleep quality and stress reactivity.

The well-being of medical students: A biopsychosocial approach.

OBJECTIVE: Mental health problems among medical students have been widely reported, but the predisposing and perpetuating factors and biological concomitants are poorly understood. Adopting a biopsychosocial approach, we studied well-being in a group of Australian medical students, focusing on sleep, autonomic and immune mechanisms, as well as mental, social and physical well-being, health-related behaviours, and daily functioning. METHODS: Fourth-year medical students (N = 151) completed comprehensive assessments, including laboratory-based and nocturnal autonomic monitoring via ambulatory bioharness, a psychiatric diagnostic interview, and questionnaires assessing sleep quality and psychosocial and physical well-being. A blood sample was taken to quantify the inflammatory marker C-reactive protein. Sleep, mood and activity was additionally monitored daily for 7 days. RESULTS: A sizable minority of students reported diminished physical, mental and psychosocial well-being. We also found concerning levels of sleep disturbance and social and occupational impairment in a subset of students. The strong co-occurrence of problems across symptom domains supported a biopsychosocial interdependence of health and well-being states. Maladaptive coping behaviours were apparent, notably hazardous alcohol consumption, which was associated with a clinically significant elevation in C-reactive protein levels (> 3 mg/L). We documented, for the first time, significantly diminished nocturnal heart rate variability in medical students with a mental health diagnosis. Nocturnal heart rate variability was strongly associated with sleep quality, daytime autonomic stress reactivity, as well as occupational and social functioning. CONCLUSION: Well-being is a multifaceted phenomenon firmly interlinked with sleep, autonomic and immune function, health behaviours and functional outcomes. Our novel findings supported a key role for nocturnal autonomic function in promoting sleep quality and mental well-being. Interventions could focus on sleep hygiene and health behaviours as a buffer for well-being and teach more adaptive strategies for coping with the stresses of medical training.

Contribution of individual psychological and psychosocial factors to symptom severity and time-to-recovery after naturally-occurring acute infective illness: The Dubbo Infection Outcomes Study (DIOS).

BACKGROUND: Substantial heterogeneity exists in both the severity of symptoms experienced as part of the sickness response to naturally-occurring infections, and the time taken for individuals to recover from these symptoms. Although contributing immunological and genetic factors have been previously been explored, less is known about the role of individual psychological and psychosocial factors, which may modulate the host immune response, or contribute independently, to symptom severity and duration. METHODS: Longitudinally-collected data from 484 Caucasian participants (mean age: 33.5 years; 51% women) experiencing a naturally-occurring acute infective illness enrolled in the prospective Dubbo Infection Outcome Study (DIOS) were analysed. At intake and subsequent follow-up assessments, self-report questionnaires were used to ascertain individual psychological and psychosocial characteristics and symptom information. Principal component analysis was applied to symptom data to derive endophenotype severity scores representing discrete symptom domains (fatigue, mood, pain, neurocognitive difficulties) and an overall index of severity. The contribution of individual psychological (trait neuroticism, locus of control, and illness behaviours) and psychosocial factors (relative socioeconomic advantage) to endophenotype severity at baseline were examined using multivariable linear regression models; interval-censored flexible parametric proportional hazards survival models were used to explore time to recovery (defined using within-sample negative threshold values). RESULTS: After controlling for time since symptom onset, greater levels of trait neuroticism consistently predicted greater symptom severity across all symptom domains (all p's < 0.015). Similarly, greater relative socioeconomic disadvantage was significantly associated with greater severity across all endophenotypes (p's < 0.025) except neurocognitive disturbance. Locus of control and illness behaviours contributed differentially across endophenotypes. Reduced likelihood of recovery was significantly predicted by greater initial symptom severity for all endophenotypes (all p's < 0.001), as well as higher levels of trait neuroticism. CONCLUSIONS: Individual psychological and psychosocial factors contribute to the initial severity and to the prolonged course of symptoms after naturally-occurring infective illnesses. These factors may play an independent role, represent a bias in symptom reporting, or reflect increased stress responsivity and a heightened inflammatory response. Objective metrics for severity and recovery are required to further elucidate their roles.

The Invisible Burden of Chronic Fatigue in the Community: a Narrative Review.

