Aarons Academy of Beauty Edema and Dexamethasone Discussion

Medical Hypotheses 145 (2020) 110307Contents lists available at ScienceDirect
Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy
COVID-19, myocardial edema and dexamethasone
T
ABSTRACT
Severe acute respiratory syndrome corona virus 2(SARS-CoV-2), the cause of coronavirus disease- 2019 (COVID-19) after emerging in china in late 2019 is spreading
rapidly across the world.
The most common cause of death in patient with COVID-19 is the rapid progression of acute respiratory distress syndrome (ARDS) shortly after the beginning of
dyspnea and hypoxemia. Patients with severe COVID-19 may also develop acute cardiac, kidney and liver injury that are associated with poor prognosis and can lead
to high mortality rate.
Numerous randomized trials are ongoing to find an effective, safe and widely available treatment. Remdisivir is the only FDA -approved antiviral agent for
treatment of severe COVID-19. Glucocorticoids (GCs) have been used for treatment of cytokine storm syndrome and respiratory failure in hospitalized patient with
severe covid-19. One of the therapeutic effects of GCs is stability of vascular endothelial barrier and decreasing tissue edema.
In our opinion, the decreasing vascular permeability effect of glucocorticoids in the injured myocardium might has an important additional factor in reducing
mortality in severe, hospitalized COVID-19 patients.
Introduction
From the beginning of the coronavirus disease 2019 outbreak in
December 2019, in Wuhan China, the COVID-19 rapidly spread across
the world [1] with an actual international public health emergency.
Myocardial Injury in COVID-19
Acute myocardial injury, mainly defined by elevated cardiac bio­
markers is not uncommon in COVID-19 patients with an incidence
ranging from 7.2% to 12% and considered as a risk factor for in-hospital
mortality among severe COVID-19 patients [2].
A recent study from china documented that 15.8% of all admitted
patients have had myocardial injury based on high blood level of tro­
ponin I (cTnI) and also patients who died had suffered more often from
myocardial injury during hospitalization compared with survivors
75.8% vs. 9.7% [3].
Although the exact pathophysiologic mechanism of myocardial in­
jury in COVID-19 remains under investigation, there are multiple pos­
sible etiologies, including acute viral myocarditis, acute ischemic injury
due to coronary artery obstruction, and inflammatory myocardial
edema due to the systemic immune response [4].
Mounting evidence indicates that vascular leakage and tissue edema
play a main role in the pathogenesis of acute lung injury (ARDS) and
myocardial injury in patients with severe COVID-19 [5]. Several me­
chanisms may contribute in the pathogenesis of myocardial edema:
First, there is invasion of endothelial cells (EC) by SARS-CoV-2. The
resultant endotheliitis is characterized by EC dysfunction, cell lysis and
a subsequent necrotic response. Second, there is a downregulation of
the angiotensin-converting enzyme 2(ACE2). SARS-CoV-2 enters cells
via binding to the cellular membrane receptor ACE2 [6], which in turn
reduces ACE2 availability, leading to and increase of angiotensin 2 and
an activation of the kallikrein–bradykinin pathway and eventually to an
increased vascular permeability. As a third mechanism, the surge of
inflammatory cytokines and vasoactive molecules leads to augmented
EC contractility and loosening of inter-endothelial junctions [7].
Cardiac magnetic resonance (CMR) has recently emerged as the
most sensitive noninvasive imaging modality for confirming myocardial
injury. In a recently published autopsy series in patients with COVID19, no significant diffuse lymphocytic inflammatory infiltration in the
heart muscle or large areas of myocardial necrosis were observed [8].
There is a significant correlation between published CMR case reports
and autopsy-based finding in showing absence of late gadolinium en­
hancement which indicates lack of myocyte necrosis and scar formation
in most of COVID-19 related- cardiac injury. However, CMR con­
sistently demonstrates diffuse myocardial edema by transitional in­
creasing left ventricular wall thickness and high signal intensity on
water-sensitive T2 -weighted images (T2 mapping and T2 -STIR)
[9–12].
Prolonged episodes of myocardial edema not only affect systolic and
diastolic function with reduced ventricular compliance, but also may
lead to the formation of diffuse myocardial fibrosis [13]. The latter may
be irreversible and have therefore longstanding consequences for ven­
tricular functional capacity.
Dexamethasone
Preliminary report of the RECOVERY trial has shown reduced death
rates of more than 20% in hospitalized COVID-19 patients who received
dexamethasone [14,15].
Glucocorticoids (GCs) are steroid hormones that have inflammatory
and immunosuppressive effects on a different cells group and lead to
many different physiological and pathological effects.
One of the systemic effects of GCs is diminishing edema formation
by altering endothelial cell barrier function. Decreasing brain edema
especially after pathologic events like acute ischemic stroke, post sur­
gery and radiotherapy has been recognized for many years [16].
Several published studies have shown that dexamethasone has a
positive effect on myocardial vascular permeability and helps maintain
the barrier function of endothelial cells during ischemic stress [17,18].
https://doi.org/10.1016/j.mehy.2020.110307
Received 20 July 2020; Received in revised form 24 August 2020; Accepted 24 September 2020
Available online 28 September 2020
0306-9877/ Crown Copyright © 2020 Published by Elsevier Ltd. All rights reserved.
Medical Hypotheses 145 (2020) 110307
Conclusion
[4] Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, Jain SS,
Burkhoff D, Kumaraiah D, Rabbani LeRoy, Schwartz A, Uriel N. COVID-19 and
cardiovascular disease. Circulation 2020;141(20):1648–55.
[5] Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS,
Mehra MR, Schuepbach RA, Ruschitzka F, Moch H. Endothelial cell infection and
endotheliitis in COVID-19. Lancet 2020;395(10234):1417–8.
[6] Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S,
Schiergens TS, Herrler G, Wu N-H, Nitsche A, Müller MA, Drosten C, Pöhlmann S.
SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically
proven protease inhibitor. Cell 2020;181(2):271–280.e8.
[7] Laure-Anne T, et al. COVID-19: the vasculature unleashed. Nat Rev/Immunol
2020;20:389–91.
[8] Fox Sharon E, et al. Pulmonary and cardiac pathology in African American patients
with COVID-19: an autopsy series from New Orleans. Lancet Respir Med
2020;20:30243–5.
[9] Luetkens JA, Isaak A, Zimmer S, Nattermann J, Sprinkart AM, Boesecke C, Rieke GJ,
Zachoval C, Heine A, Velten M, Duerr GD. Diffuse myocardial inflammation in
COVID-19 associated myocarditis detected by multiparametric cardiac magnetic
resonance imaging. Circ Cardiovasc Imag 2020;13(5). https://doi.org/10.1161/
CIRCIMAGING.120.010897.
[10] Manka R, Karolyi M, Polacin M, Holy EW, Nemeth J, Steiger P, Schuepbach RA,
Zinkernagel AS, Alkadhi H, Mehra MR, Ruschitzka F. Myocardial edema in COVID19 on cardiac MRI. J Heart Lung Transpl 2020;39(7):730–2.
[11] Bernardi Nicola et al. Covid-19 pneumonia, Takotsubo syndrome and left ventricle
thrombi JACC case reports; 2020.
[12] Philippe Meyer et al. Typical takotsubo syndrome triggered by SARS-CoV-2 infec­
tion, Eur Heart J, online publish-ahead-of-print 14 April 202.
[13] Desai KV, Laine GA, Stewart RH, Cox CS, Quick CM, Allen SJ, et al. Mechanics of the
left ventricular myocardial interstitium: effects of acute and chronic myocardial
edema. Am J Physiol Heart Circ Physiol 2008;294:H2428–34.
