What are the variables affecting illness Behaviour?

Inflammation, Sickness Behavior, and Depression

Sickness behavior is a reflection of immune activation and is commonly associated with depression, the chronic fatigue syndrome, and certain types of cancer such as pancreatic cancer. Thus fatigue, sleep disturbance, hyperalgesia, anorexia, and loss of libido are frequently associated with these conditions and often resemble infectious disease symptoms such as influenza, hence the term ‘sickness behavior.’ However, the question arises whether sickness behavior seen in psychiatric disorders is part of a continuum that develops into major depression or is separate from the pathological processes which result in depression. Perhaps the evolutionary importance of sickness behavior provides a clue!

The symptoms that arise in all animal species following a systemic infection are essentially similar. The neuro-vegetative symptoms include lethargy, anorexia, hypersomnia, loss of libido, and, in humans, anhedonia. Such symptoms would be beneficial for survival as they allow the animal to withdrawal into a safe environment so that the healing process may occur. The term ‘sickness behavior’ was devised to describe such behavior (Kent et al., 1992). The evolutionary advantage for such behavior would occur as a result of the avoidance of contact with others in the group and thereby reduce the spread of the infection. This suggests that sickness behavior is a relatively short-term reaction to an acute inflammatory challenge and reflects a strategy that is critical for the survival of the individual, a concept first proposed by Hart (1988). However, the situation which occurs when inflammation becomes chronic is likely to be detrimental to survival as occurs, for example, in autoimmune diseases, cardiovascular disease, diabetes, and as a consequence of the secondary effects of obesity when mood symptoms often predominate and even worsen the outcome (Raison and Miller, 2013). As chronic low-grade inflammation is a characteristic feature of affective disorders, it would seem reasonable to conclude that sickness behavior is distinct from depression but does serve an important survival function (Janicki-Deverts et al., 2007). In support of this view, Janicki-Deverts et al. (2007) assessed the relationship between sickness behavior and PICs by assessing the response of group of healthy adults to an influenza rhinovirus challenge. The results showed that the increase in IL-6, IL-1β, and TNF-α is associated with a reduced positive affect but not with a negative affect, thereby suggesting that there were differences between sickness behavior, depression, and the changes in peripheral PICs.

As antidepressants are reasonably effective in attenuating the symptoms of depression, are they equally effective in attenuating low-grade inflammation which occurs concurrently with the major symptoms? From rodent models of depression there is certainly evidence that antidepressants reduce the tissue concentrations of IL-6 and TNF-α (Yirmiya et al., 2001; Kenis and Maes, 2002; Yaron et al., 1999). However, these conclusions are based on the effects of antidepressants on in vitro or acute in vivo models in which LPS was used as an acute immune challenge. A more representative model of major depression is provided by the olfactory bulbectomized rat model which not only demonstrates the elevation of tissue PICs, prostaglandin E2, and NO (Song and Leonard, 2005) but also shows that chronic antidepressant treatments attenuate the depression-like symptoms concurrently with the tissue inflammatory mediators (Myint et al., 2007). By contrast, with the largely positive results from the chronic rodent studies, it has also been shown that chronically administered fluoxetine increased, rather than decreased, some of the pro-inflammatory markers (Lee et al., 2007).

Despite these results from rodent studies, those based on changes in the blood concentrations in patients are less convincing. At best, the clinical results are inconsistent and several studies have reported no changes in the cytokines in depressed patients despite an adequate response to treatment (Jazayeri et al., 2010; Maes et al., 1995). Indeed, there is evidence from experimental studies that chronic fluoxetine treatment increases the concentration of PICs (Lee et al., 2007). Thus, overall, it would appear that the antidepressants currently available have an inconsistent effect on inflammation.

