key: cord-0685648-h85n491u authors: Sargin, Gokhan; İlknur Yavaşoğlu, Sare; Yavasoglu, Irfan title: Is CoronavirusDisease 2019 (COVID-19) Seen Less in Countries More Exposed to Malaria? date: 2020-04-22 journal: Med Hypotheses DOI: 10.1016/j.mehy.2020.109756 sha: 447dfc7e67ace75a795998866be9cf4b434813cc doc_id: 685648 cord_uid: h85n491u nan . In this context, antiviral drugs and therapies that modulate the immune system are required to control the disease and reduce mortality. Many potentially effective treatments such as remdesivir, lopinavir/ritonavir, favipiravir, steroid, plasma transfusion, hydroxychloroquine (HCQ), and chloroquine (CQ) are used to control the COVID-19 (7, 8) . Treatment responses for CQ such as fever reduction and improvement in CT imaging were obtained in patients (8, 9) . In this context, clinical studies on CQ and HCQ are still ongoing for COVID-19 (10). HCQ and CQ have metabolic, anti-tumoral, anti-microbial, and antithrombotic effects and used in rheumatology practice for patients with rheumatoid arthritis and systemic lupus erythematosus (11, 12) . Quinacrine is beneficial for skin involvement of systemic lupus erythematosus, however, it is not widely used due to its side effects (11) . Although CQ and HCQ are structurally similar, the difference is in the hydroxyethyl group on the tertiary amino nitrogen side chain (11) (12) (13) . HCQ is less toxic of 4 amino quinolones and more soluble than CQ with more safety and low side effect profile. Cardiotoxicity, retinal toxicity, hypoglycemia, myopathy, hemolytic anemia, and hyperpigmentation are some of the reported side effects (13) . Toxicity varies depending on the high dose, long-term use, concomitant drug use, and kidney disease (14) . The risk of retinopathy, the most noticeable side effect, is below 1% for 5 years when used in appropriate doses (14) . Therefore, HCQ is considered to be a priority in treatment due to less side effect profile. CQ and HCQ have immunomodulatory and anti-inflammatory effects. The weak bases in its structure enter the cytoplasmic vesicles by entering through the cytoplasmic membrane, thus increasing the pH from 4.0 to 6.0, and acid-dependent subcellular functions are inhibited (12, 13) . Consequently, antigen processing in macrophages is impaired due to the increase in pH. CQ and HCQ inhibit the pro-inflammatory cytokines like TNF-α, IL-1, and IFN-γ, intracellular Toll-like receptor (TLR) 7/9 and downregulate TLR-mediated signal transduction (8, 12, 13) . Another aspect of antimalarials is the reduction of autoimmunity by the upregulation of apoptosis and the elimination of autoreactive lymphocytes (12) . HCQ and CQ have been shown to show antiviral activity by inhibiting receptor binding and membrane fusion, which play a role in the entry of coronaviruses into the cell (11, 12) . Moreover, the replication of the virus is blocked due to the change in pH required for lysosome and enzyme activities. Due to the mechanisms of action of these drugs, overactivation of the immune system triggered by SARS-CoV-2 may be suppressed and the progression to severe disease may be slowed (8) . In addition, it is suggested that CQ and HCQ could potentially be beneficial, also with low cost, wide use worldwide including rheumatic disease and lower side effect profile (11, 12) . Inhibition of the virus in cells treated with CQ before or after infection suggested that CQ is both prophylactic and therapeutically advantageous. However, there is no evidence of prophylactic use in guidelines. CQ has also been used worldwide for malaria treatment and prophylaxis over the years since CQ has been shown to inhibit coronavirus replication (9, 15) . Malarial drug use trends changed from CQ or SP to ACTs in African countries in the following years. Long after years, the reduction in the CQ use caused the reduction in drug pressure leading the return of susceptible parasite populations (23) . This is followed by the use of CQ again and CQ is still commonly used in the treatment of febrile illness children (24) . For long term chemoprophylaxis, 5 mg/kg body weight (up to 250 mg) weekly mefloquine is recommended to be xontinued two weeks before, during and four weeks after departure from the area (25) . Today, although CQ is not recommended for P. falciparum treatment in Africa. CQ use has persisted for many years especially in private sectors since CQ and SP are cheaper than ACT and available in the marketplace widely (24) . Consequently, although the number of tests and health data carried out in Africa and especially in the malaria-intensive regions is not clear, this situation will become more clear with further analysis in the post-pandemic period. 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