Findings From Critical Illness To Explain Myalgic EncephalomyelitisChronic Fatigue Syndrome

PERSPECTIVE
published: 08 March 2022

doi: 10.3389/fmed.2022.818728
Perspective: Drawing on Findings

From Critical Illness to Explain
Myalgic Encephalomyelitis/Chronic
Fatigue Syndrome
Dominic Stanculescu 1 and Jonas Bergquist 2,3*
1
Independent Researcher, Sint-Martens-Latem, Belgium, 2 Division of Analytical Chemistry and Neurochemistry, Department
of Chemistry – Biomedical Center, Uppsala University, Uppsala, Sweden, 3 The Myalgic Encephalomyelitis/Chronic Fatigue
Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden
We propose an initial explanation for how myalgic encephalomyelitis / chronic fatigue

syndrome (ME/CFS) could originate and perpetuate by drawing on findings from critical
illness research. Specifically, we combine emerging findings regarding (a) hypoperfusion
and endotheliopathy, and (b) intestinal injury in these illnesses with our previously
published hypothesis about the role of (c) pituitary suppression, and (d) low thyroid
hormone function associated with redox imbalance in ME/CFS. Moreover, we describe
Edited by:
Juarez Antonio Simões Quaresma,
interlinkages between these pathophysiological mechanisms as well as “vicious cycles”
Universidade do Estado do involving cytokines and inflammation that may contribute to explain the chronic nature
Pará, Brazil
of these illnesses. This paper summarizes and expands on our previous publications
Reviewed by:
about the relevance of findings from critical illness for ME/CFS. New knowledge on
Anthony L. Komaroff,
Brigham and Women’s Hospital and diagnostics, prognostics and treatment strategies could be gained through active
Harvard Medical School, collaboration between critical illness and ME/CFS researchers, which could lead to
United States
Katherine Sylvia Rowe,
improved outcomes for both conditions.
Royal Children’s Hospital, Australia
Keywords: post-viral fatigue, hypoperfusion, endotheliopathy, gut permeability, endotoxemia, pituitary, non-
*Correspondence: thyroidal illness syndrome, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Jonas Bergquist
[email protected]
INTRODUCTION
Specialty section:
This article was submitted to Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness that affects
Pathology, millions of people worldwide (an estimated 800,000 to 2.5 million in the USA) (1, 2). Impaired
a section of the journal
function, post-exertional malaise, and unrefreshing sleep are core symptoms (1, 3, 4). At least one-
Frontiers in Medicine
quarter of ME/CFS patients are house- or bedbound at some point in their lives (1); the illness can
Received: 25 November 2021 be completely incapacitating (5). The etiology of the illness is unclear (6, 7) and peri-onset events
Accepted: 11 February 2022
include infection-related episodes, stressful incidents, and exposure to environmental toxins (8).
Published: 08 March 2022
Critical illness refers to the physiological response to virtually any severe injury or infection,
Citation: such as head injury, burns, cardiac surgery, SARS-CoV-2 infection and heat stroke (9). Researchers
Stanculescu D and Bergquist J (2022)
make a distinction between the acute phase of critical illness—in the first hours or days following
Perspective: Drawing on Findings
From Critical Illness to Explain Myalgic
severe trauma or infection; and the chronic or prolonged phase—in the case of patients who survive
Encephalomyelitis/Chronic Fatigue the acute phase but for unknown reasons do not start recovering and continue to require intensive
Syndrome. Front. Med. 9:818728. care (10–13). Regardless of the initial injury or infection, these “chronic Intensive Care Unit (ICU)
doi: 10.3389/fmed.2022.818728 patients” experience profound muscular weakness, cognitive impairment, pain, vulnerability to
Frontiers in Medicine | www.frontiersin.org 1 March 2022 | Volume 9 | Article 818728

