Olfactory Cues of Naturally Occurring Systemic Inflammation: A Pilot Study of Seasonal Allergy.

INTRODUCTION: In an attempt to avoid contact with infectious individuals, humans likely respond to generalized rather than specific markers of disease. Humans may thus perceive a noninfectious individual as socially less attractive if they look (e.g., have facial discolouration), move (e.g., have a slower walking pace), or sound (e.g., sneeze) sick. This pilot study tested whether humans are averse to the body odour of noninfectious individuals with a low-grade systemic inflammation. METHODS: We collected the axillary body odour of individuals with severe seasonal allergy (N = 14) and healthy controls (N = 10) during and outside the allergy season and measured serum levels of two inflammatory cytokines (tumour necrosis factor-α and interleukin-5). Independent participants (N = 67) then sampled and rated these odours on intensity and pleasantness. RESULTS: While individuals with seasonal allergy had nominally more unpleasant and intense body odours during the allergy season, relative to outside the allergy season and to healthy controls, these effects were not significant. When examining immune markers, the change in perceived pleasantness of an individual's body odour (from out-to-inside pollen season) was significantly related to the change in their interleukin-5 levels but not to tumour necrosis factor-α. DISCUSSION: Our findings tentatively suggest that the human olfactory system could be sensitive to inflammation as present in a noncommunicable condition. Larger replications are required to determine the role of olfaction in the perception of infectious and noninfectious (e.g., chronic diseases) conditions.

Human sickness detection is not dependent on cultural experience.

Animals across phyla can detect early cues of infection in conspecifics, thereby reducing the risk of contamination. It is unknown, however, if humans can detect cues of sickness in people belonging to communities with whom they have limited or no experience. To test this, we presented Western faces photographed 2 h after the experimental induction of an acute immune response to one Western and five non-Western communities, including small-scale hunter-gatherer and large urban-dwelling communities. All communities could detect sick individuals. There were group differences in performance but Western participants, who observed faces from their own community, were not systematically better than all non-Western participants. At odds with the common belief that sickness detection of an out-group member should be biased to err on the side of caution, the majority of non-Western communities were unbiased. Our results show that subtle cues of a general immune response are recognized across cultures and may aid in detecting infectious threats.

Acute Systemic Experimental Inflammation Does Not Reduce Human Odor Identification Performance.

Olfactory dysfunction is a common symptom of various diseases, but the underlying pathophysiology has not been fully understood. Evidence from both animal and human studies suggests that local inflammation of the olfactory epithelium is linked to olfactory dysfunction. However, whether systemic inflammation causes olfactory dysfunction is yet to be determined. In the present behavioral study, we set out to test whether acute systemic inflammation impairs olfactory identification performance by inducing a transient and controlled state of systemic inflammation using an experimental endotoxemia model. We treated young healthy participants (N = 20) with a relatively high dose (2.0 ng/kg) of lipopolysaccharide (LPS) and a placebo treatment in a double-blind within-subject design, and assessed participants' ability to identify odors using the MONEX-40, a reliable method for experimental assessment of odor identification ability in healthy and young individuals. Our results show that olfactory identification performance was not affected by the acute systemic inflammation triggered by the injection of LPS. Moreover, odor identification performance following the LPS injection was not associated with levels of circulating proinflammatory cytokines (interleukin-6, interleukin-8, and tumor necrosis factor-α). Because experimental LPS-induced systemic inflammation does not affect olfactory identification performance, our findings suggest that chronic, rather than transient, systemic inflammation is a more likely mechanism to explore in order to explain the olfactory deficits observed in inflammatory diseases.

Regulation of emotions during experimental endotoxemia: A pilot study.

