Introduction
Coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health
Organization (WHO) on March 11, 2020 with over 3,059,642 cases and 211,028 deaths
being reported from 213 countries and territories at the time of writing this review
[1 ]
[2 ]. There is increasing evidence to suggest
that patients with endocrinopathies such as diabetes mellitus (DM), hypertension
(HTN), obesity and cardiovascular disease are at higher risk for COVID-19 related
complications [3 ]. Reports from the UK and US
have indicated a high prevalence of DM and obesity in COVID-19 non-survivors and
severe cases [4 ]
[5 ]. In the US, the most commonly reported
cardiometabolic comorbidities associated with COVID-19 are HTN (49.7%),
obesity (48.3%), DM (28.3%), and cardiovascular disease
(27.8%) ([Fig. 1 ]) [6 ]. Furthermore, DM is the most common
comorbidity in COVID-19 deaths according to one report [4 ]. Given these data, both the WHO and the US
Centers for Disease Control and Prevention (CDC) list DM, HTN and obesity as risk
factors for development of more severe COVID-19 outcomes [6 ]
[7 ]
[8 ]. In this review, we summarize common
endocrinopathies associated with COVID-19.
Fig. 1 Clinical impact of endocrine conditions on COVID-19
*Louisiana Department of Health Updates for
3/27/2020. http://ldh.la.gov
**ref [3 ].
Overview of the Novel Coronavirus-Cell Interaction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a betacoronavirus
that was identified as the causative pathogen of COVID-19 [9 ]. This virus enters the intracellular
environment by binding of the spike protein on its receptor binding domain (RBD)
to angiotensin converting enzyme 2 (ACE2) which is present on the epithelial
surface of human cells ([Fig. 2 ]) [9 ]. Notably, ACE2 is a distinct molecule
from the well-known angiotensin converting enzyme 1 (ACE1), which is a
therapeutic target. After attachment to ACE2, the SARS-CoV-2 recruits a serine
protease TMPRSS2, which facilitates viral protein priming and cytoplasmic entry
([Fig. 2 ]) [10 ]. ACE2 is cleaved by a protease
ADAMTS17, which in turn reduces its surface expression. After entering the
cytoplasm, the virus enters the nucleus via an endosomal pathway and viral
replication ensues [10 ].
Fig. 2 Molecular interplay between endocrine conditions, ACE
modulation and COVID-19: Illustration of endocrine conditions,
mitigating factors and associated risks of COVID-19. Red arrows
demonstrate deleterious effects and block arrows reflect inhibition.
ACE: Angiotensin converting enzyme; ARB: Angiotensin receptor blocker;
Ang: Angiotensin; DPP-4: Dipeptidyl peptidase-4.
Diabetes mellitus
Pathophysiology and risk
There are several reasons why DM may aggravate the risk of severe COVID-19.
First, DM may facilitate cell entry of SARS-CoV-2 by augmenting the surface
expression of ACE2 through hyperinsulinemia-mediated reduction in ADAMTS17
activity [11 ]
[12 ]
[13 ]. In humans, higher expression of
ACE2 protein in the pancreatic islets was associated with hyperglycemia and
diabetes caused by SARS-coronavirus (SARS-CoV) another coronavirus that uses
ACE2 for cell entry, suggesting that SARS-CoV-2 may act through a similar
mechanism [14 ]. Second, ACE2
modulators such as ACE1 inhibitors (ACEi), angiotensin receptor blockers
(ARBs), and thiazolidenediones, which are used frequently in DM may
upregulate ACE2 expression [9 ]
[15 ]. Third, DM is associated with
complement defects and reduced antigen stimulated IL-6, IL-8 and
TNF-α [16 ]
[17 ]; and impairment of T-regulator
cells (Tregs) and antigen presenting cells (APCs) that may exacerbate the
immunodeficiency [18 ]. Fourth,
co-existing HTN and obesity, acting via HIF-1α and toll-like
receptors, may contribute to the pre-existing chronic inflammation leading
to impaired immune-mediated clearance of SARS-CoV-2 [18 ]
[19 ]. Lastly, dipeptidyl peptidase-4
(DPP-4), a surface glycoprotein, which degrades glucagon like peptide 1
(’GLP-1’, an incretin hormone), is known to be elevated in
DM and obesity [20 ]
[21 ]
[22 ], and also functions as a surface
receptor for coronaviruses [23 ]
[24 ]. Although the latter is yet to be
shown for SARS-CoV-2, the unique role of DPP-4 in coronavirus infections
makes DPP-4 inhibition a possible therapeutic target, which may work both by
reducing DPP-4 expression and offsetting the cytokine mediated end organ
damage [19 ]
[25 ]. This assessment is further
strengthened by evidence that DPP-4 inhibition showed anti-inflammatory
effects in pre-clinical human studies [19 ]
[26 ]
[27 ]. Taken together, patients with DM
may be predisposed to cytokine storms resulting in end organ injury and
mortality ([Fig. 2 ]) [28 ].
