Allan William Cripps: a mucosal immunologist and mentor from beginning to end.

Allan Cripps was internationally recognized in the field of mucosal immunology, in particular the relationship between respiratory diseases and mucosal immunization strategies. Allan's career spanned scientific and applied research, commercialization, health education, and evolved into leadership roles in public-health and academic administration. Allan published over 400 papers and mentored over 40 research higher degree candidates. Allan was renowned for his mentorship, that did not end with the awarding of a PhD or Master's degree, but continued across a lifetime of professional engagement. Allan's key contributions to immunology included characterizing the ontogeny of the human mucosal immune system, understanding the impact of respiratory infections and otitis media in children, developing diagnostic technologies and mucosal vaccine strategies, and identifying the roles of the common mucosal immune system in human health. In this biography for the 100th anniversary of the Journal, we follow his journey of discovery and contributions to immunological research.

Risk factors associated with acute respiratory illnesses in athletes: a systematic review by a subgroup of the IOC consensus on 'acute respiratory illness in the athlete'.

OBJECTIVE: To review risk factors associated with acute respiratory illness (ARill) in athletes, including non-infectious ARill and suspected or confirmed acute respiratory infections (ARinf). DESIGN: Systematic review. DATA SOURCES: Electronic databases: PubMed-Medline, EbscoHost and Web of Science. ELIGIBILITY CRITERIA: Original research articles published between January 1990 and July 2020 in English were searched for prospective and retrospective full text studies that reported quantitative data on risk factors associated with ARill/ARinf in athletes, at any level of performance (elite/non-elite), aged 15-65 years. RESULTS: 48 studies (n=19 390 athletes) were included in the study. Risk factors associated with ARill/ARinf were: increased training monotony, endurance training programmes, lack of tapering, training during winter or at altitude, international travel and vitamin D deficits. Low tear-(SIgA) and salivary-(IgA) were immune biomarkers associated with ARill/ARinf. CONCLUSIONS: Modifiable training and environmental risk factors could be considered by sports coaches and athletes to reduce the risk of ARill/ARinf. Clinicians working with athletes can consider assessing and treating specific nutritional deficiencies such as vitamin D. More research regarding the role and clinical application of measuring immune biomarkers in athletes at high risk of ARill/ARinf is warranted. PROSPERO REGISTRATION NUMBER: CRD42020160928.

Incidence of acute respiratory illnesses in athletes: a systematic review and meta-analysis by a subgroup of the IOC consensus on 'acute respiratory illness in the athlete'.

OBJECTIVE: To determine the incidence of acute respiratory illness (ARill) in athletes and by method of diagnosis, anatomical classification, ages, levels of performance and seasons. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic databases: PubMed-Medline, EbscoHost and Web of Science. ELIGIBILITY CRITERIA: Original research articles published between January 1990 and July 2020 in English reporting the incidence of ARill in athletes, at any level of performance (elite/non-elite), aged 15-65 years. RESULTS: Across all 124 studies (n=1 28 360 athletes), the incidence of ARill, estimated by dividing the number of cases by the total number of athlete days, was 4.7 (95% CI 3.9 to 5.7) per 1000 athlete days. In studies reporting acute respiratory infections (ARinf; suspected and confirmed) the incidence was 4.9 (95% CI 4.0 to 6.0), which was similar in studies reporting undiagnosed ARill (3.7; 95% CI 2.1 to 6.7). Incidences of 5.9 (95% CI 4.8 to 7.2) and 2.8 (95% CI 1.8 to 4.5) were found for studies reporting upper ARinf and general ARinf (upper or lower), respectively. The incidence of ARinf was similar across the different methods to diagnose ARinf. A higher incidence of ARinf was found in non-elite (8.7; 95% CI 6.1 to 12.5) vs elite athletes (4.2; 95% CI 3.3 to 5.3). SUMMARY/CONCLUSIONS: These findings suggest: (1) the incidence of ARill equates to approximately 4.7 per athlete per year; (2) the incidence of upper ARinf was significantly higher than general (upper/lower) ARinf; (3) elite athletes have a lower incidence of ARinf than non-elite athletes; (4) if pathogen identification is not available, physicians can confidently use validated questionnaires and checklists to screen athletes for suspected ARinf. For future studies, we recommend that a clear diagnosis of ARill is reported. PROSPERO REGISTRATION NUMBER: CRD42020160472.