Even though dysfunctional emotion regulation is prominent in depression and a link between depression and inflammation is well established, there is little knowledge about how inflammation affects the regulation of emotions. The aim of this pilot study was to explore the effect of experimentally induced inflammation on the cognitive reappraisal of emotions, and to assess domain specificity by comparing success in regulation of emotions towards two unpleasant stimuli classes (general negative stimuli and disgust stimuli). In a between-subject design, ten healthy participants were injected with an intravenous injection of lipopolysaccharide (2 ng/kg body weight) and eleven were injected with saline. Participants performed a cognitive reappraisal task, in which they had to down-regulate or up-regulate their emotions towards general negative stimuli and disgust stimuli, 5-6 h post-injection. Contrary to our hypotheses, participants injected with lipopolysaccharide reported greater success in down-regulating emotional responses towards unpleasant stimuli as compared to the saline group. In addition, both groups were poorer at down-regulating emotions towards disgust stimuli as compared to general negative stimuli. The current pilot study indicates that cognitive reappraisal of emotions is affected during experimental endotoxemia, and suggests that disgust stimuli might be difficult to reappraise.

Behavioral and neural correlates to multisensory detection of sick humans.

Throughout human evolution, infectious diseases have been a primary cause of death. Detection of subtle cues indicating sickness and avoidance of sick conspecifics would therefore be an adaptive way of coping with an environment fraught with pathogens. This study determines how humans perceive and integrate early cues of sickness in conspecifics sampled just hours after the induction of immune system activation, and the underlying neural mechanisms for this detection. In a double-blind placebo-controlled crossover design, the immune system in 22 sample donors was transiently activated with an endotoxin injection [lipopolysaccharide (LPS)]. Facial photographs and body odor samples were taken from the same donors when "sick" (LPS-injected) and when "healthy" (saline-injected) and subsequently were presented to a separate group of participants (n = 30) who rated their liking of the presented person during fMRI scanning. Faces were less socially desirable when sick, and sick body odors tended to lower liking of the faces. Sickness status presented by odor and facial photograph resulted in increased neural activation of odor- and face-perception networks, respectively. A superadditive effect of olfactory-visual integration of sickness cues was found in the intraparietal sulcus, which was functionally connected to core areas of multisensory integration in the superior temporal sulcus and orbitofrontal cortex. Taken together, the results outline a disease-avoidance model in which neural mechanisms involved in the detection of disease cues and multisensory integration are vital parts.

Emotional expressions of the sick face.

To handle the substantial threat posed by infectious diseases, behaviors that promote avoidance of contagion are crucial. Based on the fact that sickness depresses mood and that emotional expressions reveal inner states of individuals to others, which in turn affect approach/avoidance behaviors, we hypothesized that facial expressions of emotion may play a role in sickness detection. Using an experimental model of sickness, 22 volunteers were intravenously injected with either endotoxin (lipopolysaccharide; 2 ng/kg body weight) and placebo using a randomized cross-over design. The volunteers were two hours later asked to keep a relaxed expression on their face while their facial photograph was taken. To assess the emotional expression of the sick face, 49 participants were recruited and were asked to rate the emotional expression of the facial photographs of the volunteers when sick and when healthy. Our results indicate that the emotional expression of faces changed two hours after being made temporarily sick by an endotoxin injection. Sick faces were perceived as more sick/less healthy, but also as expressing more negative emotions, such as sadness and disgust, and less happiness and surprise. The emotional expressions mediated 59.1% of the treatment-dependent change in rated health. The inclusion of physical features associated with emotional expressions to the mediation analysis supported these results. We conclude that emotional expressions may contribute to detection and avoidance of infectious individuals and thereby be part of a behavioral defense against disease.

Sleep during naturally occurring respiratory infections: A pilot study.

There is strong experimental support that infections increase the drive for sleep in animals, and it is widely believed that more sleep is part of an adaptive immune response. While respiratory infections (RI) are very prevalent in humans, there is a striking lack of systematic knowledge on how it affects sleep. We recruited 100 people, among whom 28 became sick with an RI during the study period (fulfilling criteria for influenza-like illness, ILI, or acute respiratory infection, ARI). We measured sick participants' sleep at home, both objectively (actigraphy) and subjectively (diary ratings), for one week as well as four weeks later when healthy. During the week with RI, people spent objectively longer time in bed and had a longer total sleep time compared to the healthy week. During the infection, participants also had more awakenings, but no significant differences in sleep latency or sleep efficiency. While sick, people also reported increased difficulties falling asleep, worse sleep quality, more restless sleep and more shallow sleep, while they did not report sleep to be less sufficient. Most problems occurred at the beginning of the sickness week, when symptoms were strong, and showed signs of recovery thereafter (as indicated by interactions between condition and day/night of data collection for all the 10 sleep outcomes). The degree of symptoms of RI was related to a worse sleep quality and more restless sleep, but not to any of the objective sleep outcomes or the other subjective sleep variables. Having a higher body temperature was not significantly related to any of the sleep variables. This study suggests that having a respiratory infection is associated with spending more time in bed and sleeping longer, but also with more disturbed sleep, both objectively and subjectively. This novel study should be seen as being of pilot character. There is a need for larger studies which classify pathogen type and include baseline predictors, or that manipulate sleep, in order to understand whether the sleep alterations seen during infections are adaptive and whether sleep interventions could be used to improve recovery from respiratory infections.

