COVID-19 infection: from stress-related cortisol levels to adrenal glands infarction

Abstract

Cortisol is a key element in acute stress including a severe infection. However, in coronavirus-associated disease, 20% of subjects experience hypocortisolemia due to direct or immune damage of pituitary and adrenal glands. One extreme form of adrenal insufficiency is found in 2/3 of cases with viral and post-viral adrenal infarction (AI) (with/without adrenal hemorrhage) that is mostly associated with a severe coronavirus disease 2019 (COVID-19) infection; it requires prompt glucocorticoid intervention. Some reports are incidental findings at computed tomography (CT)/magnetic resonance imaging (MRI) scans for non-adrenal complications like pulmonary spreading and others are seen on post-mortem analysis. This is a review of PubMed-accessible, English papers focusing on AI in addition to the infection, between March 1, 2020 and November 1, 2021. Exclusion criteria were acute adrenal insufficiency without the histopathological (HP) and/or imaging report of adrenal enlargement, necrosis, etc., respective adrenal failure due to pituitary causes, or non-COVID-19-related adrenal events. We identified a total of 84 patients (different levels of statistical evidence), as follows: a retrospective study on 51 individuals, two post-mortem studies comprising nine, respectively 12 patients, a case series of five subjects, seven single-case reports. HP aspects include necrosis associated with ischemia, cortical lipid degeneration (+/- focal adrenalitis), and infarcts at the level of adrenal cortex, blood clot into vessels, acute fibrinoid necrosis in arterioles and capsules, as well as subendothelial vacuolization. Collateral potential contributors to adrenal damage are thrombotic events, coagulation anomalies, antiphospholipid syndrome, endothelial dysfunction, severe COVID-19 infection with multiorgan failure, etc. Clinical picture is variable from acute primary adrenal insufficiency to asymptomatic or mild evolution, even a retrospective diagnostic; it may be a part of long COVID-19 syndrome; glucocorticoid therapy for non-adrenal considerations might mask cortisol deficient status due to AI/hemorrhage. Despite its rarity, the COVID-19-associated AI/hemorrhage represents a challenging new chapter, a condition that is essential to be recognized due to its gravity since prompt intervention with glucocorticoid replacement is lifesaving.

⧉ Introduction

The concept of adrenal infarction/hemorrhage

Adrenal infarction (AI) may associate or not adrenal hemorrhage; this is a very rare disease for both adults and pediatrics; it is caused or associated with sepsis, abdominal trauma, coagulation defects or use of anticoagulant medication, general conditions associating a high risk of hemorrhage (as active cancers, and neonatal stress, etc.) [1,2,3,4]. In one series, 40% of cases that were diagnosed with adrenal hemorrhage had a previous non-functioning adenoma at adrenal cortex level [1] (Figure 1, A and B). An adenoma at the level of adrenal cortex might or not be prior recognized; adrenal hemorrhage is sometimes the first presentation of the patient; histopathological (HP) report may identify both the tumor and the adrenal infection/hemorrhage; the immunohistochemistry (IHC) report on remnant adrenocortical adenoma might help its characterization [5,6,7,8,9,10] (Figure 2A,2B,2C,2D). Exceptional situations include syndromic context like TAFRO syndrome (which includes thrombocytopenia, anasarca, reticulin fibrosis of the bone marrow, renal dysfunction, and organomegaly) [11].

Figure 1.

(A and B) Pathological report of a non-functional adrenocortical adenoma: Hematoxylin–Eosin (HE) aspect. The tumor cells are uniformly disposed, with benign features. This is a 53-year-old female who suffered a right adrenalectomy for a tumor of 2.4 cm after doubling the maximum diameter after five years of follow-up. HE staining: (A) ×40; (B) ×100

Figure 2.

(A–D) Immunohistochemistry report on adrenocortical adenoma (×200): (A) Positive calretinin in tumor cells; (B) Positive synaptophysin in tumor cells; (C) Positive inhibin in tumor cells; (D) Positive Ki67 proliferation index of 2% in tumor cells

The clinical presentation of AI varies from acute adrenal insufficiency (in two thirds of cases – especially with bilateral lesions present – if left untreated it has a fatal evolution) and/or shock up to an incidental retrospective finding at different imaging evaluations, either as a necrotic adrenal mass, active hemorrhage or cystic tumor-like aspect or a post-mortem, HP report [12,13,14].

