CASE REPORT
Nagoya J. Med. Sci. 83. 883–891, 2021
doi:10.18999/nagjms.83.4.883

A patient with mild respiratory COVID-19 infection who
developed bilateral non-hemorrhagic adrenal infarction
Yuki Asano1, Tomomichi Koshi1, Asami Sano1, Takashi Maruno2,
Makoto Kosaka2, Yoshitaka Yamazaki2, Ako Oiwa3 and Yutaka Nishii1
Department of Endocrinology and Metabolism Internal Medicine, Nagano Municipal Hospital,
Nagano, Japan
2
Center of Infectious Diseases, Nagano Prefectural Shinshu Medical Center, Suzaka, Japan3
Department of Diabetes, Endocrinology and Metabolism, Division of Internal Medicine,
Shinshu University School of Medicine, Matsumoto, Japan

1

ABSTRACTA 76-year-old woman was admitted to the emergency room of Nagano Municipal Hospital with thecomplain of severe back pain. Chest and abdominal enhanced computed tomography scans showed bilateraladrenal infarction and minute pulmonary nodules, but she had no respiratory symptoms. After admission,a family member of the patient was found to have been in close contact with a coronavirus disease2019 (COVID-19) patient. Thus, polymerase chain reaction and antigen tests of severe acute respiratory
syndrome coronavirus 2 were conducted, and both tests returned positive. D-dimer levels were normal on
admission but increased 2 days thereafter. Anticoagulation therapy and steroid replacement were started,and the patient improved over about two weeks. One month after the onset of adrenal infarction, a
rapid adrenocorticotropic hormone loading test was conducted, which revealed that the primary adrenal
insufficiency due to adrenal infarction might have been caused by the COVID-19 infection. This case wasrare and suggestive of adrenal infarction with COVID-19, which usually presents at the severe stage. In
patients with COVID-19, attention should be paid to the onset of thrombosis, even with mild respiratory
infection. We also suggest that patients with thrombosis should be suspected of having COVID-19 evenin the absence of respiratory infectious symptoms in a situation of COVID-19 epidemic.
Keywords: COVID-19, adrenal infarction, thrombosis
Abbreviations:
ACTH: adrenocorticotropic hormone
COVID-19: coronavirus disease 2019
Cre: creatinine
CT: computed tomography
eGFR: estimated glomerular filtration rate
SARS-CoV-2: severe acute respiratory syndrome coronavirus 2
PCR: polymerase chain reaction
WBC: white blood cell countThis is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Received: April 13, 2021; accepted: June 18, 2021
Corresponding Author: Ako Oiwa, MD, PhD
Department of Diabetes, Endocrinology and Metabolism, Division of Internal Medicine, Shinshu University
School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
Tel: +81-263-37-2686, Fax: +81-263-37-2710, E-mail: akooiwa@shinshu-u.ac.jp
883

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INTRODUCTION
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that was reported for the first time in Wuhan,
China in December 2019, and as of March 2021, the pandemic continues worldwide. It has
been reported that thrombosis and adrenal infarction are likely to occur as a complication of
COVID-19,1 and in severe COVID-19 patients, respectively.2 We report a rare case of bilateral
non-hemorrhagic adrenal infarction with mild COVID-19 without respiratory symptoms, and withminute pneumonia lesions in the chest computed tomography (CT) scans.

