All components of the stress system talk together and work—as an ensemble—to regulate body state and to coordinate the body’s response to stress and threat. The immune-inflammatory system is part of this cross-talk. It is made up of cells that are scattered throughout the body or that reside in special tissues (e.g., immune cells in lymph glands or glial cells in the brain and spinal cord). The immune-inflammatory system uses cell-surface signalling molecules (immune signals), including a group of small proteins known as cytokines, to communicate cell to cell within the system. The evolutionary origins of the immune-inflammatory system are ancient (Flajnik and Kasahara 2010), with primitive systems present even in one-cell organisms (Janeway 2001).

The role of the immune-inflammatory system in infection, injury, and wound healing is well known. Immune-inflammatory responses promote the destruction and clearance of pathogens and enhance wound healing. Pro-inflammatory (defensive) cytokines function as messenger molecules to attract immune cells to sites of infection or injury, activating them to respond to the insult. Immune-inflammatory cells throughout the body retain memories of previous pathogens and facilitate rapid defensive responses if any particular pathogen is encountered again. In these ways, local inflammation enables the individual to fight infection and facilitates tissue healing.

But immune-inflammatory cells and their signalling messenger molecules are also involved in body regulation and protection more generally. They engage in intracellular communication day in and day out as the body works to regulate itself and to respond to the stress and challenges of daily life. Immune-inflammatory cells residing in the brain—glial cells (Fields 2009)—retain the memory of past stress, both physical and psychological (Brenhouse and Schwarz 2016; Frank et al. 2016). In this role the immune-inflammatory system is the body’s watchdog: always vigilant for threat, and ready to rouse from sleep to attack an intruder in the blink of an eye. In this same role as watchdog, and in response to any new threat, the immune-inflammatory system further activates and also typically interacts with, activates, and modulates other components of the stress system. In most children (including adolescents), the stress system—including the immune-inflammatory system itself—will return to baseline once the threat has passed. Importantly for us, in some children, one or more components of the stress system may remain activated or dysregulated, thereby setting the stage for the emergence of functional somatic symptoms.

In this chapter we focus primarily on the way that stress can activate the immune-inflammatory system and on how the immune-inflammatory system’s response to stress can, in turn, activate or dysregulate the stress system as a whole. Because the immune-inflammatory system is so complicated, we can only touch the surface of what is known, and share with the reader some of the key points that we raise in our discussions with children. A short, simple summary of the immune-inflammatory system is provided in a recent article by Heather Brenhouse and colleagues (2019). Further details (including reference articles) about the immune-inflammatory system—and the methodological difficulties of studying it—are provided in Online Supplement 9.1. An account of the discovery that glial cells—cells that were previously conceptualized as providing physical support to neurons—are also the brain’s immune-inflammatory cells is provided by the neuroscientist Douglas Fields in his book The Other Brain (Fields 2009). Later in this book (see Chapter 11), we look at processes on the mind system level—for example, catastrophizing (Edwards et al. 2008; Lazaridou et al. 2018)—that also maintain the immune-inflammatory system in an activated state. Additional references are listed in Online Supplement 1.3.

Shifting Gear to Systems Thinking: A Few Tips to the Reader

Like the hypothalamic-pituitary-adrenal (HPA) axis, the immune-inflammatory system is immensely complex, and clinicians from non-medical backgrounds may find this chapter challenging. The interconnections between the immune-inflammatory system and the HPA axis, autonomic nervous system, and brain stress systems are indirect and non-linear. It may be helpful for the reader to shift gear from linear to systems thinking, and to conceptualize these interconnections not as involving specific pathways but rather as involving patterns of change and shifts in patterns of communication.

An easy way to keep these interactions in mind is to visualize the overlap between circles in the stress-system model (see Fig. 4.2) and to remember in a general way that, because of the cross-talk between the immune-inflammatory system and other components of the stress system, activation or dysregulation in one part of the system will have flow-on effects in other parts.

Alternatively, the reader can think of the immune-inflammatory system as a large fishing net. Just as a fish, caught in one part of a net, causes changes in tension in other parts of the net, so do changes in immune-inflammatory signalling lead to ripples of change across the broader immune-inflammatory system and also across the stress system as a whole. Likewise, changes in particular other components of the stress system will lead to ripples of changes throughout the rest of the stress system.

Attachment Figures and the Immune-Inflammatory System

Attachment figures, in their role as biopsychosocial regulators, help to regulate the immune-inflammatory system. The mother’s exposure to stress in the prenatal period also has consequences for the development of the child’s immune-inflammatory system (Brenhouse et al. 2019) (see epigenetic mechanisms in Chapter 8 and Online Supplement 8.2).