Identification of acutely sick people and facial cues of sickness.

Detection and avoidance of sick individuals have been proposed as essential components in a behavioural defence against disease, limiting the risk of contamination. However, almost no knowledge exists on whether humans can detect sick individuals, and if so by what cues. Here, we demonstrate that untrained people can identify sick individuals above chance level by looking at facial photos taken 2 h after injection with a bacterial stimulus inducing an immune response (2.0 ng kg-1 lipopolysaccharide) or placebo, the global sensitivity index being d' = 0.405. Signal detection analysis (receiver operating characteristic curve area) showed an area of 0.62 (95% confidence intervals 0.60-0.63). Acutely sick people were rated by naive observers as having paler lips and skin, a more swollen face, droopier corners of the mouth, more hanging eyelids, redder eyes, and less glossy and patchy skin, as well as appearing more tired. Our findings suggest that facial cues associated with the skin, mouth and eyes can aid in the detection of acutely sick and potentially contagious people.

Detection of Inflammation via Volatile Cues in Human Urine.

Contagious disease is a major threat to survival, and the cost of relying on the immune system to defeat pathogens is high; therefore, behavioral avoidance of contagious individuals is arguably an adaptive strategy. Animal findings demonstrate the ability to detect and avoid sick individuals by the aid of olfactory cues, and a recent study indicated that human axillary odor also becomes more aversive as a function of immune activation. By injecting healthy human participants with lipopolysaccharide (0.6 ng/kg body weight) to experimentally induce inflammation, this study demonstrates that natural daily rhythms of urine odor-its perceived dimensions and volatile profile-are altered within hours of inflammation onset. Whereas healthy human urine decreases in averseness over the course of a single day, inflammation interrupts this process and results in an increased urine odor averseness and an altered volatile composition. These results support the notion that subtle and early cues of sickness may be detected and avoided, thereby complementing the immune system in its role of keeping us alive and healthy.

Sickness behavior is not all about the immune response: Possible roles of expectations and prediction errors in the worry of being sick.

BACKGROUND: People react very differently when sick, and there are only poor correlations between the intensity of the immune response and sickness behavior. Yet, alternative predictors of the individual differences in sickness are under-investigated. Based on the predictive coding model of placebo responses, where health outcomes are function of bottom-up sensory information and top-down expectancies, we hypothesized that individual differences in behavioral changes during sickness could be explained by individual top-down expectancies and prediction errors. METHODS: Twenty-two healthy participants were made sick by intravenously administering lipopolysaccharide (2 ng/kg body weight). Their expectations of becoming sick were assessed before the injection. RESULTS: Participants having lower expectations of becoming sick before the injection reacted with more emotional distress (i.e., more negative affect and lower emotional arousal) than those with high expectations of becoming sick, despite having similar overall sickness behavior (i.e., a combined factor including fatigue, pain, nausea and social withdrawal). In keeping with a predictive coding model, the "prediction error signal", i.e., the discrepancy between the immune signal and sickness expectancy, predicted emotional distress (reduction in emotional arousal in particular). CONCLUSION: The current findings suggest that the emotional component of sickness behavior is, at least partly, shaped by top-down expectations. Helping patients having a realistic expectation of symptoms during treatment of an illness may thus reduce aggravated emotional responses, and ultimately improve patients' quality of life and treatment compliance. REGISTRATION: "Endotoxin-induced Inflammatory and Behavioral Responses and Predictors of Individual Differences", https://clinicaltrials.gov/ct2/show/NCT02529592, registration number: NCT02529592.