Stanculescu and Bergquist Drawing on Critical Illness to Explain ME/CFS
infection, etc. (9, 11, 14). The treatment of prolonged critical lining (i.e., glycocalyx) are cytokines (31), inflammation,
illness is incomplete and remains an active area of research. exposure to oxidative stress (28, 32) and/or sympatho-adrenal
Moreover, cognitive and/or physical disability can last for months hyperactivation (33). Crucially, endothelial dysfunction during
or even years after treatment in ICUs (i.e., post intensive care critical illness has been associated with altered cerebral blood flow
syndrome, PICS) for as of yet unexplained reasons (15–17). (34, 35) and increased blood–brain barrier (BBB) permeability
Drawing on findings from critical illness, we here propose resulting in long-term cognitive impairment (36, 37). A leaky
an initial explanation for how ME/CFS could originate and BBB could also contribute to increased intracranial pressure
perpetuate. Specifically, we combine emerging findings regarding (38, 39). Finally, researchers have found that endotheliopathy
(a) hypoperfusion and endotheliopathy, and (b) intestinal injury and coagulation disorder bolster each other via inflammatory
in these illnesses with our previously published hypothesis about pathways (40). Coagulation abnormalities vary in critical illness,
the role of (c) pituitary suppression, and (d) low thyroid hormone but coagulopathy is associated with unfavorable outcomes
function associated with redox imbalance in ME/CFS. Moreover, in prolonged critical illness (i.e., length of ICU stay and
we describe interlinkages between these pathophysiological mortality) (41).
mechanisms as well as “vicious cycles” involving cytokines and We propose that similar alterations of the vascular system
inflammation that may contribute to explain the chronic nature in response to a physical, infectious and / or emotional
of these illnesses. This explanation summarizes and expands stressor (i.e., physiological insult) may also contribute to explain
on our previous publications about the relevance of findings the emergence of ME/CFS. This is consistent with recent
from critical illness for ME/CFS (18–20) and builds on the hypotheses describing vasoconstriction in muscle and brain
work by Nacul et al. (21). The general lack of large high-quality as a principal element of ME/CFS (42–46), and findings of
ME/CFS studies (a reflection of the lack of funding in this field) cerebral hypoperfusion (47–49) and intracranial hypertension
poses a challenge for the assessment of overlaps between the (50) in ME/CFS patients. It is also consistent with studies that
two conditions. have shown that endothelial function is impaired in ME/CFS
(51, 52), both in large vessels and in the microcirculation
(53, 54)—associated with redox imbalance (51). Finally, it is
PATHOPHYSIOLOGICAL MECHANISMS consistent with a new hypothesis for ME/CFS which suggests
In the following sections we describe four central that endothelial senescence underpins ME/CFS by disrupting the
pathophysiological mechanisms in critical illness, including intestinal barriers and BBBs (55), as well as with suggestions that
their relationship to inflammation. We also provide initial leakage from dysfunctional blood vessels could explain many of