COVID-19 infection and endocrine glands

Crucial effects on endocrine glands and neuroendocrine system are related to the coronavirus disease 2019 (COVID-19) infection, with a heterogeneous pattern of presentation; among major targets are pancreas, pituitary gland, thyroid, adrenal glands, and testes [15,16]. The presence of diabetes mellitus (DM) or high blood pressure (HBP) are among the factors with a poor prognostic, as also found, for instance, for advanced age, active smoking, chronic renal failure, co-presence of prior cardio-cerebrovascular conditions [17].

IHC studies showed positive reaction for angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) at cells of the adrenal cortex [18,19]. The clinical presentation is mostly related to endocrine dysfunction, meaning low cortisol levels in critical patients [18]. Acute onset of COVID-19 infection might involve a switch from a chronic to adrenal form of primary adrenal insufficiency, previously known or unknown [20,21]. Physiologically, angiotensin system serves for maintaining normal blood pressure and adequate remodeling of blood vessels walls [21,22].

Aim

Our purpose was to correlate certain aspects of adrenal response in relationship with COVID-19 infection. This type of infection is regarded as a major stress for the human body (which was reflected by cortisol levels), thus it involves severe complications of adrenal glands as AI with or without hemorrhage.

⧉ Materials and Methods

Original data includes a narrative review of coronavirus infection with adrenal involvement (especially focusing on cortex-produced cortisol hormone). This is a review of PubMed-accessible, English scientific literature including only in extenso papers focusing on AI with or without hemorrhage in addition to the infection with coronavirus (between March 1, 2020 and November 1, 2021). The search words are in different combinations “COVID-19”, “coronavirus”, “SARS-CoV-2” and “adrenal”, “cortisol”, “stress”, “adrenal hemorrhage”, “adrenal infarction”.

Exclusion criteria were acute adrenal insufficiency without the HP and/or imaging report of adrenal enlargement, necrosis, and adrenal failure due to pituitary causes, and also non-COVID-19-related cases. Overall, 97 references are cited at different subsections. Figures 1 and 2 represent captures of pathological reports and IHC analysis that are based on authors’ clinical experience. The patients agreed to anonymously use their medical records.

⧉ Literature data

We identified articles regarding COVID-19 infection and AI with different levels of statistical significance, as follows: seven case reports, a case series of five individuals, a retrospective study on 51 subjects, two post-mortem studies comprising nine, respectively 12 patients (a total of 84 adults with different types of AI +/- hemorrhage +/- adrenal insufficiency).

COVID-19 infection: adrenal involvement

Cortisol as stress hormone

COVID-19 infection may be regarded as an acute stress of the human body, thus the outburst of stress hormones like cortisol is expected [23]. During acute stress, the general biochemistry and endocrine panel includes increased traditional biomarkers of inflammation (like fibrinogen, C-reactive protein), changes of leptin, adrenalin, procalcitonin, ferritin, lactate dehydrogenase levels, a new dynamics of interleukins (ILs) profile, etc. [24,25]. Other data particularly concerning COVID-19 infection, showed, for instance, as cortisol associates with inflammation markers, so is total testosterone and calculated free testosterone in females with pneumonia due to more intense adrenal cortex activity [26]. Particular aspects related to coronavirus infection-associated stress include anomalies of coagulation profile in addition to platelets damage as reflected by increased D-dimers, fibrinogen, and coagulation factor VIII, as well as low anticoagulant protein S and activated protein C, reduced coagulation factor XII [27].

Hypocortisolism concerning COVID-19 infection

Immune response to the virus may damage pituitary gland, regardless there is a prior hypophyseal known tumor or not, either functioning or nor (including the potential of associated morbidities like DM or HBP) [28]. Post-viral necrosis and low pituitary hormones has been described in viral hypophysitis, as traditionally seen in other circumstances like spontaneous necrosis/apoplexy, dopamine agonists and somatostatin analogues use for somatotropinoma or prolactinoma, Sheehan syndrome, etc. [28,29,30].

In severe forms of coronavirus infection, hypocortisolemia was found in approximately one fifth of the patients, depending on study [31]. This is due to the presence of antibodies against adrenocorticotropic hormone (ACTH) due to hypophysitis causing secondary adrenal insufficiency or to adrenalitis [32].

One transversal, retrospective, single-center study showed that subjects with moderate-to-severe COVID-19 infection have statistically significant more frequent hypocortisolemia versus subjects with mild coronavirus infection (which was defined in this study as an oxygen saturation of more than 94% and no other comorbidities) [33]. Central-related low levels of cortisol may also associate secondary hypothyroidism due to COVID-19 infection; during acute phase, it is difficult to assess if permanent glucocorticoid and/or Levothyroxine replacements will be required [34,35,].