Correction to: Influence of Body Odors and Gender on Perceived Genital Arousal.

There were 4 cells in the original Table 2 that reported SEM values instead of SDs. A corrected version of the table is provided below. In the Results section, the corresponding corrections are as follows.

Influence of Body Odors and Gender on Perceived Genital Arousal.

Olfaction is often linked to mating behavior in nonhumans. Additionally, studies in mating behavior have shown that women seem to be more affected by odor cues than men. However, the relationship between odor cues and sexual response-specifically, sexual arousal-has not been studied yet. The aim of this study was to evaluate the impact of the exposure to human body odors (from individuals of the opposite gender) on perceived genital arousal, while these were presented concomitantly to sexually explicit video clips. Eighty university students (40 women) rated their perceived genital arousal (perceived degree of erection/genital lubrication) in response to an audiovisual sexual stimulus, while simultaneously exposed to a body odor from an opposite-gender donor or no odor. Participants also rated each odor sample's (body odor and no odor) perceived pleasantness, intensity, and familiarity. Findings indicated that odor condition had an effect on women's (but not men's) perceived genital arousal, with women showing higher levels of perceived genital arousal in the no odor condition. Also, results showed that women rated body odors as less pleasant than no odor. Notwithstanding, the odor ratings do not seem to explain the association between body odor and perceived genital arousal. The current results support the hypothesis that women, rather than men, are sensitive to odors in the context of sexual response. The findings of this study have relevance for the understanding of human sexuality with respect to chemosensory communication.

Multisensory flavor perception: The relationship between congruency, pleasantness, and odor referral to the mouth.

Our hedonic response to a food is determined by its flavor, an inherently multisensory experience that extends beyond the mere addition of its odor and taste. While congruency is known to be important for multisensory processes in general, little is known about its specific role in flavor processing. The aim of the present study was to delineate the effects of odor-taste congruency on two central aspects of flavor: odor referral (or mislocalization) to the mouth, and pleasantness. We further aimed to test whether an eventual effect on pleasantness was mediated by odor referral. Aqueous solutions containing odors and tastes were prepared to create food-like stimuli with varying degrees of congruency, ranging from maximally incongruent to maximally congruent in nine steps. Thirty participants reported where they perceived the odors, and how much they liked the solutions. Congruency had a positive linear effect both on odor referral to the oral cavity and on pleasantness. However, the effect of congruency on pleasantness was not mediated by odor referral. These results indicate that as an odor-taste mixture approximates a mental representation of a familiar food, its components are increasingly merged into one perceptual object sensed in the mouth. In parallel, the mixture is evaluated as increasingly pleasant, which promotes consumption of familiar foods that have been determined through experience to be non-toxic. While the modulatory role of congruency on pleasantness and odor referral was confirmed, our results also indicate that these effects arise through distinct perceptual mechanisms.

The Body Odor Disgust Scale (BODS): Development and Validation of a Novel Olfactory Disgust Assessment.

Disgust plays a crucial role in the avoidance of pathogen threats. In many species, body odors provide important information related to health and disease, and body odors are potent elicitors of disgust in humans. With this background, valid assessments of body odor disgust sensitivity are warranted. In the present article, we report the development and psychometric validation of the Body Odor Disgust Scale (BODS), a measure suited to assess individual differences in disgust reaction to a variety of body odors. Collected data from 3 studies (total n = 528) show that the scale can be used either as a unidimensional scale or as a scale that reflects two hypothesized factors: sensitivity to one's own body odors versus those of others. Guided by our results, we reduced the scale to 12 items that capture the essence of these 2 factors. The final version of the BODS shows an excellent internal consistency (Cronbach's αs > 0.9). The BODS subscales show convergent validity with other general disgust scales, as well as with other olfactory functions measures and with aspects of personality that are related to pathogen avoidance. A fourth study confirmed the construct validity of the BODS and its measurement invariance to gender. Moreover, we found that, compared with other general disgust scales, the BODS is more strongly related to perceived vulnerability to disease. The BODS is a brief and valid assessment of trait body odor disgust sensitivity.

