In November 2019, the Italian Society of Endocrinology (SIE) has published a consensus
statement on the tailoring of glucocorticoid replacement in adrenal insufficiency
[1]. A few months later, a novel severe acute respiratory syndrome coronavirus (SARS-CoV2)
has been recognized as responsible for COVID-19. The outbreak has now reached pandemic
level, with a high global mortality rate [2]. From February on, Italy has experienced
an exponential rise in the infected which is estimated to reach 200,000 people, with
an overall lethality of approximately 10% [3]. A recent Chinese series of nearly 50,000
patients with confirmed COVID-19 infection found that approximately one-out-of-five
(19%) evolve towards severe (14%) or critical (5%) pneumonia [4]. Several clinical
trials are now testing the therapeutic options to treat lung and extra-respiratory
complications of SARS-CoV2 infection. While awaiting for a specific treatment strategy,
the SIE task force met again to address the tailoring of corticosteroid replacement
in adrenal insufficient patients coping with the stress related to COVID-19 infection.
Pathophysiology of immune response in COVID-19
Accumulating evidences have shown that COVID-19 infection follows a distinct but related
stage progression. The acute respiratory distress syndrome (ARDS) observed in a significant
proportion of fragile patients, roughly after the second week, is apparently non-exclusively
related to uncontrolled viral replication, but rather to an out-of-control host response.
The initial immune response, involving Toll-like receptors (TLRs), retinoic acid-inducible
gene I (RIG-I), NOD-like receptors (NLRs), and other virus sensors in respiratory
epithelial cells is critical in reducing the viral load and alerting the host [5].
The response begins with the recruitment of innate immunity. If viral self-propagation
is not limited, the increasing number of infected epithelial cells and cell debrides
trigger a massive cytokine release—the so-called ‘cytokine storm’—with hyperinflammation
and immunosuppression, characterized by increased Th17 and CD8 cytotoxic activity
and decreased memory CD4 + T helper cells [6]. The antiviral immune response represents
a balancing act between the elimination of virus and immune-mediated pulmonary injury.
Pathology studies revealed that lung injury starts at the epithelial–interstitium–endothelial
interface with increasing vascular permeability and extravasation of immune cells
(mostly macrophages and granulocytes). The exudation reduces surfactant production
in the alveolar space, impeding alveolar patency and gaseous diffusion [7]. Infected
epithelial cells and debris bind immune cell receptors, triggering the release of
inflammatory cytokines (predominantly IL-6, IL-1 and TNF alpha) and activating fibroblasts.
The second phase begins when uncontrolled viral propagation induces angiotensin-converting
enzyme 2 (ACE2)-directed cytotoxicity, triggering a vicious circle leading to hyperactivation
of immune cells and worsening the hyperinflammation state. Patients also show lymphopenia
with reduced B Cells, CD4 and CD8 T cells and CD16+ Natural Killer cells count, probably
due to an increase in extravasation of dysfunctional lymphocytes and inflammation-induced
apoptosis [8]. The cytokine storm leads to increased clotting, vascular inflammation,
leading to disseminated thromboembolism, and hypotensive shock [6, 7]. Although a
balanced immune response seems to keep the viral infection under control, a small
fraction of patients evolves through all stages [9]. In these critical cases, the
priority following severe lung damage is to reduce hyperinflammation [6] and thromboembolism
that are associated the increase mortality.
Glucocorticoids in critical illness
Exogenous glucocorticoids (GCs) have traditionally been associated with immune suppression.
