Introduction
The coronavirus disease 2019 (COVID-19) is a multisystemic and dynamic disease caused
by infection with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2).
COVID-19 has been declared a pandemic by the World Health Organization in March 2020
and has accounted for more than 6 million deaths worldwide [1]. Approximately 10–14% of
individuals with symptomatic COVID-19 develop severe complications necessitating
immediate hospitalization such as, for example, life-threatening pneumonia [2]
[3].
People at risk of developing a severe COVID-19 are older persons (above 60 years of
age) having one or more comorbidities, including hypertension, diabetes, obesity
[4], chronic obstructive pulmonary disease
(COPD), or cancer [5]. Moreover, COVID-19
severity was found to be higher in men than in women [6]. The pathogenesis of COVID-19 is complex and
involves innate immune receptors (toll-like receptors), immune cells (particularly
macrophages and neutrophils), and cytokine networks (including IL-6, TNF-α,
and IFNs) as well as coagulation and complement pathways [7]
[8].
Rapid and adequate release of glucocorticoids (GC) is crucial for the survival of
systemic microbial infections, sepsis, and septic shock [9]. During critical illness, glucocorticoids
are necessary to sustain high plasma glucose levels, protect from cardiovascular
shock, and most importantly prevent the overactivation of the immune system.
Therefore, patients with known or newly acquired adrenal insufficiency (AI) are
advised to double glucocorticoid doses during COVID-19 [10]
[11].
More importantly, glucocorticoids might also be effective in preventing clinical
deterioration of certain patients with COVID-19 further indicating their protective
actions [12].
Daily cortisol production and secretion are regulated by the
hypothalamic-pituitary-adrenal (HPA) axis. In unstressed healthy individuals, plasma
cortisol secretion occurs in an ultradian, and a circadian fashion regulated by a
pulsatile release of adrenocorticotropic hormone (ACTH) from the pituitary gland
[13]. ACTH secretion is in turn controlled
by corticotrophin-releasing hormone (CRH) produced by the hypothalamus. In addition,
several metabolic and inflammatory factors might influence cortisol production such
as, for example, angiotensin II, antidiuretic hormone, prostaglandins, macrophage
inhibitory factor (MIF), interleukins, for example, IL-6, and adipokines [14]
[15].
To prevent possible side effects of GC overexposure in peripheral tissues most of
the plasma cortisol is bound to corticosteroid-binding globulin (CBG).
During sepsis, the HPA function is often impaired [16]. In some patients, reduced glucocorticoid metabolism [17] and depletion of corticoid-binding
globulins [18] enhance cortisol
bioavailability, which might inhibit ACTH release as a part of the negative feedback
mechanism. Furthermore, a substantial number of patients develop critical
illness-related corticosteroid insufficiency (CIRCI), which describes an
insufficient level of morning cortisol (<10 μg/dl)
or activity of glucocorticoid receptor alpha (GR-α) in relation to ongoing
inflammation [16]
[19]. Finally, some patients might develop
adrenal insufficiency (AI), which could be induced by direct cytotoxic actions of
pathogens [20]
[21] or hemorrhages occurring within the HPA axis [22].
Considering similarities between bacterial sepsis and severe SARS-CoV-2 infection,
a
potential dysregulation and damage of the adrenal gland might also occur in patients
with COVID-19. In fact, several studies and case reports described various forms of
adrenal insufficiency in patients with mild and severe COVID-19 [23].
The major purpose of this review is to summarize current studies focusing on the
adrenal gland function in patients with COVID-19. Moreover, we will present and
discuss potential mechanisms contributing to the adrenal gland dysfunction found in
some COVID-19 patients.
Adrenal gland damage associated with COVID-19
Due to the lack of specific biomarkers and limitations of the ACTH-stimulation
test, assessment of adrenal gland function and damage in patients with ongoing
sepsis and COVID-19 is challenging [24].
Some information might, however, be gained from histopathological analysis of
the adrenal glands of patients who died due to COVID-19 ([Table 1]).