Introduction

Abnormal illness behaviors describe maladaptive perceptions and experience of one's health status. There are seven psychiatric conditions characterized by physical symptoms that are not explainable or reducible to an organic medical illness, substance or medication use, or another psychiatric condition. Five of these disorders, the somatoform disorders, involve symptoms that are not intentionally created, but are the result of psychological factors. Malingering and factitious disorder are the results of the intentional production of signs and symptoms. All seven of the disorders that characterize abnormal illness behaviors present challenges to clinicians, who must determine the extent to which signs and symptoms reflect psychopathology versus an organic medical disease. In diagnosing any disorder characterized by predominant abnormal illness behaviors, a primary medical condition must be ruled out as an explanation of symptoms.

5.12.3.3.3 Effect of cytokines on CNS function

Sickness behavior is caused by cytokines in the periphery and brain that stimulate receptors in the brain to cause elevated body temperature, increased sleep, and changes in lipid and protein metabolism that cause weight loss (Dantzer et al. 2008). It is interesting to speculate that immunotoxicants might precipitate the sickness behavior that is often associated with exposure to them. For example, IL-1, which is strongly associated with sickness behavior, is produced by activated macrophages and is known to be an endogenous pyrogen, inducing the fever that accompanies the inflammatory and immunologic responses. Within the CNS, IL-1 has been reported to enhance slow wave sleep (Shoham et al. 1987), opioid receptor binding in the brain (Wiedermann 1989), and endorphin production in the pituitary (Fagarasan et al. 1991). Subpyrogenic doses of IL-1 injected into mice and rats increase the levels of circulating ACTH and glucocorticoids (Besedovsky et al. 1986), which suppress the production of IL-1 and complete an immunoregulatory feedback loop. IL-1 is able to activate the HPA axis at the level of the hypothalamus (Berkenbosch et al. 1987; Sapolsky et al. 1987) to increase the production of CRF. When small quantities of IL-1 are introduced directly into the brains of rats, a rapid and marked decrease occurs in blood and splenic natural killer (NK) cell activity, responsiveness to phytohemaglutinin (PHA) stimulation, and production of IL-2 (Sundar et al. 1989). On the other hand, IL-2 alters oligodendrocyte proliferation (Benveniste and Merril 1986) and inhibits cholinergic activity in various regions of the CNS (Araujo et al. 1989), while IL-6 acts synergistically with IL-1 in its ability to increase circulating ACTH levels in vivo (Troisi et al. 1991). TNF also affects brain function and the effects are divergent, depending on the responding brain region (Sriram and O’Callaghan 2007). Reviews on the subject of cytokine action on cell function within different areas of the brain are available and they discuss this subject in detail (Gosselin and Rivest 2007; Pickering and O’Connor 2007; Simi et al. 2007).

5.27.5 Assessment of Factitious Disorder

Assessment of FD cases usually begins in the medical setting as medical staff become suspicious that the patient is engaging in some form of deception. Consultation with psychiatry, psychology, or social work colleagues should be arranged sooner rather than later to help devise a plan of assessment and intervention. First steps include a careful inventory of the facts of the case and a vetting of the evidence supporting those facts. Information obtained directly from the patient or parent should be verified with previous medical records, calls to previous providers, or interviews with family members. A pattern of lies and omissions that portray a more dire clinical picture would support an FD diagnosis. Staff should be interviewed to confirm whether documented medical events that occurred in the hospital or clinic (e.g., oxygen desaturations, seizures) were actually observed, only inferred (e.g., based on monitor readings or the presence of blood or vomitus), or based solely on the patient's/parent's report. Also, staff should take an inventory of any departures from standard care that were made at the request of the patient or the family (e.g. agreeing to forego a crucial test on the patient's word that he had it performed recently). Tests that provided extreme or inconsistent results should be repeated under conditions that would make it difficult for the patient to contaminate the samples or tamper with testing equipment. Often, the correct explanation for puzzling presentations is not hard to arrive at when medical staff open themselves to the possibility that the patient or parent has been intentionally deceptive. Going forward, the medical staff should adhere strictly to evidence-based standards of medical care, making sure not to undertreat.