For this reason, their use has been discouraged, in the early days of the pandemic,
fearing that they may favor viral propagation limiting the first line of defense,
the innate immunity, that is also the most sensitive to GCs. If so, one would expect
patients with chronic obstructive pulmonary disease, asthma or rheumatological disorders
at an increased risk of severe COVID-19 presentation. Surprisingly, these comorbidities
appear under-represented in patients with severe COVID-19 [3, 10–12]. Although confounding
factors and reporting bias could account for such findings, they suggest that GCs
should not be blamed or discouraged. More, it cannot be excluded that GCs play a role
in shaping the clinical presentation of COVID-19 [12], and a retrospective study of
200 patients with ARDS apparently showed a lower mortality among those receiving methylprednisolone
[13]. The number of registered clinical trials on the use of steroids in COVID-19
pneumonia and related ARDS increases daily, aimed at investigating the effects of
different formulations, associations and dosages. Due to their proved efficacy in
different respiratory diseases, high lung bioavailability and strong anti-inflammatory
efficacy, most on-going trials are focusing on methylprednisolone (NCT04263402, NCT04323592,
NCT04343729, NCT04273321, NCT04244591), dexamethasone (NCT04327401, NCT04325061) and
budesonide (NCT04331470) alone or in combination with other therapies targeting inflammation,
such as Siltuximab (NCT04329650) or Tacrolimus (NCT04341038). The scope of this update,
however, it to review the physiological role of cortisol that is missing in adrenal
insufficient patients coping with COVID-19.
It is now recognized that GCs have both stimulating and inhibitory effects on immune
response according to their timing and circulating levels [14]. In the early phases
of infections, physiological GC levels are necessary to prime the immune system. This,
in turn, activates hypothalamic–pituitary–adrenal (HPA) axis to increase GC release
from the adrenal glands aiming to reach higher concentrations responsible for mild
immunosuppression, finally reducing autoimmunity and cytokine toxicity. This ability
to reduce inflammation and, ideally, fibrosis has been the rationale for the use of
GCs in lung damage so far, but the associated complications and the lack of a real
benefit on overall survival—with possible harm also advocated, such as gastrointestinal
bleeding, hepatic failure and thromboembolism—have relegated their use to refractory
shock or (by some authors) ARDS, when lung damage approaches an irreversible threshold
[15]. Similarly, studies of high-dose GCs in sepsis are conflicting, with the REGARDS
[16] and the more recent ADRENAL trials [200 mg hydrocortisone daily vs. placebo]
showing no beneficial effects on the 90-day mortality [17], but with the APROCCHS
trial showing a 28-day reduction in mortality of septic patients receiving hydrocortisone
plus fludrocortisone therapy [18].
One of the reasons underpinning the conflicting evidences published so far on steroid
therapy in viral respiratory infections and pneumonia could lie in the heterogeneity
of the studies included in the meta-analysis assessing the mixed results of the effects
of different GCs formulations (both short and long acting), given without considering
the two different pathophysiological phases of the infection. In fact, if in one hand,
supraphysiological dose of exogenous GCs have been shown to exerts detrimental effects
in the early phase (by increasing the plasma viral load), one can argue the possibility
to restrain the cytokine storm of the second, and more harmful, phase suppressing
the immune overreaction by steroid treatment [19]. Moreover, in critically ill patients,
the HPA axis may be unable to produce sufficient amount of corticosteroids, leading
to critical illness-related corticosteroid insufficiency (CIRCI) [20]. Although the
pathological features and clinical progression of COVID-19 resemble those seen in
other coronavirus infections for which various standardised steroid protocols have
been proposed, recent WHO guidance on the clinical management of COVID-19 advises
against corticosteroids, unless indicated for another reason [21]. Adrenal insufficiency
(AI) represent such a condition, in which the rationale to a prompt correction of
GC therapy is not addressed to treat lung disease, but rather is aimed to supplement
the abnormal adrenal function and, thus, to save patients’ life. However, specific
indications have been missing, and current standards of care actually suggest increasing
the GC dose if COVID-19 infection is suspected, applying the “sick-day-rule” [22].
COVID-19 in adrenal insufficiency do we need to change glucocorticoid therapy?
AI patients run an increased risk of infection due to their inefficient innate immune
response, characterized by increased “classical” monocytes and decreased cytotoxic
NK cells, with failure of IgG-mediated activation due to shedding of its surface receptor
(CD16) [23]. The disrupted immune response could also contribute to the worsening
of COVID-19 infection into severe ARDS due to impaired first-line defence. Additionally,
as previously mentioned, the HPA axis plays a significant role in stress-priming the
immune response and the lack of physiological increase in GC secretion in AI patients
during mild illness intuitively exposes them to higher risk of progressing to more
critical stages, especially if replacement therapy is not properly administered. Moreover,
as noted in other critical illnesses, COVID-19 pneumonia can affect residual adrenal
function [20] through cytokine release, worsening the outcome of patients with secondary
AI. This is true also for tertiary adrenal insufficiency, the commonest cause for
AI in the general population, resulting from long-term (more than 4 weeks) steroid
treatment (equal or more than 5 mg of prednisolone per day), especially if administered
in a non-circadian fashion (e.g., night doses).