In animal studies, early separations from the attachment figure result in stress, activate and sensitize the immune-inflammatory system, and lead to increased vulnerability for maladaptive responses to future stress. In humans, warm, sensitive attachment relationships in childhood are associated with healthier levels of immune-inflammatory markers later in life, whereas at-risk childhood relationships (maltreatment), childhood sexual abuse, and adverse childhood experiences (ACEs) more generally are associated with chronic, low-grade inflammation. For references see Online Supplement 1.3. For a discussion of findings pertaining to the stress system in sexual abuse, see Online Supplement 8.1. For more on low-grade inflammation, see below.

Adolescence also appears to be a period of vulnerability in the development of the immune-inflammatory system and in the programming of the immune-inflammatory system for future health and well-being or ill health and dis-ease (Brenhouse and Schwarz 2016; Brenhouse et al. 2019). Adverse life events during adolescence appear to modulate persisting immune dysregulation, with far-reaching effects on the stress system as a whole—and with a lifelong impact on health and well-being. Whether the presence or availability of attachment figures during adolescence can buffer those stress-related effects is not known.

Immune-Inflammatory Cells Hold Immunological Memory for Past Stress

An exciting recent discovery is that glial cells—the immune-inflammatory cells of the brain—hold immunological memory for past stress and can both activate and proliferate in response to stress (Brenhouse and Schwarz 2016). In this way, stress that occurs early in development can sensitize the immune-inflammatory system, a process called neuroinflammatory priming (Frank et al. 2016). Each time the child experiences significant stress, the immune-inflammatory system is activated transiently—it undergoes a short-lived neuroinflammatory response—that functions to sensitize how the brain’s immune-inflammatory cells will respond to subsequent stress (physical or psychological) in the future. With repeated activation, the child’s immune-inflammatory system may be sensitized into a state of increased readiness—with increased and ongoing vigilance, alertness, and watchfulness. This state, called low-grade inflammation, involves a small but continuing degree of excessive activation over long periods of time. Using our watchdog metaphor, the immune-inflammatory system has become hyper-vigilant, hyper-reactive, and ultimately maladaptive. As an ongoing physiological burden, this state has long-term, adverse consequences for the child’s health and well-being, and it also contributes to the generation and maintenance of functional somatic symptoms.

For example, in our studies of children presenting with functional neurological disorder (FND), 50 percent of children report a physical trigger to the illness, and 50 percent report a psychological trigger, with the majority also reporting cumulative past adverse life events (see Chapter 4). In chronic fatigue syndrome (CFS), a viral infection is the most common trigger, but psychological stress and other physical stress can also function as triggers; a history of early-childhood stress and past adverse life events are important risk factors that contribute to illness severity. For references see Online Supplement 1.3.

What is particularly important for us here is that very often, after the immune-inflammatory system has returned to baseline—or alternatively, has returned to a baseline state of ongoing readiness (low-grade inflammation)—other components of the stress system may remain activated in aberrant ways and may continue to maintain symptoms of pain, fatigue, autonomic system dysregulation, aberrant motor or sensory function, or difficulties with cognitive function. For example, in children who develop persistent fatigue following a viral infection, the autonomic nervous system remains in an activated state, and psychological factors, such as negative emotions, presence of anxiety, or depression, appear to contribute to the maintenance of stress-system activation (Pedersen et al. 2019; Kristiansen et al. 2019). Theoretically, implicit processes—for example, aberrant predictive coding (see Chapter 11)—could also contribute to stress-system activation. What this means is that, while either a physical or psychological stress can trigger the illness process via activation of the immune-inflammatory system, other factors can subsequently maintain stress-system activation or dysregulation, and also contribute to the emergence and maintenance of functional somatic symptoms. The implication for clinical practice is that treatment may require mind-body interventions that switch off the stress system, rather than interventions that target the original trigger event—for example, the viral event—which may no longer be relevant.

Inflammatory Markers Are Elevated in Patients with Functional Somatic Symptoms

Since immune-inflammatory cells hold immunological memory for past stress, and since all functional symptoms and syndromes show an association with ACEs, it is not surprising to find that inflammatory markers are elevated in patients with functional somatic symptoms. A mounting body of evidence documents that adult patients with chronic pain, fatigue, irritable bowel, musculoskeletal complaints, and other somatization syndromes have a sensitized immune-inflammatory system—an immune-inflammatory system in a state of readiness, or low-grade inflammation (increased levels of inflammatory markers compared to healthy controls). Studies with children are just beginning to emerge (for details see Online Supplement 9.1). For additional references see Online Supplement 1.3.