A review of sixteen clinical studies with a total of 9,011 patients with
COVID-19 revealed a prevalence of DM between 2.0% and 56.6%
[median (IQR)%: 13.2 (9.10–23.70)], highlighting the high
risk that patients with DM face in the wake of the global COVID-19 pandemic
([Table 1 ]) [3 ]
[6 ]
[29 ]
[30 ]
[31 ]
[32 ]
[33 ]
[34 ]
[35 ]
[36 ]
[37 ]
[38 ]
[39 ]
[40 ]
[41 ]
[42 ]
[43 ]. Additionally, hyperglycemia has
been seen in 35–58% of inpatients with COVID-19 suggesting
the burden of impaired glucose metabolism [29 ]
[34 ]. Other studies have reported a
higher DM prevalence in severe cases of COVID-19 when compared to mild cases
(14.3 vs. 5.0%, p= 0·009) [39 ], as well as an increased mortality
risk and an increased case fatality rate in patients with DM (~3x,
[Fig. 1 ]) [3 ], in comparison to persons without DM
(7.3 vs. 2.3%, respectively), indicating the amplified risk to
patients with DM [44 ]. In a different
study DM was highlighted as the most common comorbidity occurring in
41% of all COVID-19 deaths [4 ]. Additionally, one study noted that COVID-19-affected patients
with DM as a sole comorbidity had a 16.5% mortality rate compared to
0% in comorbidity free COVID-19 patients, whereas another reported
poor outcomes in COVID-19 inpatients with uncontrolled hyperglycemia
compared to their euglycemic counterparts [45 ]
[46 ]. The US CDC included DM as a risk
factor for severe COVID-19 in their clinical guidance [8 ].
Table 1 Prevalence of diabetes mellitus (DM) and
hypertension (HTN) in patients with COVID-19.
Title
Author
Sample
Diabetes prevalence
Hypertension prevalence
Obesity prevalence
Clinical Course and Outcomes of Critically Ill Patients
With SARS-CoV-2 Pneumonia in Wuhan, China: A
Single-Centered, Retrospective, Observational Study
Yang et al. [29 ]
52 critically sick patients
17%
NR
NR
Clinical Characteristics of Coronavirus Disease 2019 in
China
Guan et al. [82 ]
1099 patients
7.40%
15%
NR
Clinical characteristics of 140 patients infected with
SARS-CoV-2 in Wuhan, China
Zhang et al. [31 ]
140 patients
12.10%
30%
NR
Clinical Characteristics of 138 Hospitalized Patients
With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan,
China
Wang et al. [32 ]
138 patients
10.10%
31.20%
NR
Clinical findings in a group of patients infected with
the 2019 novel coronavirus (SARS-Cov-2) outside of
Wuhan, China: retrospective case series
Xu et al. [33 ]
62 patients
2%
8%
NR
Epidemiological and clinical characteristics of 99 cases
of 2019 novel coronavirus pneumonia in Wuhan, China: a
descriptive study
Chen et al. [34 ]
99 patients
13%
NR
NR
A familial cluster of pneumonia associated with the 2019
novel coronavirus indicating person-to-person
transmission: a study of a family cluster
Chan et al. [41 ]
Family of 6 patients
16%
32%
NR
Clinical course and risk factors for mortality of adult
inpatients with COVID-19 in Wuhan, China: a
retrospective cohort study
Zhou et al. [3 ]
191 patients
19%
30%
NR
Analysis of Myocardial Injury and Cardiovascular Diseases
in Critical Patients with New Coronavirus Pneumonia
Chen et al. [83 ]
150 patients
13.3%
32.6%
NR
A Trial of Lopinavir-Ritonavir in Adults Hospitalized
with Severe Covid-19
Cao et al. [36 ]
199 patients
11.16%
NR
NR
Characteristics and Outcomes of 21 Critically Ill
Patients With COVID-19 in Washington State
Arentz et al. [38 ]
21 critically sick patients
33.3%
NR
NR
Epidemiologic and Clinical Characteristics of 91
Hospitalized Patients with COVID-19 in Zhejiang, China:
A retrospective, multi-centre case series.
Qian et al. [40 ]
91 patients
8.79%
16.48%
NR
Host susceptibility to severe COVID-19 and establishment
of a host risk score: findings of 487 cases outside
Wuhan.
Shi et al. [39 ]
487 patients
6%
20.3%
NR
Clinical Characteristics of Covid-19 in New York City
Goyal et al. [42 ]
393 patients
25.2%
50.1%
35.8%
Hospitalization Rates and Characteristics of Patients
Hospitalized with Laboratory-Confirmed Coronavirus
Disease 2019 — COVID-NET, 14 States, March
1–30, 2020
Garg et al. [6 ]
178 patients
28.3%
49.7%
48.3%
Presenting Characteristics, Comorbidities, and Outcomes
Among 5700 Patients Hospitalized With COVID-19 in the
New York City Area
Richardson et al. [43 ]
5700 patients
56.6%
33.8%
41.7%
NR: Not reported.