Dietary Intake and Gastrointestinal Integrity in Runners Undertaking High-Intensity Exercise in the Heat.

Gastrointestinal disturbances are one of the most common issues for endurance athletes during training and competition in the heat. The relationship between typical dietary intake or nutritional interventions and perturbations in or maintenance of gut integrity is unclear. Twelve well-trained male endurance athletes (peak oxygen consumption = 61.4 ± 7.0 ml·kg-1·min-1) completed two trials in a randomized order in 35 °C (heat) and 21 °C (thermoneutral) conditions and kept a detailed nutritional diary for eight consecutive days between the two trials. The treadmill running trials consisted of 15 min at 60% peak oxygen consumption, 15 min at 75% peak oxygen consumption, followed by 8 × 1-min high-intensity efforts. Venous blood samples were taken at the baseline, at the end of each of the three exercise stages, and 1 hr postexercise to measure gut integrity and the permeability biomarker concentration for intestinal fatty-acid-binding protein, lipopolysaccharide, and lipopolysaccharide-binding protein. The runners self-reported gut symptoms 1 hr postexercise and 3 days postexercise. The heat condition induced large (45-370%) increases in intestinal fatty-acid-binding protein, lipopolysaccharide-binding protein, and lipopolysaccharide concentrations compared with the baseline, but induced mild gastrointestinal symptoms. Carbohydrate and polyunsaturated fat intake 24 hr preexercise were associated with less lipopolysaccharide translocation. Protein, carbohydrate, total fat, and polyunsaturated fat intake (8 days) were positively associated with the percentage increase of intestinal fatty-acid-binding protein in both conditions (range of correlations, 95% confidence interval = .62-.93 [.02, .98]). Typical nutrition intake partly explained increases in biomarkers and the attenuation of symptoms induced by moderate- and high-intensity exercise under both heat and thermoneutral conditions.

Embedding an economist in regional and rural health services to add value and reduce waste by improving local-level decision-making: protocol for the 'embedded Economist' program and evaluation.

BACKGROUND: Systematic approaches to the inclusion of economic evaluation in national healthcare decision-making are usual. It is less common for economic evaluation to be routinely undertaken at the 'local-level' (e.g. in a health service or hospital) despite the largest proportion of health care expenditure being determined at this service level and recognition by local health service decision makers of the need for capacity building in economic evaluation skills. This paper describes a novel program - the embedded Economist (eE) Program. The eE Program aims to increase local health service staff awareness of, and develop their capacity to access and apply, economic evaluation principles in decision making. The eE program evaluation is also described. The aim of the evaluation is to capture the contextual, procedural and relational aspects that assist and detract from the eE program aims; as well as the outcomes and impact from the specific eE projects. METHODS: The eE Program consists of a embedding a health economist in six health services and the provision of supported education in applied economic evaluation, provided via a community of practice and a university course. The embedded approach is grounded in co-production, embedded researchers and 'slow science'. The sites, participants, and program design are described. The program evaluation includes qualitative data collection via surveys, semi-structured interviews, observations and field diaries. In order to share interim findings, data are collected and analysed prior, during and after implementation of the eE program, at each of the six health service sites. The surveys will be analysed by calculating frequencies and descriptive statistics. A thematic analysis will be conducted on interview, observation and filed diary data. The Framework to Assess the Impact from Translational health research (FAIT) is utilised to assess the overall impact of the eE Program. DISCUSSION: This program and evaluation will contribute to knowledge about how best to build capacity and skills in economic evaluation amongst decision-makers working in local-level health services. It will examine the extent to which participants are able to improve their ability to utilise evidence to inform decisions, avoid waste and improve the value of care delivery.