CASE REPORTThe patient was a 76-year-old woman with a medical history of Sjögren’s syndrome, although
she was being followed-up for symptomatic treatment only. She developed cough at the end of
July 2020, after which her condition naturally improved. A few days later, back pain appeared
and she vomited about 10 times; therefore, she visited the emergency room of Nagano Municipal
Hospital. There were no remarkable blood tests or chest and abdominal enhanced CT scan findings that might have explained her symptoms; hence, the patient was sent back home. However,the next day, the patient was urgently hospitalized because of exacerbation of the back pain
and the presence of black vomitus. There were still no abnormal blood test findings as before,
but following careful observation of the chest and abdominal enhanced CT scans conducted theprevious day, bilateral adrenal infarction and minute pulmonary nodules scattered in both lungfields were found (Fig. 1 A–D).
The patient was afebrile on admission. Her blood pressure was 178/93 mmHg, pulse rate was
82 beats/min and regular, and oxygen saturation was 97 % in room air. The level of consciousness using the Glasgow Coma Scale eye opening, verbal, and motor responses was determinedas E4V5M6. The respiratory sounds were normal. Although clear bilateral back pain was noted,
there was no costovertebral angle tenderness. Hemorrhagic spots and efflorescence were notobserved on the skin of the whole body.
The result of the blood test performed on admission showed a blood cortisol, adrenocorticotropic hormone (ACTH), Na, K, and eosinophil levels of 37.6 µg/dL; 40.3 pg/mL; 142 mmol/L;
3.7 mmol/L; and 0.0%, respectively, and no findings suggestive of adrenal insufficiency (Table1). There were slight increases in the parameters suggesting inflammation, which included a
C-reactive protein level of 1.04 mg/dL and a leukocyte count of 11,560 /µL. The coagulation
markers, including D-dimer, were normal. The results of both lupus anticoagulant and anticardiolipin antibody tests were negative. No clear abnormal shadows were observed on the chest
radiographs. The chest and abdominal CT scans showed multiple minute ground-glass shadowsin the right lung (Fig. 1 A, B). The scans also showed a slight swelling of both adrenal glands
containing lesions with partially poor contrast enhancement of the parenchyma and elevated
peripheral concentrations (Fig. 1 C, D). A lower limb venous ultrasound revealed no clear
venous thrombosis.
On the zero day of illness, adrenal insufficiency, respiratory infection, and clear thrombotic
tendencies were not suspected; therefore, follow-up observations were conducted. The intense backpain was thought to be caused by the adrenal infarction, and it was treated with an intramuscular
injection of pentazocine hydrochloride.
On the first day of illness, since a fever of approximately 38°C was observed, the intravenous
administration of 6 g/day of sulbactam / ampicillin (ABPC/SBT) was started based on the sus-

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Adrenal infarction in COVID-19

Fig. 1 Transition of CT images with the course of the disease
The chest and abdominal CT the previous day on admission (A–D). Multiple minute ground-glass shadows areshown in the right lung. Swellings of both adrenal glands are observed, and the contrast enhancement of theparenchyma is partially poor (C, D). C shows the right and D the left adrenal glands.
The chest and abdominal CT on the second day of illness (E–H). New ground glass shadows are observed,
and the size of existing shadows is increased (E, F). The area of the diminished contrast effect of the bilateraladrenal glands is expanded (G, H).
CT: computed tomography

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Yuki Asano et al

Table 1

Laboratory data on admission

UN

12

mg/dL

PT

12.7

Cre

0.5

mg/dL

PT-INR

0.96

sec

eGFR

88.3

mL/min/1.73 m2

APTT

25.4

sec

AST

23

U/L

D-dimer

0.9

μg/mL

ALT

14

U/L

CRP

1.04

mg/dL

anti ds-DNA antibody

10

IU/mL (<10)

Na

142

mmol/L

lupus anticoagulant

1.27

IU/mL (≦1.2)

K

3.7

mmol/Lanti-cardiolipin antibody

5

U/mL (<10)

Cl

105

mmol/Lprotein C activity105% (64–146)

Glu (casual)

174

mg/dL

protein S activity

80% (56–126)

WBC

11560

/μL

CYFRA

1.5

ng/mL (≦3.5)(NEUT)

88.5

%

SCC

1.4

ng/mL (≦2.5)

(LYM)

5.5

%

(EOS)

0

%

Cortisol (casual)

37.6

μg/dL

RBC

488×10/μL

ACTH (casual)

40.3

pg/mL

4

HGB

14.7

g/dL

HCT

43.8

%

PLT

33.5×104/μL

UN: urea nitrogen
Cre: creatinineeGFR: estimated glomerular filtration rate
AST: aspartate amino transferase
ALT: alanine aminotransferase
CRP: C-reactive protein
Na: sodium
K: potassium
Cl: chloride
Glu: glucose
WBC: white blood cell count
NEUT: neutrophils
LYM: lymphocyte
EOS: eosinophils
RBC: red blood cells
HGB: hemoglobin
HCT: hematocrit
PLT: platelet
PT: prothrombin time
PT-INR: PT international normalized ratio
APTT: activated partial thromboplastin timeCYFRA: cytokeratin fragments
SCC: squamous cell carcinoma
ACTH: adrenocorticotropic hormone

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Adrenal infarction in COVID-19

