Key words
ACE2 - adrenal - infiltrations - COVID-19
Introduction
The unprecedented development of the pandemic coronavirus disease 2019 (COVID-19)
has
made a better understanding of the interaction between the severe acute respiratory
syndrome virus coronavirus 2 (SARS-CoV-2) and the host organism a top priority.
SARS-CoV-2 is a positive-sense single-stranded RNA virus, which uses the angiotensin
converting enzyme 2 (ACE2), a transmembrane protein as a host receptor for cellular
entry. The virus has been thought to primarily target the respiratory system,
causing the wide range of clinical manifestations from upper respiratory tract
infections to bilateral pneumonias with severe acute respiratory distress syndrome
(ARDS). Recent reports have demonstrated that SARS-CoV-2 can directly infect other
ACE2 expressing cell types, such as renal tubular epithelial cells, podocytes, and
endothelial cells [1]
[2]. Furthermore, a direct metabolic and
endocrine link to coronavirus infection has been reported [3]
[4].
Previous studies have reported strong expression of ACE2 in endocrine organs
including the adrenal glands [5]. Although it
was shown that one of the previous coronaviruses SARS-CoV, which was responsible for
the SARS 2002–2004 outbreak, could directly injure adrenal glands [6], morphological changes of the adrenal glands
in the course of COVID-19 infection have not been systematically investigated so
far.
This is of potential clinical relevance, because the adrenal glands play a central
role in the physiology of the stress response of the organism in health and disease.
The latter is highly important in the course of severe COVID-19 infection, for
example in the regulation of the immune response, and in particular in the control
of cytokine release in septic shock, regulation of fluid homeostasis, control of
blood pressure, and production of sex hormones, which might be responsible for
gender-associated difference in disease progress and survival as observed in
COVID-19 patients [7].
Particularly, an adequate adrenal hormone response is crucial for survival of severe
infection and septic shock [8]. The adrenals
and glucocorticoid hormone signaling pathways are targeted by various bacterial and
viral agents thus employing a primary immunoinvasive strategy to blunt the
organism’s life-saving glucocorticoid stress response [9]
[10].
Taking into consideration the high vulnerability of adrenal tissue and its crucial
role in critical illness a thorough examination of adrenal morphology in patients
severely affected by COVID-19 should be of great relevance. Therefore, in the
current study, we provide the first systematic morphological report of the
pathoimmunological changes in the adrenal glands in a series of autopsies of
COVID-19 patients.
Materials and Methods
Autopsies of 10 patients deceased from COVID-19 were performed in the department of
pathology at S. P. Botkin Infectious Hospital according to the national rules,
regulating such procedure.
Tissue samples and immunohistochemistry
In addition to other organs, special attention was paid to the morphology of the
adrenal glands. The adrenals of 10 patients were collected and processed for
histological and immunohistochemical analysis according to standard protocols.
During the autopsy, the macroscopical changes of the adrenals seemed to be
unremarkable. Paraffin slices were stained by hematoxylin-eosine. For immune
histochemistry we used commercial antibodies against CD3, CD8, and CD20 (IS503,
IS623, and IS604, Dako, Denmark) using standard positive and negative controls
in parallel. HIER antigen retrieval was performed using EnVision FLEX Target
Retrieval Solution (K8010, Dako, Denmark) according to the protocols of
manufacturer. Images were taken using Nikon Eclipse Ni-U microscope (Nikon,
Japan).
Results and Discussion
In the present work, we demonstrate that the adrenal glands can be seriously damaged
with distinct structural changes in the course of COVID-19. This involves both:
direct lesions due to generalization of the infection and involvement of
CD8+T-lymphocytes.
In a detailed postmortem study, we succeeded to describe two types of adrenal
lesions. Most striking was a mononuclear infiltration, which could be detected in
the different layers of the organ ([Fig 1a])
and in surrounding tissue as well. Immunohistochemistry allowed us to determine the
exact cell types of the infiltration: CD3+and CD8+([Fig 1b]). We observed changes of the adrenal
cortex with formations of small proliferations of cells with enlarged light nuclei.
Such changes are similar to those observed in the lungs, which we consider to be
caused by a direct action of SARS-CoV-2 ([Fig
1c]).
Fig. 1
a Perivascular mononuclear infiltration in adrenal of the deceased
with COVID-19. H.-E., Magnification 400×. b Diffuse
infiltration of adrenal tissue by CD3+ lymphocytes. IHC,
Magnification 100×. c Small cell proliferations in adrenals
cortex. H.-E., Magnification 400×.
Further studies will be required to prove the presence of SARS-CoV-2 in adrenal
tissue and to define the mechanisms of adrenal degeneration and the potential loss
of function. Autopsy studies of patients who passed away from SARS exhibited
degeneration and necrosis of adrenal cortical cells. Indeed the SARS virus had been
identified in adrenal cells suggesting a direct cytopathic effect of the virus in
adrenal tissue. ACE2, which serves as the receptor of entry for SARS-CoV-2 is highly
expressed [6] in human adrenals, thereby
potentially further exposing adrenal tissue to virus-mediated destruction. Moreover,
the SARS virus contains several permutations of amino acid sequences with homology
to the antigenic relevant residues of ACTH. This molecular mimicry is of potential
pathophysiological relevance, since ACTH is the key hormone regulating adrenal
glucocorticoid release and it has been discussed that autoantibodies binding ACTH
could abrogate the adrenal stress response. Further, potential cross-reactivity of
antibodies may explain local infiltrations with immunocompetent cells in the
pituitary and adrenal. In summary, these aspects imply that patients with COVID-19
may be susceptible for critical illness-related corticosteroid insufficiency (CIRCI)
due to cellular destruction of adrenal tissue by direct virus infection and further
due to secondary inflammatory and autoimmune processes located in the pituitary and
the adrenals.
Finally, the adrenal gland is one of the most highly vascularized organs of the human
body with almost every adrenal cell in very close location to endothelial cells.
Therefore, the well-described endotheliitis in COVID-19 disease may further increase
the vulnerability of adrenal tissue. This may result not only in adrenal
degeneration but possibly also in adrenal hemorrhage and a
Waterhouse–Friderichsen syndrome. Although we have not yet observed this in
our patients it cannot be ruled out in a subset of patients. It may explain some of
the severe symptoms of a Kawasaki-like syndrome with severe and acute hypotensive
shock responding to glucocorticoid treatment recently reported in some children.
Adrenal lesions due to influenza and other viruses have been described previously
[9]
[10].
In conclusion, our data demonstrate an impairment of the adrenals in COVID-19.
Hypocortisolism has been observed in SARS survivors 3 months after their recovery
[11]. Therefore, adrenal insufficiency
should be considered in patients with suggestive symptoms and signs even months
after infection with SARS-CoV-2. Further, in COVID-19 patients receiving antiviral
medications and/or steroids long-term consequences on HPA axis dysfunction
need to be considered [12] to avoid an adrenal
crisis. Finally, dysregulation of the HPA axis may result in an aggravation of other
chronic disorders including cardiometabolic and mental disease [13].
Acknowledgment
This work was supported by Transcampus and the Deutsche Forschungsgemeinschaft (GRK
2251/1, TRR 205/1).
