Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can result in coronavirus disease 2019 (COVID-19), has caused an unprecedented global pandemic. The epicenter of that pandemic in Latin America was Brazil, where more than 500,000 deaths have been attributed to COVID-19.1
The receptor-binding domain of the SARS-CoV-2 spike protein uses host angiotensin-converting enzyme 2 (ACE2) as the receptor for membrane fusion, thus potentially disrupting hypothalamic expression of ACE2. Anti-SARS-CoV-2 antibodies might destroy circulating adrenocorticotropic hormone (ACTH), which could blunt the stress-induced cortisol response.2
Here, we report the cases of 13 patients admitted to two tertiary hospitals, in the Brazilian cities of São Paulo and Goiânia, respectively. All were diagnosed with adrenal insufficiency (AI) while in the intensive care unit (ICU). Twelve of the patients were under dialysis with continuous venovenous hemodiafiltration or continuous venovenous hemodialysis, at 35 mL/kg/h, and presented with persistent hyperkalemia, hyponatremia, or both, despite hemodialysis and clinical measures. All clinical data were extracted from medical records. Enrollment was from April 1 to August 16 of 2020. Ten of the 13 patients were male. The median age was 69 years (interquartile range, 65–73 years), and the median ICU stay was 26 days (interquartile range, 19–40 days). Six patients had diabetes, 10 had hypertension, 4 had class III obesity, and 1 had a history of cancer. Eleven patients required mechanical ventilation and vasopressor support; and 2 had previously been on dialysis. The ICU mortality rate was 76.9%. Additional clinical and biochemical data were collected (Table). After being diagnosed with AI, all of the patients received glucocorticoid therapy, which normalized serum electrolytes and bicarbonate. The study was approved by the Institutional Ethics Board of the University of São Paulo School of Medicine Hospital das Clínicas (Reference no. 4.129.320).
AI is defined as the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids or mineralocorticoids. In ICU patients, cortisol deficiency can be difficult to detect, because the clinical signs are frequently nonspecific.3 Among those on dialysis, findings such as hyperkalemia and hyponatremia can be misleading. Persistence of such disturbances even after the initiation of dialysis should raise the suspicion of cortisol deficiency.
One possible explanation for AI in SARS-CoV-2-infected patients is critical illness-related corticosteroid insufficiency (CIRCI)4 which does not indicate strictly a pituitary or adrenal injury, but rather relative AI resulting from glucocorticoid-mediated anti-inflammatory activity being inadequate to counter the severe stress.3 In CIRCI, there is no organic defect of the hypothalamic-pituitary-adrenal axis, although systemic availability of cortisol is also assumed to be incommensurate with the severity of the stress.3 In critically ill COVID-19 patients with hypotension that is refractory to fluid resuscitation and vasopressor therapy, CIRCI should be considered.3 In rare cases, such patients may also have hyperkalemia or hyponatremia.
Another explanation for AI in SARS-CoV-2-infected patients could be the immune evasion that SARS viruses like influenza utilize to inhibit the host corticosteroid stress response, through viral expression of amino acid sequences that are molecular mimics of the host ACTH. The host produces antibodies against those viral antigens, which also bind to the host ACTH, thus limiting the host stress response by preventing ACTH from stimulating corticosteroid secretion.5
Yet another possibility is that the presence of the SARS-CoV-1 viral antigens and genomic sequence in the adrenal glands causes adrenal necrosis, vasculitis of the medullary capillaries, and monocyte/lymphocyte infiltration. Although that has yet to be reported in SARS-CoV-2 infection, it merits attention.6,7
It is even possible that AI in SARS-CoV-2-infected patients could be attributed to a combination of etiologies. Regardless of the etiology, such patients should respond to prompt glucocorticoid therapy.