The term low-grade inflammation distinguishes this state of readiness, which is a characteristic feature across functional presentations, from high-level activation, as seen in response to infections or in rheumatology diseases. Low-grade inflammation is also seen when the stress to the body results from obesity, a poor diet, or disrupted sleep (see Online Supplement 9.1). As noted above, what this means in clinical practice is that, while an infection or minor injury may trigger stress-system activation in some patients (via the immune-inflammatory system component), this high-level activation of the immune-inflammatory system that is a marker of significant infection or rheumatological diseases is not present in patients with functional neurological symptoms. Standard laboratory tests, which are designed to detect inflammation infections and rheumatological diseases, will be normal. In other words, once a good medical assessment has been done—including the blood workup—and has shown nothing, the child and family have nothing to gain in going from doctor to doctor in search of ‘better’ test results.

Nonetheless, low-grade inflammation marks a shift from restorative mode to defensive mode. It reflects a subtle shift of the immune-inflammatory system: low-grade inflammation signifies that the prescient watchdog stands on guard in a state of hyper-vigilant readiness.

The Immune-Inflammatory System’s Involvement in Chronic/Complex Pain

Chronic/complex pain, as we have seen in the vignettes throughout this book, is a common comorbid symptom across functional presentations. The pain is called chronic or complex because it exists in the absence of tissue injury or because, when tissue injury does initially trigger the pain, it persists long after the injury has healed or the infection has passed.

Pain has been an intense area of research over the last 60 years. One of the most exciting recent discoveries is that the immune-inflammatory system has a central role in maintaining chronic/complex pain: activated immune-inflammatory processes appear to potentiate pain in many different ways. In particular, chronic/complex pain is generated and maintained by immune-inflammatory mechanisms that sensitize neurons involved in sensing pain (in the tissues), carrying pain (through the spinal cord), and representing pain (in the brain, as pain maps). This sensitization process makes the pain neurons more excitable, with the consequence that they signal pain at the least provocation. Other names for this sensitization process in chronic pain include the following: in the tissue, neurogenic inflammation, peripheral sensitization, and visceral sensitization, and in the spinal cord and brain, central sensitization or neuroinflammation. For clinicians who commonly see children with complex/chronic pain, we explain these processes in more detail in the paragraphs below (for references on chronic/complex pain, see Online Supplement 1.3). For most readers, the simple explanation provided above (in this paragraph) may suffice; if so, skip right down to the section ‘Activation and Sensitization of the Pain System at the Brain System Level’, along with its vignette of Martin.

Activation and Sensitization of the Pain System at the Tissue Level

At the tissue level in chronic/complex pain, the endings of afferent nerves, which carry sensory and interoceptive information from the body to the spinal cord, secrete pro-inflammatory substances that cause a local inflammatory response (neurogenic inflammation). These pro-inflammatory substances attract other immune-inflammatory cells, which also secrete pro-inflammatory substances. Together, these pro-inflammatory substances irritate the pain-sensing receptors on pain neurons (peripheral sensitization or visceral sensitization), thereby activating the pain system from the periphery. See discussion of macrophages in ‘How Exercise Works to Decrease Chronic/Complex Pain’, below.

Clinically, this sensitization at the tissue level means that the child will experience pain in response to non-noxious stimuli such as a light touch to the skin (called allodynia) or the expansion of the gut lumen during normal digestion or defecation (visceral sensitivity). The child may also experience painful stimuli as more painful than they should be (hyper-algesia).

Activation and Sensitization of the Pain System at the Spinal Cord Level

At the spinal cord level in chronic/complex pain, there is also an increase in pain signalling (through a variety of processes). Pain neurons in the spinal cord release pro-inflammatory substances that function to amplify pain signals. Glial cells—the immune-inflammatory cells found throughout the central nervous system—contribute to the immune-inflammatory process of amplifying pain by also releasing pro-inflammatory molecules. Glial signalling via signalling molecules released into spinal fluid allows pain messages to be carried to distant sites, enabling the spread of pain sensitization at the spinal cord level. In addition, pain neurons sprout new axons (feet), a process that amplifies communication about pain between pain neurons (a plasticity phenomenon). It is hypothesized that the combination of these processes sensitizes and activates the pain neurons in the spinal cord segment—and possibly even segments below and above—that receives information from the affected tissue. It is also hypothesized that these processes may sensitize and activate other neurons lying in the same segment(s) that carry information about, or relate to, other parts of the body.

In this way, pain that was triggered by a local inflammatory response within some portion of the viscera—for example, the pelvic cavity—could also be associated with sensitization and activation of spinal segments representing and signalling pain or other sensory information from the skin (innervated via the same spinal segment) or with increased tone in skeletomotor muscles of the pelvic floor (again, innervated via that same spinal segment).