[14] Mahase Elisabeth, Covid-19: Low dose steroid cuts death in ventilated patients by
one third, trial finds. BMJ2020;369.
[15] The RECOVERTY Collaborative Group. Dexamethasone in hospitalized patients
with COVID-19– preliminary report. NEJM 2020; Jul. 17.
[16] Ellaine S, et al. Glucocorticoids and endothelial cell barrier function. Cell Tissue Res
2014;355:597–605.
[17] Lefer AM, Crossley K, Grigonis G, Lefer DJ. Mechanism of the beneficial effect of
dexamethasone on myocardial cell integrity in acute myocardial ischemia. Basic Res
Cardiol 1980;75(2):328–39.
[18] Oakleyand RH, Cendrowski JA. Glucocorticoid signaling in the heart: a cardio­
myocyte perspective. J Steroid Biochem Mol Biol 2015;153:27–34.
We think that dexamethasone may play a pivotal role in decreasing
deaths in COVID-19 patients by helping maintain vascular perme­
ability. Such a therapeutic effect not only resolve edema and in­
flammation in the lung but also on the myocardial tissue will likely lead
to a decrease of myocardial edema and thereby improves systolic and
diastolic ventricular function. Furthermore, it may prevent the forma­
tion of global fibrosis as a chronic, potentially irreversible complication
of COVID-19.
This hypothesis should be tested using CMR in patients with COVID19- related acute cardiac injury before and after dexamethasone treat­
ment.
Funding
Authors declare not using any grants.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ­
ence the work reported in this paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.mehy.2020.110307.
References
[1] Wu Z, Mc Googan J. Characteristic and important lessons from the Coronavirus
Disease 2019 (COVID-19) outbreak in china. JAMA 2020;323(13):1239–42.
[2] Wang D, Hu Bo, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y,
Zhao Y, Li Y, Wang X, Peng Z. Clinical characteristics of 138 hospitalized patients
with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA
2020;323(11):1061. https://doi.org/10.1001/jama.2020.1585.
[3] Shaobo Shi et al. Characteristics and clinical significance of myocardial injury in
patients with severe coronavirus disease 2019. Eur Heart J 2020;41:2070–9.
⁎
Moezedin Javad Rafieea, , Faranak Babaki Fardb, Matthias G. Friedrichc
a
Research Institute, McGill University Health Centre, Montreal, QC, Canada
b
Faculty of Medicine, University of Montreal, Montreal, QC, Canada
c
Cardiovascular Imaging, Depts. of Medicine and Diagnostic Radiology,
McGill University Health Centre, Montreal, QC, Canada
⁎
Corresponding author.
2
Infect Dis Ther (2021) 10:1907–1931
https://doi.org/10.1007/s40121-021-00500-z
REVIEW
Potential Adverse Effects of Dexamethasone Therapy
on COVID-19 Patients: Review and Recommendations
Fei Chen
. Lanting Hao . Shiheng Zhu . Xinyuan Yang .
Wenhao Shi . Kai Zheng . Tenger Wang . Huiran Chen
Received: March 24, 2021 / Accepted: July 6, 2021 / Published online: July 22, 2021
Ó The Author(s) 2021
ABSTRACT
In the context of the coronavirus disease 2019
(COVID-19) pandemic, the global healthcare
community has raced to find effective therapeutic agents against severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2). To date,
dexamethasone is the first and an important
therapeutic to significantly reduce the risk of
death in COVID-19 patients with severe disease.
Due to powerful anti-inflammatory and
immunosuppressive effects, dexamethasone
could attenuate SARS-CoV-2-induced uncontrolled cytokine storm, severe acute respiratory
distress syndrome and lung injury. Nevertheless, dexamethasone treatment is a doubleedged sword, as numerous studies have revealed
that it has significant adverse impacts later in
life. In this article, we reviewed the literature
regarding the adverse effects of dexamethasone
administration on different organ systems as
well as related disease pathogenesis in an
attempt to clarify the potential harms that may
arise in COVID-19 patients receiving dexamethasone treatment. Overall, taking the threat
of COVID-19 pandemic into account, we think
F. Chen (&)  L. Hao  S. Zhu  X. Yang  W. Shi 
K. Zheng  T. Wang  H. Chen
Department of Physiology, Jining Medical
University, 133 Hehua Rd, Jining 272067, China
e-mail: chenfei123@mail.jnmc.edu.cn;
chenfei0336@163.com
it is necessary to apply dexamethasone as a
pharmaceutical therapy in critical patients.
However, its adverse side effects cannot be
ignored. Our review will help medical professionals in the prognosis and follow-up of
patients treated with dexamethasone. In addition, given that a considerable amount of
uncertainty, confusion and even controversy
still exist, further studies and more clinical trials
are urgently needed to improve our understanding of the parameters and the effects of
dexamethasone on patients with SARS-CoV-2
infection.
Keywords: Dexamethasone;
COVID-19;
Patients; SARS-CoV-2; Necrosis of the femoral
head; Depression; Diabetes
1908
Key Summary Points
It is necessary to apply dexamethasone as
a therapy in critical COVID-19 patients,
but its adverse side effects cannot be
ignored.
Through a variety of molecular pathways,
dexamethasone can interfere with normal
organ functions and cause numerous
clinical manifestations, intensifying the
risk and severity of sequelae of COVID-19
disease, such as osteonecrosis of the
femoral head, hypertension and diabetes.
Regular follow-up and evaluation of
physical conditions in accordance with
the time line are crucial for COVID-19
patients who have received
dexamethasone treatment.
INTRODUCTION
After emerging in December 2019, coronavirus
disease 2019 (COVID-19), caused by severe
acute respiratory syndrome coronavirus 2
(SARS-CoV-2), has rapidly spread across the
world and led to high morbidity and mortality.
Globally, as of 18 April 2021, there have been
140 million confirmed cases, including 3 million deaths, reported to the World Health
Organization (WHO) [1]. The clinical spectrum
of COVID-19 appears to be wide, ranging from
asymptomatic infection to critical illness. The
common symptoms of infection are fever
(94%), cough (79%), fatigue (23%), loose stools
(16%), anosmia and dysgeusia (70–84%) [2, 3].
Sepsis (59%) is the most frequently observed
complication, followed by respiratory failure
(54%), acute cardiac injury (23%) and septic
shock (20%) [4]. Cytokine storm, clots, disseminated intravascular coagulation and thrombocytopenia have also been reported [5, 6].
Notably, advanced age and several comorbidities including impaired renal function and
thrombosis are reportedly associated with a
Infect Dis Ther (2021) 10:1907–1931
worse disease course and increased mortality
rate [7–9]. Hence, there is an urgent need to
develop effective therapies to prevent the progression of disease. An array of drugs and therapeutic agents used to be considered as having
potential efficacy against SARS-CoV-2, encompassing antiviral agents (remdesivir, chloroquine or hydroxychloroquine, azithromycin
and lopinavir), blood-derived products (convalescent plasma and immunoglobulin products), anticoagulants
(heparin
and
lowmolecular-weight heparin) and immunomodulators (corticosteroids, interferons, interleukin-1
[IL-1] inhibitors, IL-6 inhibitors and kinase
inhibitors) [10–14]. Disappointingly, on 15
October 2020, the interim results from the Solidarity trial coordinated by WHO indicated that
remdesivir, hydroxychloroquine, lopinavir and
interferon regimens appeared to have little or
no effect on hospitalized COVID-19 patients
[15], while dexamethasone, declared as the
world’s first treatment to significantly reduce
the risk of death [16], is still the only therapeutic agent shown to be effective for patients
with severe disease [17].
