COVID-19-associated SIADH: a clue in the times of pandemic!

Hyponatremia is frequently associated with atypical pneumonia. One of the underlying mechanisms is inappropriate antidiuretic hormone (ADH) secretion (4). We report the first case series of coronavirus disease (COVID-19)-associated syndrome of inappropriate antidiuretic hormone secretion (SIADH). Additionally, we review pertinent literature and discuss the potential mechanism of this phenomenon.

Case 1 is a 58-yr-old man known to have well-controlled hypertension, asthma, and dyslipidemia. He presented with fever, cough, and sore throat. His sodium level was 116 mmol/L (135–145 mmol/L). The second case is a 20-yr-old man with no comorbidities; he presented with fever, cough, nausea, vomiting, lethargy, and disorientation. His sodium level was 112 mmol/L. Case 3 describes a 47-yr-old man with no comorbidities presenting with abdominal pain, fever, and a sodium level of 117 mmol/L.

The common features across the three cases were fever, evidence of pneumonia (abnormal chest X-ray depicting bilateral infiltrates), and severe hyponatremia. The workup for hyponatremia confirmed SIADH in all three cases (Table 1). The diagnosis was based on euvolemic hyponatremia (< 135 mmol/L) with concurrent low serum and high urine osmolality (< 280 and >100 osmol/kgH2O, respectively) and high urine sodium (>40 mmol/L) (6, 15). No underlying medication or medical conditions commonly associated with SIADH were identified. The second case was symptomatic; hence, required initial management with hypertonic saline followed by fluid restriction. The other two cases improved with fluid limitation alone. Nasopharyngeal RT-PCR confirmed COVID-19. All three cases were managed in a designated COVID-19 facility in Qatar and had a favorable outcome with the resolution of hyponatremia.

Table 1.

Patient summary

Characteristics	Patient 1	Patient 2	Patient 3
Demography
Age	58	20	47
Sex	Male	Male	Male
Nationality	Sri Lankan	Nepalese	Indian
Initial findings
Past medical history	Hypertension, dyslipidemia, asthma	Not significant	Not significant
Duration of symptoms, days	5	7	3
Symptoms	Fever, cough, sore throat	Fever, cough, nausea, vomiting, lethargy	Abdominal pain, fever
GCS	15/15	12/15	15/15
Orientation	Oriented	Disoriented	Oriented
Symptoms of hyponatremia	Lethargy	Lethargy, disorientation, nausea, agitation	None
Imaging features (X-ray chest)	Bilateral perihilar infiltrates	Increased bronchovascular markings initially, organized infiltrates at 72 h	Bilateral perihilar infiltrates
Admission to ICU	No	Yes – 24 h	No
Laboratory findings
COVID-19 RT-PCR (nasopharyngeal swab)	Positive	Positive	Positive
White cells, per mm3	4.6	7.2	4.2
Differential
Neutrophils, per mm3	2.5	5.2	3.2
Lymphocytes, per mm3	0.4	0.8	0.7
Eosinophils, per mm3	0.0	0.0	0.0
Monocytes, per mm3	1.7	1.2	0.3
Platelet count, per mm3	227	222	110
Hemoglobin, g/L	15	13.5	11
CRP, mg/L	2.8	<5	113
Total protein, g/L	77	76	61
Albumin, g/L	42	34	24
Alanine aminotransferase, U/L	13	27	34
Aspartate aminotransferase, U/L	31	31	39
Glucose, mmol/L	5.7	15.5	7.8
Urea, mmol/L	3	5	4.2
Creatinine, μmol/L	74	57	65
EGFR, ml·min−1·1.73 m2)	97	141	110
Serum ferritin, μg/L	700	379	900
Potassium, mmol/L	3.7	3.8	3.8
Chloride, mmol/L	77	78	81
Bicarbonate, mmol/L	24	22	21
Corrected calcium, mmol/L	2.46	2.38	2.17
Lactic acid, mmol/L	1.6	2.4	1.6
Sodium on day 1, mmol/L	116	112	117
Volume status	Euvolemic	Euvolemic	Euvolemic
Serum osmolality, osmol/kgH2O	243	253	278
Urine osmolality, osmol/kgH2O	316	509	769
Urine spot sodium, mmol/L	51	145	71
Diagnosis for hyponatremia	SIADH	SIADH	SIADH
Total hypertonic saline received, mL	0	300 ml (3 boluses of 100ml each)	0
Fluid restriction/24 h, mL	1,200	750	1,000
Serum sodium level at 24 h, mmol/L	121	120	120
Serum sodium level at 48 h, mmol/L	122	126	124
Serum sodium level at 72 h, mmol/L	128	129	128
AM serum cortisol level, nmol/L	237	523	Not available
TSH level, mIU/L	2.22	1.0	2.3