Can exercise affect immune function to increase susceptibility to infection?

Multiple studies in humans and animals have demonstrated the profound impact that exercise can have on the immune system. There is a general consensus that regular bouts of short-lasting (i.e. up to 45 minutes) moderate intensity exercise is beneficial for host immune defense, particularly in older adults and people with chronic diseases. In contrast, infection burden is reported to be high among high performance athletes and second only to injury for the number of training days lost during preparation for major sporting events. This has shaped the common view that arduous exercise (i.e. those activities practiced by high performance athletes/ military personnel that greatly exceed recommended physical activity guidelines) can suppress immunity and increase infection risk. However, the idea that exercise per se can suppress immunity and increase infection risk independently of the many other factors (e.g. anxiety, sleep disruption, travel, exposure, nutritional deficits, environmental extremes, etc.) experienced by these populations has recently been challenged. The purpose of this debate article was to solicit opposing arguments centered around this fundamental question in the exercise immunology field: can exercise affect immune function to increase susceptibility to infection. Issues that were contested between the debating groups include: (i) whether or not athletes are more susceptible to infection (mainly of the upper respiratory tract) than the general population; (ii) whether exercise per se is capable of altering immunity to increase infection risk independently of the multiple factors that activate shared immune pathways and are unique to the study populations involved; (iii) the usefulness of certain biomarkers and the interpretation of in vitro and in vivo data to monitor immune health in those who perform arduous exercise; and (iv) the quality of scientific evidence that has been used to substantiate claims for and against the potential negative effects of arduous exercise on immunity and infection risk. A key point of agreement between the groups is that infection susceptibility has a multifactorial underpinning. An issue that remains to be resolved is whether exercise per se is a causative factor of increased infection risk in athletes. This article should provide impetus for more empirical research to unravel the complex questions that surround this contentious issue in the field of exercise immunology.

Developing a multi-component immune model for evaluating the risk of respiratory illness in athletes.

Clinical and laboratory identification of the underlying risk of respiratory illness in athletes has proved problematic. The aim of this study was to determine whether clinical data, combined with immune responses to standardised exercise protocols and genetic cytokine polymorphism status, could identify the risk of respiratory illness (symptoms) in a cohort of highly-trained athletes. Male endurance athletes (n=16; VO2max 66.5 ± 5.1 mL.kg-1.min-1) underwent a clinical evaluation of known risk factors by a physician and comprehensive laboratory analysis of immune responses both at rest and after two cycling ergometer tests: 60 min at 65% VO2max (LONG); and 6 x 3 min intervals at 90% VO2max (INTENSE). Blood tests were performed to determine Epstein Barr virus (EBV) status and DNA was genotyped for a panel of cytokine gene polymorphisms. Saliva was collected for measurement of IgA and detection of EBV DNA. Athletes were then followed for 9 months for self-reported episodes of respiratory illness, with confirmation of the underlying cause by a sports physician. There were no associations with risk of respiratory illness identified for any parameter assessed in the clinical evaluations. The laboratory parameters associated with an increased risk of respiratory illnesses in highly-trained athletes were cytokine gene polymorphisms for the high expression of IL-6 and IFN-É£; expression of EBV-DNA in saliva; and low levels of salivary IgA concentration. A genetic risk score was developed for the cumulative number of minor alleles for the cytokines evaluated. Athletes prone to recurrent respiratory illness were more likely to have immune disturbances that allow viral reactivation, and a genetic predisposition to pro-inflammatory cytokine responses to intense exercise.

Respiratory inflammation and infections in high-performance athletes.