As a broad-spectrum immunosuppressor, the
potency and duration of action of dexamethasone are greater and longer than those of cortisone. Its immunosuppressive effect is exerted
through a variety of ways. In B cells, glucocorticoids impair upstream B cell receptor and Tolllike receptor 7 signaling while promoting significant upregulation of the genes encoding the
immunomodulatory cytokine IL-10 [18]. Similarly, dexamethasone exposure causes defects in
cell division for both CD4 and CD8 T cells and
dampens T cell receptor signaling and cytokine
expression [19, 20]. Moreover, in dendritic cells,
dexamethasone could inhibit antigen presentation by increasing expression and activity of
Na?/Ca2? exchanger [21]. In parallel, the antiinflammatory actions of glucocorticoids occur
by decreasing the gene transcription of pro-inflammatory cytokines (IL-1, TNF and IL-6),
chemokines and adhesion molecules [22].
Studies have demonstrated that SARS-CoV-2induced uncontrolled cytokine storm [23], severe acute respiratory distress syndrome (ARDS)
and multiorgan failure, which are the main
Infect Dis Ther (2021) 10:1907–1931
causes of COVID-19-related mortality, can be
attenuated by the use of dexamethasone [24].
At the beginning of the pandemic, the use of
corticosteroids was considered controversial,
although Randomized Evaluation of COVID-19
Therapy (RECOVERY) trial provided evidence
that dexamethasone 6 mg once daily for 10 days
reduced mortality in COVID-19 patients
receiving oxygen therapy [16]. Some investigators noted that early corticosteroid use might
lead to increased virus replication and thus
higher viral loads [25]. Meanwhile, there is an
analysis suggesting that the initiation of treatment in the second week of symptom onset,
when the immunopathological phenomenon
dominates, may be beneficial [16]. However,
many researchers pointed out that, in practice,
the symptom onset is usually impossible to
ascertain, and the signs of severity often appear
late. In a study that assessed the association
between the dexamethasone initiation time and
mortality benefits, Sulaiman et al. (2021) found
survival benefits with the early initiation in
critically ill COVID-19 patients [26]. The WHO
panel concluded that it is preferable that critical
COVID-19 patients receive corticosteroids (even
if within 7 days of symptom onset) but noncritical patients do not (even if after 7 days of
symptoms onset) [27]. Although described as
‘low-dose dexamethasone therapy,’ the dose of
6 mg per day is five to six times higher than that
for therapeutic glucocorticoid replacement
[28–31]. At this dose, patients suffer side effects
such as skin thinning, weight gain, osteoporosis, hypertension and diabetes [20]. Hyperglycemia, gastrointestinal hemorrhage and
psychosis were also considered related to dexamethasone treatment in the RECOVERY trial
[16]. Recently, Weng and colleagues claimed
that patients with gastrointestinal sequelae at
90 days were treated more often with corticosteroids and proton pump inhibitors than were
patients without such sequelae [32]. Hence,
many researchers are cautious about its extensive use for critically ill patients. Based on
results of previous studies in SARS patients,
avascular necrosis and osteoporosis were more
likely to occur among patients with higher-dose
steroid therapy. For example, in a retrospective
study of 539 patients with steroid treatment
1909
following SARS, the incidence of steroid-induced osteonecrosis of the femoral head
(ONFH) was 24% [33]. Notably, all the metaanalyses found patients on corticosteroid treatment were more likely to have secondary
infections such as bacterial infection, invasive
fungal infection or exacerbation of pre-existing
conditions [34]. Due to the immunosuppressive
effect, a strong association exists between corticosteroid use and respiratory infectious disease
(e.g., active tuberculosis and pulmonary
aspergillosis) [35, 36]. Similarly, Strongyloides
hyperinfection/dissemination in low- and middle-income countries induced by dexamethasone treatment cannot be ignored [37].
Moreover, short-term or protracted dexamethasone therapy might contribute to other
potential side effects, such as neuromuscular
weakness, psychiatric symptoms and even
iatrogenic Cushing syndrome [38–40].
Although dexamethasone is recommended
in critical patients infected by COVID-19, it is
essential for us to develop deeper insights into
the potential damage of dexamethasone in view
of the large number of patients. Therefore, we
searched PubMed, Scopus, the Web of Science
and Google Scholar up to April 2021 for papers
on the effects of dexamethasone therapy on
different organs and summarized current
understanding of the mechanisms of complications and sequelae induced by dexamethasone in this review. This will assist medical
professionals in managing COVID-19 patients
treated with dexamethasone and directing postacute and long-term follow-up. Additionally, we
hope this will provide a valuable basis for future
studies. This article is based on previously conducted studies and does not contain any new
studies with human participants or animals
performed by any of the authors.
MUSCULOSKELETAL SYSTEM
Long-term or excessive use of glucocorticoids is
the most common non-traumatic cause of
ONFH [41, 42] and secondary osteoporosis
[43, 44] in patients (Fig. 1). Owing to the use of
glucocorticoids during the SARS epidemic in
2003, some patients had varying degrees of
Infect Dis Ther (2021) 10:1907–1931
1910
Fig. 1 Organ systems affected by dexamethasone and the side effects or sequelae
ONFH [33], and the risk of ONFH showed an
aggravating trend with the increase of cumulative doses and treatment durations of steroids in
SARS patients [45]. In 2014, Guo et al. found
that more male SARS patients (51/129, 40%)
were diagnosed with ONFH compared to female
patients (79/410, 19%) [33]. Recently, a largescale global statistical analysis revealed that
while males and females are at equivalent risk of
SARS-CoV-2 infection, male sex is associated
with a higher risk for the development of severe
disease as measured by intensive therapy unit
admission [46], which indicated that male
patients are more likely to receive dexamethasone treatment and suffer from ONFH. Therefore, to further explore the risk of ONFH in
COVID-19 patients, we sum up the mechanisms
of dexamethasone-induced ONFH. Its pathogenesis is mainly related to the differentiation
of mesenchymal stem cells (MSCs) and osteoblast apoptosis. MSCs have the potential to
differentiate into cells of mesodermal lineage,
such as adipocytes, osteocytes and chondrocytes [47]. Yin et al. proved that dexamethasone
can directly induce MSCs to differentiate into
adipocytes [48]. On the one hand, adipogenesis
of MSCs leads to excessive accumulation of
marrow fat and increased intraosseous pressure,
thus inducing venous stasis, arterial obstruction
and eventually ischemic osteonecrosis [48, 49].
On the other hand, dexamethasone inhibits
osteogenesis of stem cells, reducing the ability
to reshape bone and repair necrotic bone and
accounting for the onset of osteonecrosis
[48, 50]. In addition, previous studies have
demonstrated that dexamethasone could
induce apoptosis of MSCs in a time- and concentration-dependent manner, which is probably the mechanism of pathogenesis of steroidinduced ONFH [51, 52]. Excessive use of dexamethasone can promote the apoptosis of
osteoblasts through multiple signaling mechanisms. First, forkhead box transcription factor
O1 (FOXO1) targets genes involved in apoptosis, autophagy and cell cycle arrest [53]. Dexamethasone
could
upregulate
FOXO1
expression, inhibit the viability of osteoblasts
and promote apoptosis [54]. Second, the phosphatidylinositol 3-kinase/protein kinase 3
(PI3K/AKT) signaling pathway controls many
cellular functions by participating in the signal
transduction pertaining to proliferation, survival and motility [55]. Dexamethasone can
inhibit the activation of the PI3K/AKT pathway
in osteoblasts by suppressing the expression of
p-PI3K and p-AKT, thereby inducing osteoblast
apoptosis [56]. Third, after dexamethasone
treatment, the expression of glycogen synthase
kinase 3b (GSK3b) in osteoblasts is significantly
upregulated, which can induce mitochondrial
Infect Dis Ther (2021) 10:1907–1931
apoptotic and lead to ONFH [56, 57]. Zhu et al.
claimed that miR-124 accumulation following
circHIPK3 downregulation appears to be the
primary mechanism of dexamethasone-induced
cytotoxicity and programmed necrosis in
human osteoblasts [58]. Therefore, to prevent
dexamethasone-induced ONFH, corticosteroids
should be applied only to patients in critical
cases at low-to-moderate doses and short courses. In the 1st year after prescription of corticosteroids, patients with suspected ONFH
should receive periodic magnetic resonance
imaging examination during follow-up to
diagnose and treat the disease in the early stage
[59].