This issue is of particular importance, as the sick day rules for GC therapy during
infections are still largely tailored empirically, based on a few anecdotal case reports
[24] and disregarding timing and dosage [1], and most patients with tertiary adrenal
insufficiency are unaware or unprepared to handle stress-doses. It must to be taken
into account that mild COVID-19 symptoms such as fatigue, malaise, gastrointestinal
symptoms overlap with common symptoms experienced by AI patients, even outside adrenal
crisis. This makes it difficult to establish when an increase in GC therapy is actually
needed, and the patients’ fears may lead them to increase their dose unnecessarily.
Despite the above mentioned reports of a lower representation of subjects taking low-dose
GC among those with a more severely symptomatic COVID-19 [3, 10–12], to date there
is no evidence supporting a beneficial (nor a detrimental) role for corticosteroids
in preventing viral infection or spread. More, considering that 60–80% of infected
subjects remains completely asymptomatic [4], there is no indication to increase GC
therapy in asymptomatic patients with AI.
In contrast, for the symptomatic patients, establishing the correct timing of stress
dose administration relative to the degree of inflammatory damage and the desired
effect on the immune system is of paramount importance in COVID-19. Thus, there is
no doubt that we must to be ready to increase GC dose in AI patients. The decision
on how, when, how much to do so, requires attention and cannot be left to vague indications.
Management of glucocorticoid therapy in adrenal-insufficient patients with COVID-19
Recent studies have provided further insight into GC metabolism during stress conditions.
Hydrocortisone (HC) clearance significantly drops during stress challenges. In moderate
stress, 100 mg followed by 60 mg/24 h of HC infusion generally maintains cortisol
levels above normal the range in most of AI patients [24]. Thus, in the early phase
when patients might only develop mild COVID-19 related illness, characterized by uncomplicated
upper respiratory symptoms (sore throat, nasal congestion, mild intermittent cough),
with or without fatigue, malaise, anorexia, muscle ache, headache, mild nausea or
diarrhoea, fever < 38 °C and no signs of respiratory impairment, it appears safe to
treat AI patients with low-to-intermediate additional doses (i.e., doubling the usual
dose or adding oral 20–40 mg HC), to replace the missing stress-induced cortisol rise
(Fig. 1). At this stage of mild illness, cortisol circadian rhythm should still be
mimicked. Disturbances in circadian rhythm enhance inflammatory response to exogenous
pathogens [25] and, even in the absence of pathogenic challenge, they promote a shift
towards a pro-inflammatory state and exhaustion of the counterregulatory mechanism
necessary to drive host response [26]. In trauma patients or bacterial infections,
the disruption of circadian genes rhythmicity and the change in cortisol acrophase
favor the development of shock [27]. The indication is further strengthened by the
observation that patients undergoing major cardiac surgery maintain some circadian
rhythmicity, as the coupling between ACTH and cortisol secretion is maintained, even
if blunted because of a higher basal cortisol secretion [28]. Finally, GC excess is
associated with a high prevalence of psychiatric (depression, mania, anxiety) and
neurocognitive disorders [29]. These can overlap with the psychological impact that
the lockdown strategies have caused in many different socio-economical contexts; therefore,
if not needed, it appears reasonable to avoid an excessive GC load. However, in a
significant proportion (20%) of adrenal-sufficient subjects with COVID-19, the disease
progresses to moderate or severe. No data are yet available in AI patients, therefore,
it is mandatory that vital parameters, such as blood pressure (of utmost importance,
as hypotension develops in the late phases), heart and respiratory rate and resting
peripheral oxygen saturation, be monitored daily. In cases of incoming vomit (more
than one day and especially within 3 h from the last steroid dose) and/or diarrhea,
parenteral injection is mandatory. If fever increases or persists, symptoms worsen
(including AI-specific signs and symptoms, such as incoming hypotension), or respiratory
damage progresses with patients showing persistent cough, increased respiratory rate
(> 30 breaths per minute) and/or SpO2 less than 93%, (current definitions of moderate
COVID-19 disease, see Fig. 1), GC therapy should be immediately increased to 100 mg
(preferentially by parenteral administration according to the clinical status) and
hospitalization is needed to be ready to face an adrenal crisis and start treatment
to limit immune hyperactivation (see Fig. 1). Contrary to the general population,
the threshold for hospitalization should be low for worsening symptoms in AI patients,
considering their risk for an adrenal crisis.