arguments for suggesting that similar mechanisms may underlie the symptoms in ME/CFS (56).
ME/CFS. Readers are referred to our prior publications for
additional details about these mechanisms in critical illness
(including heat stroke) and possible lessons for understanding Intestinal Injury
ME/CFS (18–20). Critical illness researchers have found profound intestinal
alterations within hours following a physiological insult: a
dramatic shift in the composition and virulence of intestinal
Hypoperfusion and Endotheliopathy microbes (57–59), an erosion of the mucus barrier, an increase
It has long been suggested that inadequate oxygen circulation
in the permeability of the gut (i.e., “leaky gut”) (60–62), and a
is central to critical illness (22). Specifically, the redistribution
disruption in gut motility (63). This intestinal injury is thought
of blood away from the splanchnic area to critical tissues is
to be largely a consequence of local I/R and redox imbalance
considered an adaptive androgenic response to physiological
resulting from splanchnic hypoperfusion (58, 61, 64–67). Indeed,
stress (23, 24). However, the resulting ischemia / reperfusion
studies in the field of exercise immunology have shown that even
(I/R) can contribute to tissue injury driving sepsis and multi-
relatively low levels of splanchnic hypoperfusion during exercise
organ dysfunction (25, 26). The relative importance of reduced
result in intestinal injury (68).
blood flow, vasoconstriction (27), capillary flow disturbances
Critically, this intestinal injury may lead to bacterial
(28) and impaired cellular oxygen utilization (29, 30) in driving
translocation from the gut into circulation (i.e., endotoxemia)
critical illness continues to be debated.
and/or the formation of toxic gut-derived lymph (57, 60). This
Endothelial dysfunction appears to occur in parallel with
in turn can induce pro-inflammatory cytokines and systemic
circulation disturbances during critical illness. Probable drivers
inflammation (69, 70). Moreover, changes in the intestinal
of distortions in the structure and function of endothelial
microbiome or the mucus barrier may also impact the immune
Abbreviations: BBB, Blood–brain barrier; ACTH, Adrenocorticotropic hormone;
system directly (57). Thus, researchers have long considered the
GH, Growth hormone; GR, glucocorticoid receptors; HPA, hypothalamus- gut “the motor of critical illness” driving sepsis and distant organ
pituitary-adrenal axis: “Adreno-cortical axis”; HPS, Hypothalamic-pituitary- dysfunction (71). Some have suggested that a self-perpetuating
somatotropic axis: “Somatropic axis”; HPT, Hypothalamic-pituitary-thyroid: vicious inflammatory cycle centered around intestinal injury can
“Thyrotropic axis”; ICU, Intensive Care Unit; I/R, Ischemia/reperfusion; ME/CFS, hinder recovery from critical illness (61, 72).
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; NO, Nitrox oxide; NTIS,
Non-thyroidal illness syndrome; O&NS, oxidative and nitrosative stress; PACS,
We propose that the sequence during critical illness—from
Post-acute COVID-19 syndrome; PICS, Post-intensive care syndrome; TRH, splanchnic hypoperfusion to hypoxia, redox imbalance, altered
Thyrotropin-releasing hormone; TSH, Thyroid stimulating hormone. gut microbiome, intestinal injury, gut-related endotoxemia,

