Vasopressin, Cortisol, and Osmotic Regulation in Non‐hospitalized SARS‐CoV‐2 Infected Patients
Authors: Uyehara Catherine F. , Ngauy Viseth , Scrivner Susan A. , Paguirigan Carmen M. , Murata Lee‐Ann M. , Hernandez Claudia A. , Kelly Gillian C. , Watase Colby , Kurata Wendy E. , O'Connor Kelsey M. , Thompson Kristina E. 
Published: May 2022

Vasopressin (AVP) has been implicated in the inflammatory response to SARS‐CoV‐2 infection as increased disease severity has been reported to be associated with elevated levels of copeptin. Elevated AVP and cortisol levels seen in systemic inflammatory responses may be associated with severe pulmonary edema and dilutional hyponatremia caused be dysregulation of neurohormonal control of fluid and electrolyte balance. Early and effective regulation of fluid balance before acute respiratory failure spirals into hypoxemia‐induced septic shock and multisystem organ failure, may be needed to prevent progression to severe disease.

We hypothesized that control of osmotic homeostasis in non‐severe cases of COVID‐19 is an outcome of cortisol and AVP stimulation arising from an appropriate stress response. In an observational study of asymptomatic to moderately symptomatic non‐hospitalized individuals (n = 45; 14 to 71 years of age) positive for SARS‐CoV‐2 (confirmed by PCR test), we assessed osmotic regulation by measuring circulating AVP (by radioimmunoassay), cortisol (by enzyme linked immunoassay), plasma osmolality (pOsm), plasma sodium (pNa) and plasma potassium (pK). Two plasma specimens from each person were collected between 2 and 32 days from onset of symptoms or confirmed positive test. Inflammatory stimulation of the immune response was verified by quantitative measurement of IgG targeted to the SARS‐Cov‐2 spike protein (Epitope Diagnostics, Dynex Agility).

Plasma osmolality (293+1 mOsm/L) remained stable even at the peak of IgG immune response. Multiple regression analyses showed pOsm was directly related to AVP and inversely related to cortisol (p<0.001). Examination of electrolyte levels over time from positive SARS‐CoV‐2 test week 1 vs week 3 (7+1 vs 18+1 days) revealed a slight decrease in pNa (139.7+0.8 to 136.9+0.5 mEq/l p<0.05, but there was no evidence of hyponatremia or inappropriate levels of AVP (SIADH) which was 1.9+0.2 uU/ml at week 1 and 2.2+0.3 uU/ml at week 3. Vasopressin regulation was appropriately positively correlated with pOsm and cortisol and negatively related to pK (p<0.001). Cortisol levels increased from week 1 to 3 (14.7+1.2 to 22.2+2.2 ug/dL), and positively correlated with AVP and negatively correlated with pNa.

Results demonstrated that the stimulated immune response to SARS‐CoV‐2 infection in mild to moderate cases of COVID‐19 does not disrupt osmotic regulation by AVP. Thus, reports of dysregulation of osmotic homeostasis and SIADH observed in severe pneumonia and coronavirus sepsis in hospitalized patients is likely due to the dominating non‐osmotic stimulation of AVP to pathophysiological levels needed to maintain blood pressure and renal perfusion. In mild to moderate COVID‐19 cases, control of fluid and electrolyte balance at physiological levels of AVP appears to be maintained.