Activation and Sensitization of the Pain System at the Brain System Level

At the brain level in chronic/complex pain, activation of pain maps that underpin the subjective experience of pain is maintained and amplified by various processes: bottom-up signals from the tissues and spinal cord; activation of glial cells (immune-inflammatory cells in the brain); and activation of the brain stress systems (of which glial cells are also a part) (see also Chapter 11). By activating the brain stress systems—and then, in turn, the brain’s pain maps—negative emotions, catastrophizing, anticipatory anxiety, and such processes can activate and maintain pain maps, resulting in or contributing to chronic/complex pain.

The following vignette of Martin highlights how a viral illness—which activates the immune-inflammatory system—can activate/dysregulate other components of the stress system. In Martin’s case, the pain system and the autonomic nervous system were activated (see Chapter 6 for the role of the autonomic system in regulating the gut). It also highlights how the body may be unable to switch off the pain system and to re-regulate the autonomic nervous system over time, well after the infection has passed, and well after the immune-inflammatory system has settled back to baseline. In Martin’s case, stress-system dysregulation was reflected in ongoing abdominal pain (activation of pain system) and recurring constipation (activation of autonomic nervous system [sympathetic activation causes constipation]). It also highlights how asking about the pain—bringing attention to it—can activate the pain via top-down mechanisms. Martin’s presentation was complicated by the use of antibiotics that disrupt the microbiota—which may have contributed to stress-system dysregulation (see Chapter 10).

Martin, a 10-year-old boy who lived with his parents and younger sister, was an all-rounder: he enjoyed school work and sporting activities, and was in line for becoming house captain in his school. Martin’s health had always been good, but his bowel had always been sluggish: he emptied his bowels three to four times a week. Just after the start of year 6, Martin came down with a viral illness characterized by high temperatures, fatigue, lethargy, sleepiness, nausea, and pain in his head and abdomen. In the months that followed, the abdominal pain came and went. Martin’s family doctor gave him antibiotics in case he had parasites. His blood panel screening for ongoing infection or inflammation was normal. The abdominal pain still came and went. Martin then became constipated, and the constipation made the pain worse. He was admitted to hospital for disimpaction. A diagnosis of functional abdominal pain was made. Martin was referred to a therapist, who taught him hypnosis and other strategies to help him manage the pain. His capacity to manage the intermittent pain improved. Toward the end of year 6, Martin became very constipated, and his pain crescendoed. Again, he was admitted to hospital for disimpaction. From this point on, at repeated intervals throughout the day, Martin would scream suddenly and clutch his abdomen in pain. The pain would pass as suddenly as it had come, and Martin would continue on with whatever he was doing. Martin now experienced pain every time he passed a bowel motion or passed wind, and he would scream so loudly that it sounded as if he was being tortured or murdered. Sometimes the pain would wake him up at night—when he passed wind. He would scream and then go back to sleep. Martin was now worried about going to the toilet and spent a large part of the day anticipating his pain and worrying about what would happen if he needed to go or when he needed to pass wind. At school, the school counsellor, who was trying to be supportive, discovered that when she asked Martin about his pain, the question would trigger a pain episode for Martin.

Treatment involved, among other things, careful bowel management by Martin’s paediatrician to make sure that Martin did not become constipated—which would further sensitize his existing visceral hypersensitivity. He took probiotics and ate yogurt to look after his microbiota. Slow-breathing training, which down-regulates autonomic system function, was timetabled into Martin’s day. He also continued to practice the various mind-body strategies that he had learnt with his therapist. Martin was treated with an anti-anxiety mediation (20 mg fluoxetine in the morning) to help with his anxiety (which was activating the brain stress systems top-down). For a few months, Martin also used a small dose of quetiapine—a mood stabilizer with excellent anti-anxiety properties—to help him switch off the brain stress systems (6.25 mg three times a day, and 25 mg for pain that Martin could not manage). The quetiapine was particularly useful at school at those times that Martin was unable to regulate himself, had lost the capacity to control his pain and anxiety, and had lapsed into a prolonged state of screaming. The quetiapine also helped Martin sufficiently so that he could implement his mind-body strategies, even when the pain was very bad. Because a good explanation about the pain had been provided to Martin and his family, they understood how each interventionwas helpingto treat Martin’sabdominal pain.

How Exercise Works to Decrease Chronic/Complex Pain

The story about how exercise works to decrease chronic/complex pain is a useful piece of research that we often share with children and their families (Sluka 2017). It provides a clear rationale (see below) as to why exercise is important and how exercise works to help chronic pain.