Osteoporosis is a systemic skeletal disease
characterized by low bone mass and microarchitectural deterioration of bone tissue, with a
consequent increase in bone fragility and susceptibility to fracture [60]. As mentioned before,
glucocorticoids cause apoptosis of osteoblasts
and a depletion of the osteoblastic cell population, accounting for the reduction in bone formation and trabecular width [61]. On the flip
side, following dexamethasone treatment, the
decline in levels of the antiresorptive molecule
osteoprotegerin and the increase in levels of the
osteoclastogenesis-inducing
molecule,
the
receptor activator of nuclear factor-jB ligand,
promote bone resorption by osteoclasts [62].
Taken together, these changes lead to glucocorticoid-induced osteoporosis, mainly via
reduced bone formation. More recently, there
have been several discoveries of key proteins
that have further increased our understanding
of the molecular mechanism. Dexamethasoneinduced osteoporosis can be caused by suppression of the canonical Wnt signal. Secreted
frizzled-related proteins (SFRPs) could compete
with membrane-bound frizzled proteins for
Wnt binding [63], and dickkopf-1 (Dkk-1) also
mediates the inhibition of Wnt signal [64].
Then, several studies have reported dexamethasone increases the expression of Dkk-1 and
SFRP1 and represses Wnt/b-catenin signaling in
human osteoblasts to reduce mineral density
and trabecular bone volume [64–67]. Additionally, dexamethasone can downregulate the
expression of matrix marker biglycan [68], and
the lack of biglycan contributes to the reduction
1911
in trabecular bone volume, mineral deposition
rate and bone formation rate [69].
Skeletal muscle atrophy occurs also as a side
effect of dexamethasone treatment [70, 71],
leading to severe muscle weakness, inactivity
and reduced quality of life for the patients [72].
In general, muscle atrophy results from the
imbalance between protein synthesis and
degradation. Qin et al. observed that the
upregulation of myostatin gene expression
caused by dexamethasone was associated with
the myostatin gene promoter and glucocorticoid responsive element along the promoter
[73], and the increased myostatin led to the
changes in ultrastructure of skeletal muscle,
including the inhibition of myoblast proliferation and induction of muscle atrophy [74, 75].
Moreover, dexamethasone induces depletion of
myosin heavy chain protein and the upregulation of muscle RING-finger protein-1 [70, 76],
which affects muscle integrity by increasing
protein breakdown of an important component
of the sarcomere and results in muscle atrophy
[67]. Concomitantly, it has been reported that
dexamethasone could induce mitochondrial
dysfunction, bringing about ATP deprivation
and subsequently AMP-activated protein kinase
activation, which further activates the FOXO3/
Atrogenes and ultimately leads to protein
degradation as well as muscle atrophy [77].
CARDIOVASCULAR SYSTEM
As a common cardiovascular disease, hypertension is also the most frequent comorbidity
(51%) in COVID-19 patients, followed by diabetes (19%) and atrial fibrillation (11%) [78]. At
the same time, patients with severe COVID-19
infection commonly have a history of hypertension. Wu et al. (2020) reported that compared with COVID-19 patients without ARDS,
patients who developed ARDS had a higher
proportion of comorbidities such as hypertension (14% and 27%, respectively) and diabetes
(5% and 19%, respectively) [79]. In Italy, almost
75% of patients who have died from COVID-19
had hypertension [80]. It is worth noting that
dexamethasone, the first drug shown to reduce
deaths from the coronavirus disease [81], can
Necrosis of the
Musculoskeletal
Renal system
Digestive system
system
Cardiovascular
Renal
calcification
perforation
Bowel
hypertrophy
Ventricular
Hypertension
atrophy
Skeletal muscle
head
femoral
sequelae
affected
system
Symptom/
Organ system
CLD
PI with a birth weight
of 440–990 g and
of 501–1000 g
PI with a birth weight
PI with BPD
PI with CLD
(median 815 g)
of 500–2054 g
PI with a birth weight
Pediatric ALL patients
and CLD
3.8 mg/kg
9 2 days
kg/day 9 2 days ? 0.02 mg/kg/day
kg/day 9 3 days ? 0.05 mg/
0.15 mg/kg/day 9 3 days ? 0.10 mg/
intervals during the next 5 to 6 weeks)
0.5 mg/kg/day (taper at successive 3-day
fashion over a total 42-day course)
0.5 mg/kg/day (taper in a standardized
0.4–0.6 mg/kg/day 9 3 weeks
6 mg/m2/day 9 5 days
over a 3-week period
714–1920 g
(median 1087 g)
kg/day 9 3 days ? taper the dose
0.6 mg/kg/day 9 3 days ? 0.3 mg/
24 mg/day 9 4 days
16.7 mg/kg 9 56 days (median)
Dosage
weight of
Infants with a birth
Hemiplegic patients
patients
Multiple myeloma
characteristic
Subjects’
83%
13%
–
57%
94%
6%
41%
–
7%
incidence
Disease
26 days
2 weeks
Within
1 week
Within
6 weeks
Within
2–3 days
4 days
2 weeks
Within
10 days
Within
(median)
11.1 months
Onset time
Table 1 Organ systems of human affected by dexamethasone treatment: symptoms and sequelae
Precaution/
–
2. Breast feeding
1. Oral PGE2 analogs
2. Statins
1. Curcumin
Exercise training
supplementation
calcium
2. Vitamin D and
1. Physical exercises
vasodilators
anticoagulants and
vitamin E,
Bisphosphonates,
therapy
Electrocardiogram
Sonography
CT
181b, VEGF-B
2. MiR-30a, MiR-
1. Echocardiogram
2.
