Coronavirus 19 (COVID-19) and Syndrome of Inappropriate Anti-Diuretic Hormone Secretion (SIADH): A Review of Literature

Abstract

The current coronavirus disease (COVID-19) pandemic, caused by the severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) is a serious public health concern worldwide. Over time, it became more evident that COVID-19 can affect multiple endocrine organs and hormonal substances, eventually negatively affecting patients with COVID-19 infection. The mechanism underlying hyponatremia in patients with COVID-19 is not fully understood but many postulated hypotheses have been tested. The exact mechanism of hyponatremia following COVID-19 infection also has yet to be established. The management options in those patients need to be taken carefully and to be directed to the primary disease. In this chapter, we summarize the association of syndrome of inappropriate anti-diuretic hormone secretion (SIADH)-induced hyponatremia with COVID-19 infection.

1. Introduction

Coronavirus disease (COVID-19) pandemic is caused by the severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) [1, 2]. It represents a global health burden and associated with increased morbidity and mortality. COVID-19 has a diverse and variable spectrum of clinical presentations. The clinical presentations range from mild disease with just upper respiratory tract symptoms to a severe form of the disease including pneumonia and may be multiple organ failure [3].

It became evident that COVID-19 can also affect the extrapulmonary organs, this includes vascular, cardiac, renal and neurological systems [4, 5, 6, 7]. Over time, it became more evident that COVID-19 can affect multiple endocrine organs and hormonal substances, leading to negative patients’ outcomes. The COVID-19 endocrine manifestations can be found more frequently in those patients with pituitary diseases, diabetes mellitus, obesity and vitamin D deficiency [8].

Angiotensin-converting enzyme 2 (ACE2) receptors have been identified as a target for the entry SARS-CoV-2 into the cells. The systemic involvement in COVID-19 is due to the almost abundant expression of the angiotensin-converting enzyme 2 (ACE2) receptors, with resulting damage at many organ and tissue levels besides the lung [9, 10]. From the endocrine glands respective, these receptors have been found in the hypothalamus, thyroid, pancreatic, gonads, pituitary gland cells on biopsies from those patients who died from COVID-19, explaining the endocrine involvement after contracting the infection, Figure 1 [11].

Figure 1.

Endocrine COVID-19 manifestations [11].

From the initial period of the pandemic, multiple factors have been linked to a higher risk for mortality from COVID-19, including male gender, old age, obesity, DM, hypertension (HTN), cancer, chronic obstructive pulmonary disease, immunocompromised patients and patients with cardiovascular diseases [12].

2. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is characterized by impaired water excretion secondary to the inability to inhibit antidiuretic hormone (ADH) secretion for multiple reasons, which lead eventually to different clinical presentations including hyponatremia [13, 14].

SIADH-induced hyponatremia in COVID-19 patients is not fully understood. One of the speculated hypotheses is related to burst release of inflammatory cytokines, including interleukin IL-1 and IL-6. IL-6 triggers hypothalamic arginine vasopressin production with consequent hyponatremia [15, 16].

SIADH should be considered in the differential diagnosis of any patient presented with hyponatremia (serum sodium levels <135 mmol/L) particularly when it associated with plasma hypo-osmolality, diluted urine and high urinary sodium (>40 mEq/L). Notably and unlike other causes of euvolemic hyponatremia like adrenal insufficiency, in SIADH, the serum potassium level is normal, no acid-base disturbance is observed and the serum uric acid level is frequently low [17].

3. COVID-19 and SIADH-induced hyponatremia

The exact mechanism of hyponatremia following COVID-19 infection has yet to be well established. However, the animal models speculated that it could be due to an imbalance in the intravascular fluid volume and extracellular fluid osmolality. Low volume intravascularly would activate the osmoreceptor and increase the ADH secretion [15].

Stresses, whether physical or non-physical, caused by infection for an instance, as in COVID-19, trigger the hypothalamus-pituitary axis, which leads to ADH secretion. In addition, lung involvement due to COVID-19 resulted in ventilation-perfusion mismatch leading to hypoxic pulmonary vasoconstriction, eventually filling the left atrium. The inability of the left atrium to stretch appropriately and as a consequent of this filling, the ADH will be released, Figure 2 [18].

Figure 2.

Hemodynamic changes in early COVID-19 infection [18].

Several studies have reported that the association of pneumonia with SIADH; however, few case reports have discussed SIADH secondary to COVID-19 pneumonia [19, 20].

One of observed initial COVID-19 clinical manifestation was SIADH. The potential mechanism was attributed to sepsis and cytokine storm associated with it (excessive IL-6 release), which in turn leads to hypothalamic–pituitary axis activation and subsequent uncontrolled release of anti-diuretic hormone (ADH) [15, 16].

Rizki et al. recently had published a systematic review and meta-analysis to assess the prognostic value of hyponatremia in COVID-19 patients. They found that SIADH-induced hyponatremia was associated with longer intensive care unit (ICU) stay and high mortality rate [21]. This could be explained by water retention induced by high levels of the ADH. Intravascular fluid retention can lead to extravasation due to increased capillary permeability in patients with COVID-19 sepsis which may subsequently increase the requirements of ventilator settings and ICU stay [15, 16, 21, 22, 23].

Critical levels of hyponatremia can lead to serious neurological manifestations including seizures, loss of consciousness and even death due to cerebral edema and brain stem compression. On the other hand, rapid correction of hyponatremia can lead to devastating neurological insult such as the osmotic demyelination syndrome [7, 24]. Therefore, proper management of covid-19 infection may result in decreased cytokine storms and eventually decreased ADH secretion [25, 26]. The decision of fluid administration in patients with sepsis as an attempt to improve the hydration and circulation status needs to be taken very carefully. Desalination is a phenomenon in which administration of normal saline in patients with SIADH-induced hyponatremia leads to worsening of hyponatremia. The hypothesized mechanism of this phenomenon is related to the excretion of some of the administered fluids in the hyperosmolar urine leaving the remaining in the circulation which leads to more hypotonic plasma and therefore worsening of pre-existing hyponatremia [24, 27]. Thus, the primary target in treating those patients is to the primary disease i.e. the COVID-19 infection. This will consequently lead to improvement of SIADH-induced hyponatremia and improved patients’ outcomes.

4. Conclusion

COVID-19 is associated with the development of SIADH; therefore, this condition should be considered in the differential diagnosis in patients with hyponatremia. Administration of IVF warrants cautious decision-making in these settings to avoid worsening of hyponatremia.