Table 1 Summary of the histopathological studies, which
included the adrenal glands.
|
Author/Year Reference
|
Main findings
|
SARS-CoV-2 detection
|
No of cases
|
|
Wong et al. 2021 [25]
|
Adrenal glands of 62.5% (5/8) patients showed
inconspicuous chronic inflammation with perivascular
distribution. Chronic inflammation was additionally found in
one adrenal gland.
|
2/8 RT-qPCR, 3/3 FISH
|
8
|
|
Freire Santana et al. 2020 [26]
|
Adrenal lesions (12/28), necrosis (7/28),
cortical lipid degeneration (4/28), hemorrhages
(2/28), focal inflammation (4/28), and
thrombosis (1/28).
|
ND
|
28
|
|
Zinserling et al. 2020 [27]
|
Infiltration of CD3+and CD8+lymphocytes in
different layers of the adrenal cortex and in surrounding
periglandular adipose tissue. Small groups of proliferating
cells with enlarged nuclei.
|
ND
|
10
|
|
Kanczkowski et al. 2021 [28]
|
Endothellitis found in periadrenal fat tissue (6 low and 13
high) and in parenchymal tissue (10 low and 1 moderate).
Immune infiltration (38/40).
|
18/40 ISH and IHC; 15/30 RT-qPCR
|
40
|
|
Iuga et al. 2020 [30]
|
Acute fibroid necrosis of adrenal arteriole in both the
parenchyma and capsule. Adrenal parenchymal infarct or
thrombosis.
|
ND
|
5
|
|
Hanley et al. 2020 [31]
|
Microinfarctions were detected in 33% (3/9)
of investigated adrenal glands.
|
ND
|
9
|
|
Paul et al. 2022 [32]
|
Lymphohistiocytic infiltrate in the adrenal cortex of
COVID-19 patients composed of CD4 and CD8 cells. With
apoptotic center (cleaved casp.3). In 11/19
(58%) of COVID-19 patients adrenal capillaries were
expanded and showed microthrombi. Disrupted adrenal
zonation.
|
19/19 IHC, ISH, RT-RT-qPCR
|
19
|
ND: Not determined.
Histopathological examination of adrenal glands obtained from autopsies revealed
a high degree of local inflammation. While in some studies an inconspicuous
[25] or sporadic focal inflammation
[26] was found, other observations
report a more pronounced and frequent infiltration of CD3- and CD8-lymphocytes
in different layers of the adrenal cortex [27] or lymphoplasmacellular cells in perivascular regions of the
adrenal gland [28]. Furthermore, one study
reported a cellular hyperplasia in zona fasciculata of the adrenal cortex in
86% of investigated patients, which might be an indicator of impaired
hormone production [29].
However, vascular damage seems to be the most commonly confirmed complication of
COVID-19 in adrenal glands. In particular, a high degree of endotheliitis of
periadrenal adipose and parenchymal tissues was found [25]
[28], along with acute fibroid necrosis and apoptotic debris of
adrenal arteriole [30]. Moreover,
histological [31] and routine computer
tomography (CT) investigations [26]
[32] reported thrombi formation,
infarctions, and hemorrhages in the adrenal glands of patients with COVID-19
[33]
[34]. Particularly, unilateral and bilateral acute adrenal infarctions
were frequently (23%) found during routine chest CT in patients with
critical COVID-19 [33]. Similar
observations were also made in another study reporting bilateral and unilateral
gland infarctions in 13.4 and 2.6% out of 343 patients with COVID-19,
respectively [34]. Although adrenal
insufficiency has not been evaluated in those patients, adrenal infarcts were
associated with enhanced length of stay in ICU [33]
[34] and higher mortality
[34]. Adrenal infarctions might
reflect the procoagulative and prothrombotic status of those patients [35]. Indeed, an increased risk of
embolization of the adrenal cortex has been reported in patients with COVID-19
[36].
Several case studies of patients with COVID-19 demonstrated that bilateral
adrenal hemorrhages or infarcts might indeed lead to adrenal insufficiency. For
example, a patient, with positive serology against COVID-19 was admitted to
hospital with fever, fatigue, abdominal pain, and nausea. The patient presented
with low plasma sodium concentrations, but normal initial random cortisol and
ACTH concentrations. The CT scan revealed enlarged adrenal glands with
non-hemorrhagic infarction. Partial AI due to possible microvascular thrombi in
the parenchyma was suspected and GCs therapy was initiated [35]. In another patient with no prior
history of adrenal diseases, adrenal insufficiency was triggered by bilateral
hemorrhage during hospitalization due to COVID-19 [37].