Evidence of an increased risk of long term metabolic complications in
patients that have recovered from SARS, caused by SARS-CoV, raises concern
for a possible increased risk for similar complications in COVID-19. This
was demonstrated in a follow-up study of thirty one recovered SARS patients
in comparison to healthy volunteers at 12 years that revealed abnormal
glucose metabolism in 60% (vs. 16%), hyperlipidemia in
68% (vs. 40%), and cardiovascular abnormality in 44%
(vs. 0%) of study participants [47 ]. It was speculated that the use of pulse dose glucocorticoids
may have contributed to these long-term metabolic derangements [47 ]. Glucocorticoid use in hospitalized
COVID-19 patients may also play a role in acute inpatient hyperglycemia.
However, glucocorticoid use has fallen out of favor in the routine
management of COVID-19 according to CDC and WHO guidelines [48 ]
[49 ] and evidence points to
glucocorticoids attenuating anti-inflammatory angiotensin 1–7 levels
and delaying viral clearance ([Fig.
3 ]), providing a molecular basis for avoiding their universal use
[50 ]
[51 ]. A clinical trial is currently
underway to determine the efficacy of systemic glucocorticoid therapy in
COVID-19 [52 ].
Fig. 3 Effects of commonly used drugs in obesity, diabetes
mellitus, and hypertension on immune dyregulation. Red arrows
indicate negative clinical consequences, green arrows indicate
positive clinical implications, black arrows reflect stimulation and
block arrows signify inhibition. ACE: Angiotensin converting enzyme;
ARB: Angiotensin receptor blockers; Ang: Angiotensin; DPP-4:
Dipeptidyl peptidase-4; GLP-1: Glucagon like peptide-1; GC:
Glucocorticoids.
Clinical approach
Recently, the American Diabetes Association (ADA) issued patient recommendations
regarding preparedness and precautions for COVID-19 ([Table 2 ]) including keeping updated
contact information; ensuring adequate stocks of simple carbohydrates,
medications and insulin; and ensuring availability of supplies such as rubbing
alcohol, glucagon kits, ketone strips, soap and household items [53 ]. The American Association of Clinical
Endocrinologists also emphasizes adequate emergency preparedness and provided a
checklist of emergency plan action items to ensure the uninterrupted care of DM
([Table 2 ]) [54 ]
[55 ].
From a clinical practice standpoint patient counseling should include discussing
glycemic goals and sick day insulin dosing regimens, as well as adequate
hydration and maintaining access to food (including nonperishable items, glucose
and electrolyte tablets). Furthermore, adoption and continuation of a healthy
diet and recommended 150 minutes of weekly exercise such as indoor walking and
other physical distancing compatible exercises should be encouraged [56 ]. Recommended vaccinations for
influenza, pneumococcal and other infections should be emphasized (based on CDC
or equivalent local authority guidelines). The latter is of major importance
since viral co-infection has been frequent in COVID-19 [57 ]
[58 ]
[59 ]. Furthermore, patients should be
notified of insulin availability without a prescription in many countries as a
contingency measure (US, Canada, India, Mexico, etc.) [60 ]
[61 ]
[62 ]
[63 ].
For inpatient hyperglycemia management, the blood glucose target recommended by
the ADA Standards of Medical Care in Diabetes is 140–180
mg/dL for most critically-ill and non-critically ill patients, with more
stringent glycemic goals (blood glucose 110–140 mg/dL)
recommended for selected patients if hypoglycemia can be avoided [64 ]. However, specific glycemic targets for
patients with COVID-19 have not been released by the ADA to date. In the
aforementioned guidelines, the ADA recommends the consideration of more liberal
glycemic goals (blood glucose>180 mg/dL) for patients that have
severe comorbidities, are terminally ill, or where frequent glucose monitoring
or close nursing supervision is not possible. In these patients less aggressive
insulin regimens with the aim of minimizing glycosuria, dehydration, and
electrolyte disturbances may be more appropriate, however clinical judgment
combined with continuing assessment of clinical status that includes changes in
the trajectory of glucose measures, illness severity, nutritional status, or
concomitant medications that might affect glucose levels, should be incorporated
into medical decision making. Furthermore, it is reasonable to discontinue
sodium-glucose co-transporter-2 inhibitors (SGLT-2i) that have been associated
with intravascular volume depletion and increased risk of euglycemic ketosis
[56 ]. Discontinuation of sulfonylureas
is also advisable, particularly in critical patients, where drug renal clearance
may be compromised [56 ]. Chloroquine and
hydroxochloroquine, which are under investigation for efficacy in the treatment
of COVID-19, may cause hypoglycemia [65 ]
[66 ]. In contrast, antiviral drugs such as
ritonavir and lopinavir, which were used for COVID-19 previously, are associated
with hyperglycemia [67 ]. Use of these
drugs should also be accompanied by adjustments in diabetes regimens.
Because of the need for flexible management, insulin remains the safest drug for
the management of hyperglycemia in DM patients and has an added
anti-inflammatory effect in the critical illness setting [68 ]. Importantly, DPP-4 inhibitors and
GLP-1 receptor analogues may not only attenuate the chronic inflammatory state
in DM but also have independent lung-protective and immunomodulatory effects (in
pre-clinical studies) and may prove beneficial ([Fig. 3 ]) [19 ]
[69 ]
[70 ]
[71 ].