Upper respiratory illness is the most common reason for non-injury-related presentation to a sports medicine clinic, accounting for 35-65% of illness presentations. Recurrent or persistent respiratory illness can have a negative impact on health and performance of athletes undertaking high levels of strenuous exercise. The cause of upper respiratory symptoms (URS) in athletes can be uncertain but the majority of cases are related to common respiratory viruses, viral reactivation, allergic responses to aeroallergens and exercise-related trauma to the integrity of respiratory epithelial membranes. Bacterial respiratory infections are uncommon in athletes. Undiagnosed or inappropriately treated asthma and/or allergy are common findings in clinical assessments of elite athletes experiencing recurrent URS. High-performance athletes with recurrent episodes of URS should undergo a thorough clinical assessment to exclude underlying treatable conditions of respiratory inflammation. Identifying athletes at risk of recurrent URS is important in order to prescribe preventative clinical, training and lifestyle strategies. Monitoring secretion rates and falling concentrations of salivary IgA can identify athletes at risk of URS. Therapeutic interventions are limited by the uncertainty of the underlying cause of inflammation. Topical anti-inflammatory sprays can be beneficial for some athletes. Dietary supplementation with bovine colostrum, probiotics and selected antioxidants can reduce the incidence or severity of URS in some athletes. Preliminary studies on athletes prone to URS indicate a genetic predisposition to a pro-inflammatory response and a dysregulated anti-inflammatory cytokine response to intense exercise as a possible mechanism of respiratory inflammation. This review focuses on respiratory infections and inflammation in elite/professional athletes.

Genetic and Environmental Factors Affecting TNF-α Responses in Relation to Sudden Infant Death Syndrome.

Dysregulation of the inflammatory responses has been suggested to contribute to the events leading to sudden infant deaths. Our objectives were (1) to analyze a single nucleotide polymorphism (SNP) associated with high levels of tumor necrosis factor-α (TNF-α) responses, TNF G-308A, in sudden infant death syndrome (SIDS) infants, SIDS and control parents, and ethnic groups with different incidences of SIDS; (2) the effects of two risk factors for SIDS, cigarette smoke and virus infection, on TNF-α responses; and (3) to assess effects of genotype, cigarette smoke, and gender on TNF-α responses to bacterial toxins identified in SIDS infants. TNF G-308A genotypes were determined by real-time polymerase chain reaction for SIDS infants from Australia, Germany, and Hungary; parents of SIDS infants and their controls; and populations with high (Aboriginal Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. Leukocytes from Caucasian donors were stimulated in vitro with endotoxin or toxic shock syndrome toxin-1 (TSST-1). TNF-α responses were measured by L929 bioassay (IU/ml) and assessed in relation to genotype, smoking status, and gender. There was a significantly higher proportion of the minor allele AA genotype among Australian SIDS infants (6/24, 24%) compared to 3/62 (4.8%) controls (p = 0.03). There were no significant differences in TNF-α responses by TNF G-308A genotypes when assessed in relation to smoking status or gender. Given the rarity of the TNF G-308A A allele in Caucasian populations, the finding that 24% of the Australian SIDS infants tested had this genotype requires further investigation and cautious interpretation. Although non-smokers with the AA genotype had higher TNFα responses to both TSST-1 and endotoxin, there were too few subjects with this rare allele to obtain statistically valid results. No effects of genotype, smoking, or gender were observed for TNF-α responses to these toxins.

Virus Infections and Sudden Death in Infancy: The Role of Interferon-γ.

Respiratory infections have been implicated in sudden infant death syndrome (SIDS). As interferon-γ (IFN-γ) is a major response to virus infection, we examined (1) the frequency of single nucleotide polymorphism (SNP), IFNG T + 874A, in SIDS infants, their parents, and ethnic groups with different incidences of SIDS; (2) model systems with a monocytic cell line (THP-1) and human peripheral blood monocytes (PBMC) for effects of levels of IFN-γ on inflammatory responses to bacterial antigens identified in SIDS; (3) interactions between genetic and environmental factors on IFN-γ responses. IFNG T + 874A genotypes were determined for SIDS infants from three countries; families who had a SIDS death; populations with high (Indigenous Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. The effect of IFN-γ on cytokine responses to endotoxin was examined in model systems with THP-1 cells and human PBMC. The IFN-γ responses to endotoxin and toxic shock syndrome toxin (TSST-1) were assessed in relation to genotype, gender, and reported smoking. There was a marginal association with IFNG T + 874A genotype and SIDS (p = 0.06). Indigenous Australians had significantly higher proportions of the IFNG T + 874A SNP (TT) associated with high responses of IFN-γ. THP-1 cells showed a dose dependent effect of IFN-γ on cytokine responses to endotoxin. For PBMC, IFN-γ enhanced interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α responses but reduced IL-8 and IL-10 responses. Active smoking had a suppressive effect on baseline levels of IFN-γ. There was no effect of gender or genotype on IFN-γ responses to bacterial antigens tested; however, significant differences were observed between genotypes in relation to smoking. The results indicate virus infections contribute to dysregulation of cytokine responses to bacterial antigens and studies on physiological effects of genetic factors must include controls for recent or concurrent infection and exposure to cigarette smoke.