1. Blood pressure
3. Ultrasonography
2. Muscle biopsy
levels
1. Urine creatine
MRI
method
indicator or
Monitoring
[130, 131]
[124, 205, 206]
202–204]
[92, 100, 101,
[82, 83, 200, 201]
[71, 198, 199]
[42, 59]
References
1912
Infect Dis Ther (2021) 10:1907–1931
Diabetes
insufficiency
Adrenal
cancer
gastrointestinal
diagnosed
with newly
at least three cycles)
(administer every 2–4 weeks in
9 2 days (? 7-8 mg/day 9 1 day)
10–12 mg/day 9 1 day ? 7–8 mg/day
22%
3 months
level C 200 mg/dl)
(blood glucose
2. Insulin therapy
level \ 200 mg/dl)
(blood glucose
Non-diabetic patients
hypoglycemic drugs
1. Exercise, diet therapy
patients
4–5 days
glucocorticoids
Taper doses of
dependent diabetic
20%
29 days
and oral
4 mg/day 9 5 days
100%
non-insulin-
Subjects are relatives of
leukemia patients
acute lymphoblastic
Early B-cell lineage
junction
0.2 mg/kg/day 9 28 days
–
Precaution/
therapy
Sensory
method
Monitoring
indicator or
4. Hemoglobin A1c
tests
3. IVGTT
2. OGTT
concentrations
and insulin
1. Plasma glucose
testing
Adrenal stimulation
examination
2 weeks
Onset time
distal to the tibial
meta-diaphyseal
65%
Disease
incidence
neurological
3–4 mg
Dosage
surgical procedures
Patients undergoing
Subjects’
characteristic
[171, 172, 207]
[156]
[149]
References
MRI magnetic resonance imaging, CLD chronic lung disease, ALL acute lymphoblastic leukemia, PI preterm infants, BPD bronchopulmonary dysplasia, MiR microRNA, VEGF vascular endothelial growth
factor, PGE2 prostaglandin E2, CT computed tomography, OGTT oral glucose tolerance test, IVGTT intravenous glucose tolerance test
system
Endocrine
Persistent
Nervous system
nerve injury
Symptom/
sequelae
Organ system
affected
Table 1 continued
Infect Dis Ther (2021) 10:1907–1931
1913
Ocular system
Cardiovascular
system
Osteoporosis
Musculoskeletal
system
Male rats (Wistar)
Glaucoma
Mice (C57BL/6)
0.1% 9 (* 20 ll) 9 3
times/day 9 20 weeks
35 mg/kg/day 9 15 days
2 mg/kg/day 9 7 days
0.5 mg/kg ? 0.3 mg/
kg ? 0.1 mg/kg
1.5 mg/kg/day 9 8 days
Male rats (Wistar)
Neonatal rats
(Wistar)
0.5 mg/kg ? 0.3 mg/
kg ? 0.1 mg/kg
Neonatal rats
(Wistar)
0.5 mg/kg ? 0.3 mg/
kg ? 0.1 mg/kg
1000 mg/kg
Male rabbits (New
Zealand)
Female neonatal
rats (Wistar)
0.03, 0.3 or 3 mg/
kg/day 9 10 days
Male rats (Fisher
344)
20 weeks
15 days
1 week
References
[84]
[77]
[73]
Increased promoter methylation in the
CcnD2 gene
Impaired expression of CBS and CSE
–
Myocilin, actin and ECM proteins
increase
Impaired calcium handling and
calcineurin signaling pathway
activation
Increased ROS generation
[110]
[102]
[103]
[127]
[94, 96]
[90]
[127]
Increased transmembrane Ca2? in VSM [85]
Increased transcription of TH
Activation of AMPK/FOXO3/
agtrogenes signaling
Myostatin promoter activity
upregulation
Biglycan, LRP5, OPG and RUNX2
[68]
downregulation; Col1a1 upregulation
Osteocalcin decrease and leptin increase [62]
Pathogenic mechanism
Within
15 months
45 weeks
2 days
3 months
Within
6 weeks
8, 6 or
5 days
6 days
5 mg/kg/day 9 18 days
Male mice
(C57BL/J)
12 weeks
8 days
0.6 mg/kg/
3 days 9 12 weeks
Female rats
(SpragueDawley)
3 weeks
Onset time
Female mice (Kun- 20 mg/kg/day 9 8 days
Ming)
1 mg/kg/day 9 3 weeks
Dosage
Female mice
(BALB/c)
Species
Diastolic dysfunction Male rats (Wistar)
Arrhythmias
Cardiac hypertrophy
Hypertension
Skeletal muscle
atrophy
Symptom/sequela
Organ system
affected
Table 2 Organ systems of animal models affected by dexamethasone treatment: symptoms and sequelae
1914
Infect Dis Ther (2021) 10:1907–1931
Nervous system
Cerebral edema
Depressive behavior
Anxiety
Reduction of
nephron
Renal fibrosis
Glomerulosclerosis
10 mg/kg
0.5 mg/kg ? 0.3 mg/
kg ? 0.1 mg/kg
1 mg/kg
Dosage
2 mg/kg
3 mg/kg
Rats with acidosis
(SpragueDawley)
60 mg/kg/day 9 21 days
Male mice (ICR)
Male rats in SE
(SpragueDawley)
4 mg/kg/day 9 21 days
Male mice
(C57BL/6 J)
Male rats (Sprague- 5 mg/kg/day 9 7 days
Dawley)
Male albino mice
Neonatal rats
(Wistar)
Chronic progressive
glomerulonephritis
Renal system
Species
Male rats (Wister)
Symptom/sequela
Digestive system Gastric ulceration
Organ system
affected
Table 2 continued
Inhibit prostaglandin synthetase and
peroxidase
Pathogenic mechanism
4h
2 days
22 days
20 days
1 week
0.5 h
4 weeks
8 and
24 weeks
32 weeks
AQP-1–mediated pathways
–
GR protein expression reduction
GR mRNA decrease
Excessive CREB phosphorylation and
BDNF upregulation
Dysregulation of the HPA axis
Suppression of mitotic activity
Accumulation of inflammatory factors
Within
15 months
26 h
Onset time
[151]
[150]
[143]
[137]
[138]
[136]
[129]
[128]
[127]
[121]
References
Infect Dis Ther (2021) 10:1907–1931
1915
5 mg/kg/day 9 24 days
0.2–0.4 mg/
kg 9 24 days
Mice (C57BL/6 J)
Rats (Wistar)
Female rats Zucker
(fa/fa)
Hyperglycemia
Diabetes
Promptly
Within
5 days
Within
2 months
Within
1 week
Onset time
Insulin resistance
GR/KLF9/PGC1a signaling pathway
Inhibition of ACTH synthesis and
secretion
Pathogenic mechanism
[182]
[181]
[160]
References
LRP-5 low-density lipoprotein5, OPG osteoprotegerin, RUNX2 runt-related transcription factor 2, AMPK AMP-activated protein kinase, FOXO3 forkhead box O
3, TH tyrosine hydroxylase, VSM vascular smooth muscle, CBS cystathionine-b-synthase, CSE cystathionine-c-lyase, CcnD2 gene cyclinD2 gene, ROS reactive
oxygen species, ECM extracellular matrix, HPA hypothalamic-pituitary-adrenal, CREB anti-cAMP responsive element binding protein, BDNF brain-derived
neurotrophic factor, GR glucocorticoid receptor, SE status epilepticus, AQP-1 aquaporin-1, ACTH adreno-cortico-tropic-hormone, KLF9 Krüppel-like factor 9,
PGC1a peroxisome proliferator-activated receptor c coactivator 1 a
1 mg/kg/
2 days 9 2 months
0.15 mg/
kg/day 9 7 days
Female rats
(Wistar)
Adrenocortical
atrophy
Dosage
Endocrine
system
Species
Symptom/sequela
Organ system
affected
Table 2 continued
1916
Infect Dis Ther (2021) 10:1907–1931
Infect Dis Ther (2021) 10:1907–1931
induce hypertension in clinical studies (Table 1)
and animal experiments (Table 2) through a
variety of mechanisms [82, 83]. On the one
hand, dexamethasone enhances vasoconstriction. A recent study has found that dexamethasone increased synthesis of catecholamines
by inducing the transcription of the rate-limiting enzyme tyrosine hydroxylase, and excessive
catecholamine levels induce direct vasoconstriction [84]. Increasing calcium influx in vascular smooth muscle is also a way in which
dexamethasone causes hypertension [85]. On
the other hand, dexamethasone-induced
hypertension is associated with reduction of
vasodilating mediators such as prostacyclin,
nitric oxide (NO) and hydrogen sulfide (H2S).
There have been reports indicating that dexamethasone can inhibit the biosynthesis of
prostaglandins via the inhibition of phospholipase A2 activity [86–88]. Schafer et al. claimed
dexamethasone could reduce NO production by
means of several mechanisms including induction of oxidative stress as well as downregulation of cationic amino acid transporter-1 and
endothelial NO synthase [89]. H2S has been
proposed as a candidate for endotheliumderived hyperpolarizing factor, involved in
inducing vasodilation. H2S biosynthesis could
be inhibited by dexamethasone via the impairment of cystathionine-b-synthase and cystathionine-c-lyase expression [90]. The vascular
endothelial glucocorticoid receptor (GR) plays a
critical role in mediating blood pressure
response to steroids [91]. Although there is no
report confirming the use of dexamethasone in
the treatment of COVID-19 leads to hypertension, we still suggest follow-up, evaluation and
close monitoring of blood pressure after recovery from SARS-CoV-2 infection, especially for
the hypertensive patients who received dexamethasone treatment.