Macrophages are immune-inflammatory cells that eat up debris and that exist in all parts of the body. Exercise helps shift macrophages from defensive to restorative mode. When children exercise regularly, they keep their macrophages in restorative mode, in which they secrete anti-inflammatory molecules that promote analgesia (see Fig. 9.1). When children do not exercise regularly—for example, because of chronic/complex pain or symptoms of persisting fatigue—they keep their macrophages in defensive mode, in which they secrete pro-inflammatory molecules that promote pain and fatigue. When children understand how exercise will help them in the long run, even though it triggers more pain and fatigue in the short run, it helps children to push through the initial discomfort—and exacerbation of pain—and to implement exercise as part of their treatment regimes.

Fig. 9.1
An illustration of 2 restorative macrophages on the left and 2 defensive macrophages on the right.

(© Kasia Kozlowska 2017)

Macrophages in restorative mode and defensive mode. Macrophages in restorative mode (blue, on left) promote analgesia by secreting anti-inflammatory molecules. Macrophages in defensive mode (red and purple, on right) maintain chronic pain by secreting pro-inflammatory molecules that activate pain neurons

How Opioids Contribute to Chronic/Complex Pain

Children and their families also find it helpful to understand that opiate medications are contraindicated in chronic (vs. acute) pain because opiates irritate macrophage cells (and glial cells in the brain), putting them into defensive mode and thereby causing them to secrete pro-inflammatory molecules and to maintain chronic pain (for references see Online Supplement 1.3). For example, Jai—the boy with dystonia of the neck—and his family found this piece of information helpful during the painful process of trying to wean Jai off opiate medications (see Chapter 5 or, for a much more detailed account, Khachane et al. [2019]).

Sex Hormones and Chronic/Complex Pain

An emerging body of research has found that sex hormones—including oestrogen, progesterone, and testosterone—are involved in pain processing. Oestrogen, for example, acts on the oestrogen receptors on the nerve and immune-inflammatory cells that are part of body’s pain system. Via activation of these receptors, oestrogen appears to play an important role in up-regulating and down-regulating pain. Of special importance for us, oestrogen can up-regulate the immune-inflammatory component of the pain system (and stress system more generally) to sustain chronic/complex pain (Chrousos 2010), and it generally has a pro-nociceptive role in visceral pain, intensifying the subjective experience of pain (Sun et al. 2019; Traub and Ji 2013). These findings are not surprising, given that chronic/complex pain is more common in girls/women than boys/men (Traub and Ji 2013), and as many women know from their own personal experience, the susceptibility to pain and the subjective experience of pain fluctuate with the menstrual cycle. By contrast, progesterone and testosterone appear to have anti-nociceptive effects. In this context, the research community is actively investigating the potential use of sex hormones or sex hormone analogues in treating chronic/complex pain. For additional references see Online Supplement 1.3.

The Immune-Inflammatory System and Fatigue

Efforts to understand the connection between activation of the immune-inflammatory system and the symptom of fatigue have become intertwined with an intriguing bit of recent medical history. Understanding short-lived fatigue in the context of acute infection is relatively simple and well established. Every reader can bring to mind a normally healthy child who suddenly becomes lethargic and sleepy when she comes down with an infection that activates her immune-inflammatory system when fighting off an infection (see also vignette of Martin, above). This lethargy and sleepiness are caused by high levels of signalling molecules that are produced by immune-inflammatory cells. Once the immune-inflammatory system has brought the infection under control, the immune-inflammatory system deactivates, and the child bounces back to normal.

But the story is less clear in relation to persisting fatigue, and the relative lack of clarity reflects two main factors. First, research efforts to understand fatigue are still in their early stages—reaching back 30 years compared to the 60 years of research on pain. Second, because the fundamental processes underlying fatigue are still being worked out, and because so many issues therefore have yet to be resolved, there is much more room for divergent interpretations of what is known and for divergent arguments concerning the appropriate direction for future research. What has happened, in particular, is that research efforts involving persisting fatigue have become entangled in what is perhaps best understood as an ideological struggle, with some insisting that fatigue needs to be understood exclusively in physical terms, and others highlighting that fatigue involves a significant psychological component (Maxmen 2018; Komaroff 2019). A clear conceptualization with which everyone agrees has yet to emerge.

Against this background, what we attempt to do here is to build upon what is known about fatigue while sidestepping the continuing controversies. In our central case (see below), the primary presenting problem is persisting fatigue—which typifies the children we see—and we share ideas and emerging findings from the current literature that we find useful in our own clinical practice. In line with all the material in this book, our perspective is systemic—or biopsychosocial—and we presume that to understand fatigue one needs to take into account factors across the full range of system levels: from the molecular, to the mind, to the level of interpersonal interactions with others.