Position statement. Part one: Immune function and exercise.

An ever-growing volume of peer-reviewed publications speaks to the recent and rapid growth in both scope and understanding of exercise immunology. Indeed, more than 95% of all peer-reviewed publications in exercise immunology (currently >2, 200 publications using search terms "exercise" and "immune") have been published since the formation of the International Society of Exercise and Immunology (ISEI) in 1989 (ISI Web of Knowledge). We recognise the epidemiological distinction between the generic term "physical activity" and the specific category of "exercise", which implies activity for a specific purpose such as improvement of physical condition or competition. Extreme physical activity of any type may have implications for the immune system. However, because of its emotive component, exercise is likely to have a larger effect, and to date the great majority of our knowledge on this subject comes from exercise studies.

Cytokine gene polymorphisms and risk for upper respiratory symptoms in highly-trained athletes.

Physiological and immunological factors contributing to risk for upper respiratory symptoms (URS) in athletic populations remain under investigation. Single nucleotide changes (polymorphisms) in cytokine genes and alterations in associated gene expression may influence risk for URS in some athletes. The aim of this study was to compare the frequency of cytokine gene polymorphisms in athletes with or without a history of frequent URS. Cytokine gene polymorphisms were determined in samples from five previous investigations of immune function in highly-trained athletes (n=170). Participants were classified into two groups based on their self-reported number of episodes of URS in the preceding 12 months. Athletes were classified as healthy (n=82) if they reported < or =2 episodes of URS in the preceding 12 months. Athletes were classified as illness-prone (n=88) if reporting > or =3 episodes of URS. Polymorphisms in Interleukin (IL)-6, IL-8, IL-10, IL-1 receptor antagonist (IL-1ra), IL-2, IL-4 and Interferon(IFN)-gamma were determined using real-time polymerase chain reaction allelic discrimination assays. The distribution of genotype frequencies between the two groups was compared using a Chi-square test and logistic regression was used to model risk for URS as a function of cytokine gene polymorphisms. There was a tendency for IL-6 (chi2 = 5.0, p = 0.08) and IL-4 (chi2 = 4.8, p = 0.09) genotype frequencies to differ between the groups. The IL-6 high-expression genotype was associated with an increased likelihood of > or =3 URS episodes in a 12 month period (odds ratio (OR): 2.87, 95% confidence interval (CI): 1.10-7.53; p = 0.03). The IL-2 high-expression genotype was associated with a tendency for a decreased likelihood of > or =3 URS episodes in a 12 month period (OR: 0.361, 95% CI: 0.124-1.06; p = 0.06). These data suggest cytokine gene polymorphisms may account in part for differences in risk for URS in highly-trained athletes.

Developmental profiles of mucosal immunity in pre-school children.

This study investigated the effect of attending pre-school on mucosal immunity. Children 3.5 to 5 years of age who attended pre-school were observed for a 10 month period. Demographic information was collected on previous childcare experiences, the home environment and clinical information relating to the child and the family. A daily illness log was kept for each child. A multivariate longitudinal analysis of the relation between immunoglobulins in saliva and age, gender, childcare experience, pre-school exposure, number of siblings, environmental tobacco smoke (ETS), atopy and hospitalisation was conducted. There was a positive association of higher IgA levels with the winter season and with children being older than 4 years (P < .001), having attended childcare prior to commencing pre-school (P < .05), and having been exposed to ETS at home (P < .05). Lower IgA levels were associated with being atopic (P < .05). Higher IgG levels were associated with exposure to ETS (P < .001), while lower levels were associated to having atopy. Higher IgM levels were associated with previous childcare experience (P < .01) whilst having been hospitalised was associated with having low salivary IgM levels (P < .01). Lagged analyses demonstrated that immunological parameters were affected by the number of respiratory infections in the preceding 2 months.