A clinical trial suggested retardation of heart
growth among dexamethasone-treated infants
compared with control infants [92]. Cardiomyocytes can only divide within a limited time
after birth, and once the proliferation of cardiomyocytes is inhibited during this period, it
will have a negative repercussion on the total
number of cardiomyocytes later in life [93]. The
use of dexamethasone in newborn rats
1917
increased promoter methylation in the cardiomyocytes CcnD2 gene, which causes the
decrease of D2 protein and inhibition of cardiomyocyte proliferation [94, 95]. Eventually,
neonatal dexamethasone treatment in rat pups
leads to a permanent decrease in heart weight,
as well as reduced number, hypertrophy and
early degeneration of cardiomyocytes during
adult life [93, 96]. Since most COVID-19-positive newborns are mildly affected with cases of
severe disease being very rare [97] and dexamethasone is mainly shown to be effective against
the novel coronavirus for severe patients, we
believe that dexamethasone is not suitable for
the overwhelming majority of neonates. During
the treatment of 66 babies with SARS-CoV-2
infection in a UK survey, only 2 (3%) were
treated with corticosteroids [97]. Meanwhile, we
recently indicated that SARS-CoV-2 infection
poses a great threat to pregnant women and
fetuses [98], and according to the above survey,
of total 66 neonates, 16 (25%) were premature
babies [97]. Bensley et al. claimed that cardiomyocyte proliferation can be inhibited by
premature birth, which may adversely affect
heart growth, cardiac function, functional
reserve and repair ability throughout postnatal
life [99]. Therefore, dexamethasone treatment
may bring about more serious damage to the
heart in preterm infants [100, 101].
Recent evidence suggests that dexamethasone treatment in adults could result in hypertension, pathologic cardiac remodeling, cardiac
hypertrophy associated with maladaptive
remodeling and ultimate ventricular dysfunction [102, 103]. Cardiac hypertrophy, considered an adaptive response, allows heart to
withstand glucocorticoid-induced hypertension
[102]. Roy et al. (2009) and De et al. (2011)
reported that excess of dexamethasone treatment could induce cardiac hypertrophy,
myocardial fibrosis, hypoxia and ventricular
dysfunction via angiotensin II signaling pathway [104, 105]. Pathologic heart remodeling
occurs at the same time as the enhanced collagen synthesis, which leads to interstitial fibrosis
[104]. Fibrosis is directly responsible for reduced
blood flow to the heart and increase in cell
apoptosis [102]. Additionally, myocardial fibrosis increases the stiffness of the myocytes,
1918
causing systolic or diastolic disorders [106].
However, Macedo et al. demonstrated that a
short-term therapeutic regimen of dexamethasone will not decrease ventricular contractility
[103]. In terms of the effect of dexamethasone
on heart rate, cardiac fibrosis impairs the electrical conduction and subsequent generation of
reentry circuits [107, 108]. By increasing sympathetic modulation, but reducing the
parasympathetic one, dexamethasone induces
autonomic imbalance, which may make the
dexamethasone-treated animals more susceptible to develop harmful forms of ventricular
arrhythmias through increasing reactive oxygen
species generation [103].
OCULAR SYSTEM
Several ophthalmic complications, such as
glaucoma and cataracts, have been demonstrated to be probably linked with the use of
corticosteroids. Most patients (88%) with steroid-induced glaucoma experienced an increase
in intraocular pressure (IOP), a major associated
risk factor leading to glaucoma [109]. Similarly,
the murine model of dexamethasone-induced
glaucoma exhibited an elevation of IOP, structural and functional loss of retinal ganglion
cells and axonal degeneration [110] (Table 2).
This is mainly because dexamethasone treatment can increase the deposition of myocilin,
actin and extracellular matrix proteins, which
are relevant to the induction of endoplasmic
reticulum stress. It may cause dysfunction of the
trabecular meshwork, resulting in the elevated
resistance to aqueous humor outflow and subsequent IOP [111–113].
The impact of corticosteroids on the incidence of cataracts remains a source of much
controversy and considerable debate [114].
Posterior subcapsular cataract (PSC) has been
reported in a few adults and children treated
with beclomethasone dipropionate or dexamethasone aerosol, but the risk seems to be much
lower than when taking these corticosteroids
systemically [115]. Moreover, patients taking
inhaled corticosteroids were observed to have a
risk that appeared negligible, even if high doses
were used [116]. Contrarily, another review
Infect Dis Ther (2021) 10:1907–1931
claimed that exposure to inhaled corticosteroids
increased the prevalence of PSC about twofold
[117]. There is even a third view, which argues
that no firm link exists between them [118].
Further research is necessary to help elucidate
the association between dexamethasone treatment and the incidence of PSC.
DIGESTIVE SYSTEM
Compared with SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV),
SARS-CoV-2-induced adverse effects on the
gastrointestinal tract are of particular concern
[119]. Patients with COVID-19 were prone to
develop gastrointestinal symptoms such as
nausea and diarrhea, which still bothered 44%
of COVID-19 survivors at 90 days after discharge from hospital [32], even lasting C
6 months [120].
Even worse, it has been reported that dexamethasone makes the gastric mucosa susceptible to ulceration, but the mechanism of the
ulcerogenic action remains controversial.
Specifically, an earlier study indicated that
dexamethasone diminishes gastroprotection
and damages the mucosa by inhibiting the
activity of prostaglandin synthetase and peroxidase, respectively [121]. However, Filaretova
et al. held that long-lasting maintenance of
blood glucose level accompanied by the signs of
catabolic effects may be the reason for pathologic ulcerogenic caused by dexamethasone
treatment [122].
By thinning the circumferential smooth
muscle and making the bowel wall more vulnerable, dexamethasone could increase the risk
of bowel perforation [123]. Stark et al. claimed
that early treatment with dexamethasone has
no effect on mortality or chronic lung disease
but is associated with spontaneous gastrointestinal perforation and decreased growth in
preterm infants [124]. In addition, dexamethasone inhibits small intestinal growth via both
increased degradation and decreased synthesis
of protein [125]. When dexamethasone was
given to growing rats, there was a significant
decrease in the weights of the stomach, small
intestine and colon [126].
Infect Dis Ther (2021) 10:1907–1931
RENAL SYSTEM
Neonatal dexamethasone treatment might
increase the risk of renal damage in adulthood.
The number of glomeruli and kidney weight
were lower in neonatal rats with dexamethasone administration, and the kidneys showed
signs of chronic progressive glomerulonephritis
with glomerulosclerosis and extensive renal
fibrosis, presumably because of an early
inflammatory trigger that elicits a persistent
pro-fibrotic process [127–129]. On the other
hand, in clinical studies, dexamethasone could
contribute to renal calcification formation by
increasing urinary calcium excretion [130], with
nephrocalcinosis occurring in 15 (83%) of 18
infants [131] (Table 1).
NERVOUS SYSTEM
A survey of 402 adults surviving COVID-19
revealed that 42% of them suffered from anxiety, 40% from insomnia, 31% from depression,
28% from post-traumatic stress disorder and
20% from obsessive-compulsive symptoms,
while females and younger patients suffered
from higher levels of depression and sleep disturbances [132]. These psychiatric consequences can result from one or several
combined factors. Due to the neurotropic
properties with neuroinvasive activity [133],
SARS-CoV-2 could induce neuronal injuries via
directly infecting the central nervous system.