For children who are not yet verbal or cognitively capable of deception, roughly between birth and age four years, the medical deceptions are being carried out by a caregiver. For children between roughly 4 and 15 years of age, the parent may be the sole engineer of the deception, but this is only a real possibility in children with complex medical problems that began before age 5 and are being continued by the parent (often enabled by dependence on feeding tubes, or central venous access). For newly emerging medical problems in this age range, the child is acting alone or in collaboration with a parent. In any event, careful observation should be made of changes in the child's condition that occur in the presence of the parent, and staff should be watchful for contraband that the parent might deliver to the patient to effect medical deceptions.

Any acts by parents that mislead medical staff about the child's health history or current condition carry an unnecessary risk of medical harm to the child. Prolonged or frequent hospitalization pose a risk of impeded cognitive and social development. As such, the parent's behavior constitutes abuse and a report to child protective services must be made. It is important to consult mental health specialists, hospital attorneys, and patient advocates to determine the steps that must be taken to gather evidence, protect the child, and protect the parents' rights. Poorly conceived investigations can be unfair to parents or contaminate evidence. Poorly planned confrontations create the risk that the parent will flee with the child or cause acute harm to the child to reinforce the appearance of genuine illness.

If it is determined that the parent is not directly involved in the deception, and sufficient evidence of medical deception has been gathered, several difficult decisions must be made. The first has to do with the way the family will be informed. A conference that includes parents, medical staff and mental health staff can be convened to share with the parent the puzzling nature of the patient's medical problems and ask the family's opinions. Asking the parents if they have had suspicions about the patient will help staff understand how receptive the parents will be to the staff's suspicions and evidence. The task of finding out the truth should be portrayed as directed toward providing the best care for the child and avoiding the medical risks of providing excessive or misguided care should be the shared goal of providers and parents.

It is worth taking a moment to caution medical providers to avoid uncritical use of “profiles” of the perpetrators of medical child abuse. Perpetrators, usually mothers, are described in the literature as loving, caring, and doting, with an unusually high level of medical knowledge and interest in the technical aspects of their children's medical tests and treatments. They may seem unusually inured to the pain, discomfort, and fear that their child suffers as a result of the tests and procedures that the child is subjected to. The mothers may become angered with decisions to delay or withhold procedures and may try to leverage positive relations with key members of the treatment team to get their way, causing splits between the “good” doctors and the “bad” ones. While these features may be diagnostically useful in combination with other evidence, they lack adequate specificity on their own: many mothers of sick children are zealous advocates for children, and some may even be perceived as pushy or abrasive. The use of such profiles may be a particularly poor way to gauge the role of the parent in EIB in an older child or adolescent. For example, a parent who recoils at providers' suggestions that their child's problem may be exaggerated might be doing so because they are somehow involved in the exaggeration, or simply because they have an unhealthy confidence that their child would never do such a thing.

The second decision is whether to confront the child directly. The case reviews described earlier suggest a high probability that an empathic and constructive confrontation may result in the patient admitting to the deception, after which plans for further psychiatric assessment and treatment can be made. In some cases, there may be indications that the patient has gotten him or herself trapped in the deception and are looking for a face-saving way out of the sick role (Hilton and Hamilton, 2017). In such cases confrontation may be counterproductive. It may be possible to connect the patient to mental health care by instead telling them that having a complicated or puzzling medical problem can be stressful, and the stress can make the medical problems worse. Mental health counseling can be presented as a way for the patient to learn stress management and better ways to cope with illness. In that context, therapeutic rapport can be built, a deeper functional assessment can be made, and the functions that sick role enactment is serving can be determined. The therapy can be a safe and face-saving means for the child to relinquish the sick role and find more healthy ways of addressing the problems that they have been using the sick role to manage.