In some rare cases, primary adrenal insufficiency (PAI) caused by either
bilateral adrenal hemorrhage or infarcts might not be exclusively attributed to
COVID-19 and rather result from an autoimmune reaction. For example, adrenal
insufficiency was reported in two patients, who developed either adrenal
hemorrhage or infarction shortly after COVID-19 infection [38]
[39]. The medical history of both patients suggested previously
undiagnosed antiphospholipid syndrome (APLS), which progression might have been
accelerated by SARS-CoV-2 infection. However, autoimmune destruction of
adrenocortical cells might not always be associated with vascular damage. This
is exemplified by a patient with no prior history of autoimmune diseases, who
developed primary adrenal insufficiency within 5 months after recovery from
COVID-19. The patient had low morning cortisol and aldosterone levels despite a
clearly increased ACTH concentrations and normal appearance of both adrenal
during CT imaging [40]. Further
examination has linked the development of adrenal insufficiency in this patient
with the presence of anti-21-hydroxylase antibodies.
In addition, histopathological examinations of adrenal glands from patients with
COVID-19 revealed a possibility of direct SARS-CoV-2 action. In particular,
evidence of degeneration and necrosis of adrenocortical cells [26]
[28] was found, together with the presence of a small number of
sporadically proliferating cells with enlarged nuclei [27]. Further evidence includes adrenal
gland lesions and cortical lipid degeneration [26]. Adrenocortical necrosis albeit very limited was also observed in
another study [28].
Detection of SARS-CoV-2 in the adrenal glands from COVID-19 patients
Many pathogenic microbes including fungi, viruses, and bacteria can target
adrenal glands [41]. Some of those
infections like in the case of Mycobacterium tuberculosis or
cytomegalovirus might directly promote the development of Addison’s
disease, which is a manifestation of primary adrenal insufficiency [20]. In the case of other infections,
destruction of the adrenal gland cortex might not reach 90%, which is
required for Addison’s disease symptoms to manifest [42].
In order to be infected by SARS-CoV-2, adrenocortical cells should express
angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2
(TMPRSS2), which proteins are required for its binding and a cellular
internalization, respectively [43].
Expression of those factors in human adrenal glands has been demonstrated using
bulk and single-cell RNA sequencing [44]
and immunohistochemistry [45]. In
particular, high ACE2 protein expression was detected in stromal cells as well
as in small capillaries of the adrenal glands [28]
[32]
[46], and to a laser extent in
adrenocortical cells [32]
[45]. Whereas TMPRSS2 protein expression was
mostly found in adrenocortical cells [28]
[45].
In addition to TMPRSS2, also other proteins found in the adrenal glands might
facilitate SARS-CoV-2 cellular uptake. These are above all furins, neuropilin-1,
C-type lectins [47], and scavenger
receptor B type 1 (SRB1) [48].
Alternatively, SARS-CoV-2 can also enter cells through an endosomal route, which
process requires cathepsin L expression and a low pH to promote its release from
endosomes [49].
The expression of these key receptors in adrenal cells suggests that SARS-CoV-2
might target adrenal glands [45]
[50]. Indeed, SARS-CoV-2 infection was
detected in the adrenal glands of patients with COVID-19 using several
techniques including in situ RNA and DNA hybridization, immunohistochemistry,
and RT-qPCR [25]
[28]
[32]. In particular, SARS-CoV-2 was found in scattered cell
populations of adrenocortical cells and in endothelial cells [28]
[32]. Moreover, SARS-CoV-2 was also shown to infect human
adrenocortical cell lines [28]
[32].
However, a limited number of SARS-CoV-2 positive cells in the adrenal cortex and
the lack of widespread damage to adrenocortical cells of COVID-19 patients,
suggest that the development of AI due to direct cytopathic actions of this
virus is less likely.
Adrenal gland function in patients with COVID-19
The mechanisms leading to the dysfunction of the HPA axis during critical illness
are complex and poorly understood [51]. As
indicated above, a subset of patients may have structural damage to the adrenal
gland from either hemorrhage or infarction, leading to a primary insufficiency,
whereas in other patients reduced cortisol production may be caused by secondary
adrenal insufficiency resulting from damage to the pituitary glands or to the
hypothalamus (tertiary AI). In fact, the cases of secondary adrenal
insufficiency induced by sudden hemorrhages or infarctions of the pituitary
gland (apoplexies) were already reported in patients with COVID-19 [52]
[53].
