key: cord-1035777-4atarjje authors: Kleybolte, Johannes; Storek, Benjamin; Hegner, Björn title: SARS-CoV-2-induced SIADH: a novel cause of hyponatremia date: 2021-03-01 journal: Z Gerontol Geriatr DOI: 10.1007/s00391-021-01863-1 sha: 810fc07e3259af283a40c92d2a2f24cdcdcf073f doc_id: 1035777 cord_uid: 4atarjje nan Blood pressure was 110/70 mm Hg, heart rate 56 beats per minute, respiratory rate 14 per minute, oxygen saturation 96% on ambient air, and body temperature 35.9°C. Lungs, heart, and abdominal examinations were unremarkable. There were no signs of volume overload or depletion. Laboratory tests revealed elevated C-reactive protein (CRP) with procalcitonin and white cell count within normal ranges (. Table 2 ). Normocytic anemia was ascribed to surgery for the fracture 2 weeks earlier. The CRP spontaneously decreased without antibiotic treatment but lymphocytopenia and eosinopenia developed (. Table 2 ), while interleukin-6 (IL-6), D-dimer, troponin-T, NT-proBNP (Nterminal prohormone of brain natriuretic peptide), and lactate dehydrogenase (LDH) were elevated (. Table 2 ), features frequently observed in patients with COVID-19 [9] . Progressive hypoosmolar hyponatremia with a nadir of 128 mmol/L on day 13 (. Tables 2 and 3) was noted. Diagnostic work-up revealed inappropriately high urine osmolality and natriuresis (. Tables 2 and 3) . Fractional excretion of uric acid (FEUA) was increased to 14.3%. Cortisol was The findings were consistent with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Tramadol, a potential cause for the SIADH due to its central morphine receptor agonism and increase of serotonin release, was discontinued and metamizole was started at 1 g 4 times daily. Fluid intake was restricted to 1.2 L per day. Plasma sodium concentrations slowly normalized overthe following8 days. The patient remained asymptomatic with respect to both hyponatremia and COVID-19. The PCR testing for SARS-CoV-2 in pharyngeal swabs was first negative on Negative -Positive --Positive NT-proBNP N-terminal prohormone of brain natriuretic peptide, LDH lactate dehydrogenase, IL-6 interleukin-6, CRP C-reactive protein, TSH thyroid-stimulating hormone, fT3 free triiodthyronine, fT4 free thyroxine, SARS-CoV-2 severe acute respiratory distress syndrome coronavirus 2, PCR polymerase chain reaction day 33 and the patient was discharged home. Clinical presentation of patients with COVID-19 ranges from asymptomatic to severe symptoms or death [9] . In addition to respiratory tract infections and systemic inflammation, multiple other organ systems, including kidneys, heart, vasculature, and the central nervous system (CNS), may be susceptible to SARS-CoV-2 [5] . The SIADH has been described in patients with symptomatic [8] as well as asymptomatic SARS-CoV-2 infection [4] . Geriatric patients are at the highest risk as age and age-related comorbidities are associated with hospitalization and death [6] . Hyponatremia is the most frequent electrolyte disturbance in clinical practice and is particularly relevant in the older population [7] . Before the SARS-CoV-2 pandemic, the most likely causes of hyponatremia in the patient presented here would have been decompensated heart failure, dehydration caused by excessive diuretic treatment, hypothyroidism, and SIADH due to traumatic brain injury or tramadol. With the development of hyponatremia, the patient did not show volume overload or depletion although NT-proBNP was moderately elevated. Similar to troponin T, NT-proBNP was probably increased due to the SARS-CoV-2 infection without clinically apparent signs of heart failure. Urinary sodium concentration and FEUA were both elevated militating against cardiac decompensation or hypotonic dehydration. There was evidence of impaired conversion of T4 to T3 potentially indicating a SARS-CoV-2 associated nonthyroidal illness syndrome; however, Table 3 Plasma sodium levels Reference range Unit Day of hospital stay -26 -8 1 3 5 8 13 14 15 19 21 Plasma sodium 136-145 Mmol/L 142 136 129 133 130 131 128 128 128 130 136 TSH was only slightly elevated making clinically significant hypothyroidism unlikely. Instead, clinical and laboratory findings were suggestive of SIADH. A potential cause would have been brain injury incurred during the fall that resulted in fractures of the atlas and axis; however, computed tomography of the brain did not show any parenchymal lesions or intracranial hemorrhage and hyponatremia did not develop before day 18 following the trauma. Tramadol may have been the causative agent since it was started 10 days before onset of hyponatremia and sodium levels further declined after increase of the tramadol dose. This case provides a rare opportunity to precisely document the temporal coincidence of SIADH and SARS-CoV-2 infection suggesting a potential causal relationship. Both hyponatremia and SARS-CoV-2 infection demonstrably occurred within a timeframe of 8 days. Although tramadol cannot completely be ruled out as the cause of SIADH, the chronology more convincingly argues in favor of SARS-CoV-2 infection. As potential mechanisms, inappropriate secretion of ADH resulting from left atrial underfilling subsequent to pulmonary vasoconstriction induced by lung injury as well as direct nonosmotic ADH release triggered by inflammatory cytokines such as IL-6 have been discussed [8] . The report complements other cases of SIADH in COVID-19 [4, 8] since we documented elevated IL-6 levels for the first time as a possible pathophysiologic link between SARS-CoV-2 infection and SIADH. In a cohort of 29 COVID-19 patients, IL-6 levels were inversely correlated with serum sodium concentrations and blockade of IL-6 with tocilizumab was associated with an increase in sodium [2] , further substantiating causality; however, whether or not hyponatremia was caused by SIADH had not been studied. It is conceivable that infection of the CNS with SARS-CoV-2 can cause SIAHD. Impaired taste and smell, ataxia, dizziness, and loss of consciousness have been attributed to a probable neuroinvasive potential of SARS-CoV-2 [1] and other viruses have been implicated in encephalitis with SIADH [3] . Diagnostic work-up of hyponatremia in a geriatric patient with multiple comorbidities and polypharmacy is a common clinical problem. Our case illustrates that SARS-CoV-2 infection adds to the complexity of differential diagnoses and should also be considered. Potential neuroinvasive pathways of SARS-CoV-2: deciphering the spectrum of neurological deficit seen in coronavirus disease 2019 (COVID-19) Hyponatremia, IL-6, and SARS-CoV-2 (COVID-19) infection: May all fit together? Comparison of hyponatremia and SIADH frequency in patients with tick borne encephalitis and meningitis of other origin Acute symptomatic hyponatremia in setting of SIADH as an isolated presentation of COVID-19 Valsala Gopalakrishnan A (2020) Coronaviruses pathogenesis, comorbidities and multi-organ damage-a review COVID-19 and older adults: what we know Diagnosis and management of hyponatraemia in the older patient COVID-19-associated SIADH: a clue in the timesofpandemic! AmJPhysiolEndocrinolMetab Risk factors of critical & mortal COVID-19 cases: a systematic literature review and metaanalysis The authors thank C. Sehwan Park, Feinberg School of Medicine, Chicago, USA, for proofreading. Funding. Open Access funding enabled and organized by Projekt DEAL. Conflict of interest. J. Kleybolte, B. Storek and B. Hegner declare that they have no competing interests.All procedures performed in studies involving human participants or on human tissue were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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