Fig. 2 Transition of D-dimer level
D-dimer level was normal on admission. From the first day of illness, it became elevated. On the second dayof illness, anticoagulation therapy was started.

picion of pneumonia. Based on early-morning blood cortisol of 29.7 µg/dL and ACTH of 176.6
pg/mL, the secretion of cortisol was thought to be insufficient, and 25 mg/dose x 2 doses/dayof hydrocortisone were administered. D-dimer became slightly increased to 1.8 µg/dL (Fig. 2).
On the same day of the patient’s admission, in the night, a family member of the patient was
found to have been in close contact with a COVID-19 patient; hence, the patient was transferred
to a negative pressure chamber.
On the second day of illness, PCR and antigen tests of SARS-CoV2 were conducted, andboth tests returned positive. There were still no symptoms suggesting a worsening respiratory
status, such as dyspnea, cough, and poor oxygenation. According to the rule that hydrocortisone
must be administered sufficiently on sick days in patients who may have adrenal insufficiency,hydrocortisone was increased to 50 mg/dose every six hours. The D-dimer level increased to
4.3 µg/mL (Fig. 2). Chest and abdominal enhanced CT showed an increase in the ground glass
shadows in the upper right lobe compared to those taken 3 days ago, and new ground glass
shadows with indistinct boundaries were observed in the lower right and upper left lobes of thelung (Fig. 1 E, F). No new coarse thrombosis was noted, but we suspected that the adrenal
infarction might have progressed due to the diminished contrast effect of the bilateral adrenal
glands (Fig. 1 G, H). After no clear bleeding tendencies were confirmed, continuous intravenous
infusion of heparin (10000 U/day) was started.
On the third day of illness, the D-dimer level decreased to 3.0 µg/mL (Fig. 2), and backpain showed a tendency to improve. The dose of heparin was adjusted targeting activated partial
thromboplastin time (APTT). As before, no respiratory symptoms were observed.
On the seventh day of illness, the hydrocortisone dose was reduced to 30 mg/day and she
was switched to oral medication. Additionally, continuous intravenous infusion of heparin was
discontinued, and the drug was switched to 30 mg/day of edoxaban.
On the 18th day of illness, the patient was discharged from the hospital following an assessment of no infectiousness.

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Yuki Asano et al

On the 28th day of illness, a rapid ACTH loading test was conducted to evaluate the adrenal
function. Primary adrenal insufficiency was suspected by the results of the test showing cortisol
levels of 4.3 µg/dL before and 6.5 µg/dL after loading, which implied that the response ofcortisol to ACTH had almost disappeared. Therefore, oral administration of hydrocortisone wascontinued at 25 mg/day.

DISCUSSION
The main causes of adrenal infarction are antiphospholipid antibody syndrome3,4 and pregnancy.
Other rare differential diagnoses include heparin-induced thrombocytopenia and myelodysplastic
syndrome. It is thought that the onset of adrenal infarction in this patient was triggered by
COVID-19. A large amount of hydrocortisone was administered to this patient immediately after
the suspected adrenal infarction, which made an evaluation of her adrenal function impossible.
After discharge, one month after the onset of adrenal infarction, the rapid ACTH loading test
suggested the primary adrenal insufficiency. It was thought that the test results were not influenced by the oral administration of hydrocortisone which suppresses the secretion of ACTH andcortisol. This is because the latest oral administration of hydrocortisone occurred about 24 hours
before the test was performed, which possibly meant that the oral hydrocortisone was no longer
working. As there is no consensus on the amount or duration of administration of hydrocortisonethat suppresses endogenous cortisol secretion,5 there is a possibility that the prescription ofhydrocortisone at 25 mg daily for one month had caused the decreasing response of cortisol toa rapid ACTH loading test. However, it would be unlikely that this level of total hydrocortisone
dose suppressed endogenous cortisol secretion completely as in this result.
As reported, patients with COVID-19 are prone to thrombotic events.1 In particular, the report
indicated that thrombotic complications in severely ill patients occurred at a high frequency of
31% regardless of whether there were of venous or arterial nature.1 It was also reported in a
retrospective cohort analysis that, 51 out of 219 severely ill COVID-19 patients developed acuteadrenal infarction.2 From the above, it is believed that the more severe the infection, the more
likely it is for thrombosis and adrenal infarction to develop. This patient was a rare case of
adrenal infarction that occurred with mild COVID-19 infection without respiratory symptoms.
The patient had only minute pneumonia lesions in the chest CT scans and no other thrombosis
complication than adrenal infarction. This patient presented quite differently from previously
reported cases of adrenal infarction due to SARS-CoV-2 infection.2,6
According to the International Society of Thrombosis and Hemostasis (ISTH) guidelines,7
D-dimer values may be considered most significant in reflecting the severity of complications
due to coagulopathy in COVID-19. Hospitalization is recommended when D-dimer values
increase three- to four-fold even if there are no other concerns because it implies high risksof coagulopathy and disseminated intravascular coagulopathy. However, there are cases such as
in the present patient in which increases in D-dimer values may occur several days after the
onset. Therefore, both the severity of infection and the necessity of hospitalization should beconsidered comprehensively from many factors such as the clinical findings, blood tests, urine
tests, CT scans, and so on.
The ISTH guidelines recommended that when thrombosis complications related to COVID-19
are identified with no hemorrhagic lesions, anticoagulation therapy based on a continuous intravenous administration of heparin or oral warfarin should be considered. This patient was wellat discharge, due to the early start of anticoagulation therapy, administered as soon as possible.
Thrombosis by COVID-19 is associated with macrophages, inflammatory cytokines, and889
Adrenal infarction in COVID-19