pro-inflammatory cytokines and systemic inflammatory— We propose that the sequence during critical illness—from
may also contribute to explain the emergence of ME/CFS increased release of pituitary hormones during the acute phase
following a physiological insult. Our proposal is in alignment to suppression of the pituitary gland’s pulsatile secretion in the
with others’ findings that intestinal injury and resulting prolonged phase—could also contribute to explain the emergence
inflammation are central to ME/CFS (73–81) and consistent of ME/CFS following a physiological insult. This proposal is
with findings linking the gut microbiome to inflammation consistent with descriptions of ME/CFS as a progression from
(82–85) and to fatigue symptoms in ME/CFS (86). If verified, a hypermetabolic to hypometabolic state (21). It also aligns
the existence of a vicious inflammatory cycle centered around with a recent hypothesis relating many of the symptoms in
intestinal injury could contribute to explain the perpetuation of severe ME/CFS to impaired pituitary function (111). Further
ME/CFS. Post-exertional malaise—a key symptom of ME/CFS— support for this proposal is provided by the many previous
could be the manifestation of an accentuation in intestinal ME/CFS studies that have documented dysfunctions in the
injury following exertion. Moreover, the translocation of gut hypothalamic–pituitary–somatotropic (HPS) axis (112–114), the
microbes or toxin from the intestines to the brain (55) might HPT axis (115–120), and the HPA axis (121–136)—notably
contribute to explain central nervous system inflammation associated with inflammation and oxidative & nitrosative stress
in ME/CFS (87–89). Finally, leaky gut is also associated with (O&NS) (137–140). Strikingly, models relating the persistence
auto-immunity (90, 91)—an important factor in ME/CFS of a suppressed HPA axis in ME/CFS to a change in central
pathology (92–94). GRs concentrations resemble the explanations provided for
pituitary suppression in critical illness (141–146). Moreover,
Pituitary Suppression suppression of ACTH release would explain why in a small study
Almost immediately after a physiological insult, endocrine axes ME/CFS patients were found to have 50% smaller adrenals than
experience profound alterations considered a vital response to controls (147), resembling adrenal atrophy in prolonged critical
severe stress or injury to allow for a shift in energy and resources illness. However, the relationship between the pituitary’s pulsatile
to essential organs and repair (95–97). Whereas, in critically secretions, physiological alterations and severity of illness—
ill patients who begin to recover, endocrine axes essentially which proved revelatory in understanding prolonged critical
normalize within 28 days of illness, in cases of prolonged critical illness—remains unexplored in ME/CFS.
illness the pituitary’s pulsatile secretion of tropic hormones
(unexpectedly) remains suppressed. Low Thyroid Hormone Function
Why and how this central suppression is maintained in Peripheral mechanisms involving cytokines lead to the rapid
prolonged critical illness continues to be debated. Inflammatory depression of thyroid hormone activity following a severe
pathways likely play a role irrespective of the nature of the physiological insult (148–152). This is termed “non-thyroidal
original injury or infection. For example, cytokines increase the illness syndrome” (NTIS), “euthyroid sick syndrome” or “low
abundance and affinity of glucocorticoid receptors (GR) at the T3 syndrome” and is thought to be an adaptive response
level of the hypothalamus / pituitary, thereby enhancing the to conserve energy resources during critical illness (152–154).
negative feedback loop of the hypothalamic-pituitary-adrenal The mechanisms involved include alterations in the half-life
(HPA) axis, and consequently suppressing pituitary release of thyroid hormone in circulation (155–157); modifications in
of adrenocorticotropic hormone (ACTH) (95, 98). Similarly, the uptake of thyroid hormone by cells (158, 159); down- and
cytokines up-regulate deiodinase enzymes in the hypothalamus up-regulation of deiodinase enzymes that convert the thyroid
resulting in higher local levels of the active thyroid hormone (T3), hormone into active and inactive forms respectively (156, 160);
thereby enhancing the hypothalamic-pituitary-thyroid (HPT) and alterations in sensitivity of cells to thyroid hormones (161–
axis’ negative feedback loop and consequently suppressing 163). These alterations can lead to important tissue-specific
pituitary secretion of thyroid stimulating hormone (TSH) depression in thyroid hormone function (164, 165) which is,
irrespective of circulating thyroid hormone concentrations (99– however, often missed altogether in clinical settings (166) because
101). Cytokines may also suppress the release of TSH by the most of the alterations do not translate into changes in the blood
pituitary directly (102, 103) contributing to a virtual complete concentrations of thyroid hormones (164, 167, 168). Indeed, the
loss of pulsatile TSH secretion (96). decrease in the ratio of the active form of thyroid hormone
The loss of pulsatile pituitary secretions has important (T3) relative to the inactivated thyroid hormone (rT3) (150, 152,
implications for the autonomic nervous system, metabolism, 169)—considered the most sensitive marker of NTIS—may be
and the immune system. Without sufficient pulsatile stimulation just the “tip of the iceberg” of the depressed thyroid hormone
by ACTH, adrenal glands begin to atrophy (104, 105), function in target tissues (120, 170).
compromising patients’ ability to cope with external stressors While NTIS may be beneficial in the acute phase of critical
and permitting excessive inflammatory responses. Erratic rather illness, it is increasingly seen as maladaptive and hampering
than pulsatile pituitary production of growth hormone (GH) the recovery of patients in the case of prolonged critical illness
leads to an imbalance between catabolic and anabolic hormones, (96, 101, 152, 169, 171–173). Low thyroid hormone function
resulting in loss of muscle and bone mass, muscle weakness, may hamper the function of organs (170) and the activity of
and changes in glucose and fat metabolism (106–108). Finally, immune cells, including natural killer cells (174–185). Immune
suppression of the HPT axis is associated with tiredness and other dysfunctions might in turn explain other pathologies, such as
hypothyroid-like symptoms (109, 110). viral reactivation observed in ICU patients (186–188). Some