Rudi was a 15-year-old Norwegian boy with a two-year history of disabling fatigue that had developed in the wake of a long-lasting respiratory infection. At the time that he contracted the infection, he was already a promising young hurdler who trained four days a week and competed almost every weekend. Even after becoming sick, Rudi pushed himself and continued training. At the end of one tough race, he collapsed at the finish line. In the aftermath, he was completely exhausted and stayed home from school for three weeks. In the following months he attended school and resumed his training, but felt constantly drained and began to experience problems such as headache, dizziness, and problems with concentration and memory. Any physical activity left him exhausted and needing days to recover. At one point, he could not even move from his bed. Fatigue dominated his life. Every effort—physical, cognitive, or emotional—made him feel worse. As a consequence, Rudi, with the support and assistance of his parents, tried to avoid anything that sapped his energy. He was caught in a downward spiral.

Despite seeing what turned out to be many doctors, Rudi and his family were always told the same thing: the medical assessments, from various specialists, disclosed no medical problem. But his parents were unable to accept these assessments; they were convinced that Rudi had some rare immune disease.

Eventually, Rudi’s paediatrician referred Rudi and his family to the local mental health service, where they were seen by the psychiatrist and team. The family assessment interview identified a more complicated story of cumulative stress. When Rudi was born his mother had experienced a postpartum depression of one-year duration, and during that same year Rudi developed infection-triggered childhood asthma, with worsening episodes, sometimes accompanied by respiratory infections, every winter since. When he was 12, his parents underwent a difficult divorce following their conflict-filled marriage. During this same period, Rudi’s grandmother, who lived next door and to whom he was very close, died unexpectedly. But because of the turmoil in the family, Rudi kept his grief to himself. And throughout this period, he continued his gruelling schedule for hurdling. It was in the aftermath of these events that Rudi developed the respiratory infection that triggered his symptoms of persisting fatigue.

Against this background, the psychiatrist and her team, in a joint consultation with Rudi’s paediatrician, offered an alternative explanation of Rudi’s fatigue. They suggested that Rudi’s immune system appeared to be very sensitive to stress. They said that Rudi’s pattern of presentation fit with what was known about the interconnections between the immune-inflammatory system, the HPA axis, emotional stress, and increased susceptibility to infection. Emotional stress and distress could temporarily disrupt immune-inflammatory function, making the individual more vulnerable to inflammatory illnesses such as asthma and respiratory infections. This pattern of response was common and has been well described in the literature (see Online Supplement 9.1 and the vignette pertaining to cold-virus inoculation in Chapter 8). The psychiatrist said that from the history given by the family, Rudi had followed this pattern across development.

  • His initial bout of asthma developed during his mother’s postpartum depression.

  • His subsequent bouts of asthma and accompanying respiratory infections regularly emerged during the long Norwegian winter, when the family had to spend more time indoors and when Rudi was thus more exposed to his parents’ chronic conflict.

  • Given the above, Rudi’s stress system was chronically activated/dysregulated by the parental conflict.

  • At the age of 13, his infection and then disabling fatigue emerged in context of his parents’ divorce and his grandmother’s death, all while continuing to train for hurdling.

In the most recent illness, however—at the age of 15—the stress had been more pronounced, and other components of the stress system, as well as the pain system, had been activated. Autonomic nervous system activation was reflected in symptoms of orthostatic intolerance (dizziness and abnormal standing test completed by the psychiatrist). Activation of the brain stress systems was reflected in problems with memory and concentration (see Chapter 11). And activation of the pain system was reflected in his chronic headache.

In this context, the treatment offered to Rudi and his family was one that focused on rebuilding Rudi’s physical strength, on switching off the stress and pain systems, and on improving his capacity to manage emotional stress. The intervention also helped the family address some of the family stress that had contributed to Rudi’s illness.

After 14 months of treatment, Rudi had returned almost to ‘normal’. The following interventions had been useful. Rudi had engaged in physiotherapy and occupational therapy to help him mobilize gradually and participate in activities of daily living. He had learnt breathing exercises to reduce and control his arousal (autonomic nervous system activation). He had learnt self-hypnosis, and he was able to visualize himself full of energy when recovered and to rediscover how an energetic body feels. He had been able to articulate, to his parents, his emotional distress in being constantly exposed to their fighting. He had been able to work through his grief about his grandmother’s death. An individualized academic program and return-to-school plan were arranged. Finally, Rudi’s parents had decided to join a program for parent counselling as an effort to reduce the devastating conflict that continued between them, even after the divorce.

Two years after the illness had started, Rudi felt fully recovered. He was back working at his hurdling but had left behind his dream of becoming a professional athlete.

Rudi’s case highlights that, though infection may trigger activation or dysregulation of the immune-inflammatory system and set the illness process in motion, and though the immune-inflammatory system generally settles back to baseline (or nearly so, which may involve an ongoing state of readiness [low-grade inflammation]), persisting fatigue can be maintained by other factors (Russell et al. 2018). These other factors may include the following:

  • Sensitization of the pain system (increased sensory sensitivity and pain severity) (Pedersen et al. 2019).