After the recovery from COVID-19 infection, some authors also found a recovery of adrenal function. As an example, there is a prospective, observational study on 70 adults who were infected three months prior and had normal basal cortisol levels, as well as post-Synacthen test (performed with an intravenous dose of 250 μg) [34]. However, other authors suggested a potential adrenal involvement in long COVID-19 syndrome associating asthenia, fatigue, and even cognitive impairment within the first weeks up to several months after infection [36,37,38,39].

COVID-19 infection: glucocorticoids use

Generally, glucocorticoid therapy is highly recommended for its strong anti-inflammatory effect [40]. Early during pandemic, a particular candidates’ group was identified in subjects with severe respiratory distress symptoms and/or immunosuppression, septic shock (representing 5% of all infected cases) [41]. Systemic glucocorticoid medication is associated, depending on severity and comorbidity, with a large panel of intervention like drugs from antiviral medication, oxygen therapy, antibiotics, anticoagulants to extracorporeal blood purification therapy (EBPT) to immunomodulating drugs, renal replacement therapy, etc. [41,42,43,44,45].

Systemic corticosteroids administration reduces all-cause mortality in subjects hospitalized for coronavirus infection, and probably decreases the need for ventilation [46]. Also, their use was correlated to a reduced rate of conversion from a mild case into a severe one [47].

In cases with COVID-19 infection, as generally known, large doses and/long-term glucocorticoid therapy are expected to associate a multitude of side effects from HBP, bone damage in terms of bone turnover, reduced bone mineral density and abnormal microarchitecture as reflected by trabecular bone score, digestive anomalies, glucose variations, etc. [48,49]. Also, glucocorticoid treatment is indicated in critically ill COVID-19-positive patients, thus increasing the risk of venous thromboembolism with a poor outcome [50,51]. As an alternative, Methylprednisolone or Dexamethasone in high dose as pulse therapy may reduce the side effects [51]. Moreover, a corticosteroids regime of short-term was proposed in addition to the first dose of vaccination to reduce the reactogenicity surrounding the immunization against COVID-19; however, this type of approach still needs validation [52].

AI and COVID-19 infection

HP aspects

The virus uses ACE2 as a receptor; we already know that the receptor is displayed all over the human body, including in arterial and venous cells of endothelial type, also in adrenal glands [53]. Even before current pandemic outbreak, the severe acute respiratory syndrome coronavirus (SARS-CoV) family was known to target adrenal glands, mostly at cortex level, representing a clear pathogenic loop of the virus, thus cortisol levels are expected to be affected [54].

AI goes with or without hemorrhage, having different extends which are translated into endocrine anomalies of adrenal cortex especially in severe situations [55,56,57]. Associated adrenal insufficiency may be the main feature of the clinical picture or it may represent only a small part of an otherwise complicated presentation due to severe COVID-19 infection, especially with lung or multiorgan involvement [55,56,57].

One post-mortem study showed various adrenal lesions in 46% of the patients (a cohort of 28 subjects who died because of coronavirus complications): seven individuals with necrosis associated with ischemia, four persons with cortical lipid degeneration (two cases of them also associating lesions of focal adrenalitis), two subjects with adrenal necrosis associated with hemorrhage, and one 70-year-old male with isolated lesions of focal adrenalitis [58]. Interestingly, one of the cases with necrosis also had lesions of adrenocortical carcinoma [58]. Another post-mortem study showed a misalignment between general involvement and particular aspects concerning adrenal damage where a complex panel of changes is described: infarcts at the level of adrenal cortex, thrombi into vessels, acute fibrinoid necrosis at arterioles and glands capsule, as well as sub-endothelial vacuolization, etc. [59].

Contributor factors

Previous thrombotic events are an essential contributor factor [60]. Other collateral elements might be autoimmune conditions of endocrine and non-endocrine type, liver anomalies (including of coagulation factors), anti-phospholipid syndrome (APLS); endothelial dysfunction in severe shock accompanying coronavirus infection has been described including in pediatric population [60,61]. Endothelial injury, inflammation and hypoxia may similarly cause myocardial infarction [62,63,64]. Most probably, the fact that COVID-19 infection induced positive anti-phospholipid antibodies represents the key element which was also described in patients without coronavirus infection [65]. However, the actual level of statistical evidence is low, and we currently consider AI as a more complicated puzzle with multifactorial pathogenicity [60].