critical illness researchers have proposed a model that describes solving ME/CFS given that “several of the main typical symptoms
how NTIS is maintained by reciprocal relationships between in severe ME/CFS, such as fatigue, myalgia, contractility, delaying
inflammation (notably pro-inflammatory cytokines), O&NS and muscle recovery and function, exertional malaise, neurocognitive
reduced thyroid hormone function, forming a “vicious cycle” dysfunction, and physical disability may be related to severe GH
(101, 173). This model can help to explain the perplexing failure deficiency” (111).
to recover of some critically ill patients in ICUs that survive their
initial severe illness or injury.
We propose that low thyroid hormone function could also
Linkages Between Pituitary Suppression
contribute to explain the emergence of ME/CFS following and Low Thyroid Hormone Function
a physiological insult. An immune-mediated loss of thyroid There are several pathways linking the activity of the pituitary
hormone function in ME/CFS has long been suspected (117). A with that of thyroid hormones. Firstly, GH secreted by the
recent study showed that the thyroid panel of ME/CFS patients pituitary co-regulates the activity of the deiodinase enzyme
resembles that of critical illness patients, including significantly (D3) responsible for the conversion of thyroid hormones into
lower ratio of T3 to rT3 hormones (120). Moreover, the other inactive forms (i.e., rT3 and inactivate forms of T2) (106, 201).
elements for a “vicious cycle” which researchers have suggested Researchers showed that normalization of the GH secretion in
perpetuate a hypometabolic and inflammatory state in critical prolonged critically ill patients is necessary to inhibit the increase
illness are also present in ME/CFS, including inflammation (140, in plasma rT3 concentrations (96, 108, 198). In other words,
189), increased O&NS (190–192) and altered cytokine profiles dampened GH release by the pituitary during prolonged critical
(193, 194). illness enables low thyroid hormone function. Secondly, the lack
of stimulation of the adrenals by ACTH could (by causing an
atrophy of adrenals) create the condition necessary for persistent
DISCUSSION inflammation which depresses the activity of thyroid hormones
during critical illness (148–152). In other words, dampened
Hypoperfusion and endotheliopathy, intestinal injury, pituitary
ACTH release by the pituitary during prolonged critical illness
suppression, and low thyroid hormone function are each central
might permit the vicious inflammatory cycles described above.
to prolonged critical illness regardless of the nature of the initial
Thirdly, there is evidence that thyroid hormone conversely also
severe injury or infection (101, 173, 195, 196). We propose that,
stimulates ACTH secretion (202, 203). In summary, the bi-
similarly, these mechanisms and their reciprocal relationships
directional relationships between the endocrine axes and thyroid
with inflammation could underlie ME/CFS regardless of the
hormone function (in addition to reciprocal relationships with
nature of the peri-onset event (i.e., infection, stressful incident,
inflammation) could contribute to explain the persistence of
exposure to environmental toxins or other) (Table 1). Moreover,
chronic ICU and ME/CFS.
the severity of ME/CFS may be a function of the strength of
these mechanisms.
However, each of these pathological mechanisms has largely
Linkages Between Low Thyroid Hormone
been studied in isolation and rarely have the linkages between Function and Endothelial Function
them been explored. Yet, the aggregate of these mechanisms Upon binding to specific receptors on endothelial cells, thyroid
is likely necessary to fully explain the perpetuation of critical hormones (T3 and T4) activate the endothelial nitric oxide
illness—and to inform the understanding of ME/CFS (Figure 1). synthase (eNOS) responsible for nitric oxide (NO) production
Additional areas for inquiry thus include the following: (204), which in turn impacts vasodilation and inflammation
(205–207). A further line of inquiry may thus be the role
of thyroid hormone function in endotheliopathy in ME/CFS,
Linkages Between Intestinal Injury and including as it relates to the new finding that plasma
Pituitary Suppression from ME/CFS patients inhibits eNOS and NO production in
Intestinal injury during critical illness results in decreased endothelial cells (208). Relatedly, critical illness researchers
secretion of gastrointestinal hormones including ghrelin (63, have found that serum from patients with NTIS inhibits the
197). Decreased stimulation of the pituitary and hypothalamus uptake of thyroid hormone (209, 210); the mechanisms remain
by ghrelin during prolonged critical illness in turn results in unresolved (165).
lower secretion of GH by the pituitary (199). Researchers have
found that the administration of an artificial ghrelin in chronic Linkages to Mitochondrial Function
ICU patients reactivated the pulsatile secretion of GH by the The impaired perfusion, redox imbalance, lower thyroid
pituitary and—when done in combination with thyrotropin- hormone function and inflammation appear to collectively affect
releasing hormones (TRH)—had beneficial metabolic effects mitochondrial activity in critical illness (via inhibition, damage,
(96, 108, 198). Similarly, the administration of ghrelin to and/or decreased turnover of new mitochondrial protein) (30,
the I/R rats “inhibited pro-inflammatory cytokine release, 211–213). Mitochondrial activity may be similarly affected in
reduced neutrophil infiltration, ameliorated intestinal barrier ME/CFS (190). Some have suggested that this down-regulation of
dysfunction, attenuated organ injury, and improved survival” mitochondrial activity (and oxygen utilization) in critical illness
(200). The sequence between intestinal injury, ghrelin secretion may be an adaptive form of “hibernation” to protect cells from
and GH release by the pituitary could be particularly relevant for death pathways (30, 213). This suggestion echoes the hypothesis