PURPOSE OF REVIEW: Unexplained fatigue is commonly reported in the general population, with varying severity. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) sits at the extreme of the fatigue continuum, yet more individuals experience unexplained prolonged fatigue (1-6-month duration) or chronic fatigue (> 6 months) that, although debilitating, does not fulfil ME/CFS criteria. This review examines the empirical literature comparing symptoms for those with prolonged fatigue, chronic fatigue and ME/CFS. RECENT FINDINGS: Substantial overlap of self-reported psychological, physical and functional impairments exists between chronic fatigue and ME/CFS. The conversion rate from prolonged or chronic fatigue to ME/CFS is not understood. Current research has failed to uncover factors accounting for differences in fatigue trajectories, nor incorporate comprehensive, longitudinal assessments extending beyond self-reported symptoms. Distinguishing factors between prolonged fatigue, chronic fatigue and ME/CFS remain poorly understood, highlighting a need for longitudinal studies integrating biopsychosocial approaches to inform early management and targeted rehabilitation strategies.

Depression and poor outcome after an acute coronary event: Clarification of risk periods and mechanisms.

OBJECTIVE: Lifetime depression and depression around the time of an acute coronary syndrome event have been associated with poor cardiac outcomes. Our study sought to examine the persistence of this association, especially given modern cardiac medicine's successes. METHODS: For 332 patients admitted for an acute coronary syndrome, a baseline interview assessed major depression status, and psychological measures were administered. At 1 and 12 months post-acute coronary syndrome event, telephone interviews collected rates of hospital readmission and/or death and major depression status, while biomarker information was examined using medical records. RESULTS: The 12-month mortality rate was 2.3% and cardiac readmission rate 21.0%. Depression subsequent to an acute coronary syndrome event resulted in a threefold and 2.5-fold increase in 1-month and 12-month odds of cardiac readmission or death, respectively. No relationship with past depressive episodes was found. Poor sleep was associated with higher trait anxiety and neuroticism scores and with more severe depression. CONCLUSION: Lifetime depression may increase the risk of depression around the time of an acute coronary syndrome but not influence cardiac outcomes. We suggest that poor sleep quality may be causal or indicate high anxiety/neuroticism, which increases risk to depression and contributes to poor cardiac outcomes rather than depression being the primary causal factor.

Dry-Eye Disease in Recurrent Pterygium.

PURPOSE: The aim of this paper was to investigate the degree of inflammation and dry-eye disease (DED) in recurrent pterygium. METHODS: Fifty-five patients with a history of pterygium excision were divided into 3 groups - Group 1: no recurrence after the first excision; Group 2: recurrence after the first excision; Group 3: no recurrence after the second excision. Dry-eye symptoms and tear production were elicited for each patient. RESULTS: A high prevalence of DED was observed in patients with primary and recurrent pterygium based on self-reported dry-eye symptoms (63.6%) and an abnormal Schirmer test result (78.1%). There was a statistically significant difference (p = 0.025) in the Schirmer test values between patients with (5.6 mm) and without (11.4 mm) recurrence after surgery for primary pterygium. Patients who were cured after a second excision had an improved Schirmer test value (9.5 mm), although this was not significant. CONCLUSION: Pterygium recurrence is associated with a greater severity of dry eye, possibly by perpetuating ocular surface inflammation in the postoperative period.

Sex differences in the significance of isolated reactive treponemal chemiluminescence immunoassay results.