Considering that the pituitary gland and hypothalamus express ACE2 and TMPRSS2,
it is also highly plausible that SARS-CoV-2 can infect these components of the
HPA axis [54]. Particularly because
SARS-CoV-1 spike protein was already found to be able to cross the blood-brain
barrier in experimental settings [55], and
that SARS-CoV-1 had been already detected in both of these organs [56]. Although no direct evidence of
SARS-CoV-2 infection in those organs exists up to date, some histopathological
studies at least suggest such a possibility [57].
In many critically ill patients including patients with head trauma, skin burns,
and major surgery but predominantly with sepsis and septic shock, a reversible
impairment of the HPA axis is being diagnosed, which cannot be explained by
structural damage to the adrenal gland, the pituitary, or the hypothalamus [58]. CIRCI is usually associated with
systemic inflammation and is currently considered to result from the HPA axis
dysfunction, reduced cortisol metabolism, and tissue resistance to
glucocorticoids [16]. The prevalence and
existence of CRICI remain controversial as well as the criteria used for its
diagnosis, which are a delta total serum cortisol
of<9 μg/dl after ACTH administration
(250 μg), or random total cortisol
of<10 μg/dl [24]. Although measurement of serum-free cortisol and cortisone, for
example, in the saliva is increasingly considered a better indicator of stress,
it is not yet fully implemented in routine diagnostics of stress levels in
critically ill patients.
A limited number of studies employing a high number of patients, addressing
adrenal hormone production during COVID-19 have been published so far. As
summarized in [Table 2], the results of
those studies are also quite heterogeneous and require a careful interpretation.
In particular, a study with 535 critically ill patients (403 with severe
COVID-19 and 132 SARS-CoV-2 negative controls), revealed an adequate cortisol
response [59]. However, since ACTH levels
were not determined in those patients a potential AI might be concealed, for
example, by reduced cortisol metabolism. Moreover, patients having cortisol
levels exceeding 26.97 μg/dl (744 nmol/l)
cut-off were more likely to die [59],
suggesting that elevated GC levels might reflect the severity of the disease. In
this cohort, only 18 patients with COVID-19 and 13 control ICU patients
fulfilled the criteria of CIRCI [60].
Higher cortisol values among patients with severe COVID-19 were also observed in
other studies [23]
[61]. However, the frequency of CIRCI
(14.5%) in the latter cohort was higher [23].
Table 2 Summary of clinical studies showing the HPA
activity in patients with COVID-19.
|
Author/Year/Reference
|
Number of patients and main findings
|
Mortality Risk and other correlations
|
|
Kumar et al. 2021 [23]
|
Adrenal insufficiency was found in 34/235
(14.5%) patients. Cortisol level lower than
3 μg/dl was found in 7.2%
(17/235) of patients. Furthermore, 18.3% of
patients (3/17) had delta
cortisol<9 μg/dl.
|
Median serum total cortisol levels were 858 nmol/l in
non-survivors and 676 nmol/l in survivors of severe
COVID-19. Robust adrenal response correlated with severity
of COVID-19.
|
|
Tan et al. 2020 [59]
[60]
|
Adequate total cortisol values were detected in
385/403 patients, whereas 18/403 patients
matched the CIRCI criterion.
|
Among severely affected patients with COVID-19, those with
cortisol levels exceeding
26.97 μg/dl (744 nmol/l;
135/403) had an increased risk of death.
|
|
Guven et al. 2021 [61]
|
Median cortisol levels among patients admitted to ICU with
COVID-19 (n=144) was higher than those without
COVID-19 (n=141)
“21.84 μg/dl vs.
16.47 μg/dl”.
|
Patients with COVID-19 having cortisol levels exceeding
31 μg/dl (855 nmol/l)
(30/144) had enhanced mortality.
|
|
Alzahrani et al. 2021 [62]
|
9/28 (32%) patients had morning cortisol
levels below 10.8 μg/dl (300
nmol/l) indicating CIRCI.
|
Cortisol and ACTH levels were lower in patients with more
severe COVID-19.
|
|
Ahmadi et al. 2022 [63]
|
Among 154 hospitalized patients, normal cortisol level
(15.6 μg/dl) and ACTH
(11.4 pg/ml) were observed. Lower cortisol
level was observed in a non-survival group
(11.4 μg/dl, 9.09%) vs.