Children with EIB can be encountered outside the medical setting. School counselors may become concerned about recurrent bouts of illness in school or numerous illness-related absences and refer the child for mental health care. Parents may bring their child for evaluation of non-medically related problems like hyperactivity or poor peer relations, and the child's EIB problems are revealed through general assessment.e

Once the patient is connected with a mental health professional, a thorough interview of the patient and parents should be carried out, broadly covering school behavior and performance, family and social relations, physical and social development, and medical and psychiatric history, and adverse childhood experiences. The guiding principle is understanding how the EIB functions within the wider network of influences and expectations in the child's life.

Standardized parent and child assessments of the child's functioning are used to determine the presence of a wide range of psychological difficulties, including psychosomatic complaints. The Conner's Revised Parenting Scale (CRPS) includes a psychosomatic scale assessing the presence of stomach aches, general aches and pains, aches before school, headaches, and the degree to which the child complains and seems tired (Conners et al., 1998). Similarly, the Behavioral Assessment System for Children (BASC-2) is a multidimensional measure of children's functioning completed by the parent and teacher (Reynolds, 2010). In the BASC-2, there is a scale of somatization, as well as adaptability, anxiety, depression, and withdrawal. Having global measures of a child's functioning can be helpful to understand the context of the child's EIB, and can also be used to track treatment progress.

There are several measures of somatic complaints for adult populations (i.e., Somatic Symptom Inventory, Psychosomatic Symptom Checklist, Screening for Somatoform Symptoms-2, and the Patient Health Questionnaire-15). These measures are inappropriate to use with young children as the vocabulary can be too advanced and directions unclear. The Children's Psychosomatic Symptom Checklist (C-PSC) was adapted from the Psychosomatic Symptom Checklist for use with a younger population (Wisniewski et al., 1988). Wisniewski et al. (1988) established that the C-PSC was valid for use with middle school students (i.e., 6th–8th grade students) and demonstrated its discrimination between headache and non-headache groups. The accurate assessment of a child's somatic symptoms via self-report is especially valuable to understand his or her subjective experience and perspective. The Children's Somatization Inventory (CSI; Garber et al., 1991) is a scale completed by the child regarding their experience of 36 “psychophysiological” symptoms (i.e., pain, muscle weakness, headaches, blurred vision, etc.). The CSI asks the child the degree to which they have been bothered by any given symptom in the past two weeks. The scale was validated with a wider age range of children (i.e., 2nd–12th graders), than the C-PSC. The authors also created the Parent Form of the Children's Somatization Inventory with the same format. Having both child and parent report is valuable in establishing consistency of symptoms as well as perceived impact of these symptoms for the child's functioning. The Somatic Complaint List (SCL) is another self-report measure designed to be used with school aged children (Jellesma et al., 2007). It was validated with the CSI and showed acceptable stability over 6 months and is briefer (11 items).

Introduction

Owners of domestic animals, as well as veterinarians and wildlife biologists, are aware of behavioral changes that occur when animals become sick and have a fever. These signs, which include depression, inactivity, sleepiness, anorexia, increased threshold for thirst, and reduction of grooming, are often the first indications that an animal is sick. Humans are no different from animals in showing these signs as markers of a febrile illness. Admittedly, animals are nonverbal, while people may say to themselves or others, ‘I feel sick and I am depressed.’

While in many illnesses there are organ-specific signs, such as nasal discharge for respiratory illness or diarrhea from intestinal illness, the suite of behavioral signs that accompany fever are nonspecific. These nonspecific signs are seen in vertebrates in general, including mammals, birds, and reptiles. They are seen in diseases that are fatal as well as those that are rarely fatal, and in a wide range of diseases caused by viruses, bacteria, and multicellular parasites.