Relationship between C-reactive protein concentration and cytokine responses to exercise in healthy and illness-prone runners.

Differences in the immune and inflammatory response to exercise between healthy and illness-prone athletes may be one explanation why some athletes experience a greater incidence of upper respiratory symptoms than others. The aim of this study was to compare the C-reactive protein (CRP) response to acute exercise between healthy and illness-prone trained distance runners. Runners were classified as healthy (< or =2 episodes of upper respiratory symptoms per year; n = 10) or illness-prone (> or =4 episodes per year; n = 8) and completed three treadmill running protocols. CRP concentrations were determined prior to and 24 h following each exercise protocol and responses compared between the two groups. Plasma concentrations of Interleukin (IL)-6, IL-8, IL-10 and the IL-1 receptor antagonist (IL-1ra) were also determined immediately, 1 h, 10 h and 24 h post-exercise. The CRP response at 24 h post-exercise was not substantially different between healthy and illness-prone athletes (approximately 2-10%). There were small to moderate correlations between resting CRP concentrations and the peak IL-6 (r = 0.28, P = 0.04), IL-8 (r = 0.31, P = 0.03), IL-10 (r = 0.28, P = 0.05) and IL-1ra (r = 0.30, P = 0.03) concentrations post-exercise. The CRP response to exercise was not useful in distinguishing between healthy and illness-prone athletes. The relationship between resting CRP concentrations and the peak pro- and anti-inflammatory responses to exercise supports the likely involvement of CRP in the complex network regulating exercise-induced inflammatory disturbance.

Clinical and laboratory evaluation of upper respiratory symptoms in elite athletes.

OBJECTIVE: To characterize the etiology of upper respiratory symptoms in elite athletes presenting to a sports physician for treatment. DESIGN: Prospective clinical and laboratory investigations. SETTING: Sports medicine clinic. PARTICIPANTS: Seventy elite-level athletes. MAIN OUTCOME MEASUREMENTS: Physician-recorded symptoms and diagnosis; health/training questionnaires; laboratory investigations of respiratory pathogens, white blood cell differential counts, and immune parameters. RESULTS: Physicians characterized 89% of presentations as viral or bacterial upper respiratory tract infection. Only 57% of presentations were associated with an identified pathogen or other laboratory parameters indicative of infection. Demographic information, previous illness, and training history did not distinguish between presentations with or without objective measures of infection. Elevated white blood cell and neutrophil counts and lower vitamin D concentrations partially distinguished infectious episodes. The number of systemic symptoms/behaviors at presentation (cough, headache, earache, fatigue, fever/rigors, myalgia/arthralgia, or cessation of training before clinic attendance) had some predictive value for infection: odds ratio per symptom, 1.23 (90% confidence interval: 0.91 to 1.66); probability of infection, 48% with no symptoms to 77% with 6 symptoms. Laboratory investigation identified allergy in a considerable proportion of the cohort (39%). CONCLUSIONS: The discrepancy between physician and laboratory diagnosed infection in elite athletes highlights the need for consideration of alternate diagnostic options when evaluating upper respiratory symptoms in athletes. A considerable proportion of episodes of respiratory symptoms in athletes were not associated with identification of a respiratory pathogen; other potentially treatable causes of upper respiratory symptoms should be considered, particularly in athletes with recurrent symptoms.

Cytokine responses to treadmill running in healthy and illness-prone athletes.