TABLE 1 | Central pathophysiological mechanisms in prolonged critical illness, probable drivers and implications, and initial evidence suggesting similar mechanisms in
ME/CFS.
Pathophysiological mechanisms In prolonged critical illness (Probable drivers and In ME/CFS (Initial evidence)
implications)
Hypoperfusion Drivers: Initial evidence

• Redistribution of blood away from the splanchnic area • Vasoconstriction in muscle and brain (42–45)
to critical tissues (23, 24) • Cerebral hypoperfusion (47–49)
• Reduced blood flow, vasoconstriction (27) • Intracranial hypertension (50)
• Capillary flow disturbances (28)
• Additional: impaired cellular oxygen utilization (29, 30)
Implications:
• Ischemia / reperfusion (I/R)
• Tissue injury driving sepsis and multi-organ
dysfunction (25, 26)
Endotheliopathy Drivers: Initial evidence
• Cytokines (31), Inflammation, exposure to oxidative • Impaired endothelial function (51, 52), in large vessels
stress (28, 32) and microcirculation (53, 54)—associated with redox
• Sympatho-adrenal hyperactivation (33) imbalance (51)
Implications: • Endothelial senescence disrupting the intestinal barriers
• Altered cerebral blood flow (34, 35) and BBBs (55)
• Increased blood–brain barrier (BBB) permeability • Redox imbalance
(36, 37)
• Increased intracranial pressure (38, 39).
• (variable) Coagulation disorder (40)
Intestinal injury Drivers: Initial evidence
• Local I/R and redox imbalance resulting from • Intestinal injury and resulting inflammation (73–81)
splanchnic hypoperfusion (58, 61, 64–67) • Altered gut microbiome linked to inflammation (82–85).
• Disruption in gut motility (63) • Lack of beneficial gut bacteria linked to fatigue
• Shift in the composition and virulence of intestinal symptoms (86)
microbes (57–59) • Endothelial senescence disrupting the intestinal barriers
Implications: (55)
• Erosion of the mucus barrier, increase in the • Auto-immunity (92–94)
permeability of the gut (i.e., “leaky gut”) (60–62)
• Bacterial translocation from the gut into circulation
(i.e., endotoxemia) and/or the formation of toxic
gut-derived lymph (57, 60)
• Pro-inflammatory cytokines and systemic inflammation
(69, 70)
• Direct impacts on the immune system (57)
• Vicious inflammatory cycle centered around intestinal
injury (61, 72)
• Decreased secretion of gastrointestinal hormones
including ghrelin (63, 197) impacting pituitary activity
Suppression of pulsatile pituitary Drivers Initial evidence
function • Cytokines acting on abundance and affinity of • Progression from a hypermetabolic to hypometabolic
glucocorticoid receptors (GR) at central level (95, 98) state (21)
• Cytokines affecting deiodinase enzymes in the • Impaired pituitary function (hypothesis) (111)
hypothalamus (99–101) • Dysfunctions in HPS axis (112–114), HPT axis (115–
• Direct action of cytokines on TSH release by the 120) and HPA axis (121–136) – associated with
pituitary directly (102, 103) inflammation O&NS (137–140)
Implications • Changes in central GRs concentrations (models) (141–
• Loss of ACTH pulsatility: atrophy of adrenal glands 146)
(104, 105) compromising patients’ ability to cope with • Smaller adrenals (147)
external stressors and permitting excessive
inflammatory responses
• Loss of GH pulsatility: imbalance between catabolic
and anabolic hormones, resulting in loss of muscle
and bone mass, muscle weakness, and changes in
glucose and fat metabolism (106–108). Alterations in
deiodinase enzyme (D3) activity enabling low thyroid
hormone function (96, 108, 198)
• Loss of TSH pulsatility (109, 110)
(Continued)