OBJECTIVES: The significance of sera with isolated reactive treponemal chemiluminescence immunoassay (IRTCIA) results is unclear. Women have this phenotype more commonly than men. Most cohorts examining this phenotype have included predominantly men and have demonstrated evidence of past or subsequently confirmed syphilis infection in a significant proportion of cases. We hypothesised that a proportion of sera with IRTCIA results would be positive on immunoblot testing and that sera from women with IRTCIA would have different results in immunoblot testing than men. METHODS: IRTCIA sera from a tertiary referral serology laboratory serving multiple clinical sites were analysed with a syphilis line immunoblot assay (LIA) and analysed by sex. Logistic regression was undertaken to assess factors associated with LIA status. Medical record review and descriptive analysis of a separate cohort of women with the IRTCIA phenotype from a single campus was also undertaken. RESULTS: Overall, 19/63 (30.1%) subjects with the IRTCIA phenotype were positive in the LIA, including 13 men and 6 women. Women were significantly less likely to have definitive results (positive or negative) than men (p=0.015). Pregnant women were less likely than non-pregnant women to have a negative LIA result (OR 0.57; p=0.03). Record review of 22 different women with IRTCIA reactivity showed that 2/22 (9.1%) had HIV and previous syphilis infection, 15/22 (68.2%) were pregnant and 3 (13.6%) had autoimmune disease. CONCLUSIONS: A significant proportion of sera with IRTCIA results on serological tests are reactive on LIA testing and some may not be false positive results. The interpretation of IRTCIA results should be undertaken in conjunction with an assessment of factors such as sex, pregnancy, a history of syphilis and other STIs and syphilis risk.

Can you snooze your way to an 'A'? Exploring the complex relationship between sleep, autonomic activity, wellbeing and performance in medical students.

OBJECTIVE: Medical training brings with it multiple stressors, including demanding workloads in highly competitive environments, with well-documented impact on psychiatric morbidity. This study evaluated the impact of sleep-related factors on psychological wellbeing, cognitive task performance and academic standing in medical students. METHODS: A total of 59 undergraduate medical students took part in this cross-sectional study over two consecutive days. Participants responded to questionnaires about their physical and psychological health, sleep, functioning and academic performance at the initial visit. Participants then wore an ambulatory bioharness overnight (to derive heart rate variability measures), before returning to complete a computerised battery of cognitive tasks. A sleep diary was completed for the next 7 days. RESULTS: Poor sleep quality in the month preceding assessment correlated with psychological distress ( p < 0.001) and reduced nocturnal heart rate variability ( p = 0.007). Psychological distress also correlated with reduced nocturnal heart rate variability ( p = 0.031) and less refreshing sleep during the monitoring week ( p < 0.001), but not with sleep timing parameters. A greater increase in heart rate variability during the transition from awake to sleep significantly predicted better spontaneous cognitive performance ( p = 0.021). Better academic standing was predicted by consistently short, less refreshing sleep (all p < 0.001), along with earlier bedtimes ( p = 0.004) and greater psychological wellbeing ( p = 0.009). CONCLUSION: Unrefreshing, short-duration sleep and psychological distress are prevalent in medical students during university training and were associated with reduced nocturnal parasympathetic autonomic activity. Achieving higher academic grades was associated with high psychological wellbeing despite consistently short, unrefreshing sleep. The long-term repercussions of such sleep behaviours on later professional functioning remain unclear, warranting further research.

Determining the factors associated with blood-borne virus testing of substance misusers presenting to hospital.

BACKGROUND: Diagnosing blood-borne virus (BBV) infection is an essential first step in eliminating transmission and securing access to treatment amongst substance misusers. AIMS: To determine the proportion of substance misusers presenting to hospital who undergo BBV testing and the factors influencing testing. METHODS: A retrospective cross-sectional study was performed of patients presenting to two Sydney teaching hospitals with substance misuse diagnoses between January and April 2015. Proportions tested for human immunodeficiency virus, hepatitis C and hepatitis B previously and during the index hospitalisation presentation were examined. Multivariable analysis was performed to determine factors associated with testing. RESULTS: Of 239 patients, 47 (19.7%) had a documented BBV at baseline. Of those with unknown BBV status, 29 (12.8%) had undergone some attempt at testing during presentation; 3.1% had their hepatitis B immunity assessed. Factors associated with an increased likelihood of testing during presentation included documented injecting drug use (odds ratio (OR) 15.14; 95% confidence interval (CI) 4.21-54.50; P < 0.001), admission under a physician (OR 11.79; 95% CI 2.82-49.40; P = 0.001) and admission on a Friday (OR 4.46; 95% CI 1.28-15.48; P = 0.02). Patients who had had more than one previous admission in the preceding 6 months (OR 0.24; 95% CI 0.078-0.73; P = 0.01) or a length of stay of 1 day or less (OR 0.17; 95% CI 0.032-0.87; P = 0.033) were less likely to be tested. CONCLUSION: Despite the high baseline prevalence of BBV infections in the population, there were many missed opportunities for BBV testing. We found patient-, admission- and clinician-level barriers that could be addressed to enhance BBV testing uptake.