The nonspecific behavioral changes associated with sickness have been around for as long as animals and humans have harbored sickness and disease, which is to say, throughout evolutionary history. When physicians and veterinarians, or their forerunners, started thinking and learning more about the causes and treatment of illnesses, there was naturally a tendency to view the behavior of sick animals and people as the result of debilitation and reduced ability to obtain food and water. Until quite recently, in the scientific disciplines of animal behavior, and indeed in human behavior, the behavior of sick individuals was outside the field of inquiry. Such behavior was not considered ‘normal’ or adaptive; it was not recognized as being a response that could be the result of natural selection. The breakthroughs of Kluger and others, in the late 1970s, in understanding the pathophysiology of the fever response, and the physiological linkage between fever and depression, inactivity, sleepiness, and anorexia, worked out by Hart in the 1980s, revealed that the nonspecific behavioral signs are adaptive and normal for an animal in a state of illness. In contrast to earlier ideas, the absence of these signs of sickness behavior during an illness could be viewed as abnormal.

Experimental studies of the detailed behavioral changes associated with sickness have typically involved laboratory rodents in which the bacterial endotoxin, lipopolysaccharide (LPS), can be used to induce transient fever and sickness behavior without actually making the animals sick. The widespread generality of the sickness behavior syndrome, however, is seen in studies of animals much different from rodents. For example, goats given LPS show anorexia along with a reduction in grooming.

The pervasiveness of sickness behavior throughout human history is poignant in any number of literary works from a century or two ago. A befitting verse, ‘Fragment,’ was penned in the mid-1800s by the famous poet of his time, Thomas Hood, after he suffered for years from sickness-inducing maladies:

I am sick of gruel, and the dietetics,

I am sick of pills, and sicker of emetics,

I am sick of pulses, tardiness or quickness.

I am sick of blood, its thinness or its thickness,

In short, within a word, I’m sick of sickness!

The purpose of this review is, first, to document the role of sickness behavior in facilitating the fever reaction in combating active infections, especially for animals living in nature, and then discuss the recently explored ramifications of the sickness behavior phenomenon in animal and human behavior. Hart introduced the concept of the adaptive functions of the behavior of sick animals, linking the signs of sickness behavior to the survival value of the fever response. Since then, the concept of sickness behavior has been explored, apart from its link to fever, in a number of contexts and species as an interesting phenomenon on its own with widespread implications for a more comprehensive understanding of animal and human behavior.

Abnormal Illness Behavior

The term abnormal illness behavior is popular, particularly in the setting of liaison psychiatry and is briefly discussed here. Pilowsky introduced the concept based on ideas that derived from social psychology.32 Abnormal illness behavior is defined as “the persistence of an inappropriate mode of perceiving, evaluating, acting in relation to one's state of health, despite the fact that a doctor has offered a reasonably lucid explanation of the nature of the illness, and the appropriate course of management to be followed, based on a thorough medical examination.”33 This broad definition covers a number of medical conditions such as hysteria, hypochondriasis, malingering, and Munchausen syndrome, in which an abnormality in the way patients evaluate and act in relation to their symptoms (illness behavior) is central. Pilowsky pointed out that these diagnoses are usually made by nonpsychiatrists on the basis of a discrepancy between detectable somatic disease and the patient's reaction; in other words, “the doctor does not believe that the sick role that the patient assumes is appropriate to the objective pathology detected.”33 Use of the term abnormal illness behavior places understanding of these conditions in a wider sociological context.

Sickness Responses

Fever and sickness behavior are ubiquitous phenomena in vertebrate physiology. Much of our understanding of the physiological and behavioral consequences of innate immune activation has come from administration of the model inflammogen lipopolysaccharide (LPS). Animals treated with LPS, a component of gram-negative bacterial cell walls, display a coordinated suite of physiological and behavioral responses. Hart concluded that the behavioral sequelae of LPS administration are particularly salient and include lethargy, anorexia, adipsia, anhedonia, and reduced social interactions. These responses, collectively termed ‘sickness behavior,’ along with the induction of fever, are thought to be part of a coordinated, adaptive effort to aid in recovery from infection.

