Am J Physiol Endocrinol Metab 318: E882–E885, 2020;
doi:10.1152/ajpendo.00178.2020.
PERSPECTIVES
COVID-19-associated SIADH: a clue in the times of pandemic!
X Zohaib Yousaf, Shaikha D. Al-Shokri, Hussam Al-soub, and Mouhand F. H. Mohamed
Medicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
Submitted 27 April 2020; accepted in final form 4 May 2020
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 inap-
propriate 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 bilat-
eral 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.
Pulmonary involvement in the form of pneumonia is prev-
alent 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, nono-
smotic ADH secretion (1, 17). In the case of decreased intra-
vascular 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. Alter-
Correspondence: Z. Yousaf (zohaib.yousaf@gmail.com).
E882 0193-1849/20 Copyright © 2020 the American Physiological Society
Downloaded from journals.physiology.org/journal/ajpendo (082.137.009.061) on January 15, 2021.
natively, stress activates the cortical neurons, which stimulate
the hypothalamus to secrete ADH (9). Additionally, pneumo-
nia-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). Sec-
ond, 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).
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 afore-
mentioned 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 dur-
ing 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 ob-
tained.
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.
REFERENCES
1. Anderson RJ, Harrington JT, Kassirer JP, Madias NE. Hospital-
associated hyponatremia. Kidney Int 29: 1237–1247, 1986. doi:10.1038/
ki.1986.134.
2. Arndt JO, Gauer OH. Diuresis induced by water infusion into the carotid
loop of unanaesthetized dogs. Pflugers Arch Gesamte Physiol Menschen
Tiere 282: 301–312, 1965. doi:10.1007/BF00412505.
http://www.ajpendo.org
 COVID-19-ASSOCIATED SIADH E883
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, Not significant Not significant
asthma
Duration of symptoms, days 5 7 3
Symptoms Fever, cough, sore throat Fever, cough, nausea, vomiting, Abdominal pain, fever
lethargy
GCS 15/15 12/15 15/15
Orientation Oriented Disoriented Oriented
Symptoms of hyponatremia Lethargy Lethargy, disorientation, nausea, None
agitation
Imaging features (X-ray chest) Bilateral perihilar infiltrates Increased bronchovascular markings Bilateral perihilar infiltrates
initially, organized infiltrates at 72 h
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, ␮mol/L 74 57 65
EGFR, ml·min⫺1·1.73 m2) 97 141 110
Serum ferritin, ␮g/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 0
100ml each)
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.

3. Bernheim A, Mei X, Huang M, Yang Y, Fayad ZA, Zhang N, Diao K,
Lin B, Zhu X, Li K, Li S, Shan H, Jacobi A, Chung M. Chest CT
findings in coronavirus disease-19 (COVID-19): relationship to duration
of infection. Radiology. In press. doi:10.1148/radiol.2020200463.
4. Dhawan A, Narang A, Singhi S. Hyponatraemia and the inappropriate
ADH syndrome in pneumonia. Ann Trop Paediatr 12: 455–462, 1992.
doi:10.1080/02724936.1992.11747614.
5. Dunham-Snary KJ, Wu D, Sykes EA, Thakrar A, Parlow LRG,
Mewburn JD, Parlow JL, Archer SL. Hypoxic pulmonary vasoconstric-
tion: from molecular mechanisms to medicine. Chest 151: 181–192, 2017.
doi:10.1016/j.chest.2016.09.001.
6. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidi-
uresis. N Engl J Med 356: 2064 –2072, 2007. doi:10.1056/NEJMcp066837.
7. Goodman RB, Pugin J, Lee JS, Matthay MA. Cytokine-mediated
inflammation in acute lung injury. Cytokine Growth Factor Rev 14:
523–535, 2003. doi:10.1016/s1359-6101(03)00059-5.
8. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu
J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H,
Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q,
Wang J, Cao B. Clinical features of patients infected with 2019 novel
coronavirus in Wuhan, China. Lancet 395: 497–506, 2020. doi:10.1016/
S0140-6736(20)30183-5.

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E884 COVID-19-ASSOCIATED SIADH

· Stress
Intravascular volume
depletion
· Pain Decreased intravascular
osmolality
· Emotions

Activation of the renin-

Cortical neuronal Osmoreceptor
angiotensin-
activation activation
aldosterone system

Hypothalamo-
Non-osmotic
hypophyseal axis
Baroreceptor activation
activation

ADH secretion

Decreased left atrial

stretch

Inadequate filling of the

left atrium

Vasoconstriction in the
pulmonary vascular bed

Cytokine-induced Ventilation-perfusion
alveolar injury mismatch

Inflammatory cytokines
Severe pneumonia
release

Leukocyte activation SARS-COV-2 infection

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.

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 COVID-19-ASSOCIATED SIADH
9. Jezova D, Skultetyova I, Tokarev D, Bakos P, Vigas M. Vasopressin
and oxytocin in stress. Ann NY Acad Sci 771: 192–203, 1995. doi:10.1111/
j.1749-6632.1995.tb44681.x.
10. Koizumi K, Yamashita H. Influence of atrial stretch receptors on hypo-
thalamic neurosecretory neurones. J Physiol 285: 341–358, 1978. doi:10.
1113/jphysiol.1978.sp012575.
11. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson
JJ. COVID-19: consider cytokine storm syndromes and immunosup-
pression. Lancet 395: 1033–1034, 2020. doi:10.1016/S0140-6736(20)
30628-0.
12. Papageorgiou AN, Moffatt M. Bilateral pneumonia and inappropriate
secretion of antidiuretic hormone in a premature infant. Can Med Assoc J
114: 1119 –1120, 1976.
E885
13. Park SJ, Shin JI. Inflammation and hyponatremia: an underrecognized condi-
tion? Korean J Pediatr 56: 519–522, 2013. doi:10.3345/kjp.2013.56.12.519.
14. Qin C, Zhou L, Hu Z et al Dysregulation of immune response in patients
with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. In
press. doi:10.1093/cid/ciaa248.
15. Rose B, Post T. Clinical Physiology of Acid-Base and Electrolyte Disorders
(5th ed.). New York: McGraw-Hill, Medical Publishing Division, 2001.
16. Share L. Acute reduction in extracellular fluid volume and the concen-
tration of antidiuretic hormone in blood. Endocrinology 69: 925–933,
1961. doi:10.1210/endo-69-5-925.
17. Share L, Levy MN. Cardiovascular receptors and blood titer of antidi-
uretic hormone. Am J Physiol 203: 425–428, 1962. doi:10.1152/ajplegacy.
1962.203.3.425.

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