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

PerspectivesCOVID-19-associated SIADH: a clue in the times of pandemic!Zohaib Yousaf, Shaikha D. Al-Shokri, Hussam Al-soub, and Mouhand F. H. MohamedZohaib YousafMedicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar, Shaikha D. Al-ShokriMedicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar, Hussam Al-soubMedicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar, andMouhand F. H. MohamedMedicine Department, Hamad General Hospital, Hamad Medical Corporation, Doha, QatarPublished Online:01 Jun 2020https://doi.org/10.1152/ajpendo.00178.2020This is the final version - click for previous versionMoreSectionsPDF (122 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat 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 summaryCharacteristicsPatient 1Patient 2Patient 3Demography Age582047 SexMaleMaleMale NationalitySri LankanNepaleseIndianInitial findings Past medical historyHypertension, dyslipidemia, asthmaNot significantNot significant Duration of symptoms, days573 SymptomsFever, cough, sore throatFever, cough, nausea, vomiting, lethargyAbdominal pain, fever GCS15/1512/1515/15 OrientationOrientedDisorientedOriented Symptoms of hyponatremiaLethargyLethargy, disorientation, nausea, agitationNone Imaging features (X-ray chest)Bilateral perihilar infiltratesIncreased bronchovascular markings initially, organized infiltrates at 72 hBilateral perihilar infiltrates Admission to ICUNoYes – 24 hNoLaboratory findings COVID-19 RT-PCR (nasopharyngeal swab)PositivePositivePositive White cells, per mm34.67.24.2Differential Neutrophils, per mm32.55.23.2 Lymphocytes, per mm30.40.80.7 Eosinophils, per mm30.00.00.0 Monocytes, per mm31.71.20.3 Platelet count, per mm3227222110 Hemoglobin, g/L1513.511 CRP, mg/L2.8<5113 Total protein, g/L777661 Albumin, g/L423424 Alanine aminotransferase, U/L132734 Aspartate aminotransferase, U/L313139 Glucose, mmol/L5.715.57.8 Urea, mmol/L354.2 Creatinine, μmol/L745765 EGFR, ml·min−1·1.73 m2)97141110 Serum ferritin, μg/L700379900 Potassium, mmol/L3.73.83.8 Chloride, mmol/L777881 Bicarbonate, mmol/L242221 Corrected calcium, mmol/L2.462.382.17 Lactic acid, mmol/L1.62.41.6 Sodium on day 1, mmol/L116112117 Volume statusEuvolemicEuvolemicEuvolemic Serum osmolality, osmol/kgH2O243253278 Urine osmolality, osmol/kgH2O316509769 Urine spot sodium, mmol/L5114571 Diagnosis for hyponatremiaSIADHSIADHSIADH Total hypertonic saline received, mL0300 ml (3 boluses of 100ml each)0 Fluid restriction/24 h, mL1,2007501,000 Serum sodium level at 24 h, mmol/L121120120 Serum sodium level at 48 h, mmol/L122126124 Serum sodium level at 72 h, mmol/L128129128 AM serum cortisol level, nmol/L237523Not available TSH level, mIU/L2.221.02.3COVID-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.Download figureDownload PowerPointThis 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.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSZ.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.REFERENCES1. Anderson RJ, Harrington JT, Kassirer JP, Madias NE. Hospital-associated hyponatremia. Kidney Int 29: 1237–1247, 1986. doi:10.1038/ki.1986.134. Crossref | PubMed | ISI | Google Scholar2. 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. 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