LPS is first detected by TLRs expressed on a variety of cell types in the periphery. The activation of TLRs (e.g., TLR4 for LPS) induces the activation of the nuclear factor-kappa B (NF-κB) signaling cascade and the production of endogenous signaling factors. Dantzer and colleagues have been instrumental in showing that the primary mediators of the sickness response are the proinflammatory cytokines, IL-1β, IL-6, and TNF-α. Intraperitoneal LPS injections induce cytokine gene expression, in both the periphery and the CNS. Although the precise mechanisms remain under investigation, peripheral cytokines might induce central production of cytokines via active transport of cytokine proteins across the blood–brain barrier, interact with receptors on epithelial cells, activate vagal afferents, as well as via diffuse into circumventricular brain regions. Expression of cytokines in the brain appears to underlie the behavioral effects of peripheral LPS administration. In the brain, cytokines are largely expressed by microglia and perivascular and meningeal macrophages. Prendergast and others have reported that attenuated febrile and behavioral responses to LPS in short-day hamsters are associated with reduced neural cytokine gene expression and peripheral cytokine production both in vivo and in vitro.

Acute inflammation is associated with potent activation of the HPA axis. Proinflammatory cytokines are capable of activating the HPA axis at the level of the brain, pituitary gland, and adrenal gland. Inversely, glucocorticoids feed back to inhibit the expression of proinflammatory cytokines. Because of their effects on cytokines, as well as other cellular signalling pathways, glucocorticoids tend to suppress inflammation; and because of their induction by inflammatory stimuli, Besedovsky and del Rey characterize glucocorticoids as the ‘brakes’ on the immune system, having evolved to prevent runaway inflammation.

Whether engaging in sickness responses affects social status and aggression has not been adequately examined. One study by Cirulli and colleagues reports that LPS-injected male mice fail to initiate aggressive behavior toward an intruder in a resident–intruder aggression paradigm, but display normal defensive aggression if provoked. Better characterized is the impact of sickness on mating behavior. Male and female mating behavior is differentially influenced by LPS administration. Rivier and others have shown that LPS prevents the preovulatory LH surge in female rats and also eliminates mating behavior in ovariectomized, hormonally primed females via the induction of prostaglandins. In males, however, Yirmiya and associates demonstrated that LPS fails to disrupt mating at all but the highest doses despite suppressing testosterone production. Moreover, this sex difference is specific to mating because LPS affects behavior similarly between males and females in other behavioral responses that are unrelated to mating. Indeed, male rats may suppress the symptoms of their infection, putatively to ‘deceive’ females into mating.

Thus, individuals can detect sickness responses and other signals of infection to avoid infection. Numerous previous studies have focused on the tradeoffs associated with infection and reproductive success, but few have considered the more efficient adaptation of behavioral avoidance of sick animals. Maternal experience before and during pregnancy plays a critical role in offspring development. In one recent study by Curno and colleagues, the influence of social cues about disease in the maternal environment was examined in pregnant mice housed next to mice infected with noncontagious B. microti, but separated by a perforated Plexiglas barrier. Exposed females had higher levels of serum corticosterone and increased kidney growth compared with those with uninfected neighbors. Exposed females subsequently produced offspring that as adults showed an enhanced immune response to B. microti and reduced aggression. Because infection could more easily be spread by bites and other aggressive interactions, the reduction of aggression is significant. These results suggest that prevailing infections can influence responses in observers, as well as in their future offspring. The study is important because it indicates that these adaptations are elicited in future generations by glucocorticoid responses without directly incurring infection. These studies illuminate the importance of social information and maternal effects (and not necessarily only maternal condition) on life histories. Such ‘experiential’ consequences on future offspring phenotype may have important implications for understanding the epidemiology and individual disease susceptibility in both humans and non-human animals. Importantly, these results should provide a basis for the reconsideration of how rodents positive for so-called low-grade infections affect experimental observations.

What are the factors affecting illness Behaviour?

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