Cognitive Dysfunction in Chronic Fatigue Syndrome: a Review of Recent Evidence.

Cognitive difficulties represent a common and debilitating feature of the enigmatic chronic fatigue syndrome (CFS). These difficulties manifest as self-reported problems with attention, memory, and concentration and present objectively as slowed information processing speed particularly on complex tasks requiring sustained attention. The mechanisms underlying cognitive dysfunction remain to be established; however, alterations in autonomic nervous system activity and cerebral blood flow have been proposed as possibilities. Heterogeneity in the experience of cognitive impairment, as well as differences in the methods utilised to quantify dysfunction, may contribute to the difficulties in establishing plausible biological underpinnings. The development of a brief neurocognitive battery specifically tailored to CFS and adoption by the international research community would be beneficial in establishing a profile of cognitive dysfunction. This could also provide better insights into the underlying biological mechanisms of cognitive dysfunction in CFS and enhance the development of targeted treatments.

Neurocognitive improvements after best-practice intervention for chronic fatigue syndrome: Preliminary evidence of divergence between objective indices and subjective perceptions.

BACKGROUND: Neurocognitive difficulties are commonly reported by patients suffering from chronic fatigue syndrome (CFS). Moderate improvements from 'best practice' therapy are promising, but to date reported efficacy is based entirely on subjective measures. This is problematic, given the well-documented divergence between subjective perceptions and actual neurocognitive performance, including in this patient group. MATERIAL AND METHODS: Subjective and objective measures of neurocognitive performance were obtained from 25 patients with well-characterized CFS before and after the completion of a 12-week graded-activity program incorporating a cognitive training component. Additionally, self-reported symptoms, cardiac autonomic activity (a relevant biomarker of stress responsivity), and their relation to neurocognitive improvements were examined. RESULTS: Substantive post-intervention improvements in subjective (p=0.006) and objective (including faster responses speeds and greater accuracy, p's<0.001) neurocognitive performance were documented. Participants also demonstrated reduced autonomic reactivity to the cognitive challenge at follow-up (p's≤0.01). These improvements were accompanied by improvements in symptom ratings (p's≤0.01). However, subjective ratings of neurocognitive difficulties, and CFS-related symptoms were not linked to objective performance improvements. CONCLUSIONS: These initial data provide the first evidence of objective neurocognitive performance improvements accompanied by a significant reduction in responsiveness in stress-related neural pathways consequent to cognitive-behavioral/graded exercise therapy programs. These findings provide support for the effectiveness of such programs in remediating clinical status. These promising findings warrant further investigation, including replication in a larger sample utilizing more controlled study designs.

Acute coronary syndrome-associated depression: the salience of a sickness response analogy?

Depression emerging in conjunction with acute coronary syndrome (ACS) is thought to constitute a distinct high-risk phenotype with inflammatory determinants. This review critically examines the notion put forward in the literature that ACS-associated depression constitutes a meaningful subtype that is qualitatively different from depressive syndromes observed in psychiatric patients; and evaluates the salience of an analogy to the acute sickness response to infection or injury as an explanatory model. Specific features differentiating ACS-associated depression from other phenotypes are discussed, including differences in depression symptom profiles, timing of the depressive episode in relation to ACS, severity of the cardiac event, and associated immune activation. While an acute sickness response analogy offers a plausible conceptual framework, concrete evidence is lacking for inflammatory activity as the triggering mechanism. It is likely that ACS-associated depression encompasses several causative scenarios.

Characterising acute coronary syndrome-associated depression: Let the data speak.