AI may be found in patients with less severe coronavirus infection, but also, it is found accompanying the general damage due to cytokine storm, as an excessively increased status of acute inflammation in critically ill infected subjects (between 1% and 5% of COVID-19 patients depending on study), in cases with multiorgan failure underling severe thromboembolic events like ischemic stroke, myocardial infarction, acute renal failure, vasculitis, etc., thus involving vessels that are connected with adrenal glands [66]. The severe clinical picture is heterogeneous since multiple systems are damaged. For instance, in one case of a 50-year-old male, bilateral adrenal hemorrhage was first accidently detected at computed tomography (CT) scan for COVID-19 pneumonia, followed by clinical manifestation of adrenal insufficiency with hypotension, which was unfortunately followed by multiple thrombosis including massive pulmonary embolism [67]. This case also associates a prior diagnosis of adrenal tumor, which is exceptionally found until now in patients with COVID-19-positive adrenal hemorrhage [67]. Another 48-year-old male with a prior diagnosed of APLS who was under therapy with vitamin K antagonists at the moment of COVID-19 infection developed ischemia at the level of left toes due to artery occlusion, and he was synchronously diagnosed with adrenal hemorrhage before the switch was done for low-molecular-weight heparin (Enoxaparin) [68]. Another 66-year-old female who was previously known with APLS was also admitted for active COVID-19 infection and adrenal hemorrhage-related adrenal insufficiency followed by a thrombosis at the level of renal vein, an evolution that confirms so called “two-hit” theory [69].

Clinical elements

Digestive symptoms and cardiovascular deterioration may be related to the infection or to adrenal infraction [64]. Digestive involvement (like abdominal pain, diarrhea, nausea, vomiting) during COVID-19 infection is reported in almost half of cases, typically after pulmonary symptoms [70,71]. These are caused by the fact that ACE2 receptors are located at the level of gastrointestinal system, and also at pancreas [72,73]. On the other hand, the clinical presentation of acute adrenal insufficiency includes hypotension, collapse, nausea, vomiting, abdominal pain, fever, lethargy, confusion, etc., which may mimic a COVID-19 infection with digestive presentation [73]. However, an infection itself (of any type) may be the trigger of on acute form of primary adrenal failure [73]. The incidence of adrenal crisis in general population is 10/100 individuals-years (a mortality of 0.5/100 patient-years) [73]. Prompt recognition and adequate glucocorticoid therapy is lifesaving [73].

Recently, a new potential differential diagnostic of acute adrenal failure with abdominal pain was established in relationship with coronavirus infection: multisystem inflammatory disease in adults (MIS-A), syndrome that was initially described in children (MIS-C syndrome), with a Kawasaki-like pattern of presentation [74,75]. MIS-A or MIS-C syndrome causes abdominal pain, cardiac failure, shock, fever, increased markers of inflammation following the actual COVID-19 infection or being synchronous to it [76,77]. This complication of acute respiratory distress syndrome increases the mortality; the use of immunoglobulin treatment, steroids, biotherapy like anti-IL antibodies may improve the prognostic to some extent [78,79].

In one retrospective study, which aimed to identify the adrenal lesions suggestive for infarction in acute coronavirus infection with severe lung complications, the adrenal lesion was incidentally detected in 23% of subjects (male predominance, a mean age of 67±11 years) [80]. Only 8% of cases had a confirmation of endocrine panel suggestive for adrenal insufficiency; the accidental CT finding was correlated with a more prolonged hospital stay [80].

Another retrospective study on nine adult UK subjects (with mean age of 73 years) with SARS (due to coronavirus as cause of death was published in 2020 [81]. Post-mortem analysis showed that 33% of studied patients had an adrenal microinfarction, while thrombotic events were confirmed in 89% of cases, mostly at pulmonary level, in association with other three major HP elements including diffuse alveolar damage (which was confirmed in all the studied individuals), immune anomalies like lymphocyte depletion [mostly cluster of differentiation (CD)-positive T-cells], as well as hemophagocytes [as otherwise seen in other severe infections like human immunodeficiency virus (HIV) infection] [81,82]. If recognized, AI-related adrenal insufficiency requires intravenous Hydrocortisone, followed by lifetime oral Hydrocortisone and Fludrocortisone [83]. As mentioned, some severe subjects are already under systemic glucocorticoid medication [84]. A 70-year-old male case was diagnosed with bilateral adrenal hemorrhage, while he was under glucocorticoid medication in addition to a complex regime for COVID-19 bilateral bronchopneumonia [85]. Because of this aspect, baseline cortisol/ACTH assessments are not feasible; the need of glucocorticoid substitution after the subject is discharged for COVID-19 infection is an argument of chronic adrenal insufficiency; however, replacement medication may be stopped under clinical surveillance to check the hormonal panel if the patient is stable to check the spontaneous hormonal balance of glucocorticoid axes [85]. A 53-year-old male with right adrenal hemorrhage diagnosed while performing a CT scan for bilateral pulmonary embolism did not associate adrenal insufficiency and the lesion was remitted according to CT exam that was performed five months after he was discharged [86] (Table 1).