Skin colour changes during experimentally-induced sickness.

Skin colour may be an important cue to detect sickness in humans but how skin colour changes with acute sickness is currently unknown. To determine possible colour changes, 22 healthy Caucasian participants were injected twice, once with lipopolysaccharide (LPS, at a dose of 2ng/kg body weight) and once with placebo (saline), in a randomised cross-over design study. Skin colour across 3 arm and 3 face locations was recorded spectrophotometrically over a period of 8h in terms of lightness (L∗), redness (a∗) and yellowness (b∗) in a manner that is consistent with human colour perception. In addition, carotenoid status was assessed as we predicted that a decrease it skin yellowness would reflect a drop in skin carotenoids. We found an early change in skin colouration 1-3h post LPS injection with facial skin becoming lighter and less red whilst arm skin become darker but also less red and less yellow. The LPS injection also caused a drop in plasma carotenoids from 3h onwards. However, the timing of the carotenoid changes was not consistent with the skin colour changes suggesting that other mechanisms, such as a reduction of blood perfusion, oxygenation or composition. This is the first experimental study characterising skin colour associated with acute illness, and shows that changes occur early in the development of the sickness response. Colour changes may serve as a cue to health, prompting actions from others in terms of care-giving or disease avoidance. Specific mechanisms underlying these colour changes require further investigation.

The scent of disease: human body odor contains an early chemosensory cue of sickness.

Observational studies have suggested that with time, some diseases result in a characteristic odor emanating from different sources on the body of a sick individual. Evolutionarily, however, it would be more advantageous if the innate immune response were detectable by healthy individuals as a first line of defense against infection by various pathogens, to optimize avoidance of contagion. We activated the innate immune system in healthy individuals by injecting them with endotoxin (lipopolysaccharide). Within just a few hours, endotoxin-exposed individuals had a more aversive body odor relative to when they were exposed to a placebo. Moreover, this effect was statistically mediated by the individuals' level of immune activation. This chemosensory detection of the early innate immune response in humans represents the first experimental evidence that disease smells and supports the notion of a "behavioral immune response" that protects healthy individuals from sick ones by altering patterns of interpersonal contact.

Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses.

BACKGROUND: Constitutive activation of the ERK pathway, occurring in the vast majority of melanocytic neoplasms, has a pivotal role in melanoma development. Different mechanisms underlie this activation in different tumour settings. The Grey phenotype in horses, caused by a 4.6 kb duplication in intron 6 of Syntaxin 17 (STX17), is associated with a very high incidence of cutaneous melanoma, but the molecular mechanism behind the melanomagenesis remains unknown. Here, we investigated the involvement of the ERK pathway in melanoma development in Grey horses. METHODS: Grey horse melanoma tumours, cell lines and normal skin melanocytes were analyzed with help of indirect immunofluorescence and immunoblotting for the expression of phospho-ERK1/2 in comparison to that in non-grey horse and human counterparts. The mutational status of BRAF, RAS, GNAQ, GNA11 and KIT genes in Grey horse melanomas was determined by direct sequencing. The effect of RAS, RAF and PI3K/AKT pathways on the activation of the ERK signaling in Grey horse melanoma cells was investigated with help of specific inhibitors and immunoblotting. Individual roles of RAF and RAS kinases on the ERK activation were examined using si-RNA based approach and immunoblotting. RESULTS: We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in BRAF, RAS, GNAQ, GNA11 and KIT genes or alterations in the expression of the main components of the pathway. The pathway is mitogenic and is mediated by BRAF, CRAF and KRAS kinases. Importantly, we found high activation of the ERK pathway also in epidermal melanocytes, suggesting a general predisposition to melanomagenesis in these horses. CONCLUSIONS: These findings demonstrate that the presence of the intronic 4.6 kb duplication in STX17 is strongly associated with constitutive activation of the ERK pathway in melanocytic cells in Grey horses in the absence of somatic mutations commonly linked to the activation of this pathway during melanomagenesis. These findings are consistent with the universal importance of the ERK pathway in melanomagenesis and may have valuable implications for human melanoma research.