  • Activation or dysregulation of the autonomic nervous system (Wyller 2019).

  • Dysregulation of the HPA axis (hypo-activation) (Rimes et al. 2014) and other components of the body’s energy-regulation systems.

  • Changes in gene expression in tissues or the brain (e.g., dysregulated immune-gene networks [Nguyen et al. 2019]).

  • Activation of the brain stress systems (suggested by decreased verbal memory) (Pedersen et al. 2019) (see Chapter 11).

  • Activation of the brain stress systems (in particular, a shift from reflective to reflexive [defensive] modes of behaviour control [Arnsten 2015]). In defensive mode, implicit computation of salience within the brain stress systems—an evaluation of the child’s behavioural repertoire in terms of costs and benefits—may result in a shutdown of behaviour because of the unacceptably high costs to energy resources (Boksem and Tops 2008; Kleckner et al. 2017).

  • Aberrant predictive representations—namely, that the body needs much more energy than is being made available (Pedersen 2019).

  • Psychological factors that activate the stress system, that shape expectancies, and that change subjective feelings of fatigue. These factors include attention to symptoms, catastrophizing, anxiety, perfectionism, depression, negative illness beliefs, maladaptive coping strategies, and negative emotions (Loades et al. 2019; Pedersen et al. 2019; Katz and Jason 2013) (see Chapter 12). Lessons learnt from athletics are relevant in this context; as a regular part of the training regime, athletic coaches encourage the use of mind strategies to help athletes overcome feelings of fatigue (Noakes 2012) (see Chapter 15).

The vignettes of Martin and Rudi (in this chapter) and Bellynda (Chapter 8) have highlighted how activation of the immune-inflammatory system by infection, allergy, or injury can trigger different patterns of functional symptoms: chronic abdominal pain and functional constipation (Martin); chronic/complex pain, autonomic dysregulation, and persisting and debilitating fatigue (Rudi); chronic/complex pain, autonomic dysregulation, and functional neurological symptoms (Bellynda). In this way, as described earlier in this chapter, while activation of the immune-inflammatory system may serve as the initial trigger, the persisting symptoms of pain, fatigue, autonomic dysregulation, or motor or sensory dysfunction are maintained by other processes. Of particular note in this context is the activation of multiple components of the stress system, coupled with the body’s inability to switch off or re-regulate these systems back to physiological coherence.

Against this background, it is worth highlighting that when the functional presentation is triggered via activation of the immune-inflammatory system—whether or not any particular child meets the consensus diagnostic criteria for a particular functional disorder—each child and family should receive a comprehensive assessment that identifies all the relevant physical and psychological contributors to the persisting functional somatic symptoms. Regardless of the symptom pattern—which will vary from child to child—the treatment intervention needs to include targeted interventions that address all relevant areas of dysfunction, and on multiplesystem levels.

Different Metaphors That Clinicians Can Use When Working with Children with Persisting Fatigue

In recent years the research literature has produced several clinically useful metaphors for conceptualizing persisting fatigue.

Metaphor 1: Persisting Fatigue as a Biologically Ancient Response to Injury or as an Innate Defence Response

A number of clinicians and researchers have suggested that in cases in which the persisting fatigue is completely debilitating or nearly so, it is possible that the presentations reflect biologically ancient responses to stress or injury. Rudi’s presentation could potentially be viewed in the light of this metaphor.

In 2015, the first author (KK) and colleagues suggested that that extreme cases of chronic fatigue can be understood in terms of quiescent immobility—or rather quiescent immobility in maladaptive form—one of the neurophysiological states that are part of the human (and animal) defence cascade. ‘Quiescent immobility [in animals] is a reaction to “deep or inescapable” pain, chronic injury, injury by a predator, or defeat by a conspecific, and to states of exhaustion (where recuperation is needed) after a period of acute stress, once the animal has returned to a safe environment’ (Kozlowska et al. 2015, p. 275). In this way the functional symptoms experienced by patients with debilitating chronic fatigue would sit on a continuum with other presentations related to activation of the defence cascade—freezing, flight or fight, tonic and collapsed immobility, and quiescent immobility. Each of these states has a signature neural pattern accompanied by a signature state of arousal and energy use.

In 2016, Robert Naviaux, Professor of Medicine, Pediatrics, and Pathology at the University of California, San Diego, suggested that some cases of persisting fatigue may be similar to entering dauer, ‘a hypo-metabolic state capable of living efficiently by altering a number of basic mitochondrial functions, fuel preferences, behaviour, and physical features’ in response to adverse environmental conditions (Naviaux et al. 2016, p. E5477). In this hypo-metabolic state, cells of the body enter a cell danger response, a state in which mitochondria—the organelles in the cell that regulate and produce energy on a cellular level—shift into a defensive mode in which they decrease mitochondrial metabolism to enable the organisms to survive a hostile environment. The changes described by Naviaux on the cellular level may also be part of the quiescent immobility state described above.