Table 1.

The PubMed-based, English language, full-length papers published between March 1, 2020 and November 1, 2021 concerning COVID-19 infection and AI with or without adrenal hemorrhage, with or without adrenal insufficiency related to COVID-19 infection

No.	Authors / reference	Type of study	No. of patients / age [years] / sex	Presentation	Endocrine aspects	COVID-19 aspects	Observations
1.	Freire Santana et al. / [58]	Post-mortem study (autopsy)	12 out of 28 (46%) patients with adrenal lesions	Autopsy diagnostic	No adrenal insufficiency based on cortisol levels (sample within 1–2 days before death)	COVID-19 as cause of death	Prior diagnostic of APLS
			50, 65 / F
			34, 35, 48, 52, 55, 57, 65, 66, 70, 88 / M
2.	Iuga et al. / [59]	Case series	5 patients / between 59 and 90 / F/M ratio: 1/4	Autopsy diagnostic	Not available	COVID-19 as cause of death	2 patients died of cardiac arrest at emergency room
							3 patients were hospitalized (maximum 72 hours) before death
3.	Machado et al. / [60]	Case report	1 patient / 46 / F	Abdominal pain, hypotension, skin hyperpigmentation	Na↓	AI after COVID-19 infection	CT scan: bilateral adrenal enlargement (infarction)
					Cortisol↓
					ACTH↑		Other contributors: prior autoimmune hepatitis, de novo positive anti-phospholipid antibodies
					Aldosterone↓
4.	Kumar et al. / [64]	Case report	1 patient / 70 / F	Fatigue, abdominal pain, vomiting, diarrhea	Na↓	Synchronous with COVID-19 pneumonia	CT: non-hemorrhagic AI
					On admission:  random ACTH, cortisol, K normal → then adrenal insufficiency		Other elements: negative anti-cardiolipin antibodies, history of HBP, hypercholesterolemia
5.	Elkhouly et al. / [67]	Case report	1 patient / 50 / M	Fever, malaise, dyspnea, cough, bilateral flank discomfort	Adrenal lesion was accidentally detected at CT	COVID-10 pneumonia, further complicated with deep vein thrombosis, massive pulmonary embolism causing the patient’s death	Previous diagnostic of HBP and right adrenal tumor
				On day 3 after hospitalization – hypotension
6.	Maria et al. / [68]	Case report	1 patient / 48 / M	Fever, cough, myalgia + sudden abdominal pain	Not available	COVID-19 pneumonia and limb arterial ischemia	Prior diagnostic of APLS
							The patient was under vitamin K antagonists at the moment of infection
7.	Frankel et al. / [69]	Case report	1 patient / 66 / F	Fever, dyspnea, abdominal pain, nausea, vomiting	Na↓	Synchronous with COVID-19 infection	CT: enlargement of adrenal glands
					Basal cortisol↓
					ACTH↑
8.	Leyendecker et al. / [80]	Retrospective study (March 9–April 10, 2020)	51 out of 219 (23%) patients with CT for lung involvement / mean age 67±11 / 71% M	Detection as incidental CT finding	8% adrenal insufficiency	Synchronous with COVID-19 with severe/critical lung disease	CT: bilateral lesions in 88% of cases
				Correlation with a longer hospital stay versus without
9.	Hanley et al. / [81]	Retrospective (post-mortem) study (March 1–April 30, 2020)	9 patients / 73 (IQR 52–79) / 7 M, 3 F	Death due to SARS		Adrenal involvement confirmed at post-mortem analysis	Multiple organ involvement
10.	Álvarez-Troncoso et al. / [85]	Case report	1 patient / 70 / M	Fever, chills, asthenia, constipation, malaise, generalized weakness, anorexia, nausea, vomiting	Na↓	Synchronous with COVID-19 bilateral bronchopneumonia	CT: bilateral enlargement of adrenal glands (with blurring aspect)
				Hypotensive	No hormonal assessment due to glucocorticoids therapy
11.	Sharrack et al. / [86]	Case report	1 patient / 53 / M	Fever, dyspnea, pleuritic chest pain	Normal short Synacthen test	COVID-19-related bilateral pulmonary embolism	CT: right adrenal hemorrhage confirmed during infection and remitted at CT scan performed after five months