Survivals (16.7 μg/dl).
|
Enhanced cortisol but not ACTH levels correlated with lower
mortality among patients with COVID-19.
|
|
Das et al. 2021 [64]
|
In a group of patients with moderate-severe COVID-19
(n=35), 38.5% had hypocortisolism defined as
cortisol<15 μg/dl (414
nmol/l), vs. 6.8% in a group with mild
disease (n=49)
(cortisol<6 μg/dl).
|
Secondary hypoadrenalism in the moderate-to-severe group
suggests either hypophysitis or reduced cortisol clearance
associated with GR resistance
|
|
Yavropoulou et al. 2022 [65]
|
Morning salivary free cortisol levels did not differ between
the COVID-19 patients (n=52) and the healthy group
(n=33), but the COVID-19 group had higher median
levels of the evening and nocturnal salivary cortisol
compared to controls [0.391 vs.
0.081 μg/dl, and 0.183 vs.
0.054 μg/dl, respectively]
|
Increased evening and nocturnal but not morning cortisol
secretion may occur in even clinically mild COVID-19.
|
Other authors reported partly opposite findings. For example, in one study
patients with more severe COVID-19 had lower cortisol and ACTH concentrations,
suggesting a direct link between the COVID-19 infection and impaired
glucocorticoid response. Among them, 32% (9/28) of patients had
central adrenal insufficiency and fulfilled the criteria of CIRCI
(<10.8 μg/dl) [62]. Similarly, in another study with a larger number of COVID-19
patients (n=154), significantly lower cortisol but not ACTH plasma
levels were found among non-survivors [63]. Finally, adrenal hypocortisolism
(cortisol<15 μg/dl in moderate-to-severe group
vs.<6 μg/dl in mild group), was more frequently
found (38.5 vs. 6.8%) in patients with severe COVID-19 (n=35) as
compared to patients with mild disease group (n=49) [64].
In contrast to the majority of studies that only measured morning total cortisol
concentrations, a recent study determined the free salivary cortisol levels of
COVID-19 patients at different time points. Interestingly, this study reported
elevated levels of free cortisol also during the evening (0.391 vs.
0.081 μg/dl) and nocturnal (0.183 vs.
0.054 μg/dl) time points in the mild-to-moderate
COVID-19 group compared to healthy individuals [65]. However, ACTH, DHEA, and aldosterone concentrations were not
altered suggesting an intact adrenal structure [65]. On the contrary, a possible disruption of adrenocortical
steroidogenesis in patients with more severe COVID-19 was recently reported
[66]. Particularly, the measurement of
adrenal steroids by a liquid chromatography-tandem mass spectrometry revealed a
significantly increased 11-deoxycortisol concentrations compared to cortisol in
those patients. However, these results require further validation [66].
Altogether, adrenal gland function during COVID-19 is mostly preserved among
patients with COVID-19. Furthermore, elevated plasma levels of total cortisol
might be a good indicator of acute COVID-19 disease progression and mortality
risk. However, considering the heterogeneity of results from available clinical
studies reporting cortisol levels in patients with COVID-19, the design of
larger and multicenter studies might help to solve those discrepancies. Contrary
to CIRCI, primary, secondary or tertiary adrenal insufficiency induced by
hemorrhage or infarctions occurring within the HPA axis are relatively rare
complications of COVID-19. Nevertheless, considering the high lethality related
to the sudden onset of PAI, and the proinflammatory and thrombotic nature of
COVID-19, it is crucial to raise awareness about AI diagnosis among intensive
care physicians [67]. Moreover, it is
important to sensitize patients with acute and post-acute COVID-19 about
symptoms of adrenal insufficiency. Especially considering the possibility of
late-onset of central hypocortisolism [68].
Glucocorticoid treatment and the HPA axis dysfunction
Many drugs and their combinations, including antivirals (remdesivir or paxlovid),
hydroxychloroquine, interferons regiments, or anti-interleukin 6-receptor
monoclonal antibody (tocilizumab) were approved by the Food and Drug Agency
(FDA) in an emergency use authorization (EUA) mode. However, results of the
first larger clinical studies demonstrated their limited effectiveness in
reducing mortality, initiation of ventilation, or length of stay in hospital
[69]
[70]. In opposite, the use of SARS-CoV-2 neutralizing monoclonal
antibodies was associated with a reduced incidence of COVID-19–related
hospitalization and death among high-risk ambulatory patients [71], as well as a lower number of
symptomatic COVID-19 cases [72], compared
with a placebo group. Nonetheless, their high costs and low availability might
limit their potential use [73]. On that
account, the use of glucocorticoids, which are inexpensive and most commonly
used drugs, got prompt attention.