Panic-buying is a major threat in this crisis. Fortunately, to date, there is no
report of a major household or medical supply shortage and clinicians should
counsel patients against this practice to ensure adequate availability for
others [72 ]
[73 ]
[74 ].
Resources and future directions
The Endocrine Society has established a dedicated COVID-19 webpage with resources
for clinicians and researchers with many other societies such as the European
Society of Endocrinology and the Society for Endocrinology ([Table 2 ]) [75 ].
This pandemic has led to a fast-tracking of telemedicine. Authorities in the US,
Canada and France announced wider coverage of telemedicine visits, which is
likely to directly benefit patients with DM [76 ]
[77 ]. However, it is not known whether the
telemedicine visits will suffice for insulin pump follow-up, which currently
mandate inperson visits.
There are still many areas of uncertainty that warrant further investigation with
respect to DM and COVID-19. Some of these include the differences between type 1
and type 2 DM, optimal vs. poor glycemic control, and the effect of age and
other co-existing conditions in patients with DM among others.
Hypertension
Pathophysiology and risk
A high prevalence of HTN has been noted among patients with COVID-19, with
HTN possibly predisposing to an elevated risk for more severe disease. The
risk could stem from a variety of reasons. Foremost, HTN is associated with
immune dysregulation, which manifests as higher IL-17 levels, abnormal
natural killer cell function and cytotoxic T-cell anomalies partly
reversible with mineralocorticoid receptor antagonists [78 ]
[79 ]. Other contributors include
overactive sympathetic drive, dysregulated NFκB and elevations in
the pro-inflammatory peptide, angiotensin II ([Fig. 2 ]) [80 ]
[81 ].
A review of twelve studies, which included data from 8,635 patients with
COVID-19, revealed the prevalence of HTN to be between 8.0 and 50.1%
[median (IQR)%: 30.6 (17.43–33.50)] ([Table 1 ]) [3 ]
[6 ]
[30 ]
[31 ]
[32 ]
[33 ]
[35 ]
[37 ]
[39 ]
[40 ]
[41 ]
[42 ]
[43 ]
[82 ]
[83 ]. A US-based study reported a
50.1% prevalence of HTN [42 ].
Moreover, one study [34 ] of 191
patients found a 3-fold higher risk of mortality in patients with HTN while
other studies reveled a 1.57–2.71-fold risk of severe COVID-19
illness [39 ]
[84 ] ([Fig. 1 ]). Shi et al. also included HTN
as one of three indices in a COVID-19 risk assessment score [39 ]. This risk may be further enhanced
by the co-existence of DM, which is present in 60.2–85.8% of
persons with HTN (depending on the diagnostic threshold used) [85 ].
However, it should be noted that HTN is highly prevalent among the elderly,
and the elderly are over-represented among COVID-19 patients requiring
hospital admission and critical care. Thus, the risk attributed to HTN might
be the result of reverse causality. The prevalence of HTN or DM may be
greater in severe patients, but studies have failed to report if these
comorbidities co-exist with others, hence increasing the risk for severity.
Moreover, the associated risks currently remain associations. A
comprehensive isolation of the exposure of HTN or DM has not been reported.
Therefore the causal risk carried by these comorbidities individually, or
together, has not been established and remains unclear.
Renin-angiotensin-aldosterone system and COVID-19
SARS-CoV-2 enters the human body through attachment to the ACE2 receptors that
are present on the cell surface of type 2 alveolar epithelial cells in the lungs
([Fig. 2 ]) [9 ]
[86 ]
[87 ]. These receptors are also present in
other tissues, with tissue ACE2 levels not always correlating with plasma ACE2
activity [88 ]. Although ACEi/ARBs
do not directly affect ACE2 activity, some studies in experimental animal models
have shown that ACEi/ARBs can upregulate the expression and activity of
ACE2 in certain tissues including the heart and kidney, but studies regarding
their effects on ACE2 expression and activity in the lungs are lacking [89 ]
[90 ]. One study demonstrated increased
intestinal messenger RNA levels of ACE2 in patients previously treated with ACEi
but not in those treated with ARBs [91 ].
Equally, there are reports of higher ACE2 urinary levels in type 1 and 2 DM but
the clinical implications of these findings remains unclear in the context of
COVID-19 [70 ]
[92 ]
[93 ]. In light of these findings, it has
been proposed that ACEi/ARBs could enhance the risk for severe COVID-19
and re-evaluating their use has been suggested [94 ]
[95 ]
[96 ]. On the contrary, higher plasma ACE2
may bind SARS-CoV-2 and protect against lung and other tissue injury (shown in
animal models) and this is proposed as a therapeutic target [97 ]. Furthermore, angiotensin 1–7
uptitrated by the use of ACEi/ARBs may offer immunoprotection and
attenuate the severity of COVID-19 by acting via the Mas receptor pathway ([Fig. 2 ]) [98 ]
[99 ]
[100 ]
[101 ]. Similarly, ACEi may reduce
angiotensin II levels and attenuate immunodysregulation [102 ]. This position is further supported by
other recent reviews that point to the confusing nature of these unproven
assertions regarding greater risk to COVID-19 patients taking ACEi/ARBs
[98 ]
[103 ]
[104 ]
[105 ]. No direct evidence to support the
theoretical risk of ACEi/ARBs use with regards to COVID-19 severity has
been published as of April 22, 2020. One clinical study reported milder
COVID-19, improved immune function and lower viral loads in patients with HTN
who were treated with ACEi/ARBs compared to those who were not [106 ] and better clinical outcomes in
another study [107 ]. These findings refute
the theoretical concerns about these agents and support their continued use
([Table 2 ]) [106 ]
[107 ].