Fig. 1
Proposal for a stage-specific adjustment of glucocorticoid therapy in adrenal insufficient
patients with COVID-19 infection
In the hospital, if clinical condition worsens and moves towards ARDS, higher dose
should be started. In this context, Prete et al. recently identified an initial bolus
of 50–100 mg of hydrocortisone followed by continuous intravenous infusion of 200 mg
(per day?) as the most appropriate regimen in AI patients with sepsis [30]. This protocol
is able not only to cover the amount of steroid needed to cope with the infection
but also to reduce the harmful effects that peaks and troughs of GC therapy cause
to the immune system [30]. At this stage of disease, and for these steroid levels,
circadian rhythm is no longer relevant. A very recent consensus on the management
of critically ill adults with COVID-19 endorsed the same protocol in patients with
refractory shock, as it is able to reduce the time to resolution and ICU length of
stay [31]. It also recommended the use of hydrocortisone rather than other synthetic
compounds (as often used in ICUs). Although a detailed mention of the characteristics
of the several steroid formulations is beyond the scope of this paper, one should
bear in mind the different anti-inflammatory action between the available compounds.
Hydration and electrolyte balance should also be monitored and corrected promptly,
as in the second stage, peripheral shock can cause severe hypotension, requiring pharmacological
intervention. In critical setting, additional mineralocorticoid therapy is not required
for patients with primary AI, as hydrocortisone doses of more than 50 mg/day have
sufficient action at the mineralocorticoid receptor [32], although an increase to
100 μg/day of fludrocortisone has been advocated in severe hypotension. As soon as
the clinical condition allows, steroid infusion should be reduced accordingly, in
order to avoid undesired detrimental effects. Finally, a very important recommendation
comes from the increasing concern over the disseminated thromboembolic disease observed
in severe COVID-19. Given the coagulation abnormalities associated with GC use [33],
added to that of immune hyperactivation, endothelial disfunction and hepatic impairment
observed in COVID-19, we strongly recommend introducing heparin early in AI patients
[34], as soon as the symptoms evolve from mild to moderate or severe disease (4000
U every 12 h).
SARS-CoV2 pandemic has reignited the debate on GC therapy in lung injury, and many
scientific panels are working in these fateful hours to investigate their efficacy
in treating COVID-19-related pneumonia. Outside all of this, and given the severity
of COVID-19-associated syndrome, this opinion aims to underline that clinicians must
not overlook the fact that AI patients depend on exogenous GC therapy for adequate
stress response even to mild illness. In summary, available evidences on tailoring
of GC stress regimens in COVID-19 are still weak and a more evidence-based approach
is required to draw a definitive standardized protocol. The pathophysiology of immune
response and systemic complications associated with infection set the pace, and treatment
strategy should be adapted to the patient’s clinical stage. For AI patients suspected
to have COVID-19, who have mild upper respiratory track symptoms and no lung impairment,
doubling the usual dose of hydrocortisone (alongside adequate fluid replacement) in
a circadian fashion seems a safe measure to preserve the early activation of the immune
response. The latter is also because symptoms are not specific and may last, even
if minor, for 2 weeks or more. However, as soon as symptoms worsen, it is advisable
to further increase the dose up to 100 mg, commence thromboembolic prophylaxis and
consider prompt hospitalization as the condition could deteriorate within few hours.
In hospital, parenteral treatment with high doses (200 mg) of continuous intravenous
hydrocortisone is only required following evolution towards a critical stage (rapid
drop in oxygenation) or adrenal crisis (Fig. 1).