Depression in the context of acute coronary syndrome (ACS) is understood to confer increased morbidity and mortality risk. The pathophysiological mechanisms underlying this association remain poorly understood, although several candidates including inflammation, cardiac autonomic dysregulation, and behavioural factors are viewed as of key importance. No single bio-behavioural explanatory model of ACS-associated depression has emerged, likely due the substantial heterogeneity across both conditions. We studied 344 patients with ACS; 45 fulfilled diagnostic (DSM-IV) criteria for a major depressive episode occurring within 1-month of ACS, and 13 had ongoing major depression that pre-dated ACS and continued through to 1 month post-ACS. We employed two statistical methods (multinomial logistic regression; and latent class analysis) and a range of immunological, autonomic and nutritional markers in an attempt to characterise a biological basis for ACS-associated depression. Regression modelling failed to accurately predict categorical group membership of ACS-associated depression. An alternative data-driven approach produced a three-class solution, with the derived classes differing on measure of C-reactive protein, vitamin D, omega-6:omega-3 ratio, heart rate variability, and age (all p⩽0.004). The majority of participants with ACS-associated and ongoing depression were members of the class characterised by the greatest biological disturbance. Patients with depression differed from those without depression on a range of psychological trait and state variables; additionally reporting poorer sleep quality, higher levels of social isolation, and functional impairment, but had similar biological profiles. Patients with ongoing depression generally had higher scores on these psychological/behavioural measures. Our novel analytic approach identified a combination of biomarkers suggestive of a role for immune, autonomic, and nutritional pathways in the manifestation of depression during ACS, in the context of additional psychosocial and behavioural vulnerabilities. Further studies are required to confirm the causal role of these factors in perpetuating depression and increasing risk of poor-health outcomes.

Acute coronary syndrome and depression: A review of shared pathophysiological pathways.

OBJECTIVE: To examine the evidence for shared pathophysiological pathways in acute coronary syndrome and major depression and to conceptualise the dynamic interplay of biological systems and signalling pathways that link acute coronary syndrome and depression within a framework of neuro-visceral integration. METHODS: Relevant articles were sourced via a search of published literature from MEDLINE, EMBASE and PubMed using a variety of search terms relating to biological connections between acute coronary syndrome and depression. Additional articles from bibliographies of retrieved papers were assessed and included where relevant. RESULTS: Despite considerable research efforts, a clear understanding of the biological processes connecting acute coronary syndrome and depression has not been achieved. Shared abnormalities are evident across the immune, platelet/endothelial and autonomic/stress-response systems. From the available evidence, it seems unlikely that a single explanatory model could account for the complex interactions of biological pathways driving the pathophysiology of these disorders and their comorbidity. CONCLUSION: A broader conceptual framework of mind-body or neuro-visceral integration that can incorporate the existence of several causative scenarios may be more useful in directing future research and treatment approaches for acute coronary syndrome-associated depression.

Characterization of fatigue states in medicine and psychiatry by structured interview.

CONTEXT: Unexplained fatigue states are prevalent, with uncertain diagnostic boundaries. OBJECTIVE: Patients with fatigue-related illnesses were investigated by questionnaire and a novel semistructured interview to identify discriminatory features. METHODS: Cross-sectional samples of women from specialist practices with chronic fatigue syndrome (n = 20), postcancer fatigue (PCF; n = 20), or major depression (n = 16) were recruited. Additionally, two longitudinal samples were studied: women with fatigue associated with acute infection who subsequently developed postinfective fatigue syndrome (n = 20) or recovered uneventfully (n = 21), and women undergoing adjuvant therapy for breast cancer experiencing treatment-related fatigue who subsequently developed PCF (n = 16) or recovered uneventfully (n = 16). Patients completed self-report questionnaires, and trained interviewers applied the Semi-structured Clinical Interview for Neurasthenia. The receiver operating characteristics curves of the interview were measured against clinician-designated diagnoses. Cluster analyses were performed to empirically partition participants by symptom characteristics. RESULTS: The interview had good internal consistency (Cronbach alpha "fatigue" = .83), and diagnostic sensitivity and specificity for chronic fatigue syndrome (100% and 83%) and major depression (100% and 72%), with reasonable parameters for PCF (72% and 58%). Empirical clustering by "fatigue" or "neurocognitive difficulties" items allocated most patients to one group, whereas "mood disturbance" items correctly classified patients with depression only. CONCLUSIONS: The Semi-structured Clinical Interview for Neurasthenia offers reliable diagnostic use in assessing fatigue-related conditions. The symptom domains of fatigue and neurocognitive difficulties are shared across medical and psychiatric boundaries, whereas symptoms of depression such as anhedonia are distinguishing.

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.