High prevalence of long-term olfactory disorders in healthcare workers after COVID-19: A case-control study.

BACKGROUND: More than a year after recovering from COVID-19, a large proportion of individuals, many of whom work in the healthcare sector, still report olfactory dysfunctions. However, olfactory dysfunction was common already before the COVID-19 pandemic, making it necessary to also consider the existing baseline prevalence of olfactory dysfunction. To establish the adjusted prevalence of COVID-19 related olfactory dysfunction, we assessed smell function in healthcare workers who had contracted COVID-19 during the first wave of the pandemic using psychophysical testing. METHODS: Participants were continuously tested for SARS-CoV-2 IgG antibodies since the beginning of the pandemic. To assess the baseline rate of olfactory dysfunction in the population and to control for the possibility of skewed recruitment of individuals with prior olfactory dysfunction, consistent SARS-CoV-2 IgG naïve individuals were tested as a control group. RESULTS: Fifteen months after contracting COVID-19, 37% of healthcare workers demonstrated a quantitative reduction in their sense of smell, compared to only 20% of the individuals in the control group. Fifty-one percent of COVID-19-recovered individuals reported qualitative symptoms, compared to only 5% in the control group. In a follow-up study 2.6 years after COVID-19 diagnosis, 24% of all tested recovered individuals still experienced parosmia. CONCLUSIONS: In summary, 65% of healthcare workers experienced parosmia/hyposmia 15 months after contracting COVID-19. When compared to a control group, the prevalence of olfactory dysfunction in the population increased by 41 percentage points. Parosmia symptoms were still lingering two-and-a half years later in 24% of SARS-CoV-2 infected individuals. Given the amount of time between infection and testing, it is possible that the olfactory problems may not be fully reversible in a plurality of individuals.

Mind over age--stereotype activation and olfactory function.

Given that context affects olfaction and the elderly exhibit olfactory deficits, the current study tested whether a subtle change in internal context, evoked by priming the elderly stereotype, would affect performance in a variety of olfactory tasks including odor sensitivity, discrimination, and identification (Experiment 1), as well as perceived odor intensity, pleasantness and familiarity, and an odor reaction time task (Experiment 2). Such internalization of the elderly stereotype has been demonstrated with slower walking speeds and fewer words recalled in a memory task. In the current study, 76 participants first listened to a presentation about age-related declines in olfaction and then participated in 3 language tasks which, unbeknownst to them, served as the elderly stereotype priming manipulation. This priming manipulation was effective at decreasing walking speed and word recall, confirming the findings of previous researchers; however, olfaction was not affected. Whether olfaction is resistant to stereotype priming is discussed.

Humans can detect axillary odor cues of an acute respiratory infection in others.

Background and objectives: Body odor conveys information about health status to conspecifics and influences approach-avoidance behaviors in animals. Experiments that induce sickness in otherwise healthy individuals suggest that humans too can detect sensory cues to infection in others. Here, we investigated whether individuals could detect through smell a naturally occurring acute respiratory infection in others and whether sickness severity, measured via body temperature and sickness symptoms, was associated with the accuracy of detection. Methodology: Body odor samples were collected from 20 donors, once while healthy and once while sick with an acute respiratory infection. Using a double-blind, two-alternative forced-choice method, 80 raters were instructed to identify the sick body odor from paired sick and healthy samples (i.e. 20 pairs). Results: Sickness detection was significantly above chance, although the magnitude of the effect was low (56.7%). Raters' sex and disgust sensitivity were not associated with the accuracy of sickness detection. However, we find some indication that greater change in donor body temperature, but not sickness symptoms, between sick and healthy conditions improved sickness detection accuracy. Conclusion and implications: Our findings suggest that humans can detect individuals with an acute respiratory infection through smell, albeit only slightly better than chance. Humans, similar to other animals, are likely able to use sickness odor cues to guide adaptive behaviors that decrease the risk of contagion, such as social avoidance. Further studies should determine how well humans can detect specific infections through body odor, such as Covid-19, and how multisensory cues to infection are used simultaneously.