TABLE 1 | Continued
Pathophysiological mechanisms In prolonged critical illness (Probable drivers and In ME/CFS (Initial evidence)
implications)
Low thyroid hormone function Drivers Initial evidence

• Alterations in the half-life of thyroid hormone in • Immune-mediated loss of thyroid hormone function in
circulation (155–157) ME/CFS (suspected) (117)
• Modifications in the uptake of thyroid hormone by cells • Significantly lower ratio of T3 to rT3 hormones (120)
(158, 159)
• Down- and up-regulation of deiodinase enzymes that
convert the thyroid hormone into active and inactive
forms, respectively (156, 160)
• Alternations in sensitivity of cells to thyroid hormones
(161–163)
Implications
• Tissue-specific depression in thyroid hormone function
(164–166)
• Hampered function of organs (170)
• Altered activity of immune cells, including natural killer
cells (174–185)
• Viral reactivation (186–188)
• Vicious inflammatory cycle (101, 173)
FIGURE 1 | Central pathophysiological mechanisms in critical illness including selected consequences and inter-linkages. Hypoperfusion and endotheliopathy,
intestinal injury, pituitary suppression, and low thyroid hormone function are each central to prolonged critical illness regardless of the nature of the initial severe injury
or infection. These pathophysiological mechanisms are in reciprocal relationships with inflammation; specifically, researchers have proposed vicious cycles involving
intestinal injury and low thyroid hormone function. Moreover, linkages have been described between these pathophysiological mechanisms, including (i) hypoperfusion
and intestinal injury (i.e., leaky gut resulting from ischemia/reperfusion, hypoxia and redox imbalance); (ii) intestinal injury and pituitary suppression (i.e., suppressed
growth hormone release resulting from reduced ghrelin secretion by the intestines); (iii) pituitary suppression and low thyroid hormone function (i.e., increased
inactivated thyroid hormone resulting from the upregulation of D3 deiodinase as a consequence of lower growth hormone); and (iv) low thyroid hormone function and
pituitary suppression (i.e., decreased ACTH secretion resulting from lower levels of activated thyroid hormone). We propose that these mechanisms and the linkages
between them—alongside reciprocal relationships with inflammation—could also underlie ME/CFS.
that ME/CFS is a form of “dauer” or “cell danger response” (214– Relevance of Critical Illness Treatment
216). Lower mitochondrial activity in turn affects the immune Trials for ME/CFS
system and the gut endothelial “such that the host’s immune Although prolonged critical illness remains unresolved, early
response and physical barriers to infection are simultaneously treatment trials—such as the reactivation of the pituitary, or
compromised” (29). interruption of the vicious inflammatory cycles centered around