Fig. 3 Adrenal vascular structure13

coagulation cascades.8,9 Other reports have indicated that direct damage to the vascular endothelial
cells by SARS-CoV-2 activates the coagulation system. SARS-CoV-2 is thought to have an affinity
for cells that express angiotensin converting enzyme II (ACE II).10 ACE II is expressed in cells
throughout the body, but its expression rates vary according to the organ. ACE II is expressed
not only in alveolar type II cells but also in epithelial cells of the upper esophagus, ileum,and colon; the endothelial cells of arteries and veins; and the arterial smooth muscle cells.11
Furthermore, in endocrine-related organs, ACE II is expressed in the adrenal gland, pancreas,
thyroid gland, testis, ovary, and pituitary gland.12
The adrenal gland is considered vulnerable to hemorrhage and infarction, which could be dueto the anatomy of the adrenal vasculature.13 A large amount of blood is supplied to the adrenal
gland from the inferior phrenic, celiac, and renal arteries which form the subcapsular artery
plexus. A “vascular dam”13 is formed by 50 to 60 small adrenal branches. The subsequent flowof blood all at once into the single adrenal vein13,14 can cause blood flow stagnation, which isthought to increase the possibility of thrombosis and hemorrhage (Fig. 3).
Furthermore, ACTH and adrenaline play additional roles in the development of thrombosis.
Under severe stress, including sepsis, secretion of ACTH and adrenaline increases. Elevated
ACTH increases the intravascular pressure by increasing the adrenal blood flow, which leads toinfarction and hemorrhage.15 This situation is further accentuated by adrenaline acting on platelet
aggregation in the adrenal veins.
It is retrospectively reported that the adrenal gland infarct is bilateral in 88% of patients
who develop adrenal infarction due to COVID-19.2 Most adrenal infarctions in pregnancy are
unilateral,16 whereas Waterhouse-Friderichsen syndrome (WFS), primarily caused by bacterial
infections such as meningococci, is also known to cause bilateral adrenal hemorrhage.17 Bothbilateral adrenal infarction and hemorrhage due to COVID-19 and WFS may be explained not
only by a shared mechanism of adrenal anatomy but also by the shared physiological responseto the stress due to infection.

CONCLUSION
We report a patient with a rare case of a very mild COVID-19 respiratory infection who
developed bilateral non-hemorrhagic adrenal infarction. Anticoagulation therapy should be
performed immediately when thrombotic tendencies are observed, to prevent an increase in the890
Yuki Asano et al

severity of the disease, including multiple organ failure.
Even if SARS-CoV-2 infection presents with mild form, based on several findings, attention
should be given to the various complications, particularly systemic thrombosis, including adrenal
infarction. In other words, when examining a patient with thrombosis, it is important to suspect
COVID-19 infection, even in the absence of respiratory infectious symptoms when COVID-19
pandemic exists.

ACKNOWLEDGEMENTS
We would like to thank Editage (www.editage.com) for English language editing.

INFORMED CONSENT
This patient has provided permission to publish her features of this case, and the identity ofthe patient has been protected.

DECLARATION OF INTERESTNone.

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