Various societies have endorsed the continued use of ACEi/ARBs based on
the lack of evidence of harm ([Table 2 ]).
The European Society of Cardiology released a statement strongly recommending
“that patients and physicians continue their usual
anti-hypertensive therapy because there is no clinical or scientific
evidence to suggest that treatment with ACEi or ARBs should be discontinued
because of the Covid-19 infection ” [108 ]. Many others followed suit ([Table 2 ]) [108 ]
[109 ]
[110 ]
[111 ]
[112 ]. The American Heart Association
recently published a white paper reporting the lack of studies investigating and
demonstrating evidence of harm [103 ]. A
clinical trial, ’Recombinant Human Angiotensin Converting Enzyme 2
(rhACE2) as a Treatment for Patients With COVID-19 ’ (ClinicalTrials.gov
Identifier: NCT04287686), is currently examining the role of ACE2 receptor
modulation in COVID-19 and may provide conclusive evidence on this matter [113 ]
[114 ].
Obesity
Pathophysiology and risk
Obesity is a state of chronic adipose tissue hypoxia leading to a
pro-inflammatory state with increased levels of IL-1, IL-6, and
TNF-α ([Figs. 2 ] and [3 ]) [18 ]
[115 ]
[116 ]. The immunological dysfunction
in obesity could also stem from T-cell insulin resistance and exhaustion
[18 ]. We speculate that this would
presumably lead to an altered immune response, not only to the virus but
also to a future vaccine. One review raised the possibility of adipose
tissue representing a SARS-CoV-2 target and reservoir, albeit no study
reflecting this has been published to date [117 ]. Another study demonstrated prolonged influenza viral
shedding in obese persons [118 ].
Likewise, the alteration of myeloid and lymphoid responses within the
adipose tissue consequently leads to an aberration of adipokine profiles
[117 ]
[119 ]. Similarly, obesity is linearly
associated with raised C-reactive protein (CRP) levels, which is proximately
triggered by adipocytic derived IL-6 [115 ]
[120 ]. Not surprisingly, CRP has been
correlated with severe disease, providing a pathophysiological link between
obesity and poor COVID-19 outcomes [121 ]
[122 ]. There is also evidence to
suggest attenuated Mas receptor signaling (of angiotensin 1–7)
within the renin-angiotensin-aldosterone system may further aggravate the
pre-existing immune dysregulation [123 ]
[124 ]. In addition, higher levels of
pro-inflammatory DPP-4 levels seen in obesity and the consequent
hyperinsulinemia may both independently exacerbate COVID-19 risks ([Figs. 2 ] and [3 ]) [21 ]. While the benefits of DPP-4 inhibition are unproven, there
is a clear anti-inflammatory and lung-protective effect of GLP-1 receptor
analogues in obesity that may prove useful in mitigating risks for severe
disease [71 ]
[125 ]. Furthermore, co-existing
obesity hypoventilation syndrome and obstructive sleep apnea, both
complications of obesity, may compromise respiratory function that could
also account for the observed effects. Moreover, obesity is independently
linked with a higher thrombosis risk that is especially relevant as COVID-19
has an increased predilection for microangiopathy and venous thrombosis
[126 ]
[127 ]
[128 ]. The latter, in conjunction with
compromised cardiorespiratory reserve, may acutely impede mechanical
ventilation of critically-ill obese persons. Furthermore, it is vital for
future investigations to analyze the link between patients’
anthropometric characteristics and severe COVID-19 since visceral adiposity
is likely to represent a higher risk for COVID-19 illness [129 ]. On a more chronic basis, obesity
poses an additional challenge both from a nursing and a rehabilitation
standpoint [130 ].
Recently, the Louisana Department of Health reported obesity as the third
most common comorbidity (after DM and chronic kidney disease) associated
with mortality, with a prevalence of 28% in COVID-19 non-survivors
([Fig. 1 ]) [4 ]. Moreover, the CDC reported obesity
being present in 48.3% of all COVID-19 hospitalized patients [6 ]. A review of three clinical studies,
comprising of a total of 6,271 patients showed that obesity was prevalent in
35.8–48.3% [median (IQR)%: 41.7
(35.80–48.30)] of hospitalized COVID-19 patients ([Table 1 ]) [6 ]
[42 ]
[43 ]. Another study noted obesity as
an independent risk for COVID-19 hospitalization [131 ]. The National Health Service in
the UK also reported obesity as a risk factor for severe disease and
mortality in COVID-19 [5 ]. In light of
these data, the CDC updated their guidance to include a BMI>40
kg/m2 as a risk factor for severe COVID-19 [8 ].
