Abstract: Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Medical Hypotheses 142 (2020) 109783 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection T ⁎ A. Klimkea,b, , G. Hefnerc, B. Willd, U. Vossa,e a Vitos Klinikum Hochtaunus, Friedrichsdorf, Germany Heinrich Heine University Duesseldorf, Germany c Klinik für Forensische Psychiatrie, Vitos Rheingau Eltville, Germany d Rheinische Friedrich-Wilhelms-Universität Bonn, University Hospital (UKB), Germany e Goethe-Universität Frankfurt am Main, Abt. Allgemeine Psychologie II, Germany b A R T I C LE I N FO A B S T R A C T Keywords: COVID-19 Hydroxychloroquine aerosol Pharmacotherapy Prevention SARS-CoV-2 Covid-19 is a new coronavirus disease first described in December 2019. This respiratory illness is severe and potentially fatal. Severe cases make up to 15%, lethality ranges between 1.5 and more than 10%. What is urgently needed is an efficient pharmacological treatment for the treatment of severe cases. During the infection of alveolar epithelial cells of the lung, the ACE2 receptor has a central function. The antimalarial drugs chloroquine phosphate (CQ) and hydroxychloroquine (HCQ) impair in vitro the terminal glycosylation of ACE2 without significant change of cell-surface ACE2 and, therefore, might be potent inhibitors of SARS-CoV-2 infections. Starting inhibition at 0.1 µM, CQ completely prevented in vitro infections at 10 µM, suggesting a prophylactic effect and preventing the virus spread 5 h after infection. In a first clinical trial, CQ was effective in inhibiting exacerbation of pneumonia, improving lung imaging findings, promotion of virus-negative conversion, and shortening the disease. In addition, HCQ, which is three times more potent than CQ in SARS-CoV-2 infected cells (EC50 0.72 µM), was significantly associated with viral load reduction/disappearance in COVID-19 patients compared to controls. Theoretically, CQ and HCQ could thus be effectively used in the treatment of SARS-CoV pneumonia. From a pharmacological standpoint, however, the major problems of oral treatment with these drugs are possible severe side effects and toxicity. Concretely, this relates to (a) the inconsistent individual bioavailability of these drugs at the alveolar target cells, depending on intestinal resorption, hepatic first-pass metabolism and accumulation in liver, spleen and lung, and (b) the need for a relatively high concentration of 1–5 µM at the alveolar surface. Therefore, we propose in a first dose estimation the use of HCQ as an aerosol in a dosage of 2–4 mg per inhalation in order to reach sufficient therapeutic..