PURPOSE: To characterize differences in cytokine responses to exercise of different intensities and durations between healthy and illness-prone runners. METHODS: Trained distance runners were classified as healthy (no more than two episodes of upper-respiratory symptoms per year; N = 10) or illness-prone (four or more episodes per year; N = 8) and completed three treadmill tests: SHORT (30 min, 65% VO2max), LONG (60 min, 65% VO2max), and INTENSE (6 x 3 min, 90% VO2max). Blood samples were collected pre-, post-, 1 h, 10 h, and 24 h after exercise, and interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-12, and IL-1ra concentrations were determined. Repeated-measures ANOVA was used to assess changes in cytokine responses to exercise. Magnitudes of changes and differences between groups were characterized using Cohen's effect size (ES) criteria. RESULTS: Resting IL-8, IL-10, and IL-1ra concentrations were 19-38% lower (ES:0.38-0.96; small to moderate differences) in illness-prone runners. Similarly, postexercise IL-10 concentrations were 13-20% lower (ES: 0.20-0.37; small differences), and IL-1ra concentrations were 10-20% lower (ES: 0.22-0.38; small differences) in illness-prone subjects. In contrast, IL-6 elevations were 84-185% higher (ES: 0.29-0.59, small differences) in illness-prone subjects. Postexercise responses of IL-2, IL-4, and IL-12 were small and not substantially different between the groups. CONCLUSIONS: Cytokine responses to controlled treadmill running differ between healthy and illness-prone athletes. Illness-prone distance runners showed evidence suggestive of impaired inflammatory regulation in the hours after exercise that may account for the greater frequency of upper-respiratory symptoms experienced.

IL6 G-174C associated with sudden infant death syndrome in a Caucasian Australian cohort.

The aims of this study were to analyze IL6 G-174C in relation to high interleukin (IL)-6 concentrations found in some sudden infant death syndrome (SIDS) infants, and to assess the effects of IL6 G-174C, smoking status, and gender on IL-6 responses. SIDS infants, parents of SIDS infants, and populations with high (Aboriginal Australian), medium (Caucasian) or low (Bangladeshi) SIDS incidences were genotyped. Leukocytes were stimulated in vitro with endotoxin and IL-6 responses were assessed in relation to IL6 G-174C genotype, smoking status, and gender. The study findings showed that GG genotype, associated with high IL-6 responses, was predominant among Australian SIDS infants (58%) compared with control subjects (38%, p = 0.02), as well as Bangladeshis (94%) and Aboriginal Australians (88%) compared with Caucasians (42%, p < 0.01). GC smokers had higher median IL-6 responses (8.4 ng/ml(-1)) than GG (3.5 ng/ml(-1), p = 0.01) or CC smokers (2.4 ng/ml(-1), p < 0.01). GG nonsmokers had higher median IL-6 responses (4.9 ng/ml(-1)) than GG smokers (p < 0.05). Gender did not affect IL-6 responses. In conclusion, an association between IL6 G-174C and Australian SIDS infants was observed. IL6 G-174C alone cannot explain observed differences in the incidence of SIDS in the Bangladeshi and Aboriginal Australian populations. Further investigations are needed on interactions between smoking and gene polymorphisms in relation to proinflammatory responses implicated in SIDS.

Cytokine responses and sudden infant death syndrome: genetic, developmental, and environmental risk factors.

Despite the success of the campaigns to reduce the risk of sudden infant death syndrome (SIDS), it still remains the major cause of postneonatal mortality. The incidence of SIDS is higher among ethnic groups in which there are also high incidences of serious infectious diseases. The risk factors for SIDS parallel those for susceptibility to infection, and recent data have provided evidence to support the mathematical model of the common bacterial toxin hypothesis. One current hypothesis for the etiology of SIDS is that the deaths are a result of overwhelming proinflammatory responses to bacterial toxins; as in inflammatory responses to sepsis, cytokines, induced by bacterial toxins, cause physiological changes leading to death. The genetic, developmental, and environmental risk factors for SIDS are reviewed in relation to colonization by potentially harmful bacteria and the inflammatory responses induced in the nonimmune infant to microorganisms or their products.