Most importantly, results of recent clinical studies strongly suggest that GC
treatment might be effective in preventing clinical deterioration in patients
with COVID-19. Particularly, a single daily dose of dexamethasone (6 mg)
for up to 10 days reduced 28-day mortality among patients requiring invasive
mechanical ventilation [12]. Furthermore,
an early inhalation with budesonide reduced the likelihood of needing urgent
medical care and recovery time among patients with mild COVID-19 [74]. It has also reduced hospital
admissions or deaths of symptomatic persons with COVID-19 in the community who
are at higher risk of complications [75].
These studies collectively demonstrated the benefit of adrenal steroids in
improving the outcome of patients with COVID-19.
Despite the protective role of glucocorticoids for the survival of some patients
with COVID-19, excessive cortisol production (Cushing syndrome) or prolonged GC
treatment might enhance COVID-19 – associated mortality through
induction of immune deficiency, enhanced risk of secondary infections, and
development of HPA axis dysfunction [50].
Prolonged or poorly monitored GCs intake have also other serious side effects,
including among others psychosis, hyperglycemia and, the development of
iatrogenic adrenal insufficiency [76]. In
particular, patients with severe COVID-19, who received dexamethasone have
enhanced risk of developing a tertiary adrenal insufficiency. Although low to
moderate doses of this potent synthetic glucocorticoid such as those used in the
Recovery study (6 mg daily for 10 days) should not cause HPA axis
suppression upon withdrawal. However, development of AI following low doses and
short durations of glucocorticoids was already described in the literature.
Furthermore, it was shown that 50% of patients who recovered from acute
COVID-19 and received dexamethasone therapy experienced severe complications
including severe fatigue. Therefore, higher doses of glucocorticoids,
particularly dexamethasone, should be avoided in patients who do not require
oxygen support.
Limited information is available regarding the HPA axis function and cortisol
levels in patients who received glucocorticoids during COVID-19 hospitalization.
To the best of our knowledge, only one study assessed cortisol concentrations
and the HPA function in those patients and found rather normal ACTH and cortisol
values as well as an adequate adrenal response to the ACTH test 3 months after
presentation with COVID-19, regardless of reported symptoms [77]. However, in this study the possible
induction of iatrogenic adrenal insufficiency was not taken into consideration.
In fact, exclusion criteria prevented enrolment of patients with continuous
glucocorticoid treatment after recovery from COVID-19. This could potentially
explain opposite findings reported by a study with post COVID patients infected
by related coronavirus. In this report around 39.3% (24/61) of
patients who recovered from SARS-CoV-1 infection developed hypocortisolemia that
lasted for at least 3 months and resolved after 1 year. In those patients, low
cortisol levels were also associated with decreased ACTH concentrations,
suggesting central adrenal insufficiency [78].
Due to an insufficient number of studies, which evaluated the function of the HPA
axis in patients with COVID and especially in those receiving a prolonged GC
treatment, it is currently impossible to estimate the true incidence of adrenal
insufficiency. Providing such risk assessment is, however, of paramount
importance because GC therapy might be continued for weeks in many patients with
COVID-19 regardless of their infection status. Those patients are at risk of
developing secondary or tertiary adrenal insufficiency, particularly when the GC
therapy is poorly monitored in outpatient settings or was inadequately tapered
off.
In summary, the adrenal gland is a pronounced target of SARS-CoV-2. The infection
promotes local inflammation and vascular damage in this vital endocrine organ.
However, limited and scattered pattern of SARS-CoV-2 infection and lack of
widespread adrenocortical cell damage found at autopsies suggest that complete
loss of adrenal gland function is less likely. The limited number of studies
showing an adequate cortisol secretion supports this assumption. However,
adrenal insufficiency may be an important and yet frequently undetected
complication of COVID-19. As demonstrated by several case studies and clinical
reports, various forms of AI may manifest during hospitalization and also in the
recovery phase of COVID-19. Therefore, the potential development of AI in
patients with COVID-19 and in particular after tapering off GC therapy should be
considered. Furthermore, larger and multi-center studies are required to
estimate the risk of AI development in those patients.
