key: cord-0873511-k8mw83hn authors: Campana, Pasquale; Flocco, Veronica; Aruta, Francesco; Cacciatore, Francesco; Abete, Pasquale title: Can Aldosterone increase Interleukin‐6 levels in Covid‐19 Pneumonia? date: 2020-08-04 journal: J Med Virol DOI: 10.1002/jmv.26382 sha: 4ce898be7af6011aa245a9cec5c063913bcd636a doc_id: 873511 cord_uid: k8mw83hn In the last months, the importance of identifying pathophysiological mechanisms for future therapies has emerged with the rapid spread of Covid‐19 pandemic. As matter of fact, several evidences suggest the critical role of Interleukin‐6 (IL‐6) in the cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV2) infection and its correlation with the severity of acute lung injury (1, 2). This article is protected by copyright. All rights reserved. Informed consent Informed consent was obtained from all individual participants included in the study. Disclosures: On behalf of all authors, the corresponding author states that there is no conflict of interest. To the editor, In the last months, the importance of identifying pathophysiological mechanisms for future therapies has emerged with the rapid spread of Covid-19 pandemic. As matter of fact, several evidences suggest the critical role of Interleukin-6 (IL-6) in the cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection and its correlation with the severity of acute lung injury (1, 2) . In their meta-analysis, Azis M. et al. have admirably analyzed the association between elevated IL-6 and severe pneumonia. They have also clarified the necessity to define a cut-off of this cytokine in patients with high mortality risk (3). Similarly, we report a case of a 47 years-old female Covid-19 patient who has developed a severe pneumonia complicated by Guillain-Barré Syndrome (GBS). The patient was self-isolated at home after a contact with a positive individual referring fever and dry cough as onset symptoms. The rapid respiratory worsening with severe hypoxemia, and the elevated lactates and D-dimer have required a sudden hospitalization in the Intensive Care Unit and subsequently mechanical ventilation for three weeks. Lopinavir/Ritonavir, Hydroxychloroquine, Enoxaparin, Ceftriaxone and Azithromycin therapy was administered with poor clinical response. The blood test revealed a very high serum levels of IL-6 (serum IL-6: 402 pg/ml; reference value < 3.5 pg/ml) and of its soluble receptor (soluble IL-6 receptor >1900 pg/ml; reference value < 46 pg/ml). Therefore, she This article is protected by copyright. All rights reserved. was treated with two infusions of Tocilizumab which resulted in rapid clinical improvement with the interruption of mechanical ventilation. In this patient, the evidences of right adrenal adenoma ( Figure 1A ), resistant hypertension, severe hypokalemia and high serum levels of aldosterone (1194 pg/ml), with an aldosterone/renin ratio of 373 ng/dL/(ng/mL/h), were also consistent with the diagnosis of primary aldosteronism. Thus, Spironolactone therapy was administered with improvements in the clinical conditions and mostly in the respiratory symptoms. Finally, she was diagnosed with Acute Motor Sensitive Neuropathy (AMSAN) with prolonged distal motor and sensory latencies in lower limbs at the electromyography. Neurological symptoms were underestimated during the invasive ventilation period and the late diagnosis did not allow intravenous immune globulin therapy. Therefore, the patient began a rehabilitation phase and she was discharged with significant evidence of diffuse pulmonary fibrosis ( Figure 1B) . In this case, serum IL-6 is higher compared to the average values reported in the metaanalysis (3). Therefore, we suppose that an imbalance of the Renin Angiotensin System (RAS) with very high levels of aldosterone may directly stimulate IL-6 production. In particular, the involvement of RAS dysfunction with increased Angiotensin II levels in lung injury of Covid-19 patients has been previously postulated (4, 5, 6) . In turn, higher levels of Angiotensin II can lead to an increase in the production of aldosterone by adrenal cortex cells. Thus, SARS-CoV 2 infection can directly enhance serum aldosterone levels by promoting its detrimental activity systemically and mostly in lungs and endothelial cells. This article is protected by copyright. All rights reserved. Interestingly, the correlation between the serum levels of IL-6 and the plasma aldosterone has already been demonstrated in a clinical trial with patients affected by primary aldosteronism (9) . Thus, we assume that the highest levels of aldosterone may induce IL-6 and the cytokine storm in patients with primary aldosteronism and Covid-19 pneumonia, mostly by directing macrophages towards a M1 pro-inflammatory phenotype and by activating the dendritic cells (10, 11) . Furthermore, this hormone has a direct effect on IL-6 production in endothelial cells through the activation of Mineralocorticoid Receptor/ NF-KB pathway (9, 10). However, the association between primary aldosteronism and the recent coronavirus has not been described yet and the proinflammatory role of aldosterone in SARS-CoV2 infection remains unclear (7, 8) . In addition, GBS has been widely reported as a neurological complication associated to SARS-CoV 2 infection, nevertheless AMSAN represents an uncommon phenotype of Covid-19 associated GBS (11) . To date, the axonal forms such as AMSAN have been shown to develop during the acute phase of SARS-CoV 2 infection as a parainfectious disease (12) . In our hypothesis, hyperaldosteronism can promote neurological complications such as GBS and AMSAN by stimulating the infiltration of macrophages and T-cells and by enhancing the axonal injury through the secretion of IL-22 and IL-6 (13). Two major considerations emerge from the reported case. First, the correlation between IL-6 and aldosterone levels needs to be further confirmed in patients with Covid-19 pneumonia and primary aldosteronism. Indeed, the occurrence of an association IL-6/hyperaldosteronism could have a detrimental and synergic effect in the severe forms of pneumonia. Second, in Covid-19 the parainfectious manifestation of GBS increases the risk of underestimating diagnoses in patients who require early treatment with mechanical ventilation. In addition, the increase in aldosterone activity/levels may also be involved in the severity of patients with SARS-CoV2 infection and secondary aldosteronism such as in hypertension or cardiovascular diseases. In fact, these patients have shown the highest rate of hospitalization in Intensive Care Unit for Covid-19 pneumonia (14) . In conclusion, the increased levels of aldosterone may be associated with severe forms of Covid-19 pneumonia by stimulating mostly the IL-6 production. Accordingly, the inhibition of IL-6 effects induced by Tocilizumab could represent the main therapy in these patients. Serum aldosterone levels may be dosed in all patients with diagnosis of Covid-19, especially in cases with increased levels of IL-6 and/or secondary aldosteronism. 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Guillain-Barré Syndrome Associated with SARS-CoV-2 Guillain-Barré syndrome: causes, immunopathogenic mechanisms and treatment Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 FIGURE 1 (A) Abdominal computed tomography (CT) scan showing a right adrenal adenoma (B) Thoracic CT scan with diffuse fibrosis and ground glass alterations in both lungs