Common ’Bad’ actors in metabolic disease related cytokine
storm
It is important to consider the cumulative pathophysiology of commonly described
endocrinopathies and COVID-19 severity. In this section, we discuss plausible
underlying mechanisms for severe COVID-19 in hosts with these conditions.
Betacoronaviruses, including SARS-CoV-2, enter human cells by binding to ACE2 in
various tissues. However, betacoronaviruses such as MERS-CoV and SARS-CoV also
directly infect immune cells. Specifically, MERS-CoV binds to monocytes and
dendritic cells and SARS-CoV affects T-cells through DPP-4 receptors [132 ]. After being exposed to a
betacoronavirus, monocytes, macrophages and dendritic cells release the
proinflammatory cytokine IL-6. IL-6 has two major modes of pleiotropic signaling
(cis and trans ) [133 ].
Cis -signaling occurs when IL-6 attaches to its membrane bound
receptors (mIL-6R) present on immune cells, triggering activation of other
immune pathway cells such as T-cells, B-cells and natural killer cells and
leading to further IL-6 release and immune activation. Pathological activation
of this signaling leads to a cytokine release syndrome (CRS).
Trans -signaling occurs when IL-6 binds to its soluble receptor (sIL-6R)
that is present in vascular endothelium. This triggers the release of vascular
endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1).
Together with reduction of E-cadherin, the result is increased vascular
permeability and leakage causing syndromes such as CRS, acute respiratory
distress syndrome (ARDS) and shock [134 ].
A third pathological signaling mechanism is the trans -pathway (distinct
from trans -signaling), which is mediated by attachment of IL-6 on
T-helper 17 cells, which leads to pathological consequences such as ARDS [132 ].
The ’bad’ actors of immune dysregulation are increased in
obesity, DM and HTN and may account for the severity of disease. For instance,
IL-6 levels are significantly higher in type 1 and 2 DM and directly
proportional to BMI in obese persons [115 ]
[120 ]
[135 ]. IL-6 has a bidirectional
relationship with DM as it is implicated in causing insulin resistance and
disorders of glucose homeostasis [136 ].
T-cells in type 1 DM are more sensitive to IL-6 possibly leading to immune
dysregulation and CRS [137 ]. In HTN, IL-6
levels are higher, likely mediated by the increased levels of angiotensin II and
aldosterone, which directly trigger IL-6 secretion by the vasculature [138 ]. This effect is blocked by ARBs and
mineralocorticoid receptor antagonists [139 ]. Elevated CRP, another predictor of COVID-19 severity, is a
downstream effect of IL-6, and elevated in obesity, DM and HTN [140 ]. DPP-4, a known co-receptor of
beta-coronaviruses is higher in persons with obesity and DM, and has independent
pro-inflammatory effects [20 ]. Finally,
the possibility of the pathological trans -pathway signaling of IL-6 in
obesity, DM and HTN cannot be excluded given the pre-existing
immune-dysregulatory state, and may contribute to CRS and clinical consequences
such as ARDS. Taken together, the ’bad actors’ of immune
dysregulation linked with severe COVID-19 are highly prevalent in obesity, DM
and HTN, and may account for the higher severity noted in these states. [Fig. 3 ] describes the immune-pharmacology
of endocrine conditions and COVID-19.
Other endocrinopathies
Hypothalamic-pituitary-adrenal axis
Glucocorticoids have both immune-stimulatory and -inhibitory effects [141 ]. During the initial phase of viral
infection, glucocorticoids prime the immune response to counteract foreign
antigens. However, in the advanced phase of viral infection, blunting of the
hypothalamic-pituitary-adrenal axis activation may occur that may lead to
glucocorticoid insufficiency in the critical illness setting [141 ]. Given the widespread use of
glucocorticoids and the possible risk to patients with adrenal insufficiency
(AI), the Society for Endocrinology released an advisory statement conveying
the lack of evidence to support a higher risk for contracting COVID-19 in
patients with AI ([Table 2 ]). They
also reinforced sick-day glucocorticoid dosing and physical distancing rules
as these patients may theoretically be at a higher risk for COVID-19
complications and mortality due to adrenal crisis, although this has yet to
be described [142 ]. A recent opinion
piece also highlighted the increased risks faced by patients taking
physiological and supraphysiological doses of glucorticoids and encouraged
identification of these patients and counseling about possible risks and
precautions [143 ]. Patients with AI
are at an elevated risk of infection, and patients with primary AI have been
shown to have significantly decreased natural killer cell cytotoxicity that
may compromise early recognition and elimination of virally infected cells
and impair anti-viral immune defenses, although COVID-19 specific infection
risk has not been reported to date [144 ]. Recently, COVID-19 specific guidance for the management of
AI was published that advised specific sick-day rules in addition to
reinforcing the importance of education and physical distancing [145 ]. This guidance recommended that
adults with AI on physiological glucocorticoids and acute suspected or
confirmed COVID-19 should double their morning hydrocortisone dose and then
take 20mg hydrocortisone every 6 hours in order to provide evenly spaced
glucocorticoid coverage for the persistent acute inflammation and often
continuous fever experienced by patients with COVID-19. Those taking
prendisonole 5–15 mg daily should take 10mg every twelve hours while
those on doses of prednisolone>15 mg should continue to take their
usual daily prednisolone dose but should split this into a morning and
afternoon dose of at least 10mg each. Once the patient shows resolution of
fever and significant clinical improvement, the hydrocortisone dose can be
tapered to double the physiologic replacement dose and then normal routine
doses when fully recovered. If the clinical symptoms and signs of COVID-19
worsen, it is recommend that patients contact emergency medical services and
administer a subcutaneous or intramuscular injection of hydrocortisone 100
mg (or take 50–100 mg hydrocortisone orally if this injection is not
available) [145 ]. Those with AI who
contract COVID-19 and require mechanical ventilation or are severely ill,
should be dosed according to acute stress dosing guidelines ([Table 2 ]) [145 ]. Additionally, the use of venous
thromboembolism prophylaxis with heparin in patients receiving
glucocorticoids is recommended, given the increased risk of thrombotic
events in COVID-19 [141 ]. Furthermore,
an increased risk to those with posterior pituitary deficits and electrolyte
abnormalities has been logically speculated and the need to stock reasonable
supplies emphasized [143 ].