either gut injury or low thyroid hormone function—may provide predisposing genetic or environmental factors, we propose that
therapeutic avenues for ME/CFS (19). Longitudinal studies of the pathological mechanisms—and the interlinkages between
(spontaneous) recovery from critical illness may also give clues them—that prevent recovery of some critically ill patients
about prerequisites for recovery from ME/CFS. Researchers have, may also underlie ME/CFS. This initial proposal is in line
for example, found that “supranormal TSH precedes onset of with and complements several existing hypotheses of ME/CFS
recovery” from prolonged critical illness (96) and that metabolic pathogenesis. If this hypothesis is validated, past treatment
rate rises > 50% above normal in the recovery phase (213). trials for critical illness may provide avenues for a cure for
ME/CFS. Certainly, given the similarities described above, active
Commonality With Other Illnesses collaboration between critical illness and ME/CFS researchers
Researchers have suggested commonality in the illnesses induced could lead to improved understanding of not only both
by physical, infectious, and / or emotional stressors (132, 217). conditions, but also PICS, long-COVID, PACS, and fibromyalgia.
These include heat stroke, fibromyalgia, ME/CFS, prolonged
critical illness, PICS, cancer-related fatigue, post-viral fatigue,
post-acute COVID-19 syndrome (PACS) and long-COVID.
DATA AVAILABILITY STATEMENT
Specifically, it is necessary to explore whether the pathological The original contributions presented in the study are included
mechanisms described above also underlie long COVID—a in the article/supplementary material, further inquiries can be
disease which resembles ME/CFS (218–228) and can arise even directed to the corresponding author/s.
after mild COVID-19 cases.
CONCLUSION AUTHOR CONTRIBUTIONS

DS wrote the first draft of the manuscript. All authors
Decades of research in the field of critical illness medicine
contributed to manuscript revision, read, and approved the
have demonstrated that in response to the stress of severe
submitted version.
infection or injury, the vascular system, intestines, endocrine axes
and thyroid hormone function experience profound alterations.
Self-reinforcing interlinkages between these pathophysiological FUNDING
mechanisms as well as “vicious cycles” involving cytokines
and inflammation may perpetuate illness irrespective of the The Open Medicine Foundation (JB) is acknowledged
initial severe infection or injury. Without excluding possible for support.
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Findings From Critical Illness To Explain Myalgic EncephalomyelitisChronic Fatigue Syndrome

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Findings From Critical Illness To Explain Myalgic EncephalomyelitisChronic Fatigue Syndrome

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PERSPECTIVE

published: 08 March 2022

Perspective: Drawing on Findings

We propose an initial explanation for how myalgic encephalomyelitis / chronic fatigue

Frontiers in Medicine | www.frontiersin.org 1 March 2022 | Volume 9 | Article 818728

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Frontiers in Medicine | www.frontiersin.org 4 March 2022 | Volume 9 | Article 818728

Hypoperfusion Drivers: Initial evidence

Frontiers in Medicine | www.frontiersin.org 5 March 2022 | Volume 9 | Article 818728

Low thyroid hormone function Drivers Initial evidence

Frontiers in Medicine | www.frontiersin.org 6 March 2022 | Volume 9 | Article 818728

CONCLUSION AUTHOR CONTRIBUTIONS

Frontiers in Medicine | www.frontiersin.org 7 March 2022 | Volume 9 | Article 818728

Frontiers in Medicine | www.frontiersin.org 8 March 2022 | Volume 9 | Article 818728

Frontiers in Medicine | www.frontiersin.org 9 March 2022 | Volume 9 | Article 818728

Frontiers in Medicine | www.frontiersin.org 10 March 2022 | Volume 9 | Article 818728

Frontiers in Medicine | www.frontiersin.org 11 March 2022 | Volume 9 | Article 818728

Frontiers in Medicine | www.frontiersin.org 12 March 2022 | Volume 9 | Article 818728

Frontiers in Medicine | www.frontiersin.org 13 March 2022 | Volume 9 | Article 818728

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