ACTH: Adrenocorticotropic hormone; AI: Adrenal infarction; APLS: Antiphospholipid syndrome; COVID-19: Coronavirus disease 2019; CT: Computed tomography; F: Female; HBP: High blood pressure; IQR: Interquartile range; K: Potassium; M: Male; Na: Sodium; SARS: Severe acute respiratory syndrome

⧉ Discussions

Our systematic review represents a new chapter in medical field, once the COVID-19 pandemic started and changed the entire worlds, not just from a strictly medical perspective [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86].

Early during pandemic, the endocrine glands were found to be affected by the coronavirus, and the adrenal glands represent a hallmark of human body survival under different circumstances on daily basis and acute, as well as chronic stress. Assessment of cortisol levels are essential tools for practitioners to assess to body capacity to adjust under these circumstances (unless the patient is already under glucocorticoid medication). The extreme clinical presentation of adrenal involvement in a patient who is infected with coronavirus or is a survivor of disease is adrenal infraction, especially associating adrenal hemorrhage. The traditional HP panel is a milestone for this condition; however, the early recognition (based on signs and symptoms of newly detected adrenal insufficiency, as well as imaging findings like enlargement of one or both glands and blurring pattern at CT scan) and further on therapy with systemic corticoids, are essential for prognostic/survival [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86].

In relationship with COVID-19 infection, the cases that are reported so far by the medical community concern adult patients who either had a severe infection with a multiorgan failure or are during post-viral period of time. Also, valuable data are provided by post-mortem analysis in subjects who died from the disease. The recognition of clinical entity may be masked by severe general involvement of multiple organs or by the fact that the patient is already under glucocorticoid medication for a different (non-adrenal) complication, thus the lifesaving therapy is already provided to the patient. Also, after surpassing the acute phase, it remains this debatable issue of long-term need for oral corticoids, including the utility of assessing the hormonal tests, which are specific for cortisol/ACTH levels, including stimulation tests, which might indicate the need of glucocorticoids even in small doses or their supplementation under different stress circumstances [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86].

Even though current level of statistical evidence is not reliable for large meta-analysis, the topic is new, it dates from 2020–2021, and it is essential to be communicated to the practitioners at the level we are currently aware of [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86].

Adrenal hemorrhage has been exceptionally described in relationship with medulla; a first case of pheochromocytoma-related hemorrhage in a 62-year-old male admitted for coronavirus-associated pneumonia was the initial sign that led to the detection of the adrenal tumor [87].

Vaccine against coronavirus might also trigger an AI. One of the mechanisms that link COVID-19 adenoviral vector-based vaccination to immune (vaccine-induced) thrombotic thrombocytopenia that may cause acute complications like acute renal failure due to thrombosis or bleeding due to low platelets count [88,89,90]. This may also represent the pathogenic factor of adrenal hemorrhage, as several cases reported it in 2021 [91,92,93,94]. Another case of a 54-year-old female presented post-vaccine disseminated intravascular coagulation due to multiple-site thrombosis including brain, lung, and bilateral adrenal hemorrhage [95]. Moreover, a first case of pheochromocytoma detection after COVID-19 vaccine was recently reported; this 63-year-old male patient had no previous history of an adrenal tumor until adrenergic crisis starting within 24 hours since vaccination [96]. Overall, despite limited level of statistical evidence, it is mandatory to address to topic of adrenal involvement amid COVID-19 pandemic on a multidisciplinary perspective.

⧉ Conclusions

Cortisol is a key element in acute stress including a severe infection. However, in coronavirus-associated infection, hypocortisolemia is found due to direct or immune damage at pituitary and adrenal glands. One extreme form of adrenal insufficiency is COVID-19-related AI with/without hemorrhage that is mostly associated with a severe form of infection; it requires prompt glucocorticoid intervention. Some of the reports are incidental findings during CT for pulmonary lesions and others are post-mortem analysis. The presence of APLS represents an aggravating circumstance. So far, the level of statistical evidence is low, but the condition is essential to be adequately recognized due to its gravity.

Conflict of interests

The authors declare that they have no conflict of interests.