In another piece, addressing the management of Cushing syndrome during the
COVID-19 pandemic, deferring biochemical workup for mild Cushing syndrome,
appropriate management of comorbidities, risk-benefit assessment of
definitive treatment (pharmacotherapy and surgery), and Pneumocystis
jirovec i prophylaxis were emphasized [146 ]. According to the authors, for
those on maintenance pharmacotherapy, dose titration according to clinical
features or on the basis of the most recent biochemical values is reasonable
[146 ]. Authors also advised
postponement of imaging and localization studies for suspected (mild) cases.
Further, they recommended urgent treatment only in sight- or
life-threatening situations and reinforcement of sick-day rules,
highlighting the need to re-evaluate the care of these patients once the
current pandemic abates or is under control in the local geographical region
[146 ].
Hypothalamic-pituitary-thyroid axis
It is known that ACE2 receptors are expressed in thyroid tissue and play a
critical role in physiological processes [147 ]. An overexpression of ACE2 has also been implicated in thyroid
cancer progression [147 ]. In hyperthyroid
animals, cardiac angiotensin 1–7 activity was augmented, suggesting a
renin-angiotensin-aldosterone system regulating effect of thyroid hormones [148 ]. In observational studies, thyroid
abnormalities, including sick euthyroid syndrome and thyroiditis, were reported
in 3.6% of patients [108 ] and
other endocrine disorders (excluding DM and HTN) were present in 13% of
COVID-19 patients [34 ]. Direct damage to
thyroid tissue from COVID-19 has also been reported at autopsy [149 ]. Thyroid disorders were also linked
with a higher mortality risk in one report [150 ]. From a clinical practice standpoint, structural thyroid disease
management warrants careful consideration. In particular, we agree with one
opinion piece that suggested prioritization of suspected anaplastic and
aggressive medullary thyroid cancer (serum calcitonin≥10 pg/ml)
while deferring the care of less aggressive differentiated thyroid cancer [151 ].
Diabetes insipidus
Central and nephrogenic diabetes insipidus (DI) pose a particular challenge due
to reduced availability of laboratory (electrolyte) testing. An opinion piece
recently highlighted this challenge, encouraging the practice of once a week
aquaresis by omitting one dose of vasopressin in individuals with existing DI
[152 ]. This would primarily prevent
retention of excess free water and consequently maintain eunatremia. Further,
they emphasized that the major risk in these patients is that of hyponatremia,
which could be mitigated by daily bodyweight measurements, early
self-recognition of clinical features of hyponatremia and counseling patients
about drinking to thirst. In the inpatient setting, patients are vulnerable to
hyponatremia both due to overtreatment of DI, and excess vasopressin from
COVID-19 pneumonia in the context of syndrome of inappropriate antidiuretic
hormone secretion [153 ]. For that reason,
0.9% saline should be used for volume resuscitation, and in the critical
illness setting where frequent shifts in volume distribution occurs. Moreover,
frequent clinical and biochemical assessment of sodium status should occur,
while hypotonic fluids should be employed in hypernatremic patients [152 ]. Special caution should be exercised
in the care of adipsic DI patients and endocrinology consultants should be
involved early in their inpatient care [152 ].
Bone and mineral metabolism
While there is no evidence of increased risk of COVID-19 to patients with
bone-mineral metabolism disorders, the unprecedented global lockdowns have
significantly affected their care. Given that most infusion centers, outpatient
laboratories and bone scanning centers are temporarily closed, the National
Osteoporosis Foundation released a guidance statement ([Table 2 ]) [154 ]. It is advisable for those on medications such as Denosumab and
Romosozumab to receive timely infusions, however, infusions of bisphosphonates
such as Zolendronic acid may be deferred due to their long half-life [154 ].