COVID-19, coronavirus disease; CRP, C-reactive protein; EGFR, estimated glomerular filtration rate; GCS, Glasgow Coma Scale; ICU, intensive care unit; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TSH, thyroid-stimulating hormone.

Pulmonary involvement in the form of pneumonia is prevalent among COVID-19-infected individuals as depicted by our cases, and the emerging literature (3). The mechanism of SIADH in pneumonia is not well established; however, animal models determined the role of low intravascular fluid volume and low extracellular fluid osmolality (12, 16). In the setting of intravascular volume depletion, baroreceptors in the carotid sinus, carotid body, and aorta activate the renin-angiotensin system. This, in turn, triggers a baroreceptor-mediated, nonosmotic ADH secretion (1, 17). In the case of decreased intravascular osmolality, osmoreceptors activate and increase the ADH secretion (2).

Emotional, physical, or psychological stresses and pain associated with infections (such as COVID-19) stimulate the hypothalamohypophyseal axis, leading to ADH release. Alternatively, stress activates the cortical neurons, which stimulate the hypothalamus to secrete ADH (9). Additionally, pneumonia-induced lung injury can result in a ventilation-perfusion mismatch. This mismatch results in compensatory hypoxic pulmonary vasoconstriction, leading to an inadequate filling of the left atrium. Consequent on this, a decreased left atrial stretch and increased ADH secretion occur (5, 10).

Marked elevation of inflammatory cytokines is described in COVID-19, leading in certain instances to cytokine storm (8, 11, 14). This increase in cytokines can result in SIADH via two mechanisms. First, inflammatory cytokines, such as IL-6, can directly stimulate the nonosmotic release of ADH (13). Second, these cytokines can injure the lung tissue and alveolar cells, which can induce SIADH via the hypoxic pulmonary vasoconstriction pathway, as previously described (7) (Fig. 1).

Fig. 1.

Proposed mechanism for syndrome of inappropriate antidiuretic hormone secretion (SIADH) in coronavirus disease (COVID-19) infection. ADH, antidiuretic hormone secretion; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

This discussion invites a study to explore the association between ADH and inflammatory cytokine levels, measured in COVID-19 patients and controls (with and without pulmonary involvement). This will advance our knowledge about the mechanism of SIADH.

There are additional clinical implications based on the aforementioned discussion. In the time of the pandemic, when medical resources are limited, any additional clue leading to the diagnosis of COVID-19 may prove valuable. Based on this limited evidence, we suggest triaging patients presenting during this pandemic with hyponatremia and fever as a high probability for COVID-19; these patients should be prioritized for testing and isolation whenever possible. A large cross-sectional study exploring the prevalence of hyponatremia and SIADH in this cohort of patients is needed to support our findings and conclusion.

Statement of ethics.

Consent was obtained from all three subjects in this study. Approval from a select committee for COVID-19-related publications and ethics in Qatar was obtained.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

Z.Y. conceived and designed research; Z.Y. drafted manuscript; S.D.A.-S. and M.F.M. edited and revised manuscript; H.A.-S. approved final version of manuscript.