Besides, cytokine storm involved in the
immune response to coronaviruses may cause
neuroinflammation, which indirectly leads to
psychopathologic sequelae [134]. Simultaneously, the psychological impact of patients’ fear
of severe illness with a very high risk of death,
uncertainty about future, stigma, traumatic
memories of severe illness and social isolation
in an intensive care unit setting cannot be
ignored [132, 135].
Similarly, dexamethasone treatment can be
associated with neuropsychiatric diseases and
neurotoxicity. Peripheral administration of
dexamethasone induces biphasic effects on
anxiety-related behaviors: anxiolytic effects at
low and anxiogenic effects at high doses [136].
1919
According to a report from the US Food and
Drug Administration, about 4% of 50,000 dexamethasone users had developed severe anxiety
as an adverse effect of therapy [137]. A finding
has indicated that hyperphosphorylation of
cAMP-responsive element-binding protein and
reduced expression of brain-derived neurotrophic factor in the cerebral cortex might be
involved in high levels of anxiety-like behavior
in dexamethasone-treated rats [138]. Besides,
dexamethasone-treated mice demonstrated a
host of depression-like behaviors, such as
increased time of immobility in the forced swim
test and a reduced preference for saccharin
consumption. The following mechanisms are
considered: first, dexamethasone treatment can
cause insufficient cell energy supply through
glucose inhibition [139], thereby affecting the
regulation of glutamate release and reuptake.
Calcium-dependent proteases, triggered by
increased glutamate-mediated transmission,
could cause degeneration of cytoskeletal proteins and lipases, possibly generating free radicals [140], which leads to neuronal damage and
depression [141]. The second possible explanation is the hyperfunction of the hypothalamicpituitary-adrenal axis (HPAA) caused by dexamethasone treatment, which is mainly attributed to the decreased GR mRNA [137] and
protein [142, 143] expressions and consequent
impairment of GR-mediated negative feedback
[144]. The raised level of cortisol in the blood
will exacerbate depression by impairing brain
functions, such as neuronal survival, neuronal
excitability, neurogenesis and memory acquisition [144]. Notably, Skupio et al. have found
that the co-chaperone FK506 binding protein
51 and serum-and glucocorticoid-inducible-kinase-1 proteins increased in the prefrontal cortex, hippocampus and striatum of mice treated
with dexamethasone [137], which could regulate GR sensitivity [145], mediate glucocorticoid
effects on neuronal function and contribute to
major depressive disorder [146].
It is worth mentioning that peripheral nerve
block is often used for postoperative analgesia;
however, the pain relief lasts only a few hours
[147]. As dexamethasone could prolong the
analgesic duration by inducing vasoconstriction, it has been used in peripheral nerve block
1920
as an adjuvant [148]. By contrast, a recent study
reported a twofold increased risk of persistent
neurologic symptoms when perineural dexamethasone was applied after foot and ankle surgery [149] (Table 1). Besides, dexamethasone is
widely used in clinics for alleviating cerebral
edema. However, Duffy et al. (2014) found that
after status epilepticus induced by lithium-pilocarpine, regional administration of dexamethasone (2 mg/kg) led to increased transverse
magnetization relaxation time at 2 days and
reduced hippocampal volumes at 3 weeks, representing aggravated cerebral edema and brain
injury, respectively [150]. Another study
observed that under acidotic conditions, dexamethasone also worsened the cerebral edema,
which could be attenuated by selective blockage
of aquaporin-1 channels with HgCl2 [151].
Therefore, although recent studies demonstrated dexamethasone could slow Huntington’s disease progression [152] and showed
protective effects against Parkinson [153] and
Alzheimer’s disease-related cognitive impairments in mice [154], there is an urgent need to
continue to monitor the potential influence of
dexamethasone administration on mental state
and damage to nerves when it is used in
COVID-19 patients.
ENDOCRINE SYSTEM
A range of mechanisms that contributes to
endocrine disorders has been reported in association with the use of dexamethasone, one of
the most unpredictable of which is the inhibition of the HPAA. Dexamethasone mainly binds
to GRs in the pituitary, where it inhibits the
expression of proopiomelanocortin as well as
secretion of adreno-cortico-tropic-hormone
(ACTH) and subsequent adrenocortical cortisol
[155, 156]. Simultaneously, compared with
other preparations with shorter half-lives, dexamethasone, as the most effective ACTH suppressant with a longer half-life, can lead to more
serious HPAA inhibition [157, 158]. For example, in cancer patients receiving chemotherapy,
adrenal response suppression and adrenal
insufficiency have been reported after dexamethasone use [156, 159] (Table 1). Additionally,
Infect Dis Ther (2021) 10:1907–1931
low-dose dexamethasone administered chronically could give rise to partial adrenocortical
atrophy in rats [160]. There is evidence that the
suppressive effects of dexamethasone at the
hypothalamic-pituitary level are not only confined to ACTH, but the serum levels of thyroidstimulating hormone (TSH) and prolactin (PRL)
could be reduced by directly restraining the
anterior pituitary [161]. Dexamethasone also
attenuates the stimulation of the release of TSH
and PRL by thyroid-releasing hormone [161].
Concurrently, there is a decrease in serum-3, 30 ,
5-triiodothyronine (T3) and thyroxine (T4)
serum levels with dexamethasone treatment,
which is probably the consequence of the
inhibitory effect of dexamethasone on TSH
secretion by the pituitary, and a direct inhibitory effect on thyroid release of T3 and T4
cannot be neglected [161]. Therefore, more
detailed studies are needed to better determine
the mechanism involved in these effects.
Changes in growth hormone (GH), insulinlike growth factor (IGF), melatonin and
parathyroid hormone levels are associated with
dexamethasone-induced endocrine disorders.
Jux et al. demonstrated that GH- or IGF-1stimulated growth plate chondrocyte growth is
dose-dependently blunted by dexamethasone
[162]. Melatonin is considered an output signal
mediated by the circadian system. Dexamethasone could diminish melatonin synthesis by
reducing the expression of the key enzymes
such as tryptophan hydroxylase, arylalkylamine
N-acetyltransferase
and
hydroxyindole-Omethyltransferase [163]. In parallel, previous
studies have found that dexamethasone can
increase parathyroid hormone synthesis, which
may be an important pathogenic role in persisting hyperparathyroidism [164, 165].
It is well known that in skeletal muscle and
adipocytes, insulin stimulates the translocation
of glucose transporter (GLUT) 4 from intracellular vesicles to the cell membrane for glucose
uptake [166]. As soon as insulin binds to its
receptor, the receptor undergoes tyrosine
phosphorylation and recruits insulin receptor
substrates (IRSs) for tyrosine phosphorylation.
Once phosphorylated, IRSs bind to and activate
PI3K, acting as a molecular switch to phosphorylate downstream protein kinase B (PKB) [167].
Infect Dis Ther (2021) 10:1907–1931
Akt substrate of 160 kDa (also called AS160 or
TBC1D4), which is phosphorylated by activated
PKB, plays a crucial role in regulating GLUT4
transport [168]. In addition, PKB could inhibit
glycogen synthase (GS) activity by mediating
glycogen synthase kinase 3 (GSK-3) phosphorylation [169, 170].
Dexamethasone, as an exogenous glucocorticoid, can significantly influence the glucose
metabolism in the human body [171, 172]. (1)
In adipocytes, dexamethasone treatment affects
the normal absorption of glucose by reducing
the expression level of GLUT1 protein. Meanwhile, dexamethasone therapy decreases PKB
expression and insulin-stimulated phosphorylation and downregulates GS expression in adipocytes [166]. In muscle, treatment with
dexamethasone can not only reduce insulinmediated PI3K and PKB activation but also
increase the phosphorylation sites of GS
[173, 174]. Besides, under dexamethasone
treatment, the insulin-stimulated GLUT4
translocation to the cell surface decreases
without altering the GLUT4 protein in total
lysates in muscle and adipose tissue [175, 176].