In 2019, Anthony Komaroff, Professor of Medicine and Senior Physician, Brigham and Women’s Hospital, Harvard Medical School, suggested that persisting fatigue may reflect ‘the activation of biologically ancient, evolutionarily conserved responses to injury or potential injury, a pathological inability to turn these responses off, or both’ (Komaroff 2019, p. 500).

Referring back to our clinical vignette of Rudi, the reader can see that Rudi was exposed to multiple sources of stress that threatened his physical and psychological integrity, and that the combination of these threats could have activated the body’s innate responses to threat, injury, and the sustained overuse of energy resources.

Metaphor 2: Persisting Fatigue as a Vitally Protective System Gone Wrong

From this perspective, persisting fatigue, like pain, is conceptualized as a subjective feeling with protective value, gone wrong (Pedersen 2019). Fatigue—like pain—functions as a homeostatic emotion (Craig 2003) or biological alarm system (Brodal 2017) that ‘alert[s] the organism’, whether accurately or erroneously, ‘to urgent homeostatic imbalance’ (Hilty et al. 2011, p. 2151; St Clair Gibson et al. 2003; Noakes 2012). In the case of persisting fatigue, the homeostatic alarm would be erroneous. Fatigue, like pain, has protective survival value in acute situations, but it becomes maladaptive and debilitating when it becomes chronic. Using the watchdog metaphor, when the hyper-vigilant watchdog raises the alarm in response to events that have no threat value (or that no longer have any threat value), then the watchdog needs to be retired.

Metaphor 3: Persisting Fatigue as a Vitally Protective System Signalling Loss of Physiological Coherence

Yet another metaphor emerges from the perspective of this book—and the stress-system model—regarding the symptom of fatigue: fatigue as a vitally protective system working just right, signalling the loss of physiological coherence. In the stress-system model, we also conceptualize fatigue as a homeostatic emotion, a homeostatic alarm signal (see previous subsection). But we see the alarm as working just right. The fatigue alarm is signalling ongoing activation of the stress system, the body’s shift into defensive mode (and failure to return to switch off and return to restorative mode), the concurrent increase in energy use, and the concurrent loss of physiological coherence. In the stress-system scenario, the metaphor of the homeostatic alarm is right on target—it is accurate. It signals a dysregulated stress system: one that has lost harmony and physiological coherence within and between its various components, along with its capacity for efficient use of energy. Because the easy flow of life processes that is associated with health and well-being is compromised (McCraty and Childre 2010), it is not surprising that the homeostatic alarms of fatigue and pain are activated in such a large number of children with functional somatic symptoms. This idea of fatigue as a homeostatic alarm signalling disturbed homeostasis has also been put forth by Vegard Wyller (2019, p. 6), a well-known Norwegian researcher in the field of chronic fatigue syndrome.

The Full Picture Pertaining to Fatigue Is Still Emerging

Whatever the final answers, the emerging picture suggests that patients with persisting fatigue—whether the illness is triggered by an infection or by other physical or psychological stress—show dysregulation in multiple components of the stress system (autonomic nervous system, HPA axis, immune-inflammatory system, brain stress systems) and in the energy-regulation system on the cellular level, as well as changes in the gene networks (epigenetic changes in gene expression) that regulate these systems (see Online Supplements 1.3 and 9.1). The overall result is that these patients are characterized by a loss of physiological coherence. The easy flow of their life processes, including the efficient use of energy, has been disrupted—and their health and well-being, severely compromised.

The Take-Home Messages About the Immune-Inflammatory System for the Mental Health Clinician

The immune-inflammatory system functions like a watchdog that is gifted with prescience. It holds immune-inflammatory memory for past stress and activates in response to physical and psychological stress. Of special importance to us, a sensitized or unrestrained immune-inflammatory system—in a state of low-grade inflammation—can respond to commonplace physical and psychological stress in an overly robust way. In so doing, it can activate other stress-system components or the stress system as a whole, thereby contributing to the generation of functional somatic symptoms, including persisting pain or fatigue. In extreme cases, persisting debilitating fatigue may represent an innate biologically ancient response to stress or injury.

Because of technological advances and interest in systems biology, we can look forward to many new findings about the immune-inflammatory system in the coming years. Some of those findings will help us better understand and treat children with functional somatic symptoms.


In Chapter 10, we look at the gut system, which is closely connected and overlaps with the stress system in many ways.