Hyperlipidemia
Hyperlipidemia was present in 5% of patients according to a review of 190
patients hospitalized with COVID-19 [31 ].
The development of metabolic/lipid abnormalities in patients who recover
from COVID-19 may also be anticipated based on data from the SARS cohort
population [47 ]. Endocrinologists may be
healthcare providers for this group in the future and should be wary of the
possible long-term metabolic complications that may exist following COVID-19
infection.
Racial differences in COVID-19 outcomes
Several reports of higher mortality among Black and Hispanic people have emerged
[155 ]
[156 ]. The CDC recently reported that
33% of COVID-19 inpatients in the US were Black despite only
constituting 13% of the US population [6 ]. The state of Louisiana reported that Black and Asian patients
constituted 59% and 0.83% of COVID-19 non-survivors [157 ]. New York City also reported a
disproportionate mortality among Hispanics and Blacks [158 ]. While ACE2 expression is higher in
Asian populations compared to Whites or Blacks, our current knowledge of these
differences does not justify the disproportionate mortality [159 ]
[160 ]. This scourge is likely
multifactorial: 1. Higher genetic predisposition to endocrine disorders, such as
an increased prevalence of HTN in Black and obesity among Latin/Hispanic
patients and 2. Racial disparity in access to healthcare and hospitals that may
delay timely care, coupled with suboptimally controlled underlying chronic
disease. The CDC surveillance data of the COVID-19–associated
hospitalization rate among patients for the 4-week period ending March 28, 2020,
was 4.6 per 100 000 population, with the following race/ethnicity data:
261 (45.0%) were non-Hispanic white (White), 192 (33.1%) were
non-Hispanic Black (Black), 47 (8.1%) were Hispanic, 32 (5.5%)
were Asian, two (0.3%) were American Indian/Alaskan Native, and
46 (7.9%) were of other or unknown race [6 ]. These social barriers for racial minorities amplify their
vulnerability to endocrine disease in general and to COVID-19 as a
consequence.
Sex differences in COVID-19 outcomes
In the US, over half of COVID-19 related hospitalizations occurred among men (5.1
vs. 4.1 per 100 000 population). Sex differences for general infections are
likely multifactorial, including robustness of the immune responses (both innate
and adaptive), sex-dependent production of steroid hormones (including
testosterone and estrogens), immune response-related X-linked genes, and
presence of disease susceptibility genes. The estrogen receptor signaling
pathway has been identified as critical for protection in females infected with
coronaviruses [151 ]. A plausible
explanation for higher COVID-19 affection of men may be related to the
downstream steps after ACE2 binding of SARS-CoV-2. As described previously, the
SARS-CoV-2 viral capsid binds to surface ACE2 and subsequently engages a
cellular serine protease TMPRSS2 for protein priming ([Fig. 2 ]) [10 ]. From oncological studies, it is known that TMPRSS2 is an
androgen responsive gene, which is highly expressed in men [161 ]. As suggested by one study, the higher
TMPRSS2 expression in men could account for their higher vulnerability to
COVID-19 [161 ]. Further studies are
required to ascertain the sex differences in COVID-19 related outcomes.
Care of transgender persons
Human immunodeficiency virus (HIV) infection and cancer are more frequent in
transgender persons when compared to the general population [162 ]
[163 ]. These conditions coupled with
pre-existing endocrinopathies can compromise the immune function, presumably
leading to a higher COVID-19 risk in transgender persons. However, there is
currently no published evidence to support this [162 ]. Transgender persons also frequently face social challenges such
as poverty, homelessness and inadequate access to healthcare, which diminishes
their ability to observe COVID-19 precautions and seek timely care [164 ]. It is therefore advisable that
clinicians re-inforce and individualize guidance to this population while
ensuring sufficient prescription refills. A plan of action is available at
https://transequality.org/covid19/plan ([Table 2 ]) [164 ]. For elective procedures such as gender confirmation surgery,
postponement is appropriate in line with the CDC and WHO guidelines [48 ]
[49 ].
General COVID-19 precautions for patients with endocrine conditions
All patients should maintain updated contact information for their
healthcare
Adequate availability of prescription refills should be ensured
Emergency precautions and sick-day rules should be addressed on all
routine clinic visits
Providers should remain up to date with evolving COVID-19 data and
perform a careful critical appraisal of the available and increasing
literature to be able to identify high-quality evidence to facilitate
informed decisions to individualize care
Elective endocrine clinic visits should be deferred and alternative
communication means such as telehealth visits consistent with social
distancing should be encouraged
Mailing of prescriptions rather than inperson pickup should be adopted
wherever feasible
Patients should be advised to stay updated with recommended
vaccinations
Smoking (including hookah/waterpipe) cessation should be advised
[165 ]
Panic buying and stockpiling of medical supplies should be strongly
discouraged
Patients should be informed of COVID-19 resources (CDC, WHO websites
etc.) to obtain accurate information and follow best practices with
respect to COVID-19 ([Table
2 ])