All of these may lead to a decrease in insulinstimulated glucose uptake, which causes insulin
resistance (IR). (2) Moreover, it has been reported that elevated plasma free fatty acids (FFAs)
could induce IR [177], and dexamethasone
increases FFA content by interfering with fatty
acid metabolism [166]. Studies have found that
long-term incubation of soleus muscle strips
with FFAs impaired insulin-stimulated PKB and
reduced glucose uptake and glycogen synthesis
[178]. Another possible mechanism involves
peroxisome
proliferator-activated
receptor
(PPAR) [179], a transcription factor activated by
FFA, and Bernal-Mizrachi et al. have proven that
human hepatocytes treated with dexamethasone induced PPARA gene expression and
identified hepatic activation of PPAR-a as a
mechanism underlying dexamethasone-induced IR [180]. Therefore, the increase in circulating FFA caused by dexamethasone use may
make an important contribution to muscle IR
[166]. (3) Furthermore, our previous work suggests that dexamethasone induces the expression of Krüppel-like factor 9 (KLF9) in the liver,
which plays a critical role in the regulation of
1921
hepatic glucose metabolism. KLF9 may regulate
IR via KLF9/PGC1a/TRB-3 signaling pathway
and promote hepatic gluconeogenesis and
hyperglycemia. Conversely, the lack of KLF9
alleviated hyperglycemia induced by dexamethasone treatment [181]. Then, due to the
impaired function of insulin-stimulated glucose
uptake in peripheral tissues and/or the weakened effect of insulin to suppress the liver from
producing endogenous glucose, dexamethasone-induced IR can result in hyperglycemia
and diabetes [182], the current common side
effects in acute care settings such as emergency
rooms and urgent care centers [180, 183]. (4) In
addition, Guo et al. found that dexamethasone
could induce apoptosis of pancreatic b cells
through activation of GSK-3b [184].
Diabetes has seriously affected the prognosis
of patients with COVID-19, and according to
data from Wuhan, compared with non-diabetic
patients, diabetic patients have more complications and shorter overall survival time [185].
Possible explanations for this phenomenon are
as follows: (1) generally, infectious diseases are
more common and/or severe in diabetic
patients since the hyperglycemic environment
can lead to immune dysfunction, vascular disease, neuropathy and decrease in antibacterial
activity of the digestive tract [186]. (2) Acute
hyperglycemia has been shown to upregulate
the expression of angiotensin-converting
enzyme (ACE) 2 while chronic hyperglycemia
reduces ACE2 expression [187]. Recently, Wijnant et al. demonstrated increased expression of
ACE2 protein in the bronchi and alveoli of
diabetic patients may affect the infectivity and
clinical outcome of COVID-19 [188]. (3) In the
case of uncontrolled hyperglycemia, the
abnormally increased glycosylation of glycosylated ACE2 and the viral spike protein may
promote the virus binding and inflammation
[189]. (4) The fourth underlying mechanism
that may explain the link between COVID-19
and diabetes involves dipeptidyl peptidase-4
(DPP-4/CD26) [190], acting as a potential
receptor for SARS-CoV-2 [191]. Compared with
nondiabetic subjects, DPP4 expression is
enhanced on blood T lymphocytes from type 2
diabetic patients [192]. Interestingly, in 2019,
Kulcsar et al. found the diabetic DPP4H/M mice,
Infect Dis Ther (2021) 10:1907–1931
1922
which could express human DPP4 in the nonciliated epithelial cells and alveolar type 2 cells,
exhibited more severe clinical symptoms characterized by a prolonged period of weight loss
and clinical disease with a delay in the initiation of inflammation in the lung and slower
inflammatory resolution after infection with
MERS-CoV [193]. In addition, researchers discovered that COVID-19 may also cause hyperglycemia. The potential pathways are as follows:
(1) ACE2 is expressed at high levels in pancreatic islet cells [194], and in 2003 SARS produced
a transient impairment of pancreatic islet cell
function. Similarly, SARS-CoV-2 may also
impair b-cell insulin secretion, causing hyperglycemia, or exacerbate pre-existing diabetes
[195]. (2) COVID-19 infection is accompanied
by increases of many cytokines, which can
induce or exacerbate IR [196].
In summary, dexamethasone has a remarkable effect on glucose homeostasis in the body,
accounting for hyperglycemia and diabetes,
which are risk factors for COVID-19 and
adversely affect prognosis. Simultaneously,
COVID-19 infection can contribute to hyperglycemia. Based on the above evidence, we
make the following recommendations. (1)
Blood sugar changes of COVID-19 patients
treated with dexamethasone should be strictly
monitored. After stopping dexamethasone
therapy, IR will fall. Therefore, it is necessary to
adjust insulin dose to avoid hypoglycemia. (2)
More and more type 2 diabetes patients may
have an increased risk for pronounced inflammatory responses, including cytokine storms, so
screening for excessive inflammation is essential to improve the prognosis. (3) Regular follow-up is crucial for preventing new-onset
diabetes, which may be caused by the virus and
dexamethasone, and hemoglobin A1c (HbA1c),
a glycosylated hemoglobin formed by the
specific binding of glucose to the N-terminal
valine of the hemoglobin b chain, is recommended as an annual assessment indicator for
this process [197].
CONCLUSION
In conclusion, the impacts of COVID-19 are not
just confined to the lungs, but lead to the
involvement of almost all the organs of the
body, including heart, brain, kidney and intestines. While dexamethasone can reduce the
mortality in treating critically ill patients with
COVID-19, consequences for various organ
systems have also been reported. Through a
variety of molecular pathways, dexamethasone
can interfere with normal organ functions and
cause numerous clinical manifestations, which
may further intensify the risk and severity of
sequelae of COVID-19 infection, such as ONFH,
hypertension and diabetes. Hence, we suggest
close monitoring of blood pressure, HbA1c and
other necessary parameters when managing
COVID-19 patients treated with dexamethasone
and taking timely measures. Furthermore, regular follow-up and evaluation of physical conditions according to the monitoring indicators
provided in this article are crucial for patients
after recovery from SARS-CoV-2 infection.
ACKNOWLEDGEMENTS
Funding. This work was supported by the
Natural Science Foundation of Shandong Province (grant no. ZR2020QC100) and Innovation
and Entrepreneurship Training Program for
College Students of Jining Medical University
(grant no. cx2019033). The Rapid Service Fee
was funded by the Natural Science Foundation
of Shandong Province (grant no. ZR2020
QC100) and Innovation and Entrepreneurship
Training Program for College Students of Jining
Medical University (grant no. cx2019033).
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
the work as a whole and have given their
approval for this version to be published.
Infect Dis Ther (2021) 10:1907–1931
Author Contributions. Chen F conceived
the idea, analyzed the data, and drafted the
manuscript; Hao L, Zhu S and Yang X contributed towards the conception, wrote part of
the article; Shi W, Zheng K, Wang T and Chen H
proofread the manuscript and contributed to
editing; all authors provided critical review and
approved
the
final
manuscript
before
submission.
Disclosures. Fei Chen, Lanting Hao, Shiheng Zhu, Xinyuan Yang, Wenhao Shi, Kai
Zheng, Tenger Wang and Huiran Chen have
nothing to disclose.
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not contain any new studies with
human participants or animals performed by
any of the authors.
Data Availability. Data sharing is not
applicable to this article as no datasets were
generated or analyzed during the current study.
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Creative Commons Attribution-NonCommercial